3 s2.0 B9780323443296000206 Main

C HA P T E R 20
Disorders of Foals
Harold C. McKenzie III
Y EQUINE NEONATOLOGY influences before, during, and after pregnancy. These influ-
ences include numerous maternal, placental, and fetal risk fac-
Tremendous advances have been made in the medical care of tors. By assessing these variables and monitoring for changes
newborn foals over the past 50 years, thanks to the pioneer- during the course of pregnancy, it may be possible to imple-
ing efforts of many individuals and research groups and the ment medical therapies to minimize some risks, or at least to
increasing sophistication of veterinary medicine as a whole. ensure that management strategies are in place to reduce the
Although the field of human neonatology has provided criti- risk of problems during or after delivery.
cally important guidance regarding the physiology and patho- Regarding maternal risk factors one must begin with a
physiology of the neonatal foal, and will continue to do so, detailed assessment of the mare’s reproductive history includ-
fundamental insights have been achieved into the unique ing endometrial health before breeding; problems during
characteristics of this special population. The foundations of conception; vaccination history; possibility of twinning; pre-
equine neonatology were built on the earliest descriptions of vious gestational length; number of previous foals; the num-
specific conditions in foals by clinician researchers, such as ber of successful deliveries; history of and types of dystocia;
septicemia, joint ill, and hemolytic icterus,1-4 as well as the and the occurrence of any problems with previous foals after
“dummy foal” syndrome and the respiratory distress syn- birth, such as neonatal isoerythrolysis.31 In addition, a num-
drome (RDS) associated with primary surfactant deficiency.5,6 ber of maternal factors during pregnancy should be assessed,
Significant strides were also being made in the understand- including maternal under- or overnutrition, maternal illnesses
ing of the physiology of the equine fetus and neonate, in large (especially colic or other severe stressors), and endocrine or
part because of the efforts of a group of researchers working metabolic maternal abnormalities. Physical abnormalities,
in the UK.5-23 As the knowledge base grew dramatically,24-29 such as abdominal wall muscular tears or prepubic tendon
there was increasing interest in providing improved care for rupture, represent serious risks to both the dam and the fetus.
the equine neonate, in large part because of the substantial Uterine torsion represents a life-threatening situation for the
investments of time, energy, and equity involved in the lengthy mare and the fetus, and if correction is successful the fetus
process of conception, gestation, parturition, and juvenile must be regarded at high risk for the duration of the pregnancy.
development. Owners were very interested in optimizing foal Although it can be very difficult to appreciate placental
survival, and this interest, along with the increasing capability risk factors, this is a critical issue given the complete depen-
for providing effective critical care for foals, led to the develop- dence of the fetus on the dam for energy and oxygen supplies.
ment of neonatal intensive care units (ICUs) worldwide in the Conditions such as endometriosis or twinning can reduce the
1980s. Since that time there has been a steady increase in our available surface area for placental attachment, resulting in
understanding and ability to successfully treat and manage the impaired transfer of nutrients and waste products between the
critically ill foal. The result has been a dramatic improvement fetus and the dam and potentially causing intrauterine growth
not only in the likelihood of survival but also the ability of retardation (IUGR). Placental dysfunction can result from
surviving foals to mature into sound, healthy individuals that abnormalities such as placental detachment, placentitis, pla-
are able to perform their intended function.30 Our knowledge cental edema, hydrops, and vascular inflammation or injury.31
base in equine neonatology continues to grow, and the goal of Exposure of the mare to any possible infectious causes of abor-
this chapter is to provide an overview of the current knowl- tion or maternal ingestion of endophyte-infested fescue also
edge in this field as well as to provide some insights derived can represent serious risk factors to the fetus.32,33 Although
from human medicine. there are often no outward signs of placental abnormalities,
the development of excessive abdominal distention, vulvar
discharge, or premature udder development may suggest their
Y FETAL ASSESSMENT, MONITORING, presence. A number of fetal factors can complicate pregnancy
AND MANAGEMENT as well, including fetal malformations (congenital or devel-
opmental), fetal malpositioning, twinning, exposure to infec-
The efforts of owners, managers, and veterinarians to maxi- tious agents, and neonatal isoerythrolysis.
mize equine reproductive success extend far beyond success- If any potential risk factors are identified then the pregnancy
ful conception. Close attention must be paid to a variety of should be characterized as high risk, requiring assessment of
1365
1366 PART 2 DISORDERS OF SPECIFIC BODY SYSTEMS
the mare, the placenta, and the fetus. Evaluation of the mare minute at 330 to 360 days’ gestation.43 Transient alterations in
should include a thorough physical examination, paying par- fetal heart rate may be observed but do not likely indicate fetal
ticular attention to the external genitalia and the udder. The distress unless they persist. Persistent tachycardia or bradycar-
abdomen should be evaluated for signs of excessive enlarge- dia may be an indication of impending fetal death.44,45 Fetal
ment, ventral edema, or a pendulous appearance. Evidence heart rate should increase during periods of fetal activity and
of systemic illness (fever, tachycardia, tachypnea, abnormal return to normal ranges thereafter. Fetal electrocardiography
mucous membranes, etc.) will serve as an indication for addi- can be used for monitoring fetal heart rate and rhythm as well
tional diagnostic evaluation to ascertain the focus and sever- and was widely used several decades ago but has fallen out of
ity of the inflammation. A complete blood count and serum favor because of the ready availability, ease of use, and diag-
chemistry profile may be helpful in that regard. Evaluation of nostic yield associated with ultrasonographic fetal assessment.
the reproductive tract should include a rectal examination, if A recent report described the use of telemetric electrocardi-
feasible, as well as a vaginal examination and transrectal and ography equipment for monitoring fetal heart rate and fetal
transabdominal ultrasound examinations. These will allow for heart rate variability, and this tool may hold some promise for
detection of abnormalities such as cervical discharge, uterine fetal assessment in the future.46 A biophysical profile based on
torsion, hydrops, and prepubic tendon rupture. ultrasonographic fetal assessment has been developed for use
Ultrasound examination will provide the opportunity to in late gestation, and this includes fetal heart rate, fetal activity,
thoroughly evaluate the placenta to assess placental attach- fetal aortic diameter, CTUP, uteroplacental contact, and maxi-
ment, placental thickness, and the echogenicity of the fetal mal allantoic fluid depth.43,45,47
fluids.34-36 The transabdominal approach allows for prolonged Once the determination has been made that the pregnancy
periods of examination and allows for a thorough assessment is high risk, and particularly if there are uteroplacental or
of the uterus, placenta, and fetus.37 After 4 months’ gestation fetal abnormalities indicative of the risk or presence of fetal
both transabdominal and transrectal ultrasonographic exami- compromise, the next challenge is if, when, and how to inter-
nations should be performed to ensure thorough assessment. vene appropriately. Because of the very late maturation of the
After 6 months of gestation transrectal ultrasonography can equine fetus in the last 1 to 2 weeks of gestation, combined
also be used to regularly monitor variables such as fetal heart with the difficulty of determining fetal readiness for birth, it
rate, eye diameter, and fetal activity.38 Although transrectal is rarely advisable to induce delivery. It is far better in most
ultrasound examination does not allow visualization of all situations to attempt to support the fetus in utero as best as
fetal structures, it is very useful during late gestation, because possible while awaiting natural delivery.48 If there are compli-
the caudal uterine body is the most common site for ascending cations that threaten the survival of the dam, then cesarean
placentitis to develop.35 Measurement of the combined thick- section or induction of parturition may be indicated, although
ness of the uterus and placenta (CTUP) is a useful indicator the survival of the foal should be considered highly unlikely.
of placental abnormalities, but this assessment should only The other situation in which intervention may be indicated
be performed in areas of the placenta not in contact with the is if the fetus is thought to be near term and the mare suf-
fetus. Although the CTUP can be measured transabdominally, fers from a condition such as severe colic that is endangering
this approach is more challenging because of the variations in fetal survival, although the prognosis for foal survival again
the location measured as well as the potential for fetal con- remains poor.
tact compressing the placenta.39 It is preferred to measure Medical management of the high-risk pregnancy has two
the CTUP transrectally at a site near the cervicoplacental goals: the first is treatment of the primary condition, if pos-
junction, at which a branch of the uterine can be visualized sible, and the second is treatment intended to support the
between the uterus and the bladder, using the average of sev- fetus in utero and maintain the pregnancy. The primary con-
eral measurements.36 Normal measurements of the CTUP dition most commonly encountered in the mare is placentitis,
have been reported to be 0.6 cm at 7 months’ gestation, less and specific treatment consists of antimicrobial therapy and
than 0.8 cm at 9 months, less than 1.0 cm at 10 months, and antiinflammatory therapy. Antimicrobial therapy, although
up to 1.0 to 1.2 cm at the end of gestation.36,40 It is important typically empiric in nature, should ideally rely on drugs that
to remember that even though an increased CTUP may sug- are capable of reaching therapeutic concentrations within the
gest placental abnormalities it does not represent a definitive uterus. Trimethoprim-sulfamethoxazole, penicillin, and gen-
finding. There are reports of increased CTUP measurements tamicin have all been shown to reach appropriate levels within
that were not associated with placental pathology, and con- the allantoic fluid, but trimethoprim-sulfamethoxazole is most
versely ascending placentitis is not always associated with an commonly used because of the ease of oral administration and
increase in CTUP. 35,36,41 Although there may also be breed and low cost.49,50 Ceftiofur crystalline-free acid (CCFA), although
parity influences on CTUP measurements, the 1.2-cm upper appealing from the perspective of ease of administration and
limit represents a reasonable cutoff for most Light Horse and expense, did not achieve therapeutic concentrations within
Warmblood breeds.42 Placental detachment may be associ- the placenta or fetal fluids and was not effective in an experi-
ated with accumulation of exudate between the placental and mental model of bacterial placentitis.51
uterine surfaces, which is typically hyperechoic in ultrasono- Antiinflammatory therapy in most cases consists of flu-
graphic appearance. nixin meglumine and pentoxifylline, although other agents
In addition to CTUP there are a number of other ultrasono- such as aspirin and corticosteroids have been investigated.
graphic parameters that can be used for assessment and mon- Although the efficacy of antiinflammatory therapy in placenti-
itoring of the high-risk fetus. Fetal viability can be assessed tis is uncertain, they are commonly used. Flunixin meglumine
using fetal heart rate and rhythm, as well as fetal activity is the most common agent used, because it is a potent nonste-
patterns and fetal responses to stimulation. Fetal heart rates roidal antiinflammatory drug (NSAID), but it is not clear that
change throughout gestation, trending from a high of 135 ± 6 it reaches therapeutic concentrations within the placenta or
beats per minute at 91 to 120 days’ gestation to 67 ± 12 beats per uterus.52 Other antiinflammatory drugs have been of interest,
CHAPTER 20 Disorders of Foals 1367
although one study did not find any benefit to the addition of assessment are continually changing during this time. All of
an antiinflammatory (dexamethasone and aspirin) to trime- the foal’s body systems are transitioning from the protected
thoprim-sulfamethoxazole therapy in experimentally induced intrauterine environment in which many of their functions
bacterial placentitis.53 In addition to the potential antiinflam- were primarily performed by the mare via the placenta, to
matory effects of corticosteroids, their use has been of interest the external environment in which these systems assume full
because of the widespread use of this treatment to accelerate responsibility for maintaining homeostasis. The time required
fetal maturation in human patients.54 The administration of for this transition varies by body system, and the adaptations
corticosteroids to mares in late gestation was shown to accel- required of the cardiopulmonary system are the most time
erate fetal maturation in one experimental study, but there are critical. At birth the lungs must expand and clear themselves
no reports regarding the use of this therapeutic approach in of fluid for gas exchange to occur, and this process must be
clinical practice.55 coordinated with a shift in blood flow into the pulmonary cir-
Treatments that may be beneficial in supporting gesta- culation. If all elements of this transition do not occur within a
tion include exogenous progestagens, tocolytics, and agents few minutes, the foal will not be able to survive in the external
promoting oxygen delivery to the fetus. Progestagen supple- environment. The adaptations required of the nervous, mus-
mentation may have a multitude of effects, including anti- culoskeletal, endocrine, alimentary, and thermoregulatory
prostaglandin effects, but primarily it is thought to function systems are similarly critical but occur over a longer period of
as a tocolytic. This is typically accomplished using altreno- time following birth.
gest, a synthetic progestin, although injectable progesterone is There are a number of endocrine changes occurring in the
sometimes used.43 Although the use of these agents has been periparturient period, and these changes are critical in ready-
somewhat controversial, altrenogest therapy has shown some ing a number of body systems, such as the lungs, gastrointes-
indications of efficacy in reducing fetal losses from bacterial tinal tract, kidneys, and liver, for the functions they will be
placentitis.56-58 Clenbuterol, a β2-sympathomimetic drug, has responsible for following birth.61 The most critical of these
been shown to induce uterine relaxation during late gestation appears to be the activation of the hypothalamic-pituitary-
but is short-acting, with only 2 hours’ duration of effect.52 For adrenal (HPA) axis. This process begins in the period starting
this reason clenbuterol is most useful in the acute situation, approximately 5 days before birth, when the fetal cortisol con-
such as in the management of dystocia while preparing for centration rapidly begins to rise.17 This increase prepares the
cesarean section or assisted delivery.59 body for many of the processes that may have little or no role
Treatments that may improve fetal oxygen delivery in utero in utero but are critical for survival after birth, such as respi-
and during an assisted delivery include pentoxifylline and ration, renal sodium conservation, and glucose metabolism.62
intranasal oxygen administration to the mare. In addition Serum cortisol concentrations continue to rise in the first few
to its antiinflammatory effects, pentoxifylline has rheologic hours after birth before decreasing to normal basal values by
effects that may enhance oxygen delivery to the placenta by approximately 1 day of age in healthy foals.63 Very premature
improving microcirculation.60 Intranasal oxygen administra- foals (<320 days’ gestation) have low cortisol concentrations
tion (10–15 L/min) to the pregnant mare will increase the par- at birth, and these do not increase appropriately in the first 2
tial pressure of oxygen and oxygen saturation in the arterial hours of life.64 In addition to changes in the HPA axis there
blood supplying the placenta and may improve oxygen deliv- are also increases in circulating catecholamines, insulin, and
ery to the fetus.30 Vitamin E has been used in the management glucagon, as well as thyroid hormones (T3, T4) associated with
of high-risk pregnancy as an antioxidant and is administered the immediate postpartum period.62
orally to the pregnant mare.30 The neurologic system of the equine fetus is fully developed
At this time the combination of trimethoprim-sulfa- and functional because the precocious nature of foals at birth
methoxazole, flunixin meglumine, and pentoxifylline remain requires the immediate ability to ambulate and function inde-
the most commonly used treatment protocol for the medical pendently.65 The fetus is maintained in a sleeping state in utero
management of bacterial placentitis in the mare. Generally, through a combination of inhibitory factors, which include
when managing mares with high-risk pregnancies it is criti- physical factors such as warmth, cushioned tactile stimulation,
cal that a well-formed plan is developed for dealing not only and buoyancy, as well as chemical factors, which include high
with parturition but also the high-risk foal after delivery, if it circulating and/or cerebral concentrations of adenosine, pros-
survives. Ideally these mares will be housed in a facility that taglandin D2, and the pregnane neurosteroids allopregnano-
is able to provide 24-hour monitoring and that has a team lone and pregnanolone.65,66 These inhibitory neurosteroids are
available to deal with any eventualities appropriately and in synthesized from progesterone primarily within the placenta
a timely manner. All necessary equipment needs to be orga- during late gestation, and following delivery their concentra-
nized and readily available. Thorough discussions with owners tions within the normal neonate decline rapidly, usually over
and agents need to occur before any crises so that all involved the first 48 hours of life.67,68 This loss of cerebral inhibition,
know the priorities regarding what procedures are authorized in combination with potent stimulation arising from transit-
and whether the mare’s life or the foal’s life is the focus of the ing the birth canal, the onset of breathing, and the onset of
teams’ efforts. multiple external stimuli (light, cold, hard surfaces, unlimited
space, gravity, etc.), lead to a rapid increase in activity and
awareness in the neonate.66
Y EXAMINATION OF THE As the foal passes through the birth canal the chest under-
NEWBORN FOAL goes significant compression, which aids in shifting fluid out
of the airways. Once the lungs begin to inflate the action of
When assessing an equine neonate, it is important to remem- surfactant contributes to further clearance of airway fluid and
ber that the first minutes and hours after birth are a profound the maintenance of alveolar stability and lung inflation. Before
adaptive period and that the normal parameters used in birth the fetal circulation functionally bypasses the pulmonary
circulation by shunting through the ductus arteriosus and the minutes.73 There can be breed differences in the time to stand,
foramen ovale. Once the foal begins to breathe the resistance with pony foals standing in less than 60 minutes and larger
in the pulmonary vasculature dramatically decreases, allow- breed foals, such as Thoroughbreds, typically requiring 30 to
ing blood from the pulmonary artery to enter the pulmonary 60 minutes longer.9 When first standing the foal will exhibit
vasculature rather than passing through the ductus arterio- some degree of incoordination and dysmetria and will assume
sus into the aorta. As the pressure in the left side of the heart a braced position, with all limbs spread laterally, the forelimbs
increases, the foramen ovale closes, preventing the shunting positioned forward, and the hindlimbs extended posteriorly.72
of blood from the right atrium to the left atrium. Complete Once standing the normal foal will rapidly gain coordina-
closure of the ductus arteriosus may take several days, and it tion and will begin circling the mare and attempting bursts of
is not unusual to hear a “machinery”-type murmur associated speed within 1 to 2 hours.74
with patency of the ductus arteriosus in foals during the first Some foals will display flexor tendon laxity at birth, pri-
1 to 3 days of life. It is rare for the foramen ovale to remain marily noted in the form of dropped fetlocks.75 Most foals with
patent in foals. flexor tendon laxity will only demonstrate mild to moderate
The foal’s initial respirations primarily occur in response abnormalities, typically consisting of rocking back onto the
to the rapid rise of carbon dioxide in the bloodstream follow- heels and caudal hoof wall, which leads to pastern hyperexten-
ing the loss of placental gas exchange. The loss of placentally sion and upward flipping of the toe.76 Affected foals usually
derived prostaglandins that suppress breathing in utero likely recover rapidly, with increasing strength and activity over the
contributes as well, along with the initiation of cold and tactile first few days of life.77 Rarely, foals may demonstrate more dra-
stimuli associated with the external environment.69 Spontane- matic musculoskeletal abnormalities, such as a “windswept”
ous breathing may begin as soon as the chest clears the birth conformation, with either the front or hindlimbs affected
canal and should begin within 1 minute of birth. The first few by matching angular limb deformities. One limb will have
breaths may be quite exaggerated in nature because of high car- a valgus deformity, whereas the opposite limb will exhibit a
bon dioxide levels and the degree of effort required for initial matching varus deformity. Unless there are underlying bony
lung expansion. Following these initial breaths most foals will abnormalities most of these foals will also self-correct with
continue to exhibit elevated respiratory rates of 50 to 75 breaths time and activity.
per minute for the first 20 to 30 minutes of life. The respiratory The normal foal will begin displaying suckling behavior
rate will then decrease to around 30 to 40 breaths per minute, shortly after birth, even while still recumbent, and should
and this remains fairly stable for the remainder of the first 2 be able to nurse unassisted within 1 hour of standing. Foals
days of life. By 2 to 3 days of age most foals will exhibit respira- requiring more than 3 hours to suckle are considered abnor-
tory rates of approximately 20 breaths per minute. Foals show a mal. Successful nursing presents several challenges to the
much more exaggerated respiratory pattern than adult horses, newborn foal, beginning with the absolute requirement for
with both inspiration and expiration requiring active respira- successful standing and ambulation to access the udder. Very
tory effort because of the foal’s highly compliant thoracic wall. weak foals, or those suffering from musculoskeletal or neu-
Immediately following birth the foal will typically exhibit rologic problems, will have great difficulty in nursing for this
bradycardia, with heart rates of 60 to 80 beats per minute.8 reason. Once able to stand successfully, the foal must locate
The heart rate rapidly increases, peaking at 150 to 175 beats the udder, which likely requires a combination of visual and
per minute around 40 to 60 minutes after birth, with the high- olfactory abilities on the part of the foal. The ingestion of milk
est heart rates often observed in association with the foal’s first is a fairly complex neurologic process, beginning with success-
attempts to stand.70 The heart rate then gradually decreases, ful capture of the teat by the lips, followed by coordination
with a resting rate of 120 to 150 beats per minute from 1 to of the tongue, pharynx, larynx, epiglottis, and esophagus to
2 hours after birth followed by a rate of 100 to 120 beats per ensure that milk enters the gastrointestinal tract rather than
minute by 3 hours after birth. By 1 day of age the normal rest- the respiratory tract. In addition to the potential adverse
ing heart rate will be in the range of 80 to 100 beats per minute. impact of muscular weakness or neurologic dysfunction on
Because of the relatively late maturation of the HPA axis in the this process there may be physical abnormalities, such as cleft
fetal foal, the cardiovascular system at birth does not appear palate or subepiglottic cysts that may interfere with the normal
to be as fully developed in the horse compared with other spe- passage of milk.
cies.71 As a result the neonatal foal does not have well-devel- The gastrointestinal tract must undergo a number of
oped baroreceptor responses and is at risk for hypotension, changes to accommodate and use ingested colostrum and
especially if premature.71 milk. During the first 12 to 24 hours after birth the small intes-
The mare will begin interacting with the foal shortly after tine remains permeable to macromolecules, most importantly
parturition, using both vocal and tactile stimuli. The normal immunoglobulins, allowing for the absorption of ingested
foal should be responsive to stimulation shortly after birth, antibodies contained in colostrum. Absorption occurs by a
and by 20 to 30 minutes of age the foal should respond to number of mechanisms, including pinocytosis, lymphatic
visual stimuli by appropriate ocular and head movements.72 transport, and exocytosis. The period of maximal absorp-
Within 40 minutes the foal should be responding to auditory tion is the first 12 hours after birth, with approximately 50%
stimuli with independent orientation of the ears in the direc- of ingested immunoglobulins able to be absorbed during that
tion of the stimulus.72 Because of the risks associated with time period.78 From 12 to 18 hours after birth the efficiency of
prolonged recumbency for foals born in a natural environ- absorption decreases substantially, with only 28% of ingested
ment, there is a strong imperative for foals to be able to stand immunoglobulins able to be absorbed, and this rate of absorp-
quickly and become ambulatory. The normal foal will move tion is not adversely affected by the prior ingestion of macro-
into sternal recumbency within a few minutes after birth. It molecules.78 Although some absorption may be possible after
will begin making efforts to stand within 30 minutes after 18 hours, the efficiency of absorption continues to decrease
birth, and should be able to stand unassisted within 60 to 120 and absorption is essentially absent by 36 hours of age.
Following the loss of maternally derived glucose sup- nonshivering thermogenesis because of minimal or nonexis-
plied via the placenta, the foal must take control of glucose tent stores of brown fat.83 Foals also use behavioral approaches
homeostasis. This is particularly challenging because nutrient to thermoregulation, ranging from maintenance of sternal
intake transitions from a continuous mode, in which the dam recumbency to minimize heat losses to vigorous activity when
ensures a continuous, regulated supply of glucose at all times, attempting to stand and once ambulatory, which generates
to intermittent energy intake based on milk ingestion. The substantial additional heat.
pancreas must assume responsibility for the maintenance of
normoglycemia through the differential production of gluca-
gon and insulin. These dramatic alterations in energy metabo- Y PREMATURITY, DYSMATURITY,
lism may not always occur smoothly, and unfortunately the AND INTRAUTERINE GROWTH
foal possesses limited energy reserves in the form of glycogen RETARDATION
and fat. The result is that hypoglycemia occurs over the first 1
to 2 hours of life even in the normal neonatal foal, and the sick Abnormalities of gestation are associated with substantial
foal is at risk of profound hypoglycemia if deprived of energy risk for affected foals, both as a primary syndrome and as a
intake for even a few hours. The metabolic response of the risk factor for a number of other syndromes. Unfortunately,
foal is to increase production of glucagon, epinephrine, and these abnormalities of gestation, which have also been termed
cortisol and suppress insulin production, increasing circulat- unreadiness for birth, can be difficult to characterize because of
ing blood glucose concentrations. Glycogenolysis provides a the highly variable duration of equine gestation.84 In humans
ready source of glucose, but hepatic glycogen stores are mini- the generally accepted definition of prematurity is birth more
mal in the foal, so gluconeogenesis rapidly becomes the pri- than 21 days before full term. This concept has been applied
mary route of endogenous glucose production. Premature or to horses as well, with delivery before 320 days’ gestation con-
dysmature foals often have impaired glucose regulation and sidered premature.85 Unfortunately gestational duration in the
are susceptible to pathologic hypoglycemia in the absence of horse is much less consistent than in humans, with reported
appropriate dietary or parenteral supplementation. gestational lengths resulting in live foals ranging from 286 to
At birth the foal transitions from the normally sterile intra- 380 days (mean 344 days) in Thoroughbred mares and from
uterine environment into an environment teeming with non- 313 to 370 days (mean 339 days) in Warmblood mares.86-88
pathogenic and pathogenic organisms. Colonization of the Pony breeds typically have similar gestational lengths, ranging
various tissues exposed to the outside environment occurs from 337 to 343 days.89 Although there are anecdotal reports
rapidly, beginning during the birthing process. This phenom- of draft mares routinely having gestational lengths over 365
enon is particularly important in the gastrointestinal tract, days in duration, one recent report suggests that median dura-
in which microbial activity is critical for full functionality of tion of gestation in heavy horses is only 5 days longer than in
the local immune system and digestion. Colonization occurs light breeds.90 In addition to the influence of breed there are
through environmental exposure and is likely facilitated by a number of other variables that impact the duration of gesta-
the coprophagic behavior routinely exhibited by foals. Colos- tion including fetal gender; fetal weight; maternal age and par-
tral immunoglobulins and oligosaccharides may play a role ity; and environmental factors such as month of conception or
in regulating the composition of the gastrointestinal flora by foaling, maternal nutrition, and climate.88
affecting the ability of certain bacteria to attach to the muco- Because of the difficulty in defining a specific time point
sal surface and by opsonizing certain bacteria, facilitating the that would be indicative of fetal maturity, equine prematu-
mucosal immune response to these organisms.79 By 2 to 4 rity should be considered as much a physical and functional
weeks of age the microbial population has become similar in characterization as a temporal one. The foal’s size and physi-
composition and complexity to that of the foal’s dam, which cal appearance are important characteristics related to pre-
indicates a transition to an adult pattern in readiness for the maturity. Small body size and low birth weight, along with a
dietary transition from a milk-based diet to a roughage-based prominent rounded forehead, silky hair coat, entropion, and
diet.80,81 floppy ears, are all common findings in premature foals. Some
Thermoregulation can be a challenge for the neonatal affected foals may have a prominent reddish discoloration of
foal as it transitions from the uterine environment into what the tongue, and the mucous membranes may appear some-
is typically a much colder external environment. This chal- what pale. Flexor and periarticular laxity are also common,
lenge is increased by the presence of an initially wet hair coat, although some premature foals may exhibit carpal or fetlock
which enhances thermal losses to the environment as well as contracture. Incomplete ossification of the cuboidal bones
a large surface area to body mass ratio and minimal stores of in the carpus and tarsus is also a common finding in prema-
fat. The healthy foal has a high resting metabolic rate com- ture foals, and these areas are at risk of crushing injury when
pared with the adult, and in the immediate neonatal period affected foals stand and ambulate. This risk can be minimized
the metabolic rate will be increased at two to three times the by limiting the amount of time that these foals are allowed to
basal rate, in association with high concentrations of T3, T4, stand and by minimizing their activity level.
and cortisol.82 This high metabolic rate allows for substantial From a functional perspective premature foals typi-
endogenous heat production to achieve and maintain normo- cally exhibit generalized weakness and have great difficulty
thermia. This metabolic heat production requires substantial in standing without assistance. Affected foals often have
inputs of energy in the form of fats and carbohydrates derived impaired thermoregulation and abnormal glucose metabo-
from colostrum and milk, reinforcing the critical need for lism, as well as impaired cardiovascular, pulmonary, gastro-
early successful nursing in foals. Another important mecha- intestinal, and renal function. Impaired thermoregulation
nism that foals rely on for heat production in the immediate is likely caused by inadequate endocrine responses to the
neonatal period is shivering thermogenesis. This appears to change from the uterine environment to the external envi-
be particularly important, because foals do not appear to use ronment. Abnormal glucose regulation is also indicative
of endocrine dysfunction, potentially caused by impaired The severity of the abnormalities associated with prema-
insulin production or peripheral insulin insensitivity. Car- turity are to some extent associated with the duration of the
diovascular dysfunction most often presents as persistent predisposing disease process that led to premature delivery.
hypotension that is poorly responsive to pressor therapy. Foals that have suffered prolonged in utero stress caused by
Increased vascular permeability may be present as well, placental disease may be surprisingly “ready for birth” because
potentially resulting in fluid shifts from the vasculature to of stimulation of endogenous cortisol production and early
the interstitium. For these reasons fluid, inotrope, and pres- maturation of the endocrine system.100 In rare cases such
sor support should target the maintenance of perfusion, foals may survive with aggressive medical intervention even
rather than a target blood pressure range. Failure to use this if born as early as 286 days of gestational age, based on the
approach will put the patient at risk of fluid overload and author’s personal experience. Foals that have not experienced
other complications. Respiratory dysfunction may be caused in utero stress and that suffer from some acute onset condi-
by surfactant deficiency but is also frequently associated tion resulting in premature delivery are much more likely to be
with decreased respiratory drive, weak muscles of respira- “unready” for birth and will exhibit the most dramatic clinical
tion, a highly compliant chest wall, and poorly compliant abnormalities. These foals are unlikely to survive if born more
lungs. Gastrointestinal dysfunction is typically caused by than 2 weeks before their expected due date.
inadequate motility, which can result in distention, colic, Most premature and dysmature foals will require medical
and diarrhea. Renal dysfunction may manifest primarily as intervention and supportive care to survive. These conditions
decreased urine output rather than azotemia, and care must affect all body systems, so thorough evaluation is indicated.
be taken to avoid fluid overload in these patients. Because of substantial crossover in the clinical presentation of
Clinicopathologic assessment may aid in characterizing these foals with that of the term, septic foal it can be difficult
these foals. Leukopenia caused by neutropenia combined with to discriminate among syndromes. Given that premature and
lymphocytosis leads to a neutrophil:lymphocyte ratio (N:L dysmature foals are also at heightened risk of sepsis the clini-
ratio) of less than 1.0, as opposed to a normal ratio of greater cian should reasonably assume that bacterial infection is pres-
than 2.0. This reversal of the N:L ratio is a commonly used ent at presentation in most cases. Appropriate broad-spectrum
defining characteristic of equine prematurity and is directly antimicrobial therapy is indicated. Specific recommendations
associated with impaired adrenocortical function.91 This for the treatment and support of the critically ill foal will be
impairment of adrenal function happens because maturation discussed in detail in the relevant sections of this chapter.
of the HPA axis normally occurs in the last several days of The prognosis for survival of foals suffering from prematu-
gestation and continues in the first weeks, and perhaps even rity, postmaturity, and dysmaturity is good with appropriate
months, after birth.64,92-95 As a result, premature foals exhibit care. Survival rates can be as high as 80% to 85%, and many
low serum cortisol concentrations at birth, in combination of these foals will “catch up” with their peers and attain a nor-
with elevated serum adrenocorticotropic hormone (ACTH) mal adult size and normal function. It is important, however,
concentrations.92 The inability of premature foals to produce for the owners of foals born profoundly premature (less than
appropriate concentrations of cortisol is caused by an impaired 300 days’ gestation) to understand that if they survive to adult-
adrenal response to endogenous ACTH, and they exhibit hood these foals will not likely reach a normal adult size and
impaired response to exogenous ACTH as well. Assessment of morphology, and they are unlikely to be able to function as
the response to exogenous ACTH may be helpful in character- athletes.
izing foals as premature, although there is a subset of clinically
ill full-term foals that may also exhibit impaired responses to Prevention
ACTH stimulation testing.96-98 Although not specific for pre- The best approach for preventing abnormalities of gestation is
maturity, other clinicopathologic changes may include arte- close monitoring of the pregnancy to identify any conditions
rial hypoxemia and hypercapnia; hypoglycemia; acidosis; and that may affect fetal viability or that may lead to premature
low-grade macrocytic, normochromic anemia. delivery. Early treatment of placental infections with antimi-
Dysmaturity typically refers to foals that are delivered at crobials, antiinflammatories, and progesterone (altrenogest)
what appears to be full term but exhibit the characteristics of may allow for prolongation of gestation and minimization of
premature foals discussed earlier. Dysmaturity is most com- the abnormalities associated with premature delivery. Induc-
mon secondary to placental insufficiency resulting in IUGR.99 tion of parturition should be avoided if at all possible, but
Placental insufficiency can be caused by placental disease, if it must be performed then care should be taken to avoid
placental separation, or twinning. Other causes of IUGR induction of delivery in mares unless the gestational length
may include maternal undernutrition or systemic disease. is known with great certainty. Removing mares from pastures
Postmaturity should be distinguished from dysmaturity, and containing endophyte-infected fescue, in combination with
refers to foals born postterm. These foals have been in utero administration of dopamine receptor antagonists (domperi-
for an excessive length of time, most commonly secondary done), can decrease the risk of dysmaturity.
to maternal ingestion of fescue infected with the endophyte
fungus Acremonium coenophialum.32 Physical characteristics Y NEONATAL RESUSCITATION
associated with postmaturity include a normal to high birth
weight associated with a large frame size but with poor body Although the need to resuscitate a foal is uncommon, the
condition. Affected foals may also display flexor contracture, critical and time-sensitive nature of this intervention requires
a long hair coat, and fully erupted incisors. They may share that all those involved are appropriately trained in recogniz-
a number of other functional characteristics with premature ing when and how to implement resuscitation efforts. It also
foals, including impaired thermoregulation and abnormal requires that the appropriate equipment and drugs are orga-
glucose metabolism, as well as impaired gastrointestinal and nized and readily available before the event so that there are
renal function. no delays in implementation. Cardiopulmonary arrest (CPA)
in foals most commonly begins with respiratory arrest, which be implemented. The best approach to establishing an airway
subsequently leads to cardiac arrest caused by asphyxia, is to pass a cuffed nasotracheal tube, which is facilitated by
because primary cardiac disease is very rare in foals. This placing the foal’s head in an extended position. Because of the
is a very different situation from that seen in most human urgency of the situation a maximum of two attempts to place a
patients, in which cardiac arrest is usually the primary initiat- nasotracheal tube should be allowed, up to a maximum of 15
ing factor.101 Because of this the protocol for resuscitation of seconds. If nasotracheal intubation is unsuccessful then one
foals differs substantially from the approach used in human should immediately proceed with orotracheal intubation or
patients. Establishment of a patent airway and the provision of placement of a tracheotomy tube. If nasotracheal tubes are not
ventilatory support is the initial priority in foals, rather than available then mouth-to-nose ventilation can be used, because
cardiac compressions (Box 20.1). the foal is an obligate nasal breather. Care should be taken to
The first challenge is in recognizing which foals require occlude the opposite nostril manually to prevent air leakage
resuscitation, because early intervention before cardiac arrest from that site when ventilation is attempted, and the effec-
is associated with a much higher likelihood of successful tiveness of ventilation can be easily gauged by monitoring the
resuscitation, potentially as high as 50%.102 The situation in chest rise during ventilation.104
which foals are most likely to require resuscitation is parturi- After intubation ventilation should be provided with a
tion, because asphyxia can occur in utero or during dystocia, self-inflating valved manual resuscitation device (Ambu Inc.,
and the foal may have been in arrest for a prolonged period of Ballerup, Denmark) at 10 breaths per minute with a tidal
time and will be unable to establish normal respirations with- volume of 10 mL/kg.104 It is very difficult to limit breaths to
out resuscitation.30 The clinical signs that may indicate the this low rate, however, because of the stress and excitement
need for resuscitation in the immediate postparturient period of the resuscitation effort, which often leads to ventilation
include absence of breathing, irregular gasping, respiratory rates upward of 60 breaths per minute. Unfortunately exces-
rate less than 10 breaths per minute, heart rate less than 40 sive ventilation negatively affects cardiac return and coronary
beats per minute, irregular or absent muscle flaccidity, or lack perfusion and has been associated with worsened outcomes.105
of response to tactile stimulation.103 Other situations in which Another challenge is associated with monitoring tidal volume,
resuscitation may be required include primary lung disease, because there is a tremendous range of manual resuscitation
septic shock, hypovolemia, metabolic acidosis, hyperkale- bags available, all of which have different internal volumes and
mia, hypoglycemia, vasovagal reflex, and hypothermia.102,104 deliver variable amounts of air depending on how fully they are
It is important to recognize that the prognosis for successful compressed. For this reason it is best to monitor ventilation by
resuscitation and patient survival is much lower with these observing chest excursion during ventilation, keeping in mind
disease processes because of the severity of systemic illness that aggressive ventilation is contraindicated. Although some-
and likelihood of multiple organ failure. Although it may be what controversial there may be some benefit to ventilating the
possible to resuscitate the patient, unless the underlying dis- newborn foal with 100% oxygen for a brief period of time (1
ease can be effectively addressed, the likelihood of survival is minute) immediately after delivery to encourage the reversal
very low. Cardiac causes of CPA in foals may include second- of persistent fetal circulation.30,106 However, there is no indica-
ary myocardial damage associated with severe hypoxia or sep- tion for continued administration of supraphysiologic oxygen
sis, myocarditis, congenital cardiac defects, endocarditis with concentrations, because these may actually be harmful, and
coronary artery embolism, and cardiac tamponade.102,104 the delivery of room air is most appropriate in foals without
Direct monitoring of the foal during delivery by veterinary underlying respiratory dysfunction.104 Following 30 seconds
staff is unlikely except in cases of dystocia and hospitalized of assisted ventilation discontinue ventilation, and observe the
high-risk pregnancies. When foaling is attended the assess- foal for spontaneous breathing while also assessing cardiovas-
ment of the foal’s respiratory and cardiovascular function cular function by monitoring for a heartbeat. If a heart rate of
should begin during delivery. If the foal is noted to be meco- 50 or greater (or between 40 and 50 but increasing)104 is pres-
nium stained the upper respiratory tract should be suctioned ent but respirations are not, then resume ventilations, stopping
immediately, preferably while still in the birth canal and before every 2 minutes to monitor for spontaneous efforts or sooner
the first breath. After delivery suctioning of the trachea may be if such efforts are obvious. As many as 90% of foals that require
required if the foal is heavily meconium stained or if meconium resuscitation at birth will respond to ventilatory support alone
is detected in the upper respiratory tract. Mechanical suction and require no additional therapy.30
is discouraged because it is often too aggressive and may actu- If a heartbeat is absent or the rate is too low then imme-
ally worsen hypoxemia and potentiate bradycardia caused by diately initiate thoracic compressions, because any delay may
vagal reflexes, and if used it should be limited to no more than be very deleterious. No more than 10 seconds should be spent
5 to 10 seconds of suction time. Following delivery the foal trying to assess cardiac function, and the risk associated with
may gasp a few times but should establish a regular breath- unnecessary thoracic compressions is less than that associated
ing pattern within 30 seconds. Persistent gasping, open-mouth with the failure to provide compressions to an animal that
breathing, or severe respiratory distress may be an indication needs them. Place the foal in lateral recumbency on a firm
of severe or total upper airway obstruction, such as bilateral surface and quickly palpate for rib fractures before initiating
choanal atresia, dorsal displacement of the soft palate, or ste- compressions. If there are unilateral rib fractures position the
notic nares. Tactile stimulation, such as vigorous drying with foal with the affected side facing down, and if there are bilat-
towels, may aid in stimulating the initiation of respiration. A eral rib fractures place the side with more cranial rib fractures
rapid examination should be performed during this time to facing down.104 The person providing compressions should
identify any congenital defects that would render resuscitation position themselves to the dorsal aspect of the foal, with their
inappropriate or inhumane. If the foal fails to begin breath- knees against the spine, which will prevent the foal from shift-
ing spontaneously and regularly then an airway needs to be ing during compressions. Both hands should be used, with
established immediately and basic life support (BLS) should one closed in a fist and placed with the palm down over the
BOX 20.1
Cardiopulmonary Resuscitation Flowchart
Basic Life Support

Respiratory arrest
Establish airway
Ventilate at 10 breaths/min
Heart rate >50 bpm or >40

Reassess cardiac and respiratory function at 30
bpm and increasing, not
seconds – then every 2 min
spontaneously breathing
Cardiac arrest – pulseless electrical

activity
Initiate chest compressions – 100/min
Establish venous access

Advanced Life Support
Epinephrine 0.01 mg/kg every 3-5 min

+/– Atropine 0.02 mg/kg IV once
Place ECG
Attach capnograph – monitor EtCO2
Rhythm check every 2-3 minutes
Asystole Perfusing rhythm

Pulseless electrical activity Increasing EtCO2
Stop compressions and

Continue chest compressions
monitor
Vasopressin 0.6 U/kg once then Ventricular fibrillation Heart rate >60 bpm
Epinephrine 0.01 mg/kg every 3-5 min Pulseless ventriculartachycardia Respirations >16 bpm
Defibrillate 2 J/kg Success – Provide

Greater than 10-15 min CPR = Failure
2nd attempt - increase to 4 J/kg appropriate supportive care
and monitoring
Resume chest compressions
Bpm, beats per minute; EtCO2, end-tidal CO2.

foal’s heart, and the other hand placed on top of the closed fist. presents danger to the operator and anyone in contact with the
The arms should be kept straight, with the upper body weight foal, and operators should receive appropriate training before
being used to drive compressions. A rapid rate of 100 com- using a defibrillator.
pressions per minute is advised.102 The depth of compression
is difficult to gauge, but “pushing hard” is recommended.104 Monitoring Resuscitation
Chest compressions should be briefly stopped every 2 to 3 Patient status during resuscitation is extremely dynamic,
minutes to monitor for the presence of a heartbeat but should requiring constant reassessment, and it can be difficult to moni-
be resumed within 10 seconds. If there is only a single indi- tor for return of spontaneous circulation and spontaneous res-
vidual available to initiate resuscitation for a patient requiring piration without interfering with the process of resuscitation
chest compressions, then adjustments must be made. If the itself. Following initiation of resuscitation efforts cardiac and
patient is not intubated, then it is recommended to provide respiratory function should be reassessed at 2- to 3-minute
30 chest compressions to 2 ventilations, whereas for the intu- intervals unless the foal shows obvious signs of response (Box
bated patient it is recommended to provide continuous chest 20.1). Monitoring via electrocardiography can be challeng-
compressions and no ventilatory efforts.104 Although it is not ing, because electrical activity does not necessarily represent
feasible in single-rescuer resuscitation, if multiple individuals effective cardiac contractility, which is a phenomenon termed
are participating in the resuscitation effort then an intrave- pulseless electrical activity. Respiratory efforts are much more
nous (IV) catheter should be placed while resuscitation efforts readily observed and their effectiveness subjectively evaluated.
are ongoing to have IV access for administration of drugs or One technique that can greatly facilitate monitoring during
fluids. resuscitation is the monitoring of end-tidal CO2 (EtCO2), if
If the foal is not responding to BLS then more aggressive capnography is available. The sensor is placed on the endo-
measures (advanced life support) are indicated. These may tracheal tube and real-time monitoring is readily performed.
include administration of pharmacologic agents and imple- Normal resting EtCO2 in a healthy spontaneously breathing
mentation of improved monitoring. Many drugs have been patient is approximately 40 mm Hg (35–45 mm Hg), whereas
used empirically in foal resuscitation, but none has been spe- the CO2 in room air is 0.3 mm Hg. During resuscitation a rea-
cifically studied in the foal. The utility of many of these agents sonable target for EtCO2 is 10 mm Hg, because this indicates
is debatable, either because they are directed toward primary that an adequate degree of perfusion and ventilation is being
cardiac dysfunction, which is rare in foals, or because their achieved. If resuscitation is successful then a rapid increase in
use in human cardiopulmonary resuscitation (CPR) has been EtCO2 toward the normal range will be observed, indicating
discontinued. The drug that is most likely to be used is epi- that both perfusion and ventilation are improving. A decrease
nephrine, although this is the subject of ongoing debate in the in EtCO2 during resuscitation indicates inadequate ventilation
human literature.107 Epinephrine is administered at 0.01 mg/ and perfusion, requiring reevaluation of how resuscitation is
kg IV every 3 to 5 minutes. If IV access is not available then being performed. If no response is detected after 10 to 15 min-
epinephrine can be administered intratracheally at 0.1 mg/kg, utes of resuscitation it is extremely unlikely that the patient
preferably diluted in a small volume (3–5 mL) of sterile water will respond with further efforts.
or saline.104 Vasopressin has been used either in place of, or
in combination with, epinephrine in CPR.108 If used it should Postresuscitation Support
be given as a single dose of 0.6 U/kg IV following the first Following successful resuscitation the patient should be con-
dose of epinephrine.102 Doxapram has been commonly used sidered at high risk because of the presence of any primary,
in foal resuscitation as a respiratory stimulant, but it is con- initiating diseases and the likelihood of secondary hypoxic
traindicated because it does not reverse secondary apnea and injury.110 Appropriate medical care and monitoring are criti-
has been shown to decrease cerebral blood flow and increase cal during this period of time. Foals should receive intranasal
cerebral oxygen consumption.104,109 Atropine and glycopyrro- insufflation of humidified oxygen at 5 to 10 L/min until they
late have also been used in foal resuscitation, but as high vagal have been demonstrated to be stable with adequate cardio-
tone is an unlikely cause of bradycardia the benefit of these pulmonary function. Fluid therapy will likely be of benefit in
treatments is unclear. The administration of a single dose of ensuring normovolemia and supporting cardiovascular func-
atropine seems unlikely to be harmful, however, and if used tion. Care should be taken to avoid overhydration, because
atropine should be administered at 0.02 mg/kg IV. Cortico- these patients may be at risk of pulmonary edema. Pressor
steroids, calcium gluconate, lidocaine, magnesium sulfate, and and inotrope therapy may be indicated if cardiovascular func-
sodium bicarbonate, while potentially indicated in the treat- tion is inadequate. Glucose support is important, especially in
ment of primary cardiac arrest, are not recommended in rou- neonates, but care should be taken to avoid hyperglycemia. If
tine resuscitation of neonatal foals at this time.104 resuscitation occurred in the field then serious consideration
should be given to immediately referring the foal to a facility
Defibrillation equipped to provide intensive care.
Defibrillation is indicated in cases of ventricular fibrillation
and pulseless ventricular tachycardia. Access to appropriate Y NEONATAL SEPSIS
equipment is often limited, however. The widespread avail-
ability of human automated electrical defibrillators may alter The management of critically equine neonates is extremely
this situation, but at this time there are no published studies challenging, but there have been tremendous advancements in
regarding their use in foals. When performing defibrillation the care of these foals over the past several decades. The grad-
the cardiac compressions and ventilation should continue ual decline in mortality rates for hospitalized foals over the
until the moment of defibrillation and resumed immediately past 30 years, although likely because of a number of factors
afterward. The initial charge should be 2 J/kg, which should be in addition to advances in treatment, serves as strong evidence
increased to 4 J/kg for subsequent attempts.102 Defibrillation of the progress that has been achieved. Reported survival rates
for hospitalized foals in North America have slowly trended TABLE 20.1 Definitions of Terms Used to Describe Clinical
upward from approximately 60% in the 1980s to around Syndromes Associated with Systemic Inflammation
70% in the 1990s and then 70% to 80% in the 2000s.111-116 As
encouraging as these numbers are it is important to note that Inflammatory Response to the
the survival rates for foals suffering from sepsis are lower than Presence of Microorganisms or the
those for all sick foals presenting to a hospital. In the 1980s Invasion of Normally Sterile Host Tissue
it was reported that only 26% of septicemic foals survived, Infection by Microorganisms
whereas a more recent study in 2006 reported that 57% of sep- Bacteremia/septicemia Presence of viable bacteria in the
tic foals survived.117,118 This is compared with reported survival bloodstream
rates of hospitalized sick, nonseptic foals of 75% to 95%.118-122 SIRS Systemic response to an array of
The relatively poor prognosis for septic foals is caused by many severe clinical insults
factors, not least of which is the fact that sepsis represents a Shock SIRS-induced hypotension refrac-
systemic inflammatory response to infection or injury and can tory to fluid resuscitation in as-
rapidly progress to septic shock and death despite aggressive sociation with hypoperfusion
treatment. Traditionally, the term septicemia is used to refer
Sepsis SIRS caused by infection
to this process in the equine neonate and describes a systemic
disease process involving the presence of pathogenic microor- Severe sepsis Sepsis associated with organ
ganisms and/or their toxins in the blood.123,124 Historically the dysfunction, hypoperfusion, or
typical presentation of sepsis in foals was that of disseminated hypotension
gram-negative bacterial infections; however, it has become Septic shock Sepsis-induced shock
clear that an identical syndrome may occur in patients with MODS Altered organ function in an acutely
gram-positive or mixed bacterial infections, viral infections, ill patient requiring intervention to
trauma, hypovolemia, hemorrhage, and immunologic and maintain homeostasis
drug reactions.125-127
MODS, multiple organ dysfunction syndrome; SIRS, systemic inflammatory

Pathophysiology response syndrome.
Adapted from Nathens AB, Marshall, JC. Sepsis, SIRS, and MODS: What’s
The abnormalities associated with the clinical syndrome of in a name? World J Surg. 1996;20(4):386-391; Bone RC, Grodzin CJ, Balk
sepsis result from a nonspecific innate inflammatory response, RA. Sepsis: a new hypothesis for pathogenesis of the disease process.
which has been termed the systemic inflammatory response syn- Chest. 1997;112(1):235-343.
drome (SIRS).125 SIRS represents a common terminal phase of
the inflammatory response characterized by malignant global
activation of multiple proinflammatory pathways and is char- The first step in this process is the recognition of tissue injury
acterized by parameters that can be readily defined in clinical or microbial invasion. Trauma or microbial invasion results in
patients. These manifestations of disease are the same as those tissue injury, and injured cells then release or produce dam-
previously used to define sepsis, but the appreciation that age-associated molecular patterns, and these mediators can
many different stimuli can induce this response has resulted initiate a nonspecific inflammatory response.133 Alternatively,
in sepsis being redefined as SIRS because of infection (Table specific bacterial cell components, termed pathogen-associated
20.1).128,129 The changes associated with SIRS can lead to shock, molecular patterns (PAMPs), may be recognized by immune
which is characterized by severe hypotension not responsive cells that produce inflammatory mediators, leading to the ini-
to IV fluid therapy (Box 20.2). Shock can result in hypoper- tiation of an inflammatory response and subsequent amplifi-
fusion and organ dysfunction such that homeostasis cannot cation of that response.133,134 Some of the PAMPs that can be
be maintained without intervention. This process is termed recognized by the immune system include lipopolysaccharide
multiple organ dysfunction syndrome (MODS).125 MODS rep- (LPS; endotoxin), exotoxins from gram-negative bacteria, pep-
resents a progressive syndrome with initial dysfunction seen tidoglycan, lipoteichoic acids, enterotoxins, or superantigenic
in the cardiovascular system, followed by involvement of the exotoxins from gram-positive bacteria.124,135 The development
respiratory, hepatic, gastrointestinal, renal, cardiac, and neu- of an inflammatory response is dependent on the production,
rologic systems. These processes result in the development of primarily by the activated mononuclear phagocyte, of numer-
refractory hypotension, lactic acidosis, and oliguria and may ous inflammatory mediators, including proinflammatory
progress to death. SIRS criteria were proposed 15 years ago for cytokines (tumor necrosis factor-α [TNF-α,] interleukin [IL]-
the neonatal foal population and are based on human criteria 1, IL-6), proinflammatory enzymes (inducible nitric oxide
using information regarding normal values in foals.124,130 SIRS synthase, phospholipase A2, cyclooxygenase-2 [COX-2])
criteria have been used in a number of studies of clinically ill and adhesion molecules (selectins and intercellular adhesion
foals since that time and have been correlated with increases in molecules).136 The transcription of many of the genes encod-
both lactate concentration and mortality.130,131 A recent report ing for these mediators, or the enzymes that produce them,
has proposed a revised set of SIRS criteria that are age depen- is dependent on the transcription activator nuclear factor-κB,
dent and based on insight from revised human pediatric SIRS and this molecule may be a potential target for intervention in
criteria and that incorporate the changes in normal values that SIRS.137-139
occur with increasing age in foals (Table 20.2).132 It is important to understand that although bacterial infec-
Inflammation represents the response of tissues to either tion may be responsible for the initiation of an inflammatory
injury or the presence of microorganisms. It serves a vital role response, the inflammatory process itself results solely from
because it enhances the movement of phagocytic cells and the production of endogenous mediators. The initial changes
defensive molecules, such as immunoglobulin and comple- seen in an inflammatory response are primarily the result
ment, from the bloodstream to the site of infection or injury. of local vasodilatation and increased vascular permeability
BOX 20.2
Pathophysiology of Shock in the Neonatal Foal
Normal Foal
Intrauterine infection Postnatal infection
Other insults: Trauma, Hypoxia

hypovolemia,
hemorrhage, etc.
Recognition of tissue injury
or presence of microorganisms
Proinflammatory Proinflammatory cytokines

enzymes Macrophage activation
(IL-1, TNF-α, IL-6, IL-12, and IL-18)
(iNOS, phospholipase A2, COX-2)
Endothelial activation and

Increased vascular Neutrophil activation,
local vasodilatation
permeability chemotaxis, migration
Systemic
vasocontriction
Fluid Localized (transient)
hemostatic Impaired cardiac function
extravasation
dysfunction
Systemic
vasodilatation
Systemic hemostatic Refractory hypotension

dysfunction (DIC) (Shock)
Tissue injury/
Multiple organ dysfunction cellular
syndrome (MODS) dysfunction
COX-2, cyclooxygenase-2; DIC, disseminated intravascular coagulation; IL, interleukin; iNOS, inducible nitric
oxide synthase; TNF, tumor necrosis factor.
Adapted from McKenzie HC, Furr MO. Equine neonatal sepsis: the pathophysiology of severe inflammation and infection. Comp Contin Educ Pract Vet.
2001; 23:661-672.
TABLE 20.2 Proposed Systemic Inflammatory Response Syndrome Criteria for Foals That Require the Presence of at Least Three of
the Following Criteria, One of Which Must Be Abnormal Temperature or Leukocyte Count
Newborn Neonate Juvenile Weanling
Parameter (Birth to 3 Days) (4–14 Days) (15 Days to 6 Months) (7 Months to 1 Year)
Fever or hypothermia >102.6°F (39.2°C) or >102.6°F (39.2°C) >102.6°F (39.2°C) or >102.6°F (39.2°C) or
<99°F (37.2°C) or <99°F (37.2°C) <99°F (37.2°C) <99°F (37.2°C)
Tachycardia (beats/min) >115 >120 >96>44 >60>20>12.5 or <4.0
Tachypnea (breaths/min) >56 >56 >44 >20
Leukocytosis (×103), >14.4 or <6.9 >12.5 or <4.0 >12.5 or <4.0 >12.5 or <4.0
leukopenia, or >5%
band neutrophils
Venous blood lactate >5.0 >2.5 >2.5 >2.5
(mmol/L)
Venous blood glucose (mg/dL) <50 <50 <50 <50
From Wong DM, Wilkins PA. Defining the systemic inflammatory response syndrome in equine neonates. Vet Clin North Am Equine Pract. 2015;31(3):
463-381.
caused by the effects of vasoactive mediators released by the and von Willebrand factor, resulting in localized thrombosis
injured or infected cell. On their arrival at the site of tissue and platelet adherence.144
injury, neutrophils and macrophages phagocytose foreign One of the earliest systemic effects is pulmonary vasocon-
material and injured or dead tissue cells and attempt to destroy striction leading to pulmonary hypertension.145 This phase is
the phagocytosed material. In addition, macrophages release followed by systemic hypotension caused by decreased arterial
a number of factors that augment the immune response, tone resulting in decreased left ventricular afterload, combined
including the proinflammatory cytokines IL-1, TNF-α, IL-6, with venous vasodilatation in the large-capacity vessels that
IL-12, and IL-18. These proinflammatory cytokines increase decreases venous return and right ventricular preload. These
the production of secondary inflammatory mediators, includ- effects can progress to the syndrome of hyperdynamic shock,
ing phospholipid derivatives (prostaglandins, thromboxane with increases in heart rate and cardiac output developing as
A2, and leukotrienes), and reactive oxygen species (ROS), compensatory mechanisms to maintain tissue perfusion.146
further increasing the activity of the inflammatory response. This compensatory response is impaired by the reduction in
The systemic manifestations of inflammation/infection (fever, left ventricular preload resulting from decreased peripheral
lethargy, malaise, loss of appetite, and cachexia) are primar- vascular resistance, combined with decreased cardiac contrac-
ily caused by TNF-α and IL-1. The cytokines IL-6, IL-1, and tility.147 Changes occurring in the microvasculature further
TNF-α initiate the acute phase response in which the liver contribute to the impairment of tissue perfusion. Arteriolar
increases production of acute-phase proteins (fibrinogen, vasoconstriction develops because of the impairment of the
serum amyloid A, plasminogen, complement, haptoglobin, normal autoregulatory systems caused by inflammatory cyto-
ceruloplasmin, ferritin, C-reactive protein, etc.).140 These kines and endothelin-1, combined with the increased produc-
substances are important in many phases of the response to tion of vasoconstrictive substances. Adherence of neutrophils
inflammatory stimuli, including complement activation, coag- to the endothelium and endothelial cell swelling further
ulation, fibrinolysis, transport of substances within the blood- reduces blood flow. Accumulation of fibrin and aggregation of
stream, inhibition of neutrophil proteases, and modulation platelets and red blood cells secondary to activation of the clot-
of the inflammatory response.141 The acute phase response is ting system results in occlusion of the vasculature, resulting in
critical in inflammation, healing, and adaptation to noxious tissue hypoperfusion. Arteriovenous shunting occurs in some
stimuli. Also included in the acute phase response is a counter- tissues, whereas increased vascular permeability results in
regulatory antiinflammatory component that normally func- leakage of intravascular fluid into the interstitial space, further
tions to minimize and resolve the inflammatory response to contributing to hypotension and hypovolemia and contribut-
localized stimuli. This counterregulatory response consists of ing to the development of tissue edema. Progressive alteration
antiinflammatory mediators that inhibit macrophage activa- of the microcirculation leading to failure may represent the
tion (IL-4, IL-10, IL-13, adrenal corticosteroids, transform- “common final pathway” of SIRS-related injury contributing
ing growth factor-β and prostaglandin-E2), antagonists to to or resulting in MODS.148
the receptors for proinflammatory cytokines (IL-1 receptor Activation of coagulation occurs primarily through the
antagonists), and soluble receptors of proinflammatory cyto- extrinsic pathway, and endothelial injury secondary to neu-
kines (soluble IL-1 receptor type II and soluble TNF recep- trophil degranulation results in increased platelet adhesion.149
tors).142 The balance between these proinflammatory and In the normal state the accumulation of the resulting excessive
antiinflammatory components is very important in determin- amounts of fibrin would be prevented by the action of plasmin,
ing the characteristics of the inflammatory response, because the primary mediator of fibrinolysis. In the presence of SIRS
excessive activity of the antiinflammatory component may the fibrinolytic system is suppressed because of the increased
result in immunosuppression during or after a severe inflam- plasma concentration of plasminogen-activator inhibitor type
matory response, which has been termed the compensatory 1, the primary inhibitor of fibrinolysis.150 The widespread
antiinflammatory response syndrome.125 activation of the clotting system combined with impairment
In moderation the changes associated with an inflamma- of fibrinolysis and depression of the inhibitors of coagulation
tory response are protective, resulting in the enhanced killing can result in a consumptive coagulopathy potentially leading
of microbes by antigen-specific and nonspecific mechanisms, to disseminated intravascular coagulation (DIC).150,151 Several
generalized immune stimulation, and increased activity of reports have demonstrated that clinicopathologic and histo-
the systems required for healing damaged tissue. SIRS, the pathologic evidence of coagulopathy is common in septic
excessive, malignant form of the inflammatory and acute- foals, and these findings are associated with a worsened prog-
phase responses, is characterized by the systemic activity of nosis for survival.152-156
numerous proinflammatory mediators. These mediators all The progression of these processes affecting the cardiovas-
represent components of the normal inflammatory response cular system ultimately results in shock. Shock occurs when
to a localized stimulus, but the systemic activity of these pro- cardiovascular function is severely impaired to the point that
inflammatory mediators may result in an excessive, and often hypotension cannot be corrected with IV fluid administration,
detrimental, response. One of the first effects seen in SIRS is requiring the use of inotropic and/or vasopressor agents.157
widespread endothelial activation, resulting in the increased Shock represents severe cardiovascular dysfunction associ-
production of vasoactive mediators and alteration of vascu- ated with SIRS and is a primary component of MODS. The
lar homeostasis. Inflammatory cytokines are responsible for development of MODS is likely the result of cardiovascular
activation of the endothelium, and the activated cells produce dysfunction leading to tissue hypoperfusion combined with
inflammatory cytokines, as well as increased amounts of nitric changes in cellular metabolism that result in impairment of
oxide (NO), prostaglandins, and endothelin-1.143 Activated oxygen delivery and uptake.158 Tissue hypoxia is manifested
endothelial cells retract from one another, increasing the size by increased oxygen extraction ratios and metabolic acidosis
of the intercellular pores and allowing for increased vascular caused by increased lactate production. Pulmonary dysfunc-
permeability, and increase their production of tissue factor tion is manifested by refractory hypoxemia, potentially caused
by increased pulmonary vascular permeability, microthrombi capillary refill time, and a dark red or injected appearance.
formation, pulmonary epithelial injury, pulmonary edema, Petechiation of the mucous membranes or the skin of the
and impairment of surfactant production.159 Renal dysfunc- inner pinnae may be present. Fever is not consistently present,
tion is manifested by the development of azotemia and oligu- because neonatal foals may exhibit impaired thermoregula-
ria, and this acute renal failure is likely caused by alterations in tion, and hypothermia is not uncommon in this population.
the distribution of intrarenal blood flow arising from micro- There may be additional signs of localized infection, such as
vascular alterations with or without systemic hypotension.158 diarrhea, joint effusion (with or without lameness), respira-
Gastrointestinal dysfunction is primarily manifested by the tory disease or distress, lameness, uveitis, seizures, subcuta-
presence of ileus but may also result in loss of the normal bar- neous abscesses, omphalitis, or patent urachus.164 Additional
rier function of the gastrointestinal mucosa. Impairment of the diagnostic evaluation using ultrasonography may be useful in
mucosal barrier may further contribute to the pathogenesis of identifying the presence of pulmonary inflammation or infec-
MODS caused by bacterial translocation or endotoxin absorption, joint or physeal infection, and internal involvement of
tion.160 Hepatic dysfunction is manifested by the development the umbilical remnants.
of hyperbilirubinemia and in some cases increased serum Clinicopathologic evaluation of the clinically ill foal can
activities of hepatic enzymes (sorbitol dehydrogenase [SDH] be helpful in supporting the clinical suspicion of sepsis. Sep-
and aspartate aminotransferase [AST]).158 Hepatic dysfunc- tic neonatal foals have been demonstrated to exhibit lower
tion may result from hypoperfusion but may be heightened white blood cell (WBC), neutrophil and lymphocyte counts,
by the production of inflammatory mediators by the hepatic and higher band neutrophil and monocyte counts compared
Kupffer cells secondary to the actions of systemic mediators with healthy age-matched control foals.152 Azotemia is com-
or stimuli derived from the gastrointestinal tract.161 Dysfunc- monly encountered in this population but may reflect placen-
tion of the central nervous system (CNS) is frequently pres- tal insufficiency (spurious hypercreatininemia) rather than
ent and may manifest as depression, which can progress to neonatal sepsis or renal insufficiency.114,166 Azotemia typically
septic encephalopathy with extensive neuronal injury.162 The resolves rapidly with standard treatment unless underlying
development of consumptive coagulopathy (DIC) could also renal disease or uroperitoneum is present.166 Blood glucose
be considered a component of MODS, rather than merely a abnormalities are common in septic foals, with hypoglycemia
pathophysiologic process contributing to the development of being the most common.131 This is likely caused by decreased
organ failure. milk intake combined with limited endogenous energy stores
but may also be associated with SIRS. Arterial blood gas eval-
Risk Factors for Neonatal Sepsis uation is extremely useful and often reveals the presence of
A number of factors have been identified that increase the acidosis, which may be metabolic, respiratory, or mixed in
likelihood of septicemia in equine neonates. These risk factors nature. Hypoxemia and/or hypercapnia may also be identi-
may include history of placentitis, prenatal vulvar discharge, fied, typically in more severely affected patients. The measure-
dystocia, maternal illness, premature or delayed parturition, ment of blood lactate concentration is increasingly performed
premature placental separation, induced parturition, partial because of the availability of handheld lactate meters, and
or complete failure of transfer of passive immunity (FTPI), hyperlactatemia is a common finding.167-169 Blood lactate con-
poor sanitary conditions, improper umbilical care, prolonged centrations are consistently higher in normal neonatal foals
transport of the pregnant mare, and the presence of localized than normal adult horses for the first 24 to 72 hours of life,
disease in the neonate (anterior uveitis, diarrhea, pneumonia, with normal foals exhibiting values of up to 5.0 mmol/L in
infectious arthritis, and open wounds).163,164 Inadequate trans- the first 24 hours,20,64 with a recent report finding values as
fer of passive immunity (serum IgG concentration of <800 high as 10.2 mmol/L immediately after birth.167 In that study
mg/dL) represents a critical risk factor for septicemia and lactate concentrations steadily decreased over the first 3 days
death in foals, with the risk of infection and death increasing of life, but the median concentration at 72 hours remained
proportionally with decreasing IgG concentrations (see later slightly increased relative to normal adult concentrations, at
section Immunologic Disorders).165 Pathogenic organisms 1.7 mmol/L. Serial measurement of blood lactate may be use-
can infect the equine neonate by numerous routes, although ful in assessing the foal’s response to therapy, because the fail-
in the intrauterine environment the fetus may be exposed to ure to normalize lactate over time has been associated with a
organisms that have invaded the placenta or that cross the poor prognosis for survival.170
placentochorial barrier and gain direct access to the foal’s The most definitive test for antemortem identification of
bloodstream. Bacteria associated with placental disease may the septicemic equine neonate remains blood culture, which
enter the amniotic fluid and gain access to the respiratory and should be performed at presentation in any equine neonate
gastrointestinal tracts of the fetus. After birth, infection can with a clinical suspicion of sepsis, ideally before the adminis-
occur following contamination of the umbilical stump, inges- tration of antimicrobial therapy. This test has been reported to
tion, inhalation, or secondary to wounds.123,164 have fairly poor sensitivity, with false negative results obtained
in up to 37% of cases of fatal septicemia.171 It is likely that the
false negative rate would be much higher in less severely ill
Clinical Presentation and Identification of the foals that recover with antimicrobial therapy. For this reason,
Septic Neonate it has been recommended that multiple samples be collected
The presenting signs associated with sepsis in the neonatal foal to maximize the sensitivity of blood culture, but the majority
are often vague and nonspecific. Foals may exhibit depression, of isolates have been reported to be present in the first culture
lethargy, and partial or complete absence of nursing behavior. sample, and the need for immediate antimicrobial therapy
Tachycardia and tachypnea are also common initial signs but usually results in only one sample being obtained. Although
are not consistently present. Signs of systemic inflammation it is recommended that blood culture sampling should occur
may include abnormal mucous membranes, with a prolonged before the initiation of antimicrobial therapy, there is evidence
in human patients that a delay in the initiation of antimicro- TABLE 20.3 Organisms Isolated from Foals with Sepsis/
bial therapy of more than 3 hours from the onset of clinical Septicemia with Frequency of Isolation
signs is associated with increased morbidity and mortality,
and current recommendations suggest a delay of no more than Pre-2000 Post-2000
1 hour.172-175 In the referral setting most foals will have been Organism Isolates Isolates
exhibiting signs of sepsis for longer than that period of time, Gram Escherichia coli 30.6–56 22.4
so early blood culture collection and initiation of antimicro- negative Klebsiella pneumoniae 3.7–12.9 0.8–5.7
bial therapy is critical. For this reason when a case is being Actinobacillus spp. 8–30 6.5–12.4
referred from the field it is advisable to initiate antimicrobial
Enterobacter spp. 3.5–14 3.2–8.1
therapy on the farm before referral if transport to the referral
center is likely to require more than 30 minutes. Although this Pseudomonas 2–4.7 2.9
may decrease the likelihood of obtaining a positive blood cul- aeruginosa
ture, the benefit of early treatment likely outweighs the loss of Citrobacter spp. 4.7 —
diagnostic information. It is also important to obtain bacterial Pasteurella spp. 3.7 —
cultures from suspected areas of infection during the course Salmonella spp. 2.8–5 3.4
of treatment because the blood culture may be falsely nega-
Serratia marcescens 2.8–3.7 —
tive or nosocomial infection may have developed during the
course of treatment. The appropriate samples are dependent Acinetobacter spp. 5.6
on the system affected but could include transtracheal aspi- Gram β-Hemolytic 1.2–8.8 10.6
rate, blood, urine, synovial fluid, peritoneal fluid, cerebrospi- positive streptococci
nal fluid (CSF), and umbilical remnants following surgical Other streptococci 5.9–7.1 4.1
resection. Staphylococcus spp. 2.8–4.8 6.3–9.7
Although historically gram-positive organisms were Clostridium spp. 2.4–3.7 1.6
most commonly associated with neonatal infections, over
the past 30 years the most common bacteria isolated from Enterococcus spp. 4.6–14 12.0–12.1
infected foals have been gram-negative organisms (Table Data from Brewer B, Koterba A. Bacterial isolates and susceptibility pat-
20.3).120,171,176-182 Gram-positive organisms isolated from terns in foals in a neonatal intensive care unit. Comp Contin Educ Pract
infected foals are often present in mixed infections with Vet. 1990;12(12):1773-1781; Koterba AM, Brewer BD, Tarplee FA. Clinical
gram-negative organisms, and streptococcal species are and clinicopathological characteristics of the septicaemic neonatal foal:
most common. Other organisms associated with severe sys- review of 38 cases. Equine Vet J. 1984;16(4):376-382; Stewart AJ, et al.
Actinobacillus sp. bacteremia in foals: clinical signs and prognosis. J Vet
temic inflammation in the equine neonate include equine Intern Med. 2002;16(4):464-471; Theelen MJ, et al. Temporal trends in
herpesvirus type 1 (EHV-1) and equine viral arteritis.183,184 prevalence of bacteria isolated from foals with sepsis: 1979–2010. Equine
It is also possible that severe hypoxia leading to hypoxic Vet J. 2014;46(2):169-173; Wilson WD, Madigan JE. Comparison of
ischemic encephalopathy (HIE; neonatal encephalopathy bacteriologic culture of blood and necropsy specimens for determining the
cause of foal septicemia: 47 cases (1978–1987). J Am Vet Med Assoc.
[NE], neonatal asphyxia, and dummy foal syndrome) repre- 1989;195(12):1759-1763; Russell CM, et al. Blood culture isolates and
sents a causative factor for induction of SIRS in the equine antimicrobial sensitivities from 427 critically ill neonatal foals. Aust Vet J.
neonate.185 2008;86(7):266-271.
Rapid identification of the septic neonate is critically
important in ensuring that appropriate treatment is admin-
istered and in determining the prognosis for survival. The the original cutoff of ≥12, which had a sensitivity of 56.4% and
identification of the septic neonate remains problematic, how- specificity of 73.4%.187
ever, because neonates presenting with clinical abnormali- Ultimately, no sepsis score can substitute for clinical judg-
ties consistent with sepsis (SIRS) may be negative on blood ment, and these scores should be used as a diagnostic aid in
culture with no evidence of a focal site of infection. Attempts the identification of high-risk individuals, with full consider-
to identify equine neonates with septicemia have included ation given to their limitations.163,188 There has been interest
the development of a sepsis scoring system combining his- in the use of serum amyloid A (SAA) as an early and accurate
torical information, objective data, and subjective measures biomarker of bacterial infection in neonatal foals, and an early
to derive a numerical representation of the patient’s condi- report suggested a cutoff of >100 mg/L as being highly sug-
tion.24,117 Using a cutoff of ≥12 the sensitivity and specificity gestive of infection.189 A recent unpublished study by Jokisalo
of the modified version of this scoring system were reported et al.104 found that using the cutoff point of >100 mg/L yielded
to be 93% and 86%, respectively. Unfortunately the specificity a sensitivity of 68.6% and specificity of 68.5%, and the NPV
and sensitivity may not always be this high; a subsequent study was 87%.190 Unfortunately 11 of 36 foals considered to be sep-
found that the modified sepsis score yielded sensitivity of 67%, tic in that study had SAA concentrations below 25 mg/L, and
a specificity of 76%, a positive predictive value (PPV) of 84%, 9 of 36 septic foals had SAA concentrations less than 10 mg/L,
and an NPV of 55%.186 The authors of that report suggested which indicates that low SAA concentrations do not rule out
that it might be that this scoring system must be adapted to the possibility of bacterial sepsis.190 Other potential biomark-
each ICU in which it is applied to achieve reasonably high lev- ers of sepsis in foals, such as IL-1β, plasma C-reactive protein,
els of sensitivity and specificity. In another study the modified and haptoglobin, have been investigated but do not appear
sepsis scoring system failed to predict sepsis in 49% of bacte- to be strong or accurate predictors of sepsis.191,192 Although
remic foals.178 A more recent study investing the application abnormalities of blood glucose concentration and lactate
of the modified sepsis scoring system in a large population of concentration are common in septic foals, these biomarkers
1065 foals proposed a revised cutoff value of >7, resulting in a appear to be most useful in prognostication rather than iden-
sensitivity of 84.4% and a specificity of 41.8%, compared with tification of the septic neonate.126,131,193
Because of the difficulty of definitively identifying neonates greatly facilitates their nursing care, decreases the risk of decu-
with bacterial infection it is appropriate to make the assump- bital ulceration, and provides a means of monitoring urine
tion that all high-risk neonatal foals presenting with clinical output. Recumbent foals should be kept in a sternal position as
illness are septic.194 Aggressive, early antimicrobial therapy is much as possible to minimize the development of atelectasis
indicated, and although there are some risks associated with in the dependent lung, and they should be turned at no lon-
antimicrobial therapy these are greatly outweighed by the ger than 2-hour intervals. Feeding septic foals can be a chal-
risks associated with withholding antimicrobial therapy from lenge if gastrointestinal function is abnormal, and parenteral
a patient with sepsis secondary to bacterial infection. An ini- nutrition may be needed (see the later section Nutritional Sup-
tial antimicrobial regimen should provide broad-spectrum port for the Foal). Blood glucose levels should be monitored
coverage including organisms commonly identified in the frequently, especially in foals receiving parenteral nutritional
practice population or region. While a detailed discussion of support. The development of persistent hyperglycemia may
antimicrobial therapy can be found in the antimicrobial sec- require the institution of insulin therapy. If at all possible, foals
tion of this chapter, a reasonable initial approach is the use should be weighed daily; this can be another means of moni-
of penicillin or ampicillin in combination with an aminogly- toring for fluid retention.
coside, typically amikacin. If there are concerns regarding
renal insufficiency then the aminoglycoside can be replaced Prognosis
by a third-generation cephalosporin. Monotherapy with a The costs associated with the intensive care of affected foals are
third- or fourth-generation cephalosporin may be a reason- substantial, and for that reason it is important to strive to pro-
able alternative to combination therapy, particularly in the vide an accurate prognosis for survival as well as for long-term
severely dehydrated patient, but may not provide full coverage athletic function. Given the broad range of prognostic indica-
for gram-positive pathogens. tors that one can use to assess the odds for survival of a criti-
cally ill foal, it can be challenging to provide an accurate and
Management timely prognosis for the owner of such a patient. Experienced
Management of the septic neonate can be challenging because clinicians are able to provide accurate predictions for sur-
of the requirement for constant monitoring and the need for vival, but given that there will always be variations in clinician
substantial nursing care. Fluid therapy is indicated in the experience level and performance there has been substantial
resuscitation and stabilization of clinically ill foals and can interest in developing a scoring system that could be used pro-
initially take the form of intermittent 20-mL/kg boluses given spectively to enhance prognostic accuracy. In 1992 Hoffman
over 10 to 30 minutes. This typically needs to be accompanied et al. performed a study of predictive variables for survival in
by appropriate maintenance fluid therapy (see later section hospitalized neonatal foals.111 In that study they retrospectively
Fluid Therapy in the Foal). The presence of fluid-refractory identified two predictive variables, anion gap and the venous
hypotension may require the use of inotropic and vasopres- partial pressure of oxygen (Pvo2), and when these were applied
sor therapies (see later section Inotrope and Vasopressor prospectively in a population of 48 foals their model showed
Therapy). Respiratory support is beneficial, and in most cases a PPV for survival of 62% and an NPV of 100%. In 1997 Furr
it consists of intranasal insufflation of humidified oxygen at 5 et al. performed a similar study, developing a predictive equa-
to 10 L/min using a nasal cannula. Respiratory stimulants (caf- tion for outcome in a population of 99 hospitalized neonatal
feine and doxapram) may be beneficial in foals with decreased foals.112 They identified several variables associated with non-
respiratory drive. If these interventions are not adequate then survival, but their model ultimately retained a different set of
mechanical ventilation may be necessary. Additional thera- predictive variables, which were heart rate, rectal temperature,
pies may include the administration of hyperimmune plasma, and neutrophil count. This model yielded a PPV of 78% and
either for supplementation of immunoglobulins, colloidal an NPV of 78% in the retrospective population. When applied
support, or the treatment of SIRS. Antiinflammatory therapies prospectively to two populations of hospitalized foals the
are sometimes used, primarily consisting of nonsteroidals, model performed differently in the two populations, with a
but these sometimes including corticosteroid therapy if criti- PPV of 93% and an NPV of 72% in one population as opposed
cal illness–associated corticosteroid insufficiency (CIRCI) is to a PPV of 83% and an NPV of 44% in the other. This was
suspected (see later sections Antiinflammatory and Analge- likely caused by fundamental differences in the types of cases
sic Therapy and Endocrine Disorders). Care should be taken referred and the timing of presentation to the two different
regarding the use of antiinflammatory therapies in critically hospitals.
ill foals, however, because of the risk of gastrointestinal ulcer- Rohrbach et al. performed a large, multicenter study to
ation or renal injury. Gastroprotectant therapy using proton create a predictive model for the probability of hospital dis-
pump inhibitors is generally not used in the first few days of charge in hospitalized foals less than 7 days of age.196 The
life because of concerns regarding increased susceptibility variables retained in their model were foal age, ability to
to nosocomial infections, but sucralfate may be a reasonable stand, presence of a suckle reflex, WBC count, serum cre-
option to those drugs (see later section Gastrointestinal Dis- atinine concentration, and anion gap. This model yielded
orders). The use of low-molecular-weight heparin and/or the a PPV of 95% and an NPV of 65% in the retrospective
administration of fresh or fresh frozen plasma have been sug- population. When applied prospectively the model dem-
gested to address coagulopathies in the critically ill foal.190,195 onstrated a PPV of 90% and an NPV of 46%. Rohrbach
Nursing care is one of the most important aspects of treat- et al. also reported the accuracy of clinician prediction of
ing septic foals. Foals should be kept warm and dry, which outcome, which was 83% in the retrospective population,
can be difficult in the recumbent patient because of frequent as opposed to 81% accuracy for the mathematical model;
urination and defecation. The placement of a urinary catheter however, the predictions were not well correlated. Interest-
should be considered in these patients, even though it may ingly, by combining the clinician’s initial prediction with
present a risk regarding urinary tract infections, because it the model output they were able to improve the accuracy of
TABLE 20.4 Survival Scoring System Proposed by TABLE 20.5 Probability of Survival Using Survival Scoring
Dembek et al.115 System of Dembek et al.115
Variable Value Points Value Points Score Total Score Probability of Survival (%)
Cold extremities No 2 Yes 0 0 3
Prematurity (<320 No 1 Yes 0 1 8
days) 2 18
>2 infection/inflam- No 1 Yes 0 3 38
matory sites 4 62
IgG (mg/dL) <400 0 ≥400 1 5 82
Glucose (mg/dL) <80 0 ≥80 1 6 92
White blood cells × ≤4 0 >4 1 7 97
103/μL
From Dembek KA, et al. Development of a likelihood of survival scoring sys-
From Dembek KA, et al. Development of a likelihood of survival scoring system for hospitalized equine neonates using generalized boosted regression
tem for hospitalized equine neonates using generalized boosted regression modeling. PLoS One. 2014;9(10):e109212.
modeling. PLoS One. 2014;9(10):e109212.
and, subsequently, to establish neuroanatomic localization of

the survival estimate by 12%.196 Another multicenter study any lesions. This information is then used to direct further
was performed by Dembek et al., in which they developed diagnostic and therapeutic efforts.
a survival scoring system for critically ill foals.115 Their final The first stage of the neurologic examination should
model retained six variables, which were cold extremities, be assessment of the foal’s behavior and level of alertness,
prematurity, ≥2 infection/inflammation sites, IgG concen- but when doing so it is important to remember the normal
tration, glucose concentration, and WBC count. These vari- development and progression of foal behavior. In the first
ables were assigned scores depending on their respective few hours after parturition foals exhibit fairly dramatic
values, and totaling of the individual scores yields the final increases in consciousness, strength, and coordination, as
survival score (Table 20.4). A score of 0 was associated with well as awareness of and interaction with their environment.
a 3% probability of survival, whereas the maximum score of Thus it is important to understand at what point they should
7 was associated with a 97% probability of survival (Table be along that continuum based on the time since birth. Most
20.5). They validated their foal survival score (FSS) prospec- foals will be able to stand within 1 to 2 hours of birth, and it
tively using score cutoffs of ≥4 for foals predicted to survive is typical for the initial efforts at standing to be poorly coor-
and <4 for foals predicted to die, which resulted in values dinated and at times unsuccessful. The initial stance will be
for a PPV of 91% and an NPV of 86%. Foals with an FSS of 4 base wide, with prominent swaying back and forth. How-
to 5 were 24.2 more likely to survive than foals with a score ever, once the foal stands successfully rapid improvement in
<4, and foals with a score of 6 to 7 were 91 times more likely ambulation should be noted and the foal will begin seeking
to survive.115 Most recently, Giguère et al. reported a retro- the mare’s udder. A suckle reflex should be present within
spective study examining factors associated with survival in minutes after birth, and foals will actively engage in suck-
a population of 1065 hospitalized foals over 26 years at one ling behavior even while recumbent and without access to
academic referral hospital.116 The variables retained in their the udder. Most foals suckle successfully within 1 to 3 hours
model included positive blood culture, neutropenia, hypo- after birth, but this can range from 0.5 to 7 hours. Nursing
thermia, bicarbonate, Pco2, presence of infectious orthope- episodes should last from 1 to 5 minutes and are typically
dic disorders, and sepsis score. The reported sensitivity of followed by periods of drowsiness, recumbency, and sleep.197
their model was 97%, and the specificity was 75%. Of par- Foals become increasingly coordinated and confident over
ticular interest was the increase in the odds of survival for the first few days of life and will avoid handlers if possible.
foals born in the 1990s, which were 2.2 times greater com- Once restrained they typically struggle vigorously but will
pared with those born in the1980s, whereas foals born in become limp when compressed along their long axis.198 This
the 2000s had a 3.4 times greater odds of survival compared relaxation response in response to squeezing is particularly
with those born in the 1980s.116 pronounced in the first several hours after birth.199
The next stage of the examination is an assessment of the
Y NEUROLOGIC DISORDERS foal’s conformation, posture, and gait. The head should be
above the horizontal plane when foals are standing, and no
Weakness and abnormal behavior are common present- head tilt or rotation should be noted.197 Foals carry their heads
ing signs in clinically ill foals and may be associated with with pronounced flexion of the atlantooccipital joint and tend
neurologic dysfunction; however, they may also be caused to move their heads with jerky motions that may resemble
by a myriad of other conditions. For this reason thorough cerebellar dysfunction in the adult.198 The foal’s gait should
evaluation and assessment of abnormal foals is extremely be evaluated by observing the foal in unrestrained, sponta-
important. This evaluation should include the collection of neous movement, and this can be facilitated by leading the
a thorough history (to include maternal health and repro- dam and observing the foal as it follows.200 The neonatal foal
ductive history) and performance of a complete physical may appear somewhat dysmetric compared with an adult, but
examination, which should include a detailed neurologic this typically improves with exercise.201 Foals typically have a
assessment. The first objective of neurologic assessment is somewhat exaggerated “bouncy” and hypermetric gait com-
to ascertain whether true neurologic dysfunction is present pared with an adult.197
Examination of the cranial nerves is similar to the adult, etiology. This term has recently come into use in the equine
and begins by observation of facial expression, muscle tone, literature as well.65,185,197,204 HIE is a specific type of NE typi-
and symmetry. Touching the nasal septum and the inside of cally associated with adverse peripartum events that result in
the ear canal, which should elicit avoidance behavior, will aid episodes of cerebral hypoxia and ischemia. A wide variety of
in the assessment of facial sensation. The flick reflexes should terms have been used synonymously with HIE in reference to
be evaluated by gently touching the tip of a hemostat to the affected foals, including neonatal maladjustment syndrome,
pinna of the ear, the medial and lateral canthi of the eyes, and perinatal asphyxia syndrome, dummy foal, wanderer, and
the commissure of the lips.197 The eyes should be examined barker foal.185,205 The clinical presentation associated with HIE
for orientation, pupillary size, and pupillary light reflexes. The in foals can range quite dramatically from mild behavioral
globe typically shows a ventromedial deviation that will resolve abnormalities to severe neurologic abnormalities including
by 1 month of age.198 The pupil is somewhat round at birth, but central blindness, seizures, coma, and death.206 Unfortunately
direct and consensual pupillary light reflexes, although some- these clinical signs are not specific for HIE, and diagnosis is
what slow initially after birth, should be present in normal typically made based on elimination of other potential etiolo-
foals in the first day of life.202 Dazzle reflexes should be pres- gies. Indeed, the confusion associated with the nomenclature
ent as well. A menace response is not present at birth but will reflects the clinical challenges associated with determining
develop within 1 to 2 weeks of life.202 Even though a menace the etiology of neurologic dysfunction in the neonatal foal,
response is not present, most foals will show visual avoidance because it has long been recognized that many foals presenting
by moving their head away from a threatening gesture toward with the clinical signs typically associated with HIE have no
the eye.197 The eyes should be assessed for the presence of nys- documented evidence of asphyxiation or a hypoxic-ischemic
tagmus, and although lateral movements of the head will elicit event.65,207 The fact that many affected foals recover rapidly and
normal physiologic nystagmus, spontaneous nystagmus with demonstrate no neurologic sequelae, in contrast to the situa-
the head stationary is abnormal.197 The suckle reflex and jaw tion in human infants, further reinforces this dilemma.65 There
tone should be assessed by inserting a gloved finger into the is evidence that elevations in neurosteroid concentrations
mouth. The foal should also be observed to nurse, paying close may be associated with NE in some cases, particularly those
attention to swallowing movements in the pharyngeal region with no discernible history of a hypoxic insult.65,67,68,205,208,209
and observing for nasal regurgitation after nursing. A novel “squeeze” technique has been reported primarily as
Testing the cervicofacial reflex along the neck and the cuta- an aid in foal restraint and, although only anecdotal, in time
neous trunci reflex along the thorax will allow assessment of this technique may have some benefit in moderating excessive
the long spinal reflexes. If these are abnormal, then segmental inhibitory neurosteroid concentrations and improving foal
cutaneous sensation should be assessed. Further assessment consciousness.199
of spinal reflexes is best accomplished after placing the foal With the introduction of the term NE in human medicine
into lateral recumbency, which also allows for better assess- there has been an effort toward restricting the term HIE to the
ment of muscle tone in the limbs. There should be substantial subset of cases of NE in which there is evidence of a hypoxic-
extensor tone, but the limbs should be able to be flexed with ischemic cause, and that approach will be used here.203 Multi-
persistent gentle pressure. The triceps, extensor carpi radialis, ple conditions have been associated with peripartum asphyxia
biceps, patellar, sciatic, and gastrocnemius reflexes should all and HIE in foals, including dystocia, induction of parturition,
be able to be reliably elicited and are more pronounced than in cesarean section, placentitis, premature placental separation,
adults. The foal should respond to pressure on the sole of the meconium aspiration, twinning, in utero infection, severe
hoof and flexion of the upper limb with an extensor response, maternal illness or surgery, and postterm pregnancy.185,210,211
known as the extensor thrust reflex.197 A flexor or withdrawal Affected foals may appear normal at birth but will typi-
reflex should be present in response to pinching of the skin of cally demonstrate neurologic dysfunction within the first 72
the distal limb, and most foals will exhibit a crossed extensor hours of life.65 The clinical signs of HIE can be highly vari-
response by extending the opposite limb at the same time.197 able but may include behavioral changes (loss of affinity for
This crossed extensor reflex should be absent after the first 3 the mare, inappropriate nursing behavior, loss of awareness of
weeks of life.200 the environment, head-pressing, and abnormal vocalization),
Although most foals with neurologic dysfunction will dis- altered mentation (depression, stupor, somnolence, difficult to
play generalized signs, such as abnormal behavior, seizures, arouse, and coma), cranial nerve dysfunction (loss of suckle
depression, poor affinity for the mare, and loss of suckle, the reflex, weak tongue tone, tongue protrusion, and dysphagia),
findings of the neurologic examination can be used to assess and CNS dysfunction (hypotonia, tremors, hypertonia, pro-
the nature and severity of the dysfunction and to provide neu- prioceptive deficits, central blindness, irregular respiratory
roanatomic localization of any lesions that may be present patterns, opisthotonus, and seizures).65,185,210-213 Two major
(Table 20.6). categories of HIE-affected foals have been described, with Cat-
egory 1 foals born normally but then developing signs within
Selected Disorders the first 48 hours of life, and Category 2 foals being abnormal
from birth, usually in association with documented risk fac-
Neonatal Encephalopathy and Hypoxic tors for HIE.197 It is common to see multisystem involvement,
Ischemic Encephalopathy because hypoxic injury will adversely affect most body sys-
NE in humans is a clinically defined syndrome of neonatal tems. The gastrointestinal tract and renal system appear most
brain dysfunction, manifested by difficulty with the initia- susceptible, but the cardiovascular system, pulmonary system,
tion and maintenance of respiration, depression of tone and and liver and endocrine systems may all be involved.
reflexes, subnormal levels of consciousness, and frequently The pathophysiology of hypoxic injury is complex and may
seizures.203 NE represents a very broad categorization that vary to some extent in different body systems, but the focus
encompasses any neonate with neurologic signs, regardless of will be on the nervous system here. The initial insult of tissue
TABLE 20.6 Neuroanatomic Localization Based on Results of the Neurologic Examination

Evaluation Pathways Major Signs of Disorder
Behavior Forebrain (primarily cerebrum) Reduced affinity for dam, restlessness,
head pressing, compulsive walking
Alertness All of brain Lethargy, stupor, semicoma, coma
Avoidance, nasal Cranial nerve Va, pons, cerebral cortex Facial hypoalgesia
Avoidance, visual Cranial nerve II, thalamus, cerebral cortex Blindness

Head position Cranial nerve VIII, hindbrain Head tilt, turn, body lean, walking in circles,
ataxia, nystagmus
Eye position and movement Cranial nerves III, IV, VI, and VIII, midbrain, Strabismus, nystagmus
hindbrain
Flick reflexes Cranial nerves V and VII, pons, hindbrain Facial paralysis, facial hypoalgesia, absent
flick reflexes
Dazzle reflex Cranial nerve II, subcortex, midbrain, cranial Absent dazzle reflex
nerve VII
Pupillary light reflex Cranial nerve II, midbrain, cranial nerve III Absent pupillary light reflex
Suckle Cranial nerves V, VII, and XII, pons, hindbrain, Weak or absent suckle
cerebrum
Swallow Cranial nerves IX and X, hindbrain Flow of milk from the nose
Cervicofacial reflex Cervical spinal nerves and spinal cord, cranial Diminished cervicofacial reflex
nerve, VII, (hindbrain)
Cutaneous trunci reflex Thoracic spinal nerves and spinal cord, brachial Diminished reflex caudal to spinal cord lesion
plexus, lateral thoracic nerve
Cutaneous sensation Peripheral nerves, spinal cord, cerebral cortex Cutaneous hypoalgesia/anesthesia
Gait Cranial nerve VIII, cerebellum, hindbrain, spinal Ataxia
cord, peripheral nerves
Limb strength Spinal cord, peripheral nerves Limb weakness at or caudal to the level of the
lesion
Flexor reflex (pelvic), patella, Spinal cord, peripheral nerves (L3-S2) Pelvic limb weakness, diminished or absent
sciatic reflexes reflexes
Flexor reflex (thoracic), biceps, Spinal cord, peripheral nerves (C6-T2) Weakness of thoracic with or without pelvic
triceps reflexes limbs, diminished or absent reflexes
Anal/tail clamp reflex Spinal cord, cauda equine, peripheral nerves Reduced or absent anal/tail clamp reflex
(S2-Coccyx)
From MacKay RJ. Neurologic disorders of neonatal foals. Vet Clin North Am Equine Pract. 2005;21:387-406, vii.
hypoxia initiates a cascade of deleterious events. First, there further tissue damage via cell death and activation of apop-
is a shift toward anaerobic metabolism that leads to depletion totic cascades.204,214 Tissue injury initiates an inflammatory
of high-energy phosphate (adenosine triphosphate [ATP]) response, leading to increased local blood flow and vascular
reserves, accumulation of lactate, and a failure of cellular permeability, which may result in the development of edema.
homeostasis.204 Decreased activity of transcellular pumps that Inflammatory cell infiltration leads to further tissue injury
depend on ATP leads to intracellular accumulation of sodium, and upregulation of ROS production.185,216 Increased concen-
calcium, and water.214 Membrane depolarization leads to trations of neurosteroids have been documented in affected
release of the potent excitatory amino acid glutamate, which foals, but their role in the pathophysiology of HIE is unclear
accumulates in the extracellular space. Glutamate then acts on because they may actually have a neuroprotective effect.65,66,68
the N-methyl-d-aspartate (NMDA) receptor, opening NMDA In situations where the degree or duration of hypoxia is not
channels, potentiating calcium influx into the neurons, and overwhelming, a biphasic pattern of injury may be observed
contributing to neuronal injury.215 This cascade of events in which the initial acute phase of injury is stabilized, followed
results in the development and perpetuation of excitotoxic- by an ongoing latent phase of injury that results in more severe
ity, which ultimately leads to neuronal cell death and brain clinical deterioration several hours later.214
injury.204,214 Hypoxia and subsequent reperfusion also initiate The diagnosis of HIE is challenging because of the substan-
the increased production of ROS and NO, ultimately result- tial overlap between the clinical signs associated with HIE and
ing in the process known as reperfusion injury and leading to other causes of NE, as previously discussed. Unfortunately
there is no definitive test for HIE, so diagnosis is typically Seizure Disorders

made based on historical information, clinical presentation, Seizures are a common manifestation of neurologic dysfunc-
and the elimination of other potential causes. Additional tion in human neonates and in foals.65,225 Seizures in foals
diagnostics that are used in human infants include electroen- can be idiopathic, the result of primary CNS disorders, or
cephalography (EEG) as well as imaging modalities such as secondary to numerous conditions involving other body
computed tomography (CT) and magnetic resonance imaging systems or diffuse disease. Seizures are defined as abnormal,
(MRI).204 An EEG is difficult to accomplish in the unsedated stereotyped, and paroxysmal alterations in neurologic func-
foal, and interpretation can be confounded by patient move- tion and may include behavioral changes, motor dysfunc-
ment or sedation, rendering this modality of limited use in tion, autonomic dysfunction, and loss of consciousness.226
foals. Brainstem auditory evoked response testing is widely Seizure activity indicates neurologic dysfunction of the fore-
used in human neonatal ICUs to aid in the assessment of CNS brain associated with abnormal electrical activity. Neonates
function and the diagnosis of HIE, and this technique has been appear to be at increased risk of seizure activity because of
described and validated in foals.217,218 A recent report described the relative excitability of the developing brain combined
the MRI findings associated with a presumptive case of NE in with the high risk of brain injury in the neonatal period.227
a foal, and the increasing availability of MRI in equine refer- Diagnosis of seizure activity is primarily based on clinical
ral centers may render this modality of utility in the future.219 signs but can be challenging because of the subtle signs in
There has been tremendous interest in identifying biomarkers some cases, the potential confounding effects of other condi-
of HIE in human infants, and two potential biomarkers of HIE tions altering patient behavior, neurologic function, or level
have been investigated in foals.206,220 A recent study measured of consciousness. Subtle signs may include abnormal eye
the plasma concentration of the phosphorylated axonal forms movements, tremors, excessive stretching, excessive exten-
of neurofilament H (pNF-H) and ubiquitin C-terminal hydro- sor tone, hyperesthesia, and apneustic breathing, whereas
lase 1 (UCHL1) and found that the diagnostic performance of overt signs of seizures typically include rapid nystagmus,
UCHL1 was significantly higher than that of pNF-H, with the paddling, hyperextension, and excessive movements of the
sensitivity and specificity of UCHL1 for diagnosis of neonatal mouth.198 Unexplained physical trauma may represent evi-
HIE reported as 70% and 94%, respectively.206 This test is not dence of unobserved seizure activity. Confirmation of sei-
available for clinical use at this time, however. zure activity is achieved by EEG examination, but this can be
Prevention of HIE is difficult because of the occult nature challenging in foals. Specific treatment may not be required
of the injury in many cases, but all efforts should be made to in individuals with very subtle or rare signs of seizure activ-
identify mares at risk of maternal or placental disease during ity but is clearly indicated in patients with repeated, general-
pregnancy and to implement appropriate treatment and moni- ized seizure activity. Foals that exhibit seizure activity within
toring. Close observation of at-risk mares during parturition the first 24 hours of hospitalization have been shown to
may allow for early intervention and assistance, if needed. have poorer outcomes than foals that do not exhibit seizure
Foals should be closely observed during and after parturition activity.205
for signs of distress or neurologic dysfunction and appropriate
supportive care or resuscitation provided.185 Foals that exhibit Bacterial Meningitis
seizure activity within the first 24 hours of hospitalization have Bacterial meningitis is an uncommon condition but appears
been shown to have poorer outcomes than foals that do not to be more frequent in foals than adults.228 It has been
exhibit seizure activity.205 The prognosis for survival for foals reported to occur in 2.6% to 10% of foals suffering from sep-
with uncomplicated disease that survive the first 5 days of life sis and is associated with high mortality rates.25,176,228,229 The
and demonstrate neurologic improvement during that time most common clinical findings in foals with bacterial men-
appears to be good.185 ingitis are lethargy, weakness, recumbency, decreased suck-
ling reflex, abnormal pupillary light reflexes, hyperesthesia,
Sepsis-Associated Encephalopathy cervical pain, fever, blindness, seizures, and coma.228,230,231
Brain dysfunction occurring as a result of severe systemic Clinicopathologic findings may include FTPI, neutropenia
inflammation secondary to infection, but not involving overt or neutrophilia, and hyperfibrinogenemia and most often
CNS infection or other types of encephalopathies, has been reflects systemic inflammation related to sepsis.197,228,230,231
termed sepsis-associated encephalopathy (SAE).221 This syn- Definitive diagnosis is by means of CSF analysis, with neu-
drome has also been referred to as septic encephalopathy trophilic pleocytosis (total nucleated cell count >7 cells/μL)
and sepsis-associated brain dysfunction.222 SAE is thought and increased total protein (TP) concentration (TP >120 mg/
to represent a neglected cause of neurologic dysfunction in dL) being present in most cases.232,233 Cellular degeneration
human patients because of the difficulty in diagnosing a con- is frequently observed in the CSF, along with intracellular
dition that has no precise clinical or biological markers, and bacteria.197,233 Meningitis is most commonly associated with
the situation is likely similar in NE of foals.223 In humans the the same types of bacteria associated with neonatal sepsis,
clinical spectrum of SAE may include signs ranging from mild and Escherichia coli, Actinobacillus spp., Klebsiella spp., Strep-
behavioral abnormalities and altered sleep states to severe dis- tococcus spp., and Salmonella spp. are the most commonly
turbances of consciousness and even coma.224 The pathophysi- reported.228,233,234 Treatment depends on intensive antimi-
ology of SAE appears to involve direct neuronal cell injury, crobial therapy using drugs capable of achieving therapeu-
mitochondrial and endothelial dysfunction, disturbances of tic concentrations within the CNS and is ideally guided by
neurotransmission, and derangements of neuronal calcium culture results.235 Drugs such as penicillin, ceftiofur, and the
homeostasis.223,224 Given the substantial overlap between the aminoglycosides are unlikely to be effective because of poor
presentations of HIE and SAE, and the frequent involvement penetration, so consideration should be given to other treat-
of sepsis in the critically ill foal population, SAE should be ments such as ceftriaxone, cefepime, cefotaxime, imipenem,
considered as a potential cause of NE in foals. chloramphenicol, and rifampin (as an adjunct).235 Because
much of the damage occurring in the CNS in meningitis is Tetanus

secondary to the inflammatory response, there is a rationale Tetanus is a syndrome of spastic paralysis caused by the neu-
for using antiinflammatory therapy in these cases. The use of rotoxin tetanospasmin produced by C. tetani. Although rare
corticosteroids as adjunct therapy in human patients has been because of the widespread use of tetanus toxoid vaccines,
associated with a reduction in neurologic sequelae but did not recent cases have been reported in foals.242,243 This syndrome
alter mortality.236,237 The prognosis for survival in foals with usually affects foals over 7 days of age and is associated with
appropriate treatment is fair to poor, depending on the sever- the development of an anaerobic site of infection, reportedly
ity of the presenting signs.228 most often within the umbilical remnants.244 Tetanospasmin
acts to prevent the release of the inhibitory neurotransmit-
Trauma ter GABA by spinal interneurons, leading to disinhibition of
Trauma should always be considered when evaluating the foal spinal motor neurons, resulting in excessive motor activity
with acute onset of neurologic signs. Brain trauma may be and spastic paralysis.245 The primary clinical signs are rigid-
associated with blunt force trauma in the region of the frontal ity, excessive autonomic activity, and episodic muscle spasms,
or parietal bones or may be secondary to trauma to the poll which lead to trismus, facial spasm, third-eyelid protrusion,
or temporal region secondary to the foal flipping over back- and dysphagia. Progression leads to recumbency, and death
ward.197 Vertebral injury can occur as well and may be associ- is usually caused by respiratory failure. Treatment of tetanus
ated with the foal running into an immobile object. Outward depends on the administration of tetanus antitoxin, support-
signs of trauma may not be obvious, and imaging studies may ive care, control of muscle spasms, and source control.242,246
be required for confirmation. Examination may reveal super- Control of muscle spasms is often accomplished using ben-
ficial abrasions, pain on palpation of affected areas, soft tissue zodiazepines, either administered as needed or by continuous
swelling, crepitus, or bleeding from the nares or ears. Treat- rate infusion (CRI). Magnesium sulfate represents an afford-
ment is supportive in nature along with stabilization of bony able and viable option to benzodiazepines in humans and
injuries if possible. Antiinflammatory and antioxidant therapy may be a reasonable option in foals as well.197 Source control
may be of some benefit, but corticosteroid administration is may involve surgical excision or drainage of the site of infec-
not recommended. Appropriate antimicrobial therapy is indi- tion in combination with antimicrobial therapy. Penicillin has
cated when there is the possibility that the CNS may have been been the standard treatment, but metronidazole may also be
contaminated. used. The prognosis for survival is good in cases that do not
progress to recumbency, but it is guarded to poor once recum-
Botulism bency occurs, although recent success has been reported.242,243
Botulism is a syndrome of flaccid paralysis caused by the
neurotoxins produced by Clostridium botulinum, colloquially Metabolic Encephalopathies
known as “shaker foal syndrome.” Most equine cases are asso- There are a number of metabolic derangements that have the
ciated with toxin types B and C, although type A cases have potential to adversely affect neurologic function and poten-
been reported.238 The syndrome in foals is thought to be toxi- tially cause neurologic injury in foals. These include hypo-
coinfectious in nature, in which the foal ingests spores from glycemia, hyponatremia and hypernatremia, hypocalcemia,
the environment that germinate in the gastrointestinal tract hyperbilirubinemia, and hyperammonemia. Hypoglycemia
and spread toxin, as opposed to the more common form of is common in critically ill foals, and severe hypoglycemia is
“forage poisoning” associated with ingestion of a preformed associated with nonsurvival to hospital discharge.131 Persis-
toxin as seen in adults.239 Botulism toxin acts presynapti- tent, severe hypoglycemia is associated with neuronal degen-
cally at the neuromuscular junction by inhibiting the release eration in both the central and peripheral nervous systems,
of the neurotransmitter acetylcholine. Severely affected foals but interestingly this phenomenon is only seen in human
may be found dead, but more commonly there is a sudden patients receiving insulin therapy or suffering from hyperin-
development of weakness, trembling, and dysphagia in a pre- sulinemias.247,248 Although short-term hypoglycemia may not
viously healthy foal.238 Progressive deterioration is typically cause permanent injury, it certainly can cause neurologic dys-
observed, even with appropriate treatment, and respiratory function and adversely affects other body systems and should
paralysis is the cause of death in most cases. Diagnosis is typi- therefore be addressed with dextrose supplementation.249,250
cally presumptive based on the history and clinical presenta- Sodium disorders are fairly common in critically ill foals,
tion because confirmation requires demonstration of spores but they are not typically associated with neurologic dys-
and/or toxin in the feces of affected animals, which can be function unless the derangements are very severe or there
difficult. A mouse bioassay has been validated for the diag- are dramatic, acute changes in the serum sodium concentra-
nosis of botulism in horses and foals.240 This assay is highly tion. These rapid changes in sodium concentration cause dra-
specific in foals, with specificity and PPV reported as 100%, matic fluid shifts in the tissues of the CNS, with hyponatremia
but it exhibits low sensitivity (53%) and NPV (52%).240 Treat- potentially being associated with the development of cerebral
ment is based on the administration of antitoxin and the pro- edema, whereas hypernatremia may cause an osmotic demy-
vision of supportive care. Foals that become recumbent will elination syndrome.250 Hyponatremia is more common than
likely die unless they receive ventilatory support in the form hypernatremia, and neurologic signs are most typically associ-
of mechanical ventilation, which may be required for as long ated with sodium concentrations less than 120 mEq/L.249,251
as 2 weeks.238 With early and appropriate care the prognosis The neurologic manifestations of hyponatremia may include
for survival in cases of types B and C botulism is reported to an abnormal stance or gait, depression, blindness, or sei-
be good.238 Type A botulism has been associated with more zures.252,253 Treatment of these disorders involves correction of
severe clinical signs and a higher case fatality rate, but a recent the underlying whole body sodium/water imbalances, because
report described the successful treatment of a foal affected by hyponatremia represents a free-water excess and hypernatre-
type A botulism.241 mia a free-water deficit.254 Hyponatremia should be addressed
by administering fluids that are relatively hypertonic com- clinical signs are typically euthanized because of the poor
pared with the plasma osmolality, and although the litera- long-term prognosis.
ture suggests that initial correction should be rapid followed
by slower correction, a more conservative approach may be Cerebellar Abiotrophy
appropriate in foals.249 Hypernatremia should be addressed Equine cerebellar abiotrophy is a neurodegenerative condition
using fluids that are relatively hypotonic but should be gradual affecting the cerebellum, which results in ataxia, head tremors,
(<0.5 mEq/L/h).249 and loss of equilibrium.270,271 Cerebellar abiotrophy is relatively
Hypocalcemia is often asymptomatic but can be associated rare in horses, and, although it can occur in multiple breeds, it
with tetany and seizures.254 Rapid decreases in the ionized cal- is most common in Arabian horses. It is inherited as an auto-
cium concentration appear more likely to be associated with somal recessive trait, with clinical signs generally detectable
clinical signs in critically ill foals.250 A syndrome of hypocal- between 4 weeks and 6 months of age.270-272 Diagnosis is typi-
cemic seizures has been described in young foals, typically cally presumptive based on breed association and clinical pre-
from 2 to 5 weeks of age.255,256 This condition is thought to be sentation because definitive antemortem diagnosis is difficult.
caused by primary hypoparathyroidism.249,256
Bilirubin is capable of crossing the blood-brain barrier, Epilepsy
especially when plasma concentrations of bilirubin are very A syndrome of juvenile idiopathic epilepsy (JIE) has been
high and in neonates where the blood-brain barrier is more described in Arabian foals of Egyptian lineage.273,274 This syn-
permeable. Bilirubin is neurotoxic and can cause neurologic drome is characterized by recurrent tonic-clonic seizures and
dysfunction and irreversible brain damage, which is a clinical resembles benign-familial neonatal convulsion syndrome in
syndrome termed kernicterus.257,258 The most important cause humans.275 JIE exhibits an early onset of clinical signs in the
of clinical icterus in equine neonates is neonatal isoeryth- first days to months of life but appears to be self-limiting and
rolysis (NI). Treatment of NI is discussed elsewhere in this resolves by 1 to 2 years of age.273,275
chapter, but primarily it consists of supportive care and blood
transfusions. These treatments do not address the hyperbiliru- Narcolepsy and Cataplexy
binemia, which can only be reduced using therapeutic plasma Narcolepsy in the horse is characterized by paroxysmal sleep
exchange.258 attacks, and affected animals may remain standing, whereas
Hyperammonemia has been associated with neurologic cataplexy represents the complete loss of muscle tone com-
dysfunction in foals and adult horses, and the clinical signs bined with areflexia leading to recumbency.276 Narcolepsy
associated with hyperammonemia include depression, blind- without cataplexy has been described in Thoroughbred,
ness, aimless wandering, head pressing, ataxia, circling, Warmblood, and Icelandic horses, and in some cases there
recumbency, and death.259-262 Hyperammonemia may may be a familial component.276,277 Narcolepsy with cataplexy
develop secondary to hepatic insufficiency, portosystemic is very rare, but it has been described in horses.276,278
shunts, or increased gastrointestinal production (intestinal
hyperammonemia).259-262 A disorder suspected to represent Treatment of Neonatal Encephalopathy
hyperornithinemia-hyperammonemia-homocitrullinuria Because of the broad range of disease processes associ-
(HHH) syndrome, a genetic defect in the urea cycle resulting ated with the development of NE in foals, there is no single
in persistent hyperammonemia, has been reported in Morgan treatment strategy. This discussion will focus on treatments
foals.263 Intestinal hyperammonemia is typically seen in asso- directed toward the prevention of CNS injury and normal-
ciation with clinical signs of gastrointestinal disease.261 ization of nervous system function. Foals with NE are typi-
cally suffering from severe systemic inflammation as well,
and specific treatment recommendations for supportive care;
Congenital Disorders infection control; correction of metabolic disorders; and nor-
Hydrocephalus malization of cardiovascular, pulmonary, gastrointestinal,
Hydrocephalus is a condition resulting from impaired drain- and renal function in critically ill foals is covered in detail
age of CSF caused by congenital defects or inflammation that elsewhere in this chapter.
results in the compression of the brain caused by increased The first objective is stabilization of the patient systemically,
intracranial pressure.264,265 This condition is considered to be because the restoration and maintenance of CNS perfusion is
uniformly fatal and is rare in horses but may be more frequent critical in ensuring adequate delivery of oxygen and glucose.
in the Friesian breed.265 Diagnosis is typically presumptive and IV fluid therapy is often required to correct hypovolemia
confirmed on postmortem examination, but CT and MRI can and support cardiovascular function, but vasopressors and
be used for definitive antemortem diagnosis if necessary.266 inotropes may be required to normalize blood pressure. It is
important to avoid overhydration or hypertension, however,
Occipitoatlantoaxial Malformation because these may potentiate CNS injury.185,279 Normalization
Foals born with occipitoatlantoaxial malformation typically of blood glucose concentrations is important as well, but care
exhibit paresis and ataxia of all four limbs, but in some cases must be taken to avoid hyperglycemia, because critically ill
foals may be born dead or comatose.197 Foals may have a head foals may be intolerant of dextrose infusions. Intranasal oxy-
tilt or abnormal head carriage, movement of the head may gen supplementation is recommended in weak or recumbent
reveal a clicking sound, and neurologic deficits may range foals, or those with documented arterial hypoxemia, to sup-
from inapparent to severe enough to result in quadriple- port oxygen delivery, and blood transfusions may be needed
gia.197,267 The condition is familial in the Arabian breed but in anemic patients for the same reason.
may occur in other breeds as well.267 Diagnosis is typically The second objective is to control seizure activity, if pres-
confirmed radiographically, although contrast myelography, ent. Specific treatment may not be required in individuals
CT, or MRI may be useful in some cases.268,269 Foals exhibiting with very subtle or rare signs of seizure activity, but it is clearly
TABLE 20.7 Drugs Used for the Control of Seizures in Foals

Drug Dosage Route Frequency Comments
Diazepam 0.1–0.4 mg/kg IV As needed Short-term seizure control
Midazolam 0.04–0.1 mg/kg IV As needed Short-term seizure control
0.02–0.06 mg/kg/h IV CRI For persistent seizures
Phenobarbital 2–10 mg/kg IV 12 h For persistent seizures
3–10 mg/kg PO 12 h Monitor serum concentrations
Pentobarbital 2–10 mg/kg IV Single dose For status epilepticus—use caution
Phenytoin 1–5 mg/kg IV, PO 4 h, up to 6 doses —
1–5 mg/kg PO 12 h
Potassium bromide 10 mg/kg PO 8 Monitor serum concentrations
60 mg/kg PO 24 h

CRI, Continuous rate infusion; IV, intravenously; PO, orally.

From Wilkins PA. Disorders of foals In: Reed SM, Bayly WM, Sellon DC, eds. Equine internal medicine. St. Louis, MO: Saunders Elsevier; 2010; Morresey
PR. Neurological conditions and seizure management. AAEP Focus on the First Year of Life. 2014;29-35; Wong D, Wilkins PA, Bain FT, et al. Neonatal en-
cephalopathy in foals. Comp Contin Educ Pract Vet. 2011;33:E5; Magdesian KG. Foals are not just mini horses. In: Cole C, Bentz B, Maxwell L, eds. Equine
pharmacology. Oxford, UK: Wiley-Blackwell; 2015:99-117.
indicated in patients with repeated, generalized seizure activ- which has been used because of its purported free radical scav-
ity. Benzodiazepines (diazepam and midazolam) represent enging and antiinflammatory effects, which are perhaps rein-
the first-choice therapy for control of acute seizures in foals forced by ease of administration and low cost.284 DMSO has
because of their rapid onset of action and minimal depressive osmotic and diuretic effects, which may be helpful in reducing
effects (Table 20.7).30,198 Bolus IV doses are used for the control intracranial pressure, and reportedly blocks sodium channel
of single seizure episodes, but CRI of midazolam can be used activation, suppresses calcium influx and prevents glutamate
to control persistent seizures. Other options for the control excitotoxic cell death.284 As promising as this appears, there
of persistent seizures include phenobarbital, pentobarbital, is actually little to no scientific evidence of efficacy regarding
and potassium bromide. Phenobarbital can cause substantial DMSO treatment of HIE, and clinical consensus on its use is
CNS depression when first administered but is generally well lacking.30,211 Mannitol has been administered to reduce cere-
tolerated, even with prolonged use. Serum phenobarbital lev- bral edema, but evidence of efficacy is also lacking for this
els should be monitored when used long term to ensure that treatment modality, and it is not commonly used.185 Mag-
concentrations remain within the therapeutic range, which nesium sulfate treatment has been of interest because of its
has been reported to be 5 to 30 μg/mL in foals.280 Pentobar- NMDA-receptor antagonist effects, and magnesium may also
bital should only be used in cases with status epilepticus that stabilize cell membranes, inhibit free radical production, and
cannot be controlled with other medications and is associated reduce secondary CNS inflammation and associated injury.285
with substantial risk caused by profound respiratory and car- The use of magnesium sulfate in foals with HIE has been
diovascular depression. Phenytoin has unpredictable kinetics reported, and treatment appears to be well tolerated, although
and is not widely used but has been suggested for anticonvul- excessive doses can cause muscular weakness and hyoten-
sant use in foals. Potassium bromide may be useful for long- sion.279 No data are available regarding efficacy in foals and,
term maintenance in foals with epilepsy because it has fewer although there are some studies with encouraging results, this
side effects than phenobarbital and is well tolerated. Reported therapeutic approach currently remains preclinical in human
effective plasma concentrations of bromide in other species infants with HIE.285,286 Pentoxifylline, a phosphodiesterase
are 70 to 240 mg/dL, but this has not been validated in foals.281 inhibitor, has antiinflammatory and immune-modulating
The next goal is to control ongoing CNS injury and prevent effects and may improve local tissue perfusion.287 It has been
further damage. Hypothermia is considered the standard of care suggested that pentoxifylline may inhibit TNF-α production
in the treatment of human neonates suffering from HIE. This in foals with NE.185 Antioxidant administration may be of
involves cooling the patient to 92.3 to 95.0°F using whole body some benefit in addressing CNS inflammation, and vitamins C
hypothermia, although selective head-cooling approaches can and E and thiamine (vitamin B1) have all been administered to
be used as well.214 A recent systematic review confirmed that foals with HIE.65 Allopurinol is an antioxidant that has shown
therapeutic hypothermia is beneficial in human infants suffer- promise in human infants, but it remains preclinical at this
ing from HIE, because hypothermia reduced mortality with- time.288 Allopurinol administration has been suggested for
out increasing long-term neurologic disability in survivors.282 foals with HIE, but there are no reports of its use.185 A myriad
There are some complications associated with hypothermia, of additional treatments have been investigated in human neo-
most notably overcooling, skin problems, altered drug metabo- natal HIE, and some of those that appear promising include
lism, and an increased risk of seizure during rewarming.283 The inhaled xenon as an antiexcitotoxic agent, melatonin as an
logistics of providing therapeutic hypothermia in foals, includ- antioxidant, erythropoietin as a growth factor, and stem cell
ing the appropriate techniques of cooling, patient selection, therapy.204,289,290
and duration of cooling remain, is to be defined before clinical
application of this approach in equine medicine. Y RESPIRATORY DISORDERS
A number of pharmacologic approaches to neuroprotec-
tion have been used empirically in foals with HIE, but their Lower respiratory tract disease is common in foals and
use has not been validated (Table 20.8). One of the most widely accounts for substantial morbidity and mortality. Foals are
used drugs for decades has been dimethyl sulfoxide (DMSO), at risk for the development of respiratory disease caused by
TABLE 20.8 Drugs Used for the Treatment of Central Nervous System Disorders
Drug Dosage Route Frequency Comments
DMSO 0.1–1 g/kg as a 10% solution IV 12–24 Hemolysis, dehydration, OSHA
restrictions
Mannitol 0.25–2.0 g/kg as a 20% solution over IV 12–24 Dehydration
15–20 min
Magnesium sulfate 0.05 mg/kg/h (loading) IV CRI Can precipitate other fluids
0.025 mg/kg/h
Pentoxifylline 10 mg/ kg PO 12 —
Gabapentin 3–5 mg/kg PO 6–8 —
Allopurinol 44 mg/kg PO Once in first 4 h —
Vitamin E 5000 IU PO 24 —
Vitamin C 100 mg/kg IV, PO 24 —
Thiamine 1–20 mg/kg IV Added to fluids —

CRI, Continuous rate infusion; DMSO, dimethyl sulfoxide; IV, intravenously; OSHA, Occupational Safety and Health Administration; PO, orally.
From Wilkins PA. Perinatal asphyxia syndrome. In: Sprayberry KA, Robinson NE, eds. Robinson’s current therapy in equine medicine. St. Louis, MO:
Elsevier Saunders; 2015:732-736; Wong D, Wilkins PA, Bain FT, et al. Neonatal encephalopathy in foals. Comp Contin Educ Pract Vet. 2011;33:E5.
complex interactions between innate immunologic factors and These syndromes are associated with an exaggerated and
a number of risk factors. Immunologic factors include possible self-perpetuating inflammatory response, which results in
FPTI, delayed endogenous immunoglobulin production, and severe tissue damage within the lungs. Protein-rich edema
potentially impaired immunologic responses. Risk factors in fluid accumulates within the alveoli and interstitium, result-
neonates include systemic sepsis, congenital abnormalities, ing in impairment of gas exchange leading to hypoxemia.294
meconium aspiration, milk aspiration, and birth trauma. Risk ALI and ARDS are not primary disease syndromes and always
factors in older foals include the stresses of weaning, sales occur secondary to other disease processes. Risk factors for
preparation, and transport, as well as confinement in crowded ALI and ARDS in human patients include processes result-
or dusty conditions that result in heavy exposure to potential ing in both direct pulmonary injury (pneumonia, aspiration
respiratory pathogens. of gastric contents, smoke inhalation, pulmonary contusion,
and drowning) and indirect pulmonary injury (nonpulmo-
Respiratory Distress nary sepsis, pancreatitis, multiple transfusions, and major
There are several syndromes associated with respiratory dis- trauma).294
tress in the foal, and these syndromes can result from a vari- Accurate assessment of respiratory function in the neonate
ety of initiating causes. The defining characteristics change requires arterial blood gas analysis, and the ready availability
with age, caused by the normal maturation of pulmonary of portable blood gas analyzers has greatly improved access
function in the newborn foal, and to some extent caused by to this important diagnostic tool. Management of critically ill
the changing nature of the insults that result in respiratory foals without this information is extremely difficult, because
distress. The finding of acute respiratory distress immediately it is important in initial evaluation, formulation of an appro-
after birth is likely associated with extrapulmonary disorders priate treatment plan, monitoring the response to treatment,
causing upper respiratory obstruction, such as bilateral cho- and prognostication. Foals are most readily sampled in lateral
anal atresia, stenosis of the nares, severe laryngeal edema or recumbency using the lateral metatarsal artery and the bra-
collapse, dorsal displacement of the soft palate, subepiglottic chial or transverse facial artery. Sampling should be performed
cysts, or severe congenital pulmonary abnormalities.30 Con- quickly after placing the foal in lateral recumbency, and the
genital cardiac anomalies, such as malpositioning of the great patient should be returned to a sternal or standing position as
vessels, resulting in severe right-to-left shunts may also be soon as possible, because positioning in lateral recumbency
involved.30 has a substantial negative impact on arterial oxygenation (10–
14 mm Hg). Diagnostically this impact can be addressed by
using appropriate reference ranges derived from foals sampled
Acute Lung Injury and Acute Respiratory in lateral recumbency (Table 20.9). The other major element
Distress Syndrome that has to be factored in to interpretation of arterial blood
When dealing with respiratory distress in foals beyond the gas data in neonatal foals is the changes in pulmonary func-
immediate postpartum period the situation can become tion that occur over the course of the first several days of life,
confusing because of the broad range of etiologies involved because newborn foals have a small degree of shunt fraction
and the broad spectrum of the clinical syndromes. Although that renders them relatively hypoxemic and less responsive to
this has been appreciated in human and veterinary medicine oxygen supplementation than adults. This phenomenon is also
for many years, it is only in the past decade that a consen- addressed in Table 20.9.
sus approach to this situation has been developed in veteri- The most common arterial blood gas abnormalities iden-
nary medicine.291 The terms acute lung injury (ALI) and acute tified in neonatal foals are hypoxemia with normocapnia or
RDS (ARDS) were originally developed in human medicine hypocapnia and hypoxemia with hypercapnia. Hypoxemia
to refer to a syndrome of respiratory failure associated with can result from several mechanisms: hypoventilation, venti-
noncardiogenic pulmonary edema, decreased pulmonary lation/perfusion mismatching, impaired diffusion, intrapul-
compliance, and ventilation/perfusion mismatching.292,293 monary or extrapulmonary (cardiac) shunts, and decreased
TABLE 20.9 Normal Arterial Blood Gas Values for Foalsa

BOX 20.3
Definition of Neonatal Equine Respiratory Distress
Gestational Postnatal Syndrome
Age Age Pao2 Paco2 pH
Term 2 min 56.4 ± 2.3 54.1 ± 2.0 7.31 ± 0.02 Etiology: Primary surfactant deficiency caused by the failure
15 min 57.5 ± 3.6 50.4 ± 2.7 7.32 ± 0.03 of final fetal pulmonary surfactant metabolism maturation.
30 min 57.0 ± 1.8 51.5 ± 1.5 7.35 ± 0.01 Diagnosis requires meeting all criteria listed next:
1. Persistent hypoxemia in combination with progressive
60 min 60.9 ± 2.7 47.3 ± 2.2 7.36 ± 0.01
hypercapnia
2h 66.5 ± 2.3 47.7 ± 1.7 7.36 ± 0.01 a. Hypoxemia defined as Pao2 <60 mm Hg with the foal
4h 75.7 ± 4.9 45.0 ± 1.9 7.35 ± 0.02 breathing room air and in lateral recumbency
12 h 73.5 ± 3.0 44.3 ± 1.2 7.36 ± 0.02 2. The presence of at least one of three appropriate risk
48 h 74.9 ± 3.3 46.1 ± 1.1 7.37 ± 0.01 factors:
a. Very early gestational age: less than 290 days’ ges-
4 days 81.2 ± 3.1 45.8 ± 1.1 7.40 ± 0.01
tational age or less than 88% of the average of the
7 days 86.9 ± 2.2 46.7 ± 1.1 7.37 ± 0.01 dam’s previous gestation lengths
Premature 0.5–11 53.7 ± 1.5 55.3 ± 3.6 7.21 ± 0.05 b. Induction of parturition
hours c. Caesarean section
3. Failure to develop normal immediate postpartum respira-
Adapted from Wilkins PA: Disorders of foals. In: Reed SM, Bayly WM, Sellon
tory patterns: development/persistence of paradoxic
DC, eds. Equine Internal Medicine. St. Louis, MO: Saunders Elsevier;
2010:1311-1363; Stewart JH, Rose RJ, Barko AM: Respiratory studies in breathing over the first several hours of life, persistent
foals from birth to seven days old. Equine Vet J. 1984;16:323-328; Rose tachypnea
RJ, Rossdale PD, Leadon DP: Blood gas and acid-base status in spontane- 4. Ground glass appearance of lateral thoracic radiographs
ously delivered, term-induced and induced premature foals. J Reprod Fertil at ≤24 hours of age (standing or lateral recumbency)
Suppl. 1982;32:521-528.
5. Absence of evidence of fetal inflammation
a. Normal white blood cell count, differential, and fibrino-
concentration of oxygen in the inspired air (high altitude or gen concentration for gestational age
inappropriate ventilator setting). Weak, recumbent neona- 6. Congenital cardiac disease ruled out as a cause of hy-
tal foals will frequently suffer from hypoventilation, whereas poxemia
the presence of intrapulmonary inflammation or surfactant
Adapted from Wilkins PA, Otto CM, Baumgardner JE, et al. Acute lung injury
deficiency will cause substantial ventilation/perfusion mis- and acute respiratory distress syndromes in veterinary medicine: consen-
matching with intrapulmonary shunting of blood. Severe sus definitions: the Dorothy Russell Havemeyer Working Group on ALI and
inflammation or pulmonary edema can cause diffusion ARDS in Veterinary Medicine. J Vet Emerg Crit Care. 2007;17:333-339.
impairment, whereas extrapulmonary shunts are most com-
monly associated with persistent fetal circulation or cardiac
anomalies. Foals suffering from pneumonia typically show pulmonary compliance, and to facilitate recruitment of col-
profound hypoxemia initially, but the development of hyper- lapsed airways.296 Surfactant deficiency leads to progressive
capnia and respiratory acidosis indicates substantial worsen- atelectasis and decreased pulmonary compliance, worsening of
ing of pulmonary function and is associated with a poorer ventilation/perfusion mismatching caused by intrapulmonary
prognosis for survival.111,295 and possibly extrapulmonary shunting of blood, hypoventila-
ALI in human patients is characterized by an acute onset, tion, and increased work of breathing. If not addressed the end
the presence of bilateral pulmonary infiltrates on thoracic result is progressive hypoxia and hypercapnia and ultimately
radiographs, a decreased ratio of the partial pressure of oxy- respiratory failure.296
gen in arterial blood (Pao2) to the fraction of inspired oxygen Treatment of NERDS is challenging, because the primary
(Fio2) of ≤300 mm Hg, and a pulmonary arterial wedge pres- interventions used in human infants are not readily available
sure of less than 18 mm Hg or the absence of clinical evidence in equine medicine (exogenous surfactant) or are only avail-
of left atrial hypertension.292 ARDS represents a more severe able in tertiary care referral centers (mechanical ventilation).
degree of dysfunction and is characterized by the same crite- Given the benefits of surfactant therapy in human respira-
ria but with a lower Pao2/Fio2 ratio of ≤200 mm Hg.292 Simi- tory distress syndrome (RDS) patients,297 this intervention
lar terminology and definitions have been proposed for foals is of great interest in affected foals, but the author’s personal
suffering from respiratory distress.291 Multiple classifications experience and the limited references to this therapy in the
have been defined, including neonatal equine RDS (NERDS), literature suggest that the effect of this therapy has a short
equine neonatal ALI (EqNALI) and equine neonatal ARDS duration and needs to be repeated frequently, making it dif-
(EqNARDS), and veterinary ALI (VetALI) and veterinary ficult to justify the significant expense, if surfactant is even
ARDS (VetARDS).291 The diagnostic criteria for these syn- available.298,299 Interestingly, one of the primary changes
dromes are provided in tabular form (Boxes 20.3–20.5). in the management of human neonates with RDS has been
Although the term NERDS is new, the syndrome of severe, driven by the recognition that mechanical ventilation via
progressive respiratory distress in foals within the first 24 endotracheal intubation, although life-saving in many cases,
hours of life has been recognized for at least 50 years.5 NERDS is also associated with the potential for serious acute com-
is very similar to infant RDS in human infants, which is caused plications and long-term pulmonary dysfunction.300 The
by primary surfactant deficiency associated with premature acute complications may include trauma to the upper respi-
delivery.291 Surfactant has three primary roles within the lung: ratory tract associated with intubation, increased risk of
to prevent atelectasis at the end of expiration, to increase lower respiratory tract infections, pulmonary barotrauma
BOX 20.4
Definition of Veterinary Acute Lung Injury and BOX 20.5
Definition of Equine Neonatal Acute Lung Injury/
Acute Respiratory Distress Syndrome Respiratory Distress Syndrome
Must meet at least one each of the first four criteria; criterion Normal NALI NARDS
five is a recommended but optional measure. Normal Pao2/Fio2 Pao2/Fio2 Pao2/Fio2
1. Acute onset (<72 hours) of tachypnea and labored Postnatal Pao2 (mm Ratio (mm Cutoff Cutoff
breathing at rest Age Hg) Hg) (mm Hg) (mm Hg)
2. Known risk factors 60 min 60.9 ± 2.7 >300 <175 <115
3. Evidence of pulmonary capillary leak without increased
12 h 73.5 ± 3.0 >350 <200 <140
pulmonary capillary pressurea (any one or more of the
following): 24 h 67.6 ± 4.4 >350 <200 <140
a. Bilateral/diffuse infiltrates on thoracic radiographs 48 h 74.9 ± 3.3 >350 <200 <140
(more than one quadrant per lobe) 4 days 81.2 ± 3.1 >400 <250 <160
b. Bilateral dependent density gradient on CT
7 days 90.0 ± 3.1 >430 <280 <190
c. Proteinaceous fluid within the conducting airways
d. Increased extravascular lung water
This is for VetALI/VetARDS but adheres to the following age-dependent
4. Evidence of inefficient gas exchange (any one or more of adaptation of the Pao2/Fio2 ratio in term foals in lateral recumbency breathing
the following): room air (Fio2 = 0.21) based on age-dependent normal values for Pao2 under
a. Hypoxemia without PEEP or CPAP and known Fio2 similar conditions.
i. Pao2/Fio2 ratio Fio2, fraction inspired oxygen; NALI, neonatal acute lung injury; NARDS,
neonatal acute respiratory distress syndromes; VetALI, veterinary acute lung
ii. ≤300 mm Hg for VetALI
injury; VetARDS, veterinary acute respiratory distress syndrome.
iii. ≤200 mm Hg for VetARDS From Wilkins PA, Otto CM, Baumgardner JE, et al. Acute lung injury and
iv. Increased alveolar-arterial oxygen gradient acute respiratory distress syndromes in veterinary medicine: consensus defi-
v. Venous admixture (noncardiac shunt) nitions: the Dorothy Russell Havemeyer Working Group on ALI and ARDS in
b. Increased “dead-space” ventilation Veterinary Medicine. J Vet Emerg Crit Care. 2007;17:333-339.
5. Evidence of diffuse pulmonary inflammation
a. Transtracheal wash/bronchoalveolar lavage sample
neutrophilia was investigated in healthy foals.303 If nasal cannulation is
b. Transtracheal wash/bronchoalveolar lavage biomark- not possible or is not achieving adequate flow rates, then an
ers of inflammation intratracheal catheter can be used for oxygen insufflation,
c. Molecular imaging (PET) but this rarely represents anything more than a short-term
aNo
solution.304
evidence of cardiogenic edema (one or more of the following): PAOP
<18 mm Hg (adult horse). No clinical or diagnostic evidence supporting left Although oxygen insufflation can be tremendously helpful,
heart failure, including echocardiography. it is unlikely to be sufficient in foals with severe respiratory
CPAP, Continuous positive airway pressure; CT, computed tomography; impairment secondary to surfactant deficiency caused by pro-
Fio2, fraction inspired oxygen; PAOP, pulmonary artery occlusion pressure; gressive alveolar collapse and worsening ventilation/perfusion
PEEP, positive end expiratory pressure; PET, positron emission tomography;
VetARDS, veterinary acute respiratory distress syndrome; VetALI, veterinary
mismatching. In the most severely affected cases mechanical
acute lung injury. ventilation will represent the only viable means of respiratory
From Wilkins PA, Otto CM, Baumgardner JE, et al. Acute lung injury and support, and this technique is discussed in detail later in this
acute respiratory distress syndromes in veterinary medicine: consensus defi- section. However, noninvasive respiratory support strategies
nitions: the Dorothy Russell Havemeyer Working Group on ALI and ARDS in that provide continuous positive distending pressure, such as
Veterinary Medicine. J Vet Emerg Crit Care. 2007;17:333-339.
continuous positive airway pressure (CPAP), are widely used
in human neonates with RDS and have been shown to reduce
respiratory failure and mortality.305 There are a few older
and volutrauma, air leak syndromes (pneumothorax), and reports of noninvasive ventilatory support techniques for foals
hemodynamic complications caused by impaired venous that used mechanical ventilators and either nasal prongs or
return, whereas the primary long-term complication is face masks.306,307 A recent report described the adaptation of
bronchopulmonary dysplasia.301 Because of these concerns a commercial human CPAP device and face mask to provide
noninvasive forms of respiratory support are widely used in CPAP to foals.308 The authors reported that although both
human infants with RDS, which include all forms of respira- CPAP and nonpressurized oxygen supplementation with a face
tory support not delivered with an endotracheal tube.302 The mask normalized pretreatment hypoxemia, oxygen extraction
simplest and most readily implemented form of noninvasive and CO2 elimination were highest with CPAP at a lower respi-
respiratory support in foals is the intranasal administration ratory rate than nonpressurized oxygen administration. Both
of humidified oxygen via intranasal cannula. Although a treatments were associated with the development of modest
single cannula is most often used, this may not provide suf- hypercarbia, but this was not associated with adverse effects.
ficient oxygen flow rates, in which case a second cannula can This treatment modality holds promise for foals suffering from
be placed in the opposite nostril, and combined flow rates NERDS, but further evaluation in affected foals is needed.
of up to 20 L/minute can be readily delivered.303 A poten- The syndromes of EqNALI and EqNARDS represent a
tial downside to bilateral cannula placement is that this may subset of ALI and ARDS that occurs in foals in the first
cause some degree of upper respiratory obstruction in small week of life. The criteria for EqNALI/EqNARDS differ from
foals, potentially impairing exhalation and CO2 elimination, those for ALI/ARDS because of the changes that occur in
although this effect was not detected when this technique the efficiency of pulmonary gas exchange as foals develop
during this time frame. Diagnosis of these syndromes is although not definitive, may be suggestive of Rhodococcus
fundamentally similar to that of VetALI and VetARDS with equi infection.318,319
the exception of the use of an age-specific scale of Pao2/ Thoracic imaging is extremely helpful in staging the degree
Fio2 ratios based on blood gas values obtained from foals of pulmonary inflammation and identifying underlying pri-
breathing room air and positioned in lateral recumbency, mary disease processes. Thoracic ultrasonography is readily
as is typically encountered in clinical practice. It is impor- performed and may provide useful information, such as the
tant to remember that EqNALI/EqNARDS is not a primary presence of severe atelectasis, pleural effusion, or pulmo-
diagnosis, and affected foals may be suffering from a broad nary abscesses. Diffuse lung inflammation, such as occurs in
range of disease processes. There certainly may be overlap ALI, will be seen as thickening of the visceral pleura and the
with NERDS, but bacterial sepsis and bacterial pneumonia appearance of echogenic projections arrayed perpendicular
will be the most common disease processes in foals of this to the surface of the lung (comet-tail artifacts).320 Thoracic
age. Other potential etiologies include meconium aspira- radiographs provide much more detailed information regard-
tion, milk aspiration, viral pneumonia, fungal pneumonia, ing the severity and extent of pulmonary inflammation, and
or thoracic trauma, all of which are covered in detail in the reasonable image quality can be obtained with stall-side digi-
following sections. tal radiographic equipment.321 The radiographic abnormalities
Treatment of EqNALI/EqNARDS is primarily focused on observed in affected foals may range from a diffuse interstitial
addressing hypoxemia and hypercapnia while pursuing cor- pattern to a focal or diffuse coalescing alveolar pattern with
rection of the primary etiology where possible. Respiratory multiple air bronchograms, and serial radiography can be very
support may involve the provision of intranasal oxygen, CPAP, helpful in monitoring the progression of disease and response
or mechanical ventilation, depending on the severity of pul- to treatment.293,321 The presence of pulmonary abscesses on
monary dysfunction. Because of the substantial inflammation thoracic ultrasonographic examination or in thoracic radio-
present, there may be an indication for antiinflammatory ther- graphs is strongly suggestive of R. equi involvement but is not
apy. Nonsteroidal antiinflammatories are unlikely to be suffi- definitive.318 CT imaging of the thorax for the evaluation of
cient, but there is evidence in adult humans with ARDS309,310 foals with pulmonary disease has been recently reported as
and in older foals with VetARDS311,312 that corticosteroid ther- well.321,322 CT imaging provides much more detailed informa-
apy may be beneficial. Although specific therapeutic protocols tion regarding the nature and degree of pulmonary changes
have not been defined, recent work has suggested that hydro- but is only available in a few specialty referral settings at this
cortisone administration at a dosage of 1 to 4 mg/kg per day time.
IV divided into four to six doses may be appropriate for septic Foals affected with VetALI/VetARDS most commonly
foals with CIRCI, but this approach has not been investigated suffer from a primary bacterial pneumonia, but other causes
in septic foals or foals with EqNALI/EqNARDS.313-315 Because such as viral pneumonia are possible. A transtracheal aspi-
of the likelihood that bacterial infection may be involved in rate should be performed unless the patient is too unstable
this age group, broad-spectrum antimicrobial therapy is also to undergo the procedure; this sample can provide impor-
indicated along with judicious fluid therapy and supportive tant cytologic evidence regarding the type and severity of
care. pulmonary inflammation and the presence of extracellular
The most definitive descriptions of acute respiratory dis- and intracellular bacteria and should also be submitted for
tress in foals have been associated with bronchointerstitial bacterial culture and sensitivity. Neutrophilic inflamma-
pneumonia in foals 1 to 12 months of age.311,312,316,317 Affected tion is typically present, and the detection of intracellular
foals often appear clinically normal until they are found in gram-positive coccobacilli within pulmonary macrophages
acute respiratory distress or dead.311 Some cases may have a is strong evidence of the presence of R. equi.318 Polymerase
history of previous respiratory disease associated with sudden chain reaction (PCR) testing of tracheal aspirates may be
clinical deterioration.293 Physical examination finds affected helpful in confirming rhodococcal involvement.323 Treat-
foals depressed, lethargic, and inappetent, with severe respi- ment of ALI/ARDS-affected foals should focus on addressing
ratory distress characterized by tachycardia, tachypnea, and the hypoxemia, treating the primary underlying disease pro-
nostril flare. A paradoxic breathing pattern may be pres- cess, controlling the excessive inflammatory response, and
ent, in which the thorax and abdomen move opposite from providing supportive care. Intranasal oxygen insufflation, as
one another, rather than synchronously, during inspiration described previously, should be initiated as soon as possible
and expiration. Auscultation may reveal widespread abnor- in foals suffering from respiratory distress and represents the
mal sounds, with prominent wheezes and crackles, or lung primary means of respiratory support in these older foals.
sounds may be very quiet to absent with only large airway Antimicrobial therapy should target the most likely bacterial
sounds detectable. Fever and injected mucous membranes pathogens based on the overall assessment. In younger foals
are common as well. Care should be taken to auscult the in which sepsis may be playing a primary role, broad-spec-
heart thoroughly, which may be difficult in the presence of trum antimicrobial therapy is recommended. In older foals
diffuse abnormal respiratory sounds, to rule out a cardiac empiric treatment should address the possible involvement
cause of pulmonary edema. Clinicopathologic evaluation is of R. equi. Aggressive systemic antiinflammatory therapy
important both for assessment of pulmonary function and using potent corticosteroids, such as dexamethasone and
identification of the primary underlying disease process. methylprednisolone sodium succinate, has been shown to
Arterial blood gas analysis is extremely helpful and should be the most important intervention in effecting survival of
be performed before initiation of intranasal oxygen insuffla- affected foals.311,312,324 Corticosteroid therapy should be grad-
tion, if clinically appropriate. Complete blood count, fibrino- ually tapered as the clinical condition improves, rather than
gen concentration, and SAA concentration are all helpful in rapidly withdrawn. Prolonged therapy has been shown to be
characterizing the severity of systemic inflammation, and beneficial in human ARDS patients.310 Bronchodilator ther-
very high WBC counts, fibrinogen, or SAA concentrations, apy has been used in affected foals because of the severity of
respiratory distress, but bronchoconstriction is not a promi- 0.5 to 2.5 mg/kg PO, up to every 4 hours, starting at the lower
nent feature of ARDS, and bronchodilator administration end of the dosage range to avoid systemic hypotension.330
may actually worsen the ventilation/perfusion mismatch- Although supported by only one case report in humans, the
ing and result in clinical deterioration or even death.293 If use of pentoxifylline, a nonselective phosphodiesterase inhibi-
used, bronchodilator therapy should only be administered tor, as an adjunctive therapy may be worthy of consideration
after nasal insufflation of oxygen has been instituted, and in foals because of availability, low cost, and an accepted safety
the clinician should be prepared to address sudden changes profile.331,332
in clinical status. The use of the inhalational route for the
administration of corticosteroids and bronchodilators in Congenital Upper Respiratory Tract Disorders
patients suffering from severe pulmonary dysfunction with There are a number of congenital upper respiratory tract dis-
substantial ventilation/perfusion mismatching is often unre- orders in foals, although none is common. These can include
warding because of poor pulmonary penetration and deliv- wry nose, choanal atresia, cleft palate, nasopharyngeal cysts,
ery, so the systemic route is recommended. The prognosis for and subepiglottic cysts.333 Wry nose involves lateral and
survival in affected foals is poor to guarded, with early and rotational deviations in the structure of the nose; in mod-
aggressive corticosteroid and antimicrobial therapy offering erate to severe cases it will cause significant upper airway
the best chance of survival.324 obstruction.334 Surgical repair is possible, but this must be
regarded as a salvage procedure, because the prognosis for
Persistent Pulmonary Hypertension athletic function is poor.334 Choanal atresia is rare in foals
Persistent pulmonary hypertension of the newborn (PPHN), but involves unilateral or bilateral soft tissue narrowing or
also known as persistent fetal circulation or reversion to fetal complete obstruction of the caudal aspect of the nasal pas-
circulation, is a syndrome characterized by sustained increases sages.335 Foals born with bilateral complete obstruction will
in pulmonary vascular resistance. Increased pulmonary vas- die without rapid intervention to establish an airway because
cular resistance, possibly combined with decreased right ven- of the obligate nasal breathing nature of equines.333 Foals
tricular function, results in right-to-left shunting through with unilateral choanal atresia often remain undiagnosed
the ductus arteriosus and/or foramen ovale.325 PPHN can be until later in life.336 Diagnosis is most often made using
idiopathic, but in human infants it is more commonly associ- endoscopy, but CT examinations have been useful in some
ated with pulmonary disease, such as meconium aspiration, cases.336 Surgical correction is feasible, but the prognosis for
perinatal asphyxia, surfactant deficiency, and pneumonia.326 performance remains guarded because of the persistent air-
In foals PPHN may also develop secondary to systemic sepsis, way narrowing in many cases. Cleft palate deformities are
hypoxemia, or acidosis.327,328 The pathophysiology of PPHN rare and are reported in only 0.1% to 0.8% of foals.337 Most
is complex but fundamentally represents dysfunction of the affected foals will show clinical signs of dysphagia when
factors that regulate pulmonary vascular tone. PPHN should nursing, including coughing or nasal milk drainage, but this
be suspected in any neonatal foal exhibiting progressive or is inconsistent.338 Aspiration pneumonia is a common com-
refractory hypercapnic hypoxemia. Care should be taken to plication. The primary site of involvement is the soft palate,
rule out the presence of congenital cardiac anomalies that may and the defect can range from a small, focal site to essentially
be causing extrapulmonary shunting of blood and other causes the absence of the entire soft palate. Diagnosis is most readily
of hypoxemic respiratory failure, such as sepsis or infectious made endoscopically, although surgical correction is theo-
pneumonia. PPHN should be suspected in cases of hypoxemia retically possible; the approach is difficult and the outcome
that do not show a significant increase in Pao2 following the uncertain, especially with large defects.337 There is one recent
institution of intranasal oxygen therapy. Definitive diagnosis report of successful transoral endoscopically assisted repair
can be challenging, but ultrasonography can be very helpful in in a foal.339 Subepiglottic cysts are also rare in foals, but when
ruling out congenital cardiac anomalies and detecting primary present they can interfere with epiglottal placement, result-
pulmonary disease. ing in persistent palate displacement and severe dysphagia
Treatment of PPHN is challenging but depends on address- and aspiration pneumonia.333,340 Diagnosis is primarily by
ing any predisposing or underlying factors while addressing endoscopic examination, although visualization may be dif-
the severe hypoxia. Foals that do not respond well to nasal ficult if the cyst is positioned below the palate. Radiographs
insufflation of oxygen will require intubation and mechani- or CT may be helpful in detecting these lesions. Treatment
cal ventilation with 100% oxygen.30 This can be useful both is by cyst removal, either via laryngotomy or by nasal or oral
in addressing the hypoxia and in potentially stimulating pul- endoscopic approaches.333
monary vascular relaxation.327,328 Following a brief period of
hyperoxia, it is recommended to taper the inhaled oxygen con- Meconium Aspiration
centration to target a Pao2 of 60 to 100 mm Hg.325 Therapeutic Meconium aspiration syndrome (MAS) is defined as respi-
agents that directly address the pulmonary vasoconstriction ratory distress in a foal born through amniotic fluid stained
are widely used in human neonates, but inhaled nitric oxide with meconium in which the symptoms cannot be explained
(iNO) is the only approved pulmonary vasodilator for human by other etiologies. Meconium staining can occur before, dur-
use. The successful use of iNO therapy in foals has been ing, or immediately after parturition, and meconium passage
reported,327 but unfortunately it is impractical in most settings in utero is thought to primarily occur in response to fetal
because it requires mechanical ventilation along with special- hypoxia leading to fetal stress. Fetal hypoxia also may result
ized equipment for introducing the NO gas into the ventilator in fetal gasping, facilitating introduction of meconium into
circuit.328 Sildenafil (Viagra, Pfizer Inc., New York), a phos- the respiratory tract while in utero. Meconium aspiration
phodiesterase type 5 inhibitor, has been used in humans and may also occur in association with the first few breaths after
is reported to be effective.326,329 There are anecdotal reports of birth. The presence of meconium-stained amniotic fluid does
the use of sildenafil in foals with PPHN, at a dosage rate of not guarantee that MAS will occur, however, because only
2% to 9% of human infants born through meconium-stained structural abnormalities of the pharynx, larynx, or esophagus
amniotic fluid develop MAS.341 When meconium contamina- suggestive of aspiration, or pharyngeal dysfunction may be
tion of the lower respiratory tract occurs there are a number observed. Thoracic radiographs typically reveal an alveolar
of pathophysiologic mechanisms leading to pulmonary dys- pattern with or without air bronchograms in the caudoventral
function, including mechanical airway obstruction, regional lung, but this may be localized to the perihilar region.321 It is
air trapping, surfactant inactivation, surfactant displacement, important to pursue the identification and correction of the
chemical pneumonitis and alveolitis, and persistent pulmo- cause of aspiration, if possible, to prevent further aspiration.
nary hypertension.327,341 Placement of a nasoesophageal feeding tube will allow for the
If meconium aspiration is suspected then aspiration of the safe delivery of milk pending correction of the underlying dis-
material from the nasal passages and pharynx can be per- order. Broad-spectrum antimicrobial therapy is indicated to
formed, even while the foal is in the birth canal, if the birth address the bacterial pneumonia accompanying milk aspira-
is attended. If more severe contamination is suspected then tion, and successful treatment may require several weeks of
nasotracheal intubation followed by aseptic suctioning is sug- treatment.
gested, although care must be taken to avoid contamination of
the lower respiratory tract or overly zealous suction. Intrana- Transient Tachypnea
sal oxygen supplementation is recommended in affected foals, Idiopathic or transient tachypnea has been reported in Clydes-
but mechanical ventilation will be required in more severely dale, Thoroughbred, and Arabian foals and is generally seen
affected cases and is associated with a worsened prognosis. during hot, humid weather conditions.352 This condition is
Mechanical ventilation is challenging in these cases because believed to be the result of immature or dysfunctional ther-
of the degree of pulmonary inflammation and airway compro- moregulatory mechanisms.327 Affected foals are usually nor-
mise as well as the severity of ventilation/perfusion mismatch- mal at birth and of a normal gestational age, but they develop
ing and strategies to minimize barotrauma, such as CPAP hyperthermia and tachypnea at variable times following
ventilation and synchronized intermittent mandatory ventila- birth.342 It is critical that other potential causes of respiratory
tion (SIMV), which may be helpful.342,343 Surfactant admin- disease are ruled out before making the diagnosis of idiopathic
istration and lung lavage with dilute surfactant appear to be tachypnea, because the consequences of withholding anti-
effective in human neonates with MAS but are not routinely microbial treatment could be severe. Treatment is primarily
used in foals.344 Antiinflammatory therapy may be beneficial directed at controlling the hyperthermia and may include
because of the substantial pulmonary inflammation associated body clipping; alcohol baths; and movement to a cool, shady
with MAS. Pentoxifylline has shown some promise in animal environment.342 In most foals the condition is self-limiting
models, appears safe in foals, and is easily administered.345,346 and will resolve within a few days to a few weeks.
Corticosteroids, either inhaled or systemically administered,
are commonly used in human infants with MAS.347,348 Rib Fractures, Pneumothorax, and Hemothorax
Although meconium aspiration is not associated with primary Rib fractures are a fairly common problem, having been
bacterial pneumonia, affected foals are at risk of secondary reported in 3% to 5% of the general population of neonatal
bacterial infection, and broad-spectrum antimicrobial therapy foals and as many as 30% of foals presenting to a neonatal
is recommended. ICU.353 Fractured ribs can cause a number of traumatic insults
to the thoracic viscera, including pulmonary contusions and
Milk Aspiration lacerations of the lungs, major arteries, heart, or diaphragm.
Neonatal foals may aspirate milk into the lower respiratory Pneumothorax, hemothorax, and diaphragmatic herniation
tract secondary to a number of conditions, although this is may all occur as a result of these traumatic insults, and myo-
most common secondary to generalized weakness, a poor cardial injury is typically fatal. Rib fractures can be single, but
suckle reflex, or dysphagia related to prematurity or NE.349 are often multiple, most often affecting adjacent ribs on one
This risk may be exacerbated by attempts at bottle feeding side of the chest. The most common site of injury is at the cos-
foals affected with these problems. Other potential causes of tochondral junction or immediately dorsal to it.354 Flail chest,
aspiration include physical abnormalities such as subepiglot- or paradoxic thoracic wall motion, may occur when multiple
tic cysts, cleft palate, megaesophagus, esophageal stenosis, ribs are fractured, and the affected region will move inward
esophageal compression by vascular anomalies, or persistent during inspiration and outward during expiration, counter to
dorsal displacement of the soft palate.342,349,350 Functional the movements of the intact portions of the thoracic wall. Rib
abnormalities of the pharynx, larynx, and esophagus resulting fractures are commonly found on physical examination by
in aspiration have been associated with pharyngeal dysfunc- palpation of the fracture itself or by the detection of crepitus
tion of unknown etiology, botulism, and hyperkalemic peri- at the site of the fracture. Auscultation may reveal grinding or
odic paralysis.342,349,351 Incorrect placement of nasoesophageal “clicking” sounds in the area of the fracture as well. Confirma-
feeding tubes has also been associated with direct instillation tion of the diagnosis is best accomplished ultrasonographically
of milk into the lungs, leading to aspiration pneumonia. Detec- because this modality is much more sensitive than radiography
tion of milk aspiration can be difficult because some affected for this purpose.355 Ultrasonography may also be used to doc-
foals may not cough or show nasal milk regurgitation. Diag- ument the presence of air, blood, or abdominal viscera within
nosis is based on historic information that may reveal episodes the thoracic cavity, although radiography may be helpful in
of nasal milk regurgitation, physical examination findings this evaluation. Treatment depends on the structures involved
demonstrating abnormal lower respiratory sounds, and clini- and the severity of the complications observed. Most mini-
copathologic evidence of systemic inflammation (inflamma- mally displaced rib fractures, particularly those involving the
tory leukogram and hyperfibrinogenemia or increased SAA) costochondral junction, can be managed conservatively with
and pulmonary dysfunction (arterial hypoxemia).342 Endo- stall rest and avoidance of pressure on the affected area when
scopic examination of the upper respiratory tract may reveal the foal is handled. Mild to moderate pneumothorax may not
require intervention, but if substantial air is presented within treatment for EAV, and despite attempts at aggressive medical
the pleural cavity it will cause respiratory distress and should therapy there are no reports of successful treatment of neona-
be evacuated. Placement of an indwelling thoracic catheter will tal EAV infections. Diagnostic confirmation of EAV involve-
facilitate ongoing drainage. If multiple ribs are fractured, and ment is most readily achieved by PCR testing of blood,
particularly if sharp bony projections are exposed and threat- respiratory secretions, or tissues (lung, kidney, and spleen).372
ening internal injury, then surgical repair may be indicated.356 EAdV infections are rare in immunocompetent foals, and
Hemothorax can be life-threatening because of pulmonary the primary concern is in immunocompromised foals. The
compression and/or severe blood loss anemia, and treatment best described syndrome associated with EAdV infections
should focus on addressing the primary cause of hemorrhage is in Arabian foals with severe combined immunodeficiency
and patient stabilization and support.357 syndrome, although a similar syndrome may occur in Fell
pony foals with an unidentified immunodeficiency.373-375
Viral Infections Two distinct EAdVs have been identified, with EAdV1 being
Viral pneumonia is uncommon in neonatal foals but has ubiquitous and readily isolated from normal and diseased
been associated with EHV-1, EHV-4, equine influenza virus foals and horses, whereas EAdV2 is only isolated from foals
(EIV), equine arteritis virus (EAV), and equine adenovirus with upper respiratory tract disease and diarrhea.373,376,377
(EAdV). EHV-1 infections in neonatal foals are severe and Experimental infection of healthy foals with EAdV has been
typically fatal, despite aggressive treatment. One of the chal- associated with pneumonia regardless of breed.378,379 PCR
lenges associated with these cases is the difficulty of ascer- testing for EAdV1 and EAdV2 is available, but care must
taining EHV-1 involvement, because the presenting signs are be taken with interpretation because EAdV1 is frequently
very similar to neonatal sepsis. Foals may be delivered some- detected in normal animals. Confirmation of diagnosis may
what early and with little or no warning of impending par- require histopathologic evidence of EAdV infection or virus
turition, and the placenta is usually grossly normal.328 Farm isolation.373
outbreaks have been reported.184,358,359 Clinical signs are of Viral respiratory infections are more common in older
cardiovascular and respiratory insufficiency, and the mucous foals than in neonatal foals, and respiratory disease in this
membranes are severely congested and icteric. Clinicopatho- age group has been associated with EHV-1, EHV-4, EIV, and
logic abnormalities include severe leukopenia with neutro- EAV.380 The clinical signs associated with EHV and EIV infec-
penia, toxic neutrophil morphology, and lymphopenia. The tions in this age group are very similar and are consistent
combination of severe leukopenia and icterus may be sug- with those reported in adult horses. Clinical signs typically
gestive of EHV-1 infection.183 Bone marrow examination will include a dry cough and fever, although a mucopurulent nasal
reveal depletion of the myeloid cell lines. Many affected foals discharge may be present as well. The presence of such a dis-
will display dilation of the retinal vasculature with reddish charge may be suggestive of secondary bacterial involvement,
discoloration of the optic disk. Diagnostic confirmation is however. EIV and EHV infections in older foals are typically
most readily accomplished by PCR testing of nasal secretions much less severe than in neonates and ultimately self-limiting.
or whole blood. Treatment of affected foals with acyclovir has A rare, fatal pulmonary vasculotropic form of EHV-1 infec-
been attempted, and this appeared to have some efficacy in tion has also been described in young horses.381 EAV infec-
less severely affected foals.184 Given the superior bioavailabil- tions typically show similar respiratory signs and fever, but
ity of valacyclovir in adult horses, this drug may represent a affected individuals often exhibit substantial ventral and limb
more suitable choice for use in EHV-1–infected foals.328,360 edema secondary to vasculitis.369
EHV-4 appears to be a rare cause of neonatal disease and is The potential role of the gammaherpesviruses, EHV-2
more commonly associated with abortion or stillbirth, but it and EHV-5, in foal pneumonia is intriguing but currently
has been associated with neonatal mortality caused by multi- unclear. Both of these viruses are ubiquitous in equine popu-
systemic disease.361,362 lations worldwide, and foals become infected within the first
Infections with EIV in neonatal foals are not common, par- several months of life.382 Infection in foals is generally consid-
ticularly in endemic areas in which mares are routinely vac- ered to occur without clinical signs, but EHV-2 infection has
cinated and foals are typically protected by maternal colostral been associated with mild to severe chronic pharyngitis of
antibodies.363-366 Outbreaks have been reported when EIV has foals following natural and experimental infection.383 Other
been introduced into naïve populations.364,366 EIV infection signs of upper respiratory tract disease, such as lymphade-
in susceptible foals is associated with severe bronchointersti- nopathy, mild pyrexia, and rhinitis may be associated with
tial pneumonia leading to respiratory distress.364 Antemortem natural infections.384-387 Some intriguing evidence exists that
diagnosis is by PCR of nasal secretions. There is no specific EHV-2 may play a role in potentiating lower respiratory bac-
treatment for EIV infection. terial infections; there are reports that use of an EHV-2 vac-
Neonatal infections with EAV are associated with severe cine protected foals from R. equi pneumonia.388,389 Natural
interstitial pneumonia, which has been reported to be uni- infection of foals with EHV-2 has been associated with fever
formly fatal.367-369 Both solitary cases and farm outbreaks and immunopathologic changes similar to those observed in
have been reported.367,368,370-372 The clinical signs associated human adolescents suffering from infectious mononucleosis
with neonatal EAV infection are severe and primarily respi- following infection with Epstein-Barr virus.390 In addition,
ratory and initially include edema, weakness, and depres- the EHV-2 genome contains an IL-10 homolog as well as
sion, ultimately progressing to terminal respiratory distress, encoding for several other proteins that may have immuno-
although acute death has also been reported.368,372 Gastroin- modulatory effects that could predispose a patient to bacte-
testinal involvement has been reported in some cases but is rial infections.382 The case for a pathogenic role for EHV-5
not consistently present.367,369 Clinicopathologic abnormali- is stronger, because this virus has been convincingly associ-
ties are not specific to EAV infection but often include leuko- ated with the syndrome of equine multinodular pulmonary
penia and thrombocytopenia.368 There is no specific antiviral fibrosis.391-394
Fungal Diseases occur as well.404 The most common isolate is E. coli, with
Although fungal pneumonia is very rare in neonatal foals, Klebsiella spp., Actinobacillus spp., Pasteurella spp. Salmonella
there are a few conditions to be aware of in this population. spp., Streptococcus spp., Enterococcus spp., and Staphylococ-
In utero infection with Histoplasma capsulatum has been cus spp. also occurring with some frequency.25,171,176,178,180,181
associated with placentitis, abortion, and the birth of infected Successful treatment depends on early and effective support
foals.395,396 Affected foals have multisystemic disease, includ- of respiratory function with correction of hypoxemia, control
ing granulomatous pneumonia.395 Antemortem diagnosis is of systemic and pulmonary inflammation, and appropriate
challenging but may be facilitated by tracheal aspirate or bron- antimicrobial therapy. Unfortunately antimicrobial selection
choalveolar lavage cytology, in which characteristic yeastlike is almost always empiric initially, but collection of blood
organisms (3- to 5-μm diameter) may be detected within the culture samples before initiation of antimicrobial therapy is
macrophages.342 Serology is useful as well. The mare and foal encouraged to provide confirmation of bacterial involvement
should be positive for anti-Histoplasma antibodies, which and to guide future antimicrobial therapy on the basis of anti-
can be detected using an agar gel immunodiffusion test.328 microbial sensitivity patterns. Transtracheal aspirates are not
Although successful treatment of infected adults has been commonly performed in neonatal foals because they can be
reported using amphotericin B, there are no reports of suc- technically challenging and may worsen the foal’s respiratory
cessful treatment in neonatal foals.328 distress. They can be very useful diagnostically, especially
Although Candida spp. infections are a major problem in when the respiratory infection is secondary to aspiration.404
human intensive care patients, they appear to be an infrequent Because of the possibility of polymicrobial and mixed infec-
problem in foals. Systemic candidiasis has been reported in tions, broad-spectrum therapy is recommended initially. This
foals, but superficial infections of the mucous membranes often consists of a β-lactam (penicillin) in combination with
(thrush) appear to be more common.397-400 The presence of an aminoglycoside, but a third-generation cephalosporin,
superficial infections may be related to the development of such as ceftiofur, may represent a better choice because of its
systemic infections, so these lesions should be taken seriously superior pulmonary penetration.328
and treatment implemented in a timely manner. This concern
is reinforced by the fact that the clinical signs associated with Older Foals
systemic candidiasis are indistinguishable from those seen in Pneumonia is common in foals from 1 to 6 months of age
bacterial sepsis.400 Confirmation of the diagnosis of systemic and is the most common cause of death in this age group.405
candidiasis is by blood culture of the organism. Successful The most common etiologic agent of bacterial pneumonia in
treatment has been reported with IV amphotericin B and/or these older foals is Streptococcus equi subsp. zooepidemicus,
oral fluconazole, with fluconazole preferred.400 which is a normal upper respiratory commensal organism.
This age group of foals may be at risk for the development of
Parasitic Pneumonia respiratory infections caused by decaying levels of maternal
Following ingestion of the larvated eggs of Parascaris equo- immunoglobulins in conjunction with delayed endogenous
rum the infective larvae emerge in the intestinal lumen and immunoglobulin production and possibly impaired immu-
migrate through the liver and lungs before being coughed up nologic responses to pathogen exposure. Additional risk fac-
and reingested, returning to the small intestine in which they tors in older foals include the stresses of weaning and sales
mature into adults.401 Passage through the lungs is associated preparation and transport, as well as confinement in crowded
with substantial inflammation, and infected foals may present or dusty conditions that result in heavy exposure to poten-
with clinical signs of lower respiratory disease when the larvae tial respiratory pathogens. Secondary infection with gram-
are migrating through the lungs.402 Infestation is ultimately negative organisms is not uncommon, and foals in which this
self-limiting, and the pulmonary signs rarely require medi- occurs may exhibit a poor response to treatment or deterio-
cal treatment. Because of concerns regarding possible colic rate clinically in the face of treatment. Viral infections such as
secondary to intestinal obstruction by the adult parasites, it is EHV-1, EHV-4, and EIA may cause pulmonary inflammation
recommended that foals suspected of parasitic pneumonia be and injury, whereas other viral infections such as EHV-2 may
dewormed. Ivermectin has been recommended traditionally, directly impair pulmonary immune responses, facilitating the
but the widespread emergence of macrocyclic lactone–resis- development of secondary bacterial pneumonia.
tant strains has led to the recommendation that benzimidazole The second most common agent of pneumonia in this age
or pyrimidine anthelmintics should be used.401 Resistance has group is R. equi, which is a facultative, intracellular gram-
been demonstrated in these classes as well, unfortunately, positive coccobacillus. This organism was first isolated from
requiring individuals to be monitored with fecal egg counts to foals with pyogranulomatous pneumonia in Sweden in 1923
ensure efficacy of anthelmintic therapy.403 and was originally named Corynebacterium equi.406 Although
it has been known as R. equi for several decades, the taxo-
nomic nomenclature for this organism is a matter of ongoing
Bacterial Infections debate, and the alternative names Prescottella equi and Prescot-
Neonatal Foals tia equi have been recently proposed.407,408 The conventional
Bacterial pneumonia in neonates is most often associated terminology R. equi will be used here. R. equi is considered to
with hematogenous spread secondary to bacteremia, but it be a ubiquitous bacterium with a worldwide distribution,409
may also occur secondary to infection in utero or meconium although a recent study suggests that it may not be present in
or milk aspiration. The bacteria associated with neonatal Iceland.410 All isolates capable of causing disease in foals carry
pneumonia are typically the same as those involved in neo- a plasmid encoding a virulence-associated protein (VapA).
natal sepsis, and gram-negative bacteria are the organisms Although VapA is required for virulence, it alone is not suf-
most commonly involved. Gram-positive infections appear ficient, and other plasmid-encoded genes also influence vir-
to be increasing in prevalence, however, and mixed infections ulence.349 Rhodococcal pneumonia is occasionally seen as a
sporadic disease but is more common on endemic farms, on found dead.429 Auscultation typically reveals diffuse crackles
which there is often substantial variation in the incidence of and wheezes, with prominent large airway sounds (rattles)
disease on an annual basis.411 On endemic farms as many as caused by the accumulation of exudate in the cranial tho-
one third of the foals are affected with clinical disease, and up racic region. Rebreathing examination is typically not neces-
to 50% of affected foals may die.412 The most likely route of sary because of the prominence of the abnormal lung sounds,
infection in foals is by inhalation, and increased airborne con- and it is contraindicated in animals in respiratory distress. It
centrations of virulent R. equi are positively associated with is important to perform a thorough examination in affected
the development of pneumonia.413,414 High stocking densities foals, because extrapulmonary disorders are common.432 The
of mares and foals have also been associated with an increased most common of these are diarrhea, ulcerative enterotyphlo-
incidence of rhodococcal pneumonia.415,416 Higher concen- colitis, presumed immunomediated synovitis, intraabdominal
trations of R. equi have been detected in stalls and barns, as lymphadenitis, or abscessation and uveitis.432 Arterial blood
opposed to pastures and paddocks,417,418 and this could lend gas analysis is extremely helpful in assessing the degree of pul-
support to the suggestion that dusty conditions are associated monary dysfunction and should be performed before initia-
with an increased incidence of rhodococcal infection.419 tion of intranasal oxygen insufflation if clinically appropriate.
R. equi infections are rare in adult horses unless they are Complete blood count, fibrinogen concentration, and SAA
suffering from some form of immunodeficiency. Given the concentration are all helpful in characterizing the severity of
ubiquitous nature of R. equi in the environment, this suggests systemic inflammation, and very high WBC counts, fibrino-
that foals are in some way uniquely susceptible to infection by gen, or SAA concentrations, although not definitive, may be
this organism. Several studies have investigated the immune suggestive of R. equi infection.318,319 Serial monitoring of these
responses of foals, but the results have been inconclusive and values can be helpful in assessing the response to treatment
there is no clear evidence of an age-related immunodeficiency and in determining the duration of therapy.
that renders them susceptible.420,421 Recent studies have inves- Thoracic imaging is extremely helpful in staging the degree
tigated the potential for genetic predispositions to rhodococ- of pulmonary inflammation and supporting the diagnosis of
cal infections, with some intriguing findings. Polymorphisms rhodococcal involvement, and serial imaging studies can be
in the transferrin and SLC11A1 genes have been associated very helpful in monitoring the progression of disease and
with rhodococcal pneumonia in Thoroughbred and Ara- response to treatment. Thoracic ultrasonography is readily
bian foals, respectively.422,423 More recently a genetic region performed and is very effective for the detection of periph-
on chromosome 26 that contains the TRPM2 gene, which is eral pulmonary consolidation or abscesses, but it is unable
associated with neutrophil function, was found to be posi- to detect axial lesions unless peripheral lesions are pres-
tively associated with rhodococcal pneumonia, and foals with ent.349 Despite these limitations ultrasonography is the most
a single nucleotide polymorphism in this region were three widely used imaging technique in evaluating foals suspected
to four times more likely to be clinically affected than their to have rhodococcal pneumonia because of the combination
herdmates.424 of ready availability, ease of performance, and diagnostic util-
Because of the occult nature of this disease, there has been ity. Abdominal ultrasonography should also be performed in
tremendous interest in identifying infected foals as early as foals with suspected rhodococcal pneumonia because of the
possible so that treatment can be implemented early in the frequency of abdominal extrapulmonary disorders. Thoracic
disease process. To this end a number of screening programs radiographs provide more detailed information regarding
for early detection of infected foals have been investigated, the severity and extent of pulmonary disease, however, and
including serial monitoring of physical examinations, WBC should be considered in more severely affected cases, par-
concentration, fibrinogen assays, SAA concentration, and ticularly given that reasonable image quality can be obtained
quantitative fecal VapA PCR testing, but none has proven to with stall-side digital radiographic equipment.321 The radio-
be clinically effective.349,425 Serology has been unrewarding as graphic abnormalities observed in affected foals may include
well,426 although there are recent reports that VapA-specific a diffuse interstitial or alveolar pattern, tracheobronchial
serum IgG(T) measurement may be useful in identifying lymphadenopathy, intrapulmonary abscesses, and pleural effu-
infected foals, although this requires further validation in the sion. A scoring system has been developed to assess the sever-
field setting.410,427 Ultrasonographic screening programs were ity of alveolar pattern, interstitial pattern, tracheobronchial
developed, and these demonstrated that large numbers of lymphadenopathy, pleural effusion, and the number of nodu-
foals had pulmonary lesions in the absence of clinical signs.428 lar opacities and cavitary lesions in affected foals.433 Foals with
Because of the widespread implementation of these ultrasono- higher median scores (≥15) were less likely to survive (odds
graphic screening protocols on endemic farms, subclinical R. ratio [OR] 6.15, 95% confidence interval [CI]: 1.35–28.2) than
equi infections have become the most common form of this foals with a lower score, with only the severity of the alveolar
disease.429 This approach has also resulted in the treatment of pattern and number of cavitary lesions being associated with
many foals in which the pulmonary lesions would likely have decreased survival. Care should be taken to avoid overinter-
resolved spontaneously, contributing to the development of pretation of imaging studies, especially thoracic ultrasonogra-
macrolide resistance.430,431 phy, because many of the lesions detected may resolve without
Clinically evident rhodococcal pneumonia is often insidi- therapeutic intervention. A recent study on an endemic farm
ous, ultimately presenting with signs consistent with lower found that 80% of foals developed ultrasonographic evidence
respiratory tract infection, and fever, lethargy, coughing, of pulmonary consolidation or abscess formation, but only
tachypnea, and dyspnea are common clinical signs. Dyspnea 21% developed clinically apparent R. equi pneumonia.434 As
can be severe, with nostril flaring and prominent abdominal a result of this concern a thoracic ultrasonographic scoring
expiratory effort. Although relatively rare, some foals may system has been used in several prospective studies of rho-
present with a subacute, severe form of respiratory disease, dococcal pneumonia therapies in an effort to more effectively
consistent with ARDS, and severely affected foals may be identify foals that require treatment.431,435-438 This scoring
system defines a pulmonary abscess as a focal hypoechoic with macrolide absorption after coadministration.444,445 It
area with a diameter of ≥1.0 cm, and the number of abscesses is still recommended to use rifampin in combination with
identified is recorded along with the diameter of each abscess. a macrolide to aid in minimizing the development of resis-
The diameter of each individual abscess is totaled to generate tant strains, because these combinations have been shown
a total abscess score in centimeters, with foals that have a total to have lower mutant prevention concentrations than any of
score less than 8 cm or 10 cm typically not receiving treatment. the individual macrolides or rifampin alone.440,446 Reports of
Following the completion of any imaging studies a trans- the emergence of macrolide-resistant and rifampin-resistant
tracheal aspirate should be performed unless the patient is too strains of R. equi, especially on endemic farms in which large
unstable to undergo the procedure; this sample can provide numbers of foals have received treatment for subclinical pul-
important cytologic evidence regarding the type and sever- monary lesions identified on survey ultrasonographic exami-
ity of pulmonary inflammation and presence of extracellular nation, reinforce the need for this approach.430,447,448 Indeed,
and intracellular bacteria. This sample should also be submit- one can reasonably question the need to treat foals that are
ted for bacterial culture and sensitivity. Profound neutrophilic not suffering from more severe forms of the clinical disease;
inflammation with degranulation of neutrophils is typically recent studies examining treatment efficacy have also reported
present, and the detection of intracellular gram-positive coc- that 78% to 88% of foals in the untreated control groups recov-
cobacilli within pulmonary macrophages is strong evidence ered without intervention.431,435 The prognosis for survival and
of the presence of R. equi.318 PCR testing of tracheal aspirates athletic function in foals with R. equi pneumonia are good, at
may also be helpful in confirming rhodococcal involvement, 60% and 54%, respectively.349 Unfortunately the odds of sur-
because the culture is frequently negative even when intra- vival are approximately sevenfold lower in foals infected with
cellular bacteria are seen on cytologic examination.323 Quan- macrolide-resistant strains.448
titative PCR testing of feces was recently investigated on an There has been tremendous interest in reducing the inci-
endemic farm and was found to be useful in diagnosing R. dence of rhodococcal infections on endemic farms for many
equi in foals with clinical signs of pneumonia and, although years, but no highly effective approaches have been identified.
these results are preliminary, this technique may prove useful The mainstay of prevention on many farms has been the admin-
in situations where tracheal aspirates cannot be collected.439 istration of hyperimmune plasma, despite some conflicting
Treatment of foals with rhodococcal pneumonia should evidence regarding efficacy, and widespread acceptance that
focus on addressing respiratory distress, if present, and treat- even in the best-case scenario protection is incomplete.449-453
ment of the infection. Oxygen insufflation should be provided, Despite the expense, difficulty of administration, and potential
if possible, to animals with dyspnea. Nonsteroidal antiin- for complications, the administration of hyperimmune plasma
flammatory therapy may be helpful in controlling the fever, will likely continue to be used in prevention efforts until better
and affected animals should be kept in a cool, shaded area approaches become available. Chemoprophylactic strategies
if possible because of the risk of exacerbation of physiologic have been investigated using azithromycin and gallium malto-
hyperthermia. Antimicrobial therapy of rhodococcal pneu- late, with azithromycin yielding conflicting results and gallium
monia has been based on the combination of a macrolide and showing no evidence of efficacy.438,454,455 The prophylactic use
rifampin for over 30 years, which is an approach that was vali- of macrolides should be discouraged, however, because of the
dated by a recent ACVIM consensus statement.440 Although emergence of resistant strains on farms in which large num-
erythromycin was initially the primary macrolide used, it bers of foals receive these drugs.430 Ultimately vaccination
has been supplanted by azithromycin and clarithromycin for represents the ideal prevention strategy, but despite intensive
a variety of reasons, including less frequent administration, investigation no effective vaccine is yet available.420,456
superior drug distribution, and pharmacokinetics as well as
evidence of superior efficacy in a retrospective study.420,441,442
There has been interest in the use of gamithromycin for the Respiratory Therapeutics
treatment of R. equi infections in foals because the pharma- Bronchodilators
cokinetics support once-weekly intramuscular administra- In foals suffering from respiratory dysfunction or respiratory
tion.443 A recent study reported that gamithromycin therapy distress there may be some utility in using bronchodilators to
was noninferior to the combination of azithromycin and increase the airway diameter, decreasing the work of breathing
rifampin, although they also reported that 58% of foals treated and improving ventilation. The clinical utility of this approach
with gamithromycin showed adverse reactions consisting is limited, however, because bronchoconstriction does not
of either colic or hindlimb lameness following drug admin- appear to play a prominent role in ARDS.457 The other fac-
istration, which is likely caused by tissue irritation from the tor limiting the utility of bronchodilator therapy is the risk
drug.435 The potential efficacy of the macrolide tulathromycin that the resulting increase in ventilation may actually worsen
has been investigated, but despite early reports of efficacy437 the degree of ventilation/perfusion mismatching caused by
it has unacceptable pharmacokinetics and has subsequently increased ventilation of areas of the lung that are poorly per-
been demonstrated to be ineffective.436 fused. To determine whether bronchodilator therapy may be
Rifampin has been used in combination with macrolide beneficial, one can perform a bronchodilator response test
therapy on the basis of in vitro evidence of synergistic effects under close clinical monitoring. Because of the risk of worsen-
with erythromycin and limited evidence of enhanced treating hypoxemia, it is best if the foal is already receiving oxygen
ment efficacy.440 A recent study compared the efficacy of an by nasal insufflation, but at the very least oxygen should be
azithromycin-rifampin combination to azithromycin alone readily available in case of clinical deterioration. Adminis-
and found that both treatments were superior to placebo, ter a single dose of a short-acting bronchodilator, preferably
but there was no difference in efficacy between treatments.436 by inhalation rather than systemically, and then monitor the
Despite this evidence of efficacy the combination has been response using clinical assessment and ideally with repeated
called into question because of the interference of rifampin arterial blood gas analysis.324 If the patient responds favorably,
TABLE 20.10 Inhaled Drugs Used for Treating the Respiratory Tract
Class Drug Dose Route Frequency (h)
Bronchodilator Albuterol 90–180 μg (young foals) MDI, Neb 2–6
360 μg (weanlings)
Ipratropium bromide 18–36 μg MDI, Neb 8–12
Ipratropium bromide with albuterol 18–36 μg ipratropium, MDI, Neb 8–12
90–180 μg albuterol
Aerosolized antimicrobial Ceftiofur 2.2 mg/kg Neb 24
Gentamicin 2.2 mg/kg Neb 24

MDI, Metered dose inhaler; Neb, nebulization.

Adapted from Wilkins PA, Lascola KM: Update on interstitial pneumonia. Vet Clin North Am Equine Pract. 2015;31:137-157; Mckenzie HC: Treating foal
pneumonia. Comp Equine. 2006;47-53.
with decreased respiratory effort and improved arterial oxy- Mechanical Ventilation
genation, then it may be reasonable to continue bronchodilator The goals of mechanical ventilatory support are to achieve
therapy. Regarding the choice of bronchodilator, the methyl- and maintain adequate pulmonary gas exchange, reduce the
xanthines (aminophylline and theophylline), although read- work of breathing, and minimize patient discomfort and
ily available, are not recommended because of their systemic distress.467,468 Mechanical ventilation provides pressure and
effects and narrow therapeutic index.458 Generally, the use of volume support to ensure that adequate minute ventilation
the aerosol route is preferred; this targeted application allows is achieved and also provides control over the composition
for the use of smaller dosages, reducing the risk of systemic of the inspired gases to provide sufficient oxygen to support
toxicity. β2-Adrenergic agonists (albuterol and clenbuterol) arterial oxygenation. Patients requiring mechanical ventila-
are easily administered and may have additional benefits tion typically are suffering from arterial hypercapnia and/or
including enhancement of mucociliary clearance. Albuterol arterial hypoxemia. Treatment of hypercapnia, defined as a
is inexpensive and the metered dose inhaler (MDI) formula- Paco2 of greater than 60 mm Hg, is fundamentally to increase
tion is most often used (Table 20.10). This drug has a fairly the patient’s alveolar ventilation by increasing the rate and/
short duration of action of 1 to 2 hours. The anticholinergic or depth of breathing. For initial therapy some clinicians will
bronchodilator ipratropium bromide (Atrovent, Boehringer use respiratory stimulants to increase the patient’s ventilatory
Ingelheim) has a longer duration of action than albuterol (6–8 efforts and try to avoid the need for mechanical ventilation,
hours) and can be used alone or in combination with a β2- but if respiratory stimulant therapy is unsuccessful at resolving
agonist (Combivent, Boehringer Ingelheim). Ipratropium is the hypercapnia, or if the hypercapnia is more severe (Paco2 >
only available as an aerosol preparation, either as an MDI or a 70 mm Hg) one should consider instituting mechanical ven-
solution for nebulization. tilation. Early intervention is preferable, because there is no
benefit to the patient from prolonged hypercapnia and the
Aerosolized Antimicrobials duration of the requirement for mechanical ventilation is usu-
The targeted administration of antimicrobial drugs to the ally shorter with early intervention.
respiratory tract is of interest because it achieves very high Treatment of hypoxemia, defined here as a Pao2 of less than
local drug concentrations, which may allow for a more rapid 60 mm Hg, is initially by increasing the fraction of inspired
response while minimizing the risk of systemic toxicity.459 oxygen (Fio2) through the provision of supplemental oxygen
Although controlled studies in horses are lacking, there is by intranasal insufflation, but this will be inadequate in patients
evidence in human medicine that the use of aerosolized anti- with significant hypoventilation or ventilation/perfusion mis-
microbials as an adjunct to systemic therapy is well tolerated matching. Mechanical ventilation allows for much higher Fio2
and may improve outcomes in certain subsets of patients.460,461 than can be achieved with insufflation, up to 100%, dramati-
Although a number of antimicrobial drugs have been admin- cally increasing alveolar oxygen tension. Mechanical ventila-
istered via nebulization empirically in the clinical setting, only tion is also useful in terms of increasing minute ventilation
a few drugs have been investigated for aerosolized adminis- through controlled respiratory rate and volume and in recruit-
tration in horses, including ceftiofur, cefquinome, gentamicin, ment of alveoli for participation in gas exchange. An additional
and marbofloxacin.459,462-466 Aerosol administration of these benefit is the decrease in the effort required for respiration,
drugs to horses has been shown to achieve high respiratory which can be dramatically increased in the face of pulmonary
drug concentrations, is well tolerated, and appears safe. Anec- disease, which allows for a substantial decrease in the patient’s
dotally, the two most widely used inhaled antimicrobials in energy and oxygen needs. This can also ease patient distress
horses are ceftiofur and gentamicin458 (Table 20.10). A variety and increase patient comfort.
of devices have been used to aerosolize these drugs, including In equine patients the provision of mechanical ventilatory
jet and ultrasonic nebulizers, but the recently developed vibrat- support is indicated in only a few basic situations. The first of
ing mesh nebulizers yield the most uniform and appropriately these is the patient lacking normal respiratory drive, such as
sized aerosols with a wide variety of drugs. The availability of the obtunded or comatose neonatal foal, or the patient with
a vibrating mesh nebulizer that is integrated into a face mask impaired ventilatory effort, such as a patient with botulism.
device specifically designed for horses (Flexineb, Nortev, Gal- These types of patients are fairly easy to ventilate because the
way, Ireland) has greatly facilitated the ability to routinely lungs are not diseased and pulmonary function is relatively
deliver aerosolized medications in the clinical or field setting. normal. The prognosis for survival of these foals is excellent if
mechanical ventilation is instituted early.469,470 A fundamen- Alternatively a passive humidifier can be used, which consists
tally different situation is present in the patient with severe of a heat–moisture exchange (HME) filter device placed in
pulmonary disease resulting in respiratory failure, such as a between the ventilator circuit and the patient.469 These devices
foal with severe sepsis, ARDS, meconium aspiration, or severe are effective with small foals but may not be adequate for foals
pneumonia. In these patients the presence of pulmonary dis- over 70 kg and may need to be supplemented with a cold active
ease results in profound alterations in pulmonary function, humidifier in the ventilator circuit.469 The primary limitation
primarily in the form of increased pulmonary resistance and to HME filters is that they tend to clog with airway discharge,
decreased dynamic compliance, making these patients much which can result in obstruction and failure of mechanical ven-
more challenging to ventilate. The prognosis for survival in tilation.470,471 For these reasons the author typically uses HME
this population of foals is much more guarded. The decision filters only for short periods of time, such as when first initiat-
to initiate mechanical ventilation can be an agonizing one ing mechanical ventilation, and relies on active humidification
because of concerns regarding prognosis, client cost, poten- for the duration of ventilation.
tial complications, and the intimidation factor associated The settings on the ventilator should be established before
with managing the ventilator. Unfortunately this can result in attaching the patient to the ventilator to avoid inadvertent over-
delays in the initiation of therapy that dramatically decrease inflation of the lungs. Although there are several different ven-
the likelihood of a successful outcome. The development of tilator modes to select from, on most ventilators there are some
some familiarity with the process of mechanical ventilation on basic settings that are fairly universal including Fio2, tidal vol-
the part of the neonatal intensive care team often results in a ume, peak flow, and breath rate. Fio2 should be set to the mini-
willingness to use mechanical ventilation earlier. Training ses- mum level required to maintain an adequate Pao2 but no lower
sions that provide familiarity with ventilator setup and initial than atmospheric O2 (0.21% or 21%). The tidal volume is the
settings are extremely useful, and so is a pictorial guide to set- volume of gas delivered with each machine-controlled breath,
ting up a circuit and attaching it to the patient. and this should be set such that the peak inspiratory pres-
PPV functions by generating a positive pressure within the sure (PIP) does not exceed 25 to 35 cm H2O to avoid trauma
patient’s airways, which is used to overcome the resistance to to the pulmonary tissues. Peak flow is the maximal gas flow
airflow arising from the airways themselves, the lungs, and the rate delivered by the ventilator during the inspiratory phase of
thoracic wall. Invasive PPV relies on intubation for the estab- ventilation. Excessive peak flow rates will result in overly rapid
lishment of an airway for gas exchange and aids in prevent- inflation of the lungs and high peak airway pressures. Low peak
ing the aspiration of upper respiratory secretions or refluxed flow rates will result in an overly long inspiratory phase, result-
stomach contents. Intubation is best achieved in the conscious ing in a loss of synchrony with the ventilator, especially at high
patient by the nasal route, and this is easiest to do with the head respiratory rates. Reasonable initial settings for these parame-
fully extended. Nasotracheal tubes in the range of 7 to 10 mm ters are an Fio2 of 0.5 (0.3–1.0), a tidal volume of 5 mL/kg (up to
outside diameter will accommodate most horse foals, and these 8 mL/kg), a peak flow of 70 L/min (60–80 L/min) and a breath
tubes should be cuffed. The largest tube that can be passed rate of 20 to 30 breaths/min.469 These values may require adjust-
through the upper respiratory tract without trauma should be ment once ventilation is instituted, and the response to ventila-
used. Care should be taken to ensure that the tip of the tube tion should be closely monitored. Additional variables that may
is located in the cervical portion of the trachea, because it is be controlled with the ventilator are positive end-expiratory
possible to insert the tube too deeply, resulting in placement pressure (PEEP), which should be set at 3 to 5 cm H2O, trigger
within a mainstem bronchus and ventilation of only one lung. sensitivity (−2 cm H2O), pressure support (8–10 cm H2O), and
After final positioning of the tube the cuff should be inflated inspiration:expiration ratio (I:E ratio = 1:2).
with only enough pressure to maintain a seal during PPV, When considering mechanical ventilation one encounters a
because excessive cuff pressure can cause tracheal injury and bewildering array of modes of ventilation, but the ideal mode
necrosis. The tube should be anchored to the patient’s head to is one that maintains consistent and adequate tidal volume and
prevent inadvertent removal resulting from patient movement, minute ventilation at moderate airway pressures, is synchro-
and this can be done by tying a section of umbilical tape to nized to the patient’s respiratory efforts, responds to patient
the hub of the tube and anchoring the ends of the tape to an demands, and allows for the lowest possible work of breath-
elastic tape bandage placed around the muzzle or to a soft cot- ing.468 This discussion will be limited to the most commonly
ton halter around the patient’s head. Endotracheal tubes should used modes of mechanical ventilation. SIMV is a modifica-
be changed at least every 12 to 24 hours, because respiratory tion of assist-control ventilation that still delivers a set mini-
secretions and exudate will accumulate within the lumen of the mum rate of mandatory breaths, which are rigidly controlled;
tube, impeding gas flow and potentially causing obstruction of however, the ventilator attempts to synchronize these breaths
the tube. The presence of large amounts of pulmonary exudate with the patient’s inspiratory efforts if possible. The primary
may require even more frequent changing of the tube. advantage of this mode is that it is well tolerated by the patient
The ventilator gases must be appropriately pretreated before because of the synchronization of mandatory breaths with
delivery to the patient to ensure that the gases are humidified patient effort. In addition, SIMV ensures a minimum breath
and warmed and avoid injury to the respiratory mucosa. This rate in patients with variable respiratory efforts or that are
can be achieved with an active humidifier, which is typically exhibiting periods of apnea. The limitation of SIMV is that the
a component of the mechanical ventilator, and these devices spontaneous breaths are not supported by the ventilator and
are very effective in humidifying and warming the large vol- require a large degree of patient inspiratory effort. Pressure
umes of gases involved. Unfortunately the gases tend to cool support ventilation (PSV) allows the patient complete control
as they pass through the tubing from the ventilator to the over all aspects of the ventilatory cycle except for the pressure
patient, resulting in substantial condensation (rain out) within limit. In this mode each patient breath is supported by a preset
the circuit that must be periodically drained. This effect is assist pressure, which is stopped when the flow rate decreases
accentuated if the hospital environmental temperature is low. below a set fraction of peak flow at end inspiration. This allows
the patient to determine the size of the breath and the inspira- oxygen tension. Assessment of pulmonary oxygenation relies
tory flow rate, substantially decreasing the work of breathing. primarily on the measured Pao2, because the Fio2 is known.
The risk of PSV is that there is no mandatory minimal breath In the patient with normal pulmonary function there should
rate guaranteed by the ventilator. The limitations of SIMV and be a linear increase in Pao2 with increasing Fio2, but this rela-
PSV can be overcome by using SIMV with pressure support. tionship breaks down in the presence of pulmonary disease
SIMV provides a guaranteed minimal breath rate, and the PS caused by ventilation/perfusion mismatching. The presence of
provides pressure support of the patient-initiated breaths to intrapulmonary shunts, resulting from the perfusion of poorly
overcome the inherent resistance of the ventilator circuit and ventilated regions of the lungs, will cause the Pao2 to be lower
endotracheal tube. CPAP is used to provide for a positive air- than expected. A reasonable target for Pao2 is 80 to 100 mm
way pressure throughout the ventilatory cycle. The pressure Hg or slightly higher, because values above 150 mm Hg are not
provided is typically the clinician-selected PEEP level. CPAP beneficial and are an indication to decrease the Fio2. The goal
is often combined with PS to aid in overcoming the resistance is to use the Fio2 closest to room air (0.21) that achieves the
of the circuit and decreasing the work of breathing. desired Pao2, and Fio2 values above 50% are associated with
It is generally desirable when ventilating a patient to not oxygen toxicity to the respiratory mucosa. Additional infor-
only provide for the minimal ventilatory needs of the patient mation can be derived from knowledge of the exhaled EtCO2
but to use the ventilator to recruit poorly ventilated regions concentration, which is measured using capnography. The
of the lung back into participating in gas exchange. The most EtCO2 is representative of the Paco2 in patients with normal
commonly utilized recruitment maneuver is PEEP, which func- pulmonary function, usually with a value 2 to 5 mm Hg less
tions to maintain positive pressure within the ventilatory cir- than the Paco2.469 Decreases in EtCO2 indicate decreased pul-
cuit during exhalation and between breaths to prevent alveolar monary perfusion secondary to decreases in cardiac output or
collapse that might result during periods of negative pressure. increases in pulmonary vascular resistance.469
Over time the presence of PEEP will keep open the alveoli that An important aspect of clinical monitoring is to check the
are “recruited” during the inspiratory cycle, and this allows for endotracheal tube for exudate accumulation when the tube
gradual improvement in the functional capacity of the lungs. is changed, which should be done at least daily (more often
This can result in substantial increases in Pao2 and may allow if copious exudate is present). An increase in the amount of
for a decrease in the Fio2.472 By preventing cyclical alveolar col- exudate within the tube, or a change in the character of the
lapse and reopening PEEP, the amount of shear stress-induced exudate to a more purulent appearance, may be an early
pulmonary injury may also decreased.472 The use of PEEP is indication of ventilator-associated pneumonia (VAP). A
not always benign, however, because it can cause compression hemorrhagic appearance to the tube exudate may suggest
of the intrathoracic venous system and impair cardiac return ventilator-associated lung injury (VILI) or worsening of pul-
with detrimental effects on cardiac output. When first initiat- monary inflammation caused by other insults.
ing mechanical ventilation it is reasonable to use PEEP in most The administration of mechanical ventilation is inherently
patients, especially at moderate settings, because the benefits unnatural and unphysiologic and has the potential to disrupt
appear to outweigh the potential negative effects. the normal functioning of many body systems. The provision
The provision of mechanical ventilation is a very dynamic of PPV, especially in the form of excess PEEP, has the potential
process requiring substantial involvement of the clinician in to substantially decrease venous return, leading to impaired
the supervision of ventilator setup and adjustment. Appropri- cardiac output. This is a serious concern, especially in the criti-
ate monitoring is critical to effective mechanical ventilation, cal patient where cardiac output is often already impaired. The
and this cannot be overemphasized. The two most impor- presence of an endotracheal tube has a number of potential
tant aspects of monitoring are the assessment of pulmonary adverse effects. First, the tube causes an increase in airway
mechanics and pulmonary function. When considering the resistance because of its long narrow lumen and increases
assessment of pulmonary mechanics one is really analyzing the the work of breathing associated with spontaneous respira-
interaction of the mechanical ventilator and the patient, and tions. Second, the presence of the endotracheal tube results
the three most important parameters are the driving pressure, in a bypass of the normal protective functions of the upper
the tidal volume, and the tidal airflow. The primary parameters respiratory tract and can allow access to the respiratory tract
of ventilator function and ventilator/patient interaction are the for pathogenic organisms. Infections arising by this route are
PIP and tidal volume (VT). These parameters are interrelated, termed VAP, and the likelihood of VAP developing is increased
because increasing pressures will be associated with increas- with prolonged duration of mechanical ventilation. The pres-
ing tidal volume in normal lungs within normal physiologic ence of inflammation secondary to the process of mechanical
limits. In ventilated patients, especially those with substantial ventilation itself will also increase the likelihood of VAP, as
pulmonary disease, one will often find that this relationship will impairment of the patient’s immune function associated
is abnormal, with normal pressures resulting in inadequate with systemic illness. The organisms involved in VAP are often
tidal volumes, or excessively high pressures being required nosocomial in nature, which can be associated with a pattern of
to achieve a desired VT. Continuous monitoring of PIP is increased resistance to antimicrobials, complicating treatment
extremely important, because sudden decreases may indicate a of the condition. Aerosolized ceftazidime has been shown to
circuit leak, ventilator failure, inadequate gas supply, or a leak be effective in the prevention of VAP in human patients, while
in the endotracheal tube cuff.469 Increases in PIP may indicate also attenuating the proinflammatory response in the lung.473
obstruction of the endotracheal tube caused by kinking or The author has subjectively observed a decreased rate of VAP
accumulation of exudate, bronchospasm, or pneumothorax.469 in mechanically ventilated foals when aerosolized amikacin is
The other critical aspect of monitoring involves monitor- nebulized into the ventilator circuit starting within 24 hours of
ing pulmonary function, which fundamentally consists of the the initiation of mechanical ventilation.
evaluation of pulmonary ventilation, in the form of elimination Ventilator-induced lung injury (VILI) should be consid-
of CO2, and pulmonary oxygenation, in the form of arterial ered to be inevitable, and the clinician’s goal is fundamentally
to minimize the severity of this effect. There are three funda- acute abdominal pain, despite the many possible underlying
mental types of VILIs: barotrauma, volutrauma, and atelecto- etiologies. Foals are typically more demonstrative of abdomi-
trauma.474 In patients with poor pulmonary compliance and nal pain than adult horses, and signs of colic in foals may range
areas of pulmonary atelectasis, high positive inspiratory pres- from very nonspecific signs such as tachycardia, tachypnea,
sure may be required to achieve adequate ventilation, and this anorexia, agitation, and bruxism to more classic signs such as
causes overdistention of the ventilated regions of the lung (local abdominal distention, recumbency, rolling, and lying in dorsal
volutrauma).475 Volutrauma results from exceeding the nor- recumbency.480 Causes of colic in neonatal foals can include
mal physiologic functional residual capacity of the ventilated meconium impaction, infectious and noninfectious enteroco-
regions of the lung, resulting in the development of pulmonary litis, dysmotility associated with other disease processes, small
edema and initiation/amplification of the local inflammatory intestinal strangulating obstructions, congenital abnormali-
response. PEEP is somewhat protective in that it appears to slow ties, intussusceptions, hernias, gastric or duodenal ulceration,
the development of pulmonary edema unless it too is excessive, aerophagia, foreign body obstructions, lactose intolerance,
at which point it contributes to overinflation and causes further hypoxic injury, and ovarian or testicular torsion.480 Causes
harm.476 Atelectotrauma is caused by the repeated opening and of colic in older foals are similar but also include conditions
closing of lung units during tidal ventilation and essentially such as ascarid impactions, displacements, pyloric or duo-
represents a syndrome of low-volume injury resulting in the denal strictures, abdominal adhesions, and nonstrangulating
initiation of an inflammatory response.474 By appreciating that obstructions such as fecaliths. Nonintestinal pain may cause
the lungs are susceptible to both high- and low-volume injury clinical signs indistinguishable from true colic in foals, and
it is apparent that optimal mechanical ventilation is achieved this may result from pain in the thorax, liver, or urogenital
within a fairly narrow range of tidal volumes and that this tract; distention associated with uroperitoneum; or nongas-
range may vary dramatically from patient to patient. trointestinal inflammation such as peritonitis.
The discontinuation of mechanical ventilation (weaning) Examination of foals with colic is somewhat facilitated by
can be the most challenging part of the entire process, and their small size, which allows for repositioning and external
in human patients this phase may constitute as much as 50% abdominal palpation, as well as thorough ultrasonographic
of the time the patient is being mechanically ventilated.477 examination. The inability to perform a rectal examination
Arguably the process or weaning begins as soon as the patient beyond digital palpation can be a frustrating limitation, how-
is placed on the ventilator, because the clinician constantly ever. Just as in adults the initial goals of colic evaluation are
strives to identify the minimum level of support required to stabilization of the patient and differentiation of cases requir-
maintain adequate ventilation and oxygenation. By minimizing surgical versus medical management. Although most
ing the degree of support, one can accelerate the patient’s cases of colic in foals can be successfully managed medically,
recovery of strength and stamina in the muscles of respira- there are cases in which prompt surgical intervention will
tion (or minimize its loss) while also increasing the clinician’s be required, and small intestinal strangulating obstruction
ability to identify when the patient no longer requires ventila- is the most common.479 The presence of diarrhea is usually
tory support. Gradually decreasing the level of pressure sup- an indication that medical management will be sufficient, but
port provided and increasing the trigger sensitivity level can this may be present in association with a surgical problem.
accomplish progressive challenge of the patient’s ability to Unrelenting pain that is poorly controlled with analgesics is
ventilate on its own. Ultimately, however, the determination a strong indication of a surgical problem, just as in adults.
of readiness to be removed from the ventilator is a subjective Severe intestinal distention on ultrasonographic examination,
one, and the question can only be answered by an extubation particularly caused by fluid or mixed fluid and gas rather than
challenge. This is preferable to simply removing the patient gas alone, may also suggest the presence of a surgical lesion.
from the ventilator while leaving the endotracheal tube in The most common cause of intestinal obstruction in neona-
place, because the tube causes significant resistance to air- tal foals is meconium impaction.480,481 Meconium is a mixture
flow and increases the patient’s work of breathing. Intranasal of glandular secretions, mucus, bile, digested amniotic fluid,
oxygen insufflation should be provided immediately follow- and epithelial cells and should normally be expelled within
ing tube removal in most cases, unless the patient has been the first few hours of life following the foal’s first feedings.
maintaining normal oxygenation at an Fio2 of 0.21 while on Colostrum feeding may be helpful in the expulsion of meco-
the ventilator. Care must also be taken so that one is fully pre- nium because of the laxative effects of colostrum, but the lack
pared to immediately reintubate the patient if the challenge of colostrum intake in a recent study had no effect on meco-
is not successful and mechanical ventilation must be reinsti- nium release compared with foals fed milk replacer.482 If the
tuted. The primary endpoints of the challenge are respiratory meconium is not passed by 12 hours of age it will likely cause
rate, respiratory effort, and arterial blood gas evaluation, intestinal obstruction, typically at the level of the small colon
and some patients may fail within minutes while others fail or the pelvic inlet.481,483 Progressive intestinal and abdominal
over several hours. Several challenges may be required over a distention will develop over the next several hours secondary
period of hours to days before one is certain that the patient to gas accumulation orad to the obstruction. Identification of
is able be maintained without ventilatory support. the mass of meconium may be possible on manual palpation
of the abdomen, but ultrasonography is a more sensitive and
specific means of identifying meconium obstructions. In some
Y GASTROINTESTINAL DISORDERS cases retrograde contrast radiography may be helpful in con-
firming the presence and level of the obstruction and in rul-
Colic ing out other causes of obstruction such as congenital defects.
Colic is a common presenting complaint in foals.478,479 Unfor- Administration of an enema can be useful both as a therapeu-
tunately the evaluation of foals with colic can be frustrating tic intervention and a diagnostic test and is indicated in all
because of the common clinical presentation associated with cases of suspected meconium impaction. Sodium phosphate
enemas are widely used because of their ready availability in a tachypnea, recumbency, rolling, and anorexia), tenesmus may
premixed human preparation that is easily administered. Care be noted. No fecal material will have been passed, and there
must be taken to avoid hyperphosphatemia caused by exces- will be no meconium staining noted in enema fluids that have
sive administration, however, and for this reason this type of been administered. Atresia ani is readily diagnosed on visual
enema should be administered no more than twice in the first examination and digital palpation, whereas rectal and colonic
24 hours of life. Soapy water enemas given by gravity flow lesions are more challenging to identify.491 Ultrasonography
have also been frequently used, but because of the likelihood may be useful in demonstrating distention orad to the site of
of rectal irritation and limited efficacy they should not be used the lesion but rarely is able to characterize the lesion. Retro-
repeatedly. grade contrast radiography can be helpful in further charac-
The most effective type of enema for the treatment of terizing the lesion and differentiating atresia from meconium
meconium impaction is the acetylcysteine retention enema.481 impaction. Colonoscopy may aid in diagnosing lesions in the
These enemas can be prepared using commercially available terminal colon and rectum. This procedure can be performed
acetylcysteine (N-acetyl-l-cysteine powder, Sigma-Aldrich, under standing sedation, and the use of n-butyl scopolamine
St. Louis, MO) by adding 8 g of acetylcysteine to a solution bromide (Buscopan, Boehringer Ingelheim Vetmedica Inc.,
of 20 g of baking soda in 200 mL of water. Commercially St. Joseph, MO) has been shown to aid visualization.492 Ulti-
prepared acetylcysteine enemas for foals are also available mately surgical exploration may be the only way a definitive
(http://www.scahealth.com/e-z-pass-foal-enema-kit.html). diagnosis of atresia coli can be made. Surgical correction of
The foal is placed in lateral recumbency and restrained and atresia ani is straightforward and typically successful, although
sedated, if necessary. A 30-Fr Foley catheter with a 30-mL anal sphincter function may not be normal.491 Atresia ani may
balloon is placed 2.5 to 5 cm into the rectum, and the bal- be accompanied by penile malformations (hypospadias) that
loon is filled, taking care not to overinflate. The acetylcyste- will also require surgical correction.493 Surgical resection and
ine solution is infused using gravity flow to a volume of 100 anastomosis has been attempted in some cases of atresia coli
to 200 mL and left within the rectum for 30 to 45 minutes.481 in which the lesion was accessible, but outcomes have been
Because this type of enema does not seem to be highly irritat- poor.491 This is likely caused by additional underlying neu-
ing, this procedure can be repeated as many as three times, rologic and motility disorders and means that this condition
usually at 12- to 24-hour intervals. Additional treatments that should be considered typically fatal.
are helpful in managing affected foals include IV fluid therapy Congenital aganglionosis, or overo lethal white syndrome,
to address any deficits and ongoing maintenance needs, as well is a syndrome that affects white American Paint Horse foals
as analgesic therapy. Butorphanol administration may be suffi- born from overo-overo matings, although it has been reported
cient to control discomfort in many foals, but individuals with in one foal with one solid color Quarter Horse parent.494 This
more pain may require flunixin administration to control their syndrome occurs when foals receive one copy of the mutated
pain while medical management is pursued. Cases refractory endothelin receptor B gene (EDNRB, overo lethal white gene)
to medical management may require surgical correction of the from each parent.495,496 Affected foals suffer from agangli-
meconium impaction, but this is uncommon since the intro- onosis of the distal small intestine and large intestine, which
duction of acetylcysteine enemas.481 results in a lack of intestinal motility leading to colic.494 Recent
Roundworm (P. equorum) infestation is a common condi- work suggests that the extrinsic innervation may be affected
tion among foals, with a reported prevalence around 40%.484 as well.497 Not all foals born from overo-overo matings will be
Most foals will not show evidence of infestation, but the clini- affected, so care should be taken to ensure that the foal is not
cal signs associated with the presence of this parasite may simply suffering from meconium impaction before making a
include lethargy, anorexia, decreased weight gain, coughing, potentially terminal decision. A mutagenically separated PCR
hypoproteinemia, nasal discharge, colic from gastrointesti- was recently developed for the detection of the EDNRB geno-
nal impaction, and occasionally rupture or perforation of the type in horses.498
small intestine.485,486 The colic signs result from acute small
intestinal obstruction caused by a large burden of the parasite, Diarrhea
and in most cases the colic is associated with recent admin- Diarrhea is a common problem in foals, with substantial
istration of anthelmintic medications but may be associated morbidity and mortality.405 It is associated with a number of
with a stressor such as transportation or weaning.485 Horses potential pathophysiologic mechanisms and many etiologies,
with impaction of the small intestine caused by P. equorum making diagnosis and management challenging. Syndromes
commonly suffer from secondary intestinal abnormalities involving noninfectious etiologies as well as bacterial, viral,
caused by luminal obstruction, including small intestinal vol- protozoal, and parasitic etiologies are all reported in foals.
vulus or intussusception, and surgical intervention is typically Although many of the conditions associated with diarrhea can
required to prevent intestinal rupture.486,487 As a result of the affect foals of any age, some conditions, such as necrotizing
increasing resistance of P. equorum to commonly used anthel- enterocolitis (NEC) and asphyxia-associated enteric dysfunc-
mintics, especially the macrocyclic lactones, it seems likely tion, are primarily seen in neonates, whereas others, such as
that the prevalence of this condition will increase.403,488-490 proliferative enteropathy, are seen in older, weanling age foals.
Although congenital defects of the gastrointestinal tract Foal heat diarrhea is a mild, self-limiting condition seen in
are rare, they must be ruled out when evaluating the neona- foals from 5 to 15 days of age, and is temporally associated
tal foal with colic because of the similarities in clinical pre- with the occurrence of the mare’s first heat following parturi-
sentation with meconium impaction. The most common tion. This temporal association has implied causation, but this
congenital defects are atresia of the colon, rectum, or anus. is not the case. Foals raised on milk replacer also exhibit diar-
Affected foals typically present within the first 2 to 48 hours of rhea during this time frame, and analysis of the composition
life and exhibit signs of acute, progressive colic and abdomi- of mares’ milk has not revealed any changes that might pre-
nal distention.338 In addition to signs of colic (tachycardia, cipitate the development of foal diarrhea.499 Affected foals are
clinically normal with the exception of diarrhea and remain broad-spectrum antimicrobial therapy. Because of concerns
bright with good appetites. It appears more likely that changes that enteral feeding may precipitate or worsen NEC, it has
occurring within the gastrointestinal tract in relation to solid been recommended that enteral feeding should be avoided,
feed ingestion and development of the fecal microbiota are which is generally recommended in the foal with colic, ileus, or
responsible.500,501 Additionally there may be hypersecretion reflux. Parenteral nutrition will be required until enteral feed-
of the small intestinal mucosa that is inadequately compen- ing can be gradually reintroduced. Human studies have sug-
sated for by immature colonic absorption that contributes to gested that a minimal enteral nutrition approach, rather than
foal heat diarrhea.502 Diarrhea in a foal of this age should not complete withdrawal of enteral feeding, using less than 20 mL/
be taken lightly, however, because rapid clinical progression is kg per day for the first several days, then gradually advancing
possible. Any sign of systemic illness, dullness, or inappetence to normal intake levels over several days, appears to be well
should prompt rapid assessment for a more severe condition tolerated and safe.516,517 Human studies have shown that breast
than foal heat diarrhea that may warrant medical intervention. milk is protective against NEC in low-birth-weight infants,
A common cause of diarrhea in hospitalized neonatal foals and for this reason it makes sense to use the mare’s milk for
is perinatal asphyxia-associated gastrointestinal dysfunction. feeding the foal if possible.503,518 Metronidazole therapy may
Affected foals typically have associated risk factors such as be indicated because of the reported association of NEC with
dystocia, delivery by cesarean section, umbilical problems clostridial infection in foals, although a recent human report
during delivery, or some cause of inadequate oxygenation found that metronidazole therapy may not prevent clinical
immediately postpartum.503 These foals may exhibit dysmotil- deterioration in cases of NEC.519
ities leading to ileus, gastroduodenal reflux, intolerance of Other causes of noninfectious diarrhea can include dietary
enteral feeding, abdominal distention, colic, and diarrhea.503 intolerance, particularly when milk replacers are fed rather
Evidence of perinatal asphyxia syndrome may be observed in than mare’s milk.503,520 This can be the result of products used
other body systems, especially the neurologic system. Affected in the milk replacers that are poorly digested by foals, such
foals should be considered at risk for developing sepsis, and a as maltodextrins, corn syrup, oligosaccharides, or glucose
similar presentation may be observed in foals suffering from polymers.520 Gastrointestinal irritation secondary to inges-
sepsis, likely caused by the presence of severe systemic inflam- tion of sand, grit, or dirt may also result in diarrhea caused by
mation. For these reasons appropriate broad-spectrum anti- mechanical irritation of the mucosa.521
microbial therapy is indicated in these cases.
Another condition affecting hospitalized neonatal foals is Infectious Causes of Diarrhea
NEC. This syndrome is the most frequent and lethal disorder The most common cause of infectious diarrhea in foals is
affecting preterm human infants and is associated with dis- rotavirus, which is detected in the feces of foals with diar-
ruption of the intestinal barrier leading to intestinal necrosis, rhea in 20% to 77% of cases.522-524 Equine coronavirus has
multiorgan failure, and death.504 NEC has been sporadically been associated with clinical disease in adult horses525 and has
reported in foals for many years, but it appears likely that it been detected in the feces of diarrheic foals, but the role of
represents an underdiagnosed condition.505-511 A broad vari- this virus in foal disease is unclear.524,526-528 EAdV2 has also
ety of infectious agents, including not only bacteria but also been detected in the feces of foals with diarrhea, but the actual
viruses and fungal species, have been associated with NEC in involvement of adenovirus in the development of disease is
humans.512 Although most of the cases reported in foals have unclear, especially in the immunocompetent individual.529-532
been linked to the presence of a variety of pathogenic bacteria, There are older reports of parvovirus-like particles identified
the cause of NEC remains the subject of much discussion in in foals with diarrhea, but no further evidence has emerged
human literature, and it is not clear if it is primarily an infec- regarding the potential pathogenic role of such organisms in
tious condition. It appears likely that the pathophysiology is the foal.533,534
truly multifactorial, involving a complex interplay between The pathogenesis of rotaviral diarrhea is multifactorial,
intestinal immaturity, hemodynamic instability, inflamma- and this organism is frequently detected in combination with
tion, genetic factors, formula feeding, and dysbiosis.513-515 other potential gastrointestinal pathogens. Rotavirus infects
The clinical presentation may be similar to that described for the epithelial tips of the villi of the duodenum, jejunum, and
the asphyxia-associated disorders mentioned previously, and ileum, but it does not affect the crypt epithelium.523 The virus
certainly those foals may be considered at risk for NEC. In a replicates within the villous epithelium and is released follow-
recent report foals diagnosed with NEC presented most com- ing cell lysis, which results in destruction of the infected cell
monly with colic or diarrhea, but these signs were absent in and desquamation of the villous tips. This leads to a loss of the
the majority of affected foals.511 Other abnormalities observed normal absorptive capacity of the villi, but the secretory crypt
in association with NEC included prematurity, gastric reflux, epithelium is unharmed, resulting in malabsorption that likely
abdominal distention, bloody feces, and pneumonia.511 Inter- contributes to the development of diarrhea. Villous injury also
estingly, the authors of that report found no evidence of an results in the decreased production of disaccharidases, par-
association of C. difficile, C. perfringens, or Salmonella species ticularly lactase, which may impair the digestion of lactose
with NEC. and contribute to the development of diarrhea by osmotic
The diagnosis of NEC is made through radiographic or mechanisms. Other factors contributing to the development
ultrasonographic evidence of intramural gas in the intestinal of rotaviral diarrhea may be the activity of viral enterotoxins,
wall (pneumatosis intestinalis) or surgical or postmortem evi- inhibition of sodium-glucose cotransport, dysregulation of
dence of gastrointestinal necrosis.511 Although as many as 80% calcium homeostasis, and activation of the enteric nervous
of affected human neonates are reported to survive, the pres- system.523
ence of NEC is associated with a poor prognosis for survival Clinically rotaviral diarrhea often occurs in large, comin-
in foals.511,513 Treatment of foals with NEC will be as for any gled groups of mares and foals, and affected foals are typically
critically ill foal and will likely include IV fluid therapy and from 5 to 35 days of age.535 Foals initially exhibit anorexia and
depression, which quickly progresses to acute, profuse watery suggest that both toxins are important in the development of
diarrhea. Affected foals may become rapidly dehydrated and clinical disease.546,547 An additional toxin, termed C. difficile
frequently develop electrolyte abnormalities and metabolic transferase (CDT), appears to play a role in virulence as well;
acidosis. Although the morbidity associated with rotavirus CDT-producing strains have been associated with increased
infections is high, which is caused by the highly contagious mortality in human patients.547 Confirmation of a diagno-
nature of the virus, the prognosis for survival is good. Treat- sis of CDAD is based on the detection of TcdA and/or TcdB
ment is generally supportive and symptomatic, but IV fluid in the feces of the affected individual, and this is most often
therapy is often needed to effectively address the fluid and performed using a commercial ELISA (C. difficile Tox A/B II,
electrolyte deficits. Balanced electrolyte replacement solutions Techlab, Inc., Blacksburg, VA) or RT-PCR.524,541
are most effective given the frequent involvement of hypona- C. perfringens has also been associated with enterocolitis
tremia and hypochloremia. Severely affected foals may also in foals, and this syndrome is typically quite severe in nature,
benefit from a brief period of enteral rest (1–2 days), which with high mortality rates.508 Both type A and type C C. perfrin-
necessitates the provision of parenteral nutrition until feeding gens have been implicated in these cases, but the more severe
can be reintroduced. Supplementation with lactase enzymes form of the disease is typically associated with type C, and
(Lactaid, McNeil Nutritionals, LLC, Ft. Washington, PA) at affected foals do not typically respond to treatment.508 C. per-
9000 U (one tablet) PO every 3 to 8 hours may be helpful in fringens produces four major toxins, but the β-toxin appears to
improving milk digestion in foals that remain on the mare, be the primary one responsible for intestinal injury.509 A novel
or when nursing is reintroduced.503 The diagnosis of rotaviral β-pore-forming toxin, NetF, has recently been described and
diarrhea is by detection of viral particles using electron micros- has been associated with severe NEC in dogs and foals.548,549
copy, virus isolation, enzyme-linked immunosorbent assay Risk factors may include birth on dirt, sand, or gravel and
(ELISA), immunochromatography tests, and real-time reverse- housing in stalls or dry lots in the first few days of life. Clini-
transcriptase PCR (RT-PCR). Of these the immunochro- cal signs are similar to CDAD, but because of enterotoxemia
matography tests and RT-PCR are the most rapid and simplest affected foals may show more pronounced signs of systemic
to perform and provide high sensitivity and specificity.523,536 inflammation and shock. Hemorrhagic diarrhea has been
Control of rotaviral diarrheal outbreaks can be challenging, reported in some cases but may be transient in nature. Diagno-
especially in crowded environments because of the highly con- sis of C. perfringens enterocolitis can be challenging, because
tagious nature of the virus, its persistence in the environment, the organism may be present in the feces of healthy foals. A
and the resistance to disinfectants.523 Prevention can be facili- positive fecal culture in combination with appropriate signal-
tated by the use of maternal vaccination, which has been associ- ment and clinical presentation may be supportive, however,
ated with a reduction in the frequency and severity of rotaviral because healthy foals will generally shed very low numbers
diarrhea on endemic farms, and a conditionally licensed com- of the organism. Fecal Gram stain may also be supportive if
mercial vaccine is available for provisional use (equine rotavirus it demonstrates large numbers of large gram-positive rods or
vaccine, Zoetis, Kalamazoo, MI). spores. Commercial assays are available for detection of fecal
The primary bacterial agents of concern in foal diarrhea enterotoxin, but they lack sensitivity.
are C. difficile and C. perfringens. Discerning the relationship Treatment of CDAD and C. perfringens enterocolitis is pri-
between these organisms and clinical disease has been chal- marily supportive in nature, similar to other causes of entero-
lenging because either or both organisms can be identified in colitis. Broad-spectrum antimicrobial coverage is indicated,
normal animals as well as diseased animals, but both organ- even in situations in which AAD is suspected, because of the
isms are isolated significantly more frequently from foals with risk of bacteremia secondary to bowel wall inflammation and
enterocolitis than from healthy foals.506,509,522,537-540 C. dif- injury. Metronidazole therapy represents the primary specific
ficile–associated diarrhea (CDAD) is commonly associated therapy for clostridial infections, but metronidazole-resistant
with a history of antimicrobial therapy and likely represents strains of C. difficile have been reported.550 A recent pharma-
the primary agent of antimicrobial-associated diarrhea (AAD) cokinetic study suggests that the metronidazole dosing regi-
in foals.541 Spontaneous cases of CDAD can occur without mens used in foals should be revised to 10 mg/kg orally every
exposure to antimicrobials, however, both sporadically and 12 hours for newborn foals and 15 mg/kg orally every 12 hours
in outbreaks.509,537,542,543 Additional risk factors that may pre- for the 10- to 12-day-old foal.551 After that age the current
dispose foals to CDAD include hospitalization, stress, dietary recommendation of 15 mg/kg orally every 8 hours remains
alterations or starvation, transportation, nasogastric intuba- unchanged. Additional therapies that may be of some benefit
tion, and surgical or medical treatment.544 Clinically CDAD in CDAD include enterally administered adsorbents, such as
can be quite variable both in terms of the clinical signs and di-tri-octahedral smectite.552 Probiotic therapy is of interest
the severity of the disease. The primary clinical sign of CDAD because of the positive results reported in human patients, but
is diarrhea, which may be watery or bloody, typically accom- the limited studies do not support the efficacy of probiotics in
panied by signs of systemic inflammation and hypovolemia foal diarrhea at this time.553,554
(hyperemic mucous membranes, prolonged capillary refill A number of other bacteria have been associated with diar-
time, pyrexia, tachycardia, and tachypnea) and occasionally by rhea in foals, including Salmonella spp., E. coli, Enterococcus
abdominal distention and colic.545 Unfortunately these signs spp., Aeromonas spp., and Bacteroides fragilis, although causa-
are nonspecific, and although CDAD may be suspected on the tion can be difficult to establish.531,555-558 Given that diarrhea is
basis of history and clinical presentation, diagnostic testing is a common clinical abnormality associated with sepsis in foals,
required for confirmation of the diagnosis. Because normal it is important to be aware that bacterial involvement may be
animals may carry the organism and these often represent present, even if not in the form of a primary enteric patho-
nonpathogenic strains, culture is not useful for diagnosis of gen. One retrospective study found that of foals less than 30
CDAD. Virulence of C. difficile depends on the elaboration of days of age presenting with diarrhea, 50% were bacteremic at
toxin A (TcdA) and toxin B (TcdB), and there is evidence to admission, further reinforcing this concern.120 Blood cultures
should be collected routinely at admission in this population, staining techniques, but RT-PCR testing can be performed,
not only to confirm bacteremia but also to yield information and rapid and easily performed immunofluorescence assays
regarding antimicrobial sensitivities. are commercially available (Xpect Giardia/Cryptosporidium
R. equi, although primarily a respiratory pathogen, com- Test, Thermo Scientific, Waltham, MA; Merifluor Cryptospo-
monly exhibits extrapulmonary involvement and has been ridium/Giardia, Meridian Bioscience, Inc., Cincinnati, OH).
associated with enteric disease, primarily in older foals.558 Strongyloides westeri is a nematode primarily transmitted
Diarrhea, ulcerative enterotyphlocolitis, abdominal abscessa- to foals by the transmammary route. Although this organ-
tion, mesenteric lymphadenitis, and peritonitis have all been ism has been suspected as a cause of diarrhea in young foals,
reported.432 In one study 33% of foals with R. equi infections it appears likely that clinical disease would only be present
were reported to have diarrhea, and in half of those foals diar- when the parasite is present in very high numbers.503,569 Con-
rhea only began following the initiation of treatment for the trol is typically by means of ivermectin administration to the
primary infection.432 mare shortly after delivery, but the prevalence of this parasite
Equine proliferative enteropathy (EPE) is an infectious appears to be increasing, perhaps related to the decrease in
disease affecting young horses, primarily foals from 2 to 8 ivermectin administration to foals because of concerns for
months in age.559,560 EPE is caused by the obligate intracel- ivermectin resistance in P. equorum.576
lular bacterium Lawsonia intracellularis. This disease causes
dramatic structural changes in the mucosal epithelium of the Gastric Ulceration
small intestine caused by proliferation of the crypt epithe- Gastric ulceration has been frequently reported in foals, with
lial cells. These alterations lead to a protein-losing enteropa- prevalence ranging from 22% to 57%.577-580 The clinical signs
thy that can result in variable degrees of hypoalbuminemia, associated with gastric ulceration in foals are often nonspe-
hypoproteinemia, ventral edema, lethargy, diarrhea, fever, cific and may include diarrhea, colic, rolling, restlessness,
weight loss, and colic.561,562 Diagnosis of proliferative lying in dorsal recumbency, excessive salivation, bruxism,
enteropathy is by a combination of clinical signs (ventral and anorexia.581 For this reason diagnosis should not be made
edema), clinicopathologic abnormalities (hypoalbumin- on clinical grounds alone but should rely on gastroscopic
emia), abdominal ultrasonographic examination, immuno- examination. In addition to confirming the presence of gas-
peroxidase monolayer assay serology, and fecal PCR testing tric ulceration, gastroscopic examination allows for thorough
for Lawsonia DNA.563 Treatment is best accomplished using characterization of the site(s) involved and the severity of the
lipophilic antimicrobials administered for 3 weeks, such as lesions present. Noninvasive techniques for diagnosing gastric
tetracyclines (oxytetracycline, doxycycline, or minocycline), ulceration in foals are of interest but are not well validated and
macrolides (azithromycin and clarithromycin), or chloram- would not provide detailed information regarding the extent
phenicol.564 Rifampin has been used in combination with and severity of gastric ulceration.
macrolides but does not appear necessary to achieve a posi- The greatest challenge associated with the diagnosis and
tive clinical response. Regarding prevention, unfortunately treatment of gastric ulceration in foals is the fact that many of
passively acquired antibodies have been demonstrated to the animals with endoscopically evident ulceration do not show
have no effect on the occurrence of subclinical or clinical any clinical signs suggesting that the ulcers are causing dys-
EPE.565 Promising results regarding prevention have been function or discomfort.580 Therefore the clinical significance
seen with the intrarectal administration of a commercial of gastric ulceration in some foals, and the need for treatment,
avirulent porcine vaccine against L. intracellularis, which has is unclear. Despite this fact there has been substantial concern
been demonstrated to result in complete protection against related to the risk of intestinal perforation secondary to the
EPE and reduces fecal shedding.566 The prognosis for sur- progression of clinically silent gastric ulcers, because this con-
vival with appropriate treatment is good, but affected ani- dition is fatal when it occurs.582 For this reason prophylactic
mals often exhibit a decrease in growth rate and as a result antiulcer therapy has often been administered to clinically ill
may be at a slight disadvantage relative to their peers for sev- foals or those receiving nonsteroidal therapies. The efficacy of
eral months.560 Recent reports have detailed a more severe these prophylactic approaches has not been confirmed in clin-
form of EPE that is associated with fatal outcomes, but these ically ill foals, however, and the response of sick foals to acid-
cases appear to be unusual.567,568 suppressive therapy is less consistent than in healthy foals.583
The pathogenic role of Cryptosporidium spp. in foal diar- Indeed, two large retrospective studies reported that the prev-
rhea has been the subject of debate because normal foals have alence of gastric ulceration on postmortem examination of
been shown to shed the organism, but there have been several hospitalized foals was not related to whether or not prophylac-
studies that implicate this organism in both sporadic and out- tic treatments were administered.578,584 Unfortunately prophy-
break situations.569-572 Although the most commonly identi- lactic acid suppression may be associated with some risks, and
fied species has been C. parvum, another Cryptosporidium (the human studies have documented an increased risk of pneu-
horse genotype) has been identified in horses, humans, and a monia and CDAD in non-ICU hospitalized patients treated
calf.573,574 Affected foals usually do not exhibit substantial sys- with acid-suppressive drugs.585,586 Proton-pump inhibitors
temic inflammation, and the disease is typically self-limiting. (PPIs) are more potent inhibitors of acid suppression than his-
Profuse watery diarrhea may necessitate IV fluid therapy in tamine 2-receptor antagonists (H2RAs), and for this reason
addition to routine supportive therapy. This disease has clear PPIs appear to be associated with a greater risk of these com-
zoonotic potential, so appropriate biosecurity precautions are plications.587,588 In human ICU patients there does not appear
indicated to protect in-contact individuals. Indeed, a recent to be an increased risk of pneumonia or differences in overall
report detailed an outbreak of human cryptosporidiosis in mortality associated with acid suppression, but the use of PPIs
veterinary students associated with exposure to infected foals is associated with an increased risk of CDAD.586 A recent mul-
in an equine perinatology unit.575 Diagnosis has traditionally ticenter study found that the use of acid-suppressive therapy
relied on the identification of oocysts in the feces using acid-fast in hospitalized foals was associated with an increased risk of
undifferentiated diarrhea but not of CDAD.589 Together these GDUS is most commonly seen in foals 2 to 6 months of
concerns suggest that such use should be avoided and that age and is often associated with an unthrifty, pot-bellied
treatment be limited to those foals with documented disease appearance and foals being small relative to their peers.590
requiring treatment. Ultrasonographic examination is indicated in foals suspected
The pathophysiology of gastric ulceration in the foal is to be suffering from GDUS because it allows for noninvasive
likely complex and multifactorial and may differ between the assessment for gastric and duodenal distention. When gastric
squamous and glandular mucosal regions of the stomach. distention is present a nasogastric tube should be passed to
Within the stomach there is a constant interplay between pro- extract the fluid and facilitate gastroscopic evaluation. Gastro-
tective factors and aggressive factors. The protective factors scopic abnormalities commonly observed with GDUS include
maintain a healthy gastric mucosa by promotion of mucosal esophagitis, gastric squamous and glandular ulceration,
blood flow, mucus and bicarbonate production, prostaglandin pyloric ulceration, and pyloric stricture. Examination of the
E2 production, promotion of epithelial growth factors, epithe- duodenum is usually not possible because of the presence of
lial cell restitution, gastric afferent innervation, and gastrodu- pyloric stricture. Treatment of affected foals is challenging and
odenal motility. The aggressive factors, which include gastric requires intensive management. Frequent gastric decompres-
acid, bile salts, pepsin, and numerous enzymes, act to induce sion is required, and parenteral nutrition is typically neces-
and potentiate gastric epithelial injury. As gastric acid produc- sary because of the inability of the foal to eat. Supportive care
tion is highly variable in neonatal foals and the intragastric including IV fluids, antimicrobials, and analgesics is also indi-
environment is often alkaline,583 it seems likely that ulceration cated. Acid-suppressive therapy is required, and this is usually
results most commonly from suppression of the protective accompanied by gastroprotectants and prokinetics. Although
factors rather than from excess acid production. Perinatal medical management may be helpful in resolving delayed gas-
hypoxia, systemic illness, or the administration of nonsteroi- tric emptying, many affected foals will have severe fibrosis and
dal antiinflammatory medications may lead to gastric mucosal constriction of the pylorus and duodenum, necessitating sur-
hypoxia or ischemia, impairing the local protective factors and gical correction. The goal of surgical correction is to bypass
predisposing the patient to mucosal ulceration. Ulceration the pylorus and proximal duodenum, which typically involves
may occur in the squamous mucosa, the glandular mucosa, gastrojejunostomy. Surgery is challenging, and success likely
or both, and may extend to involve the duodenum and/or the depends on early intervention, surgical expertise, and appro-
esophagus. The clinical syndromes associated with ulceration priate postoperative care.590 Reported surgical outcomes have
include subclinical, clinically significant ulceration, perforat- improved over time, with the most recent report demonstrat-
ing ulceration, and gastroduodenal ulcer syndrome (GDUS). ing 100% survival to hospital discharge and 50% long-term
This scheme should perhaps be expanded to include gastro- survival.591
esophageal ulceration, although this is most commonly asso- The cornerstones of treatment of gastric ulceration in foals
ciated with reflux esophagitis secondary to GDUS-induced are acid-suppressive drugs, primarily the H2RA drugs cimeti-
delayed gastric emptying. The classification of ulceration as dine and ranitidine and the PPI omeprazole (Table 20.11).
subclinical or clinical may be challenging and cannot be based The acid-suppressive effects of the H2RAs are variable and
solely on the number and severity of lesions identified on gas- less dramatic than those seen with PPIs, but these drugs may
troscopic evaluation. Instead, it must involve consideration of suppress acid production sufficiently to facilitate ulcer heal-
the history and clinical signs associated with those findings. ing.592 Because of the more consistent and pronounced acid-
The diagnosis of perforation may also be difficult and can- suppressive effects of the PPI omeprazole, this drug has become
not be based on gastroscopic assessment alone because of the the mainstay of gastric ulcer therapy in horses.593 Dosing for
sometimes benign surface appearance of these lesions. For this foals can be challenging, because there is no labeled form spe-
reason abdominal ultrasonography and abdominocentesis cifically designed for use in foals, but the product marketed
are important in confirming the presence of perforation. The for use in adults can be measured out on a volume basis and
diagnosis of GDUS is based on gastroscopic evaluation com- administered orally at a body weight–appropriate dosage to
bined with the presence of one or more of the signs of gastric foals. An IV formulation of omeprazole is not readily avail-
ulceration listed previously, although signs of gastric-outflow able for administration to foals that cannot take medications
obstruction, such as ptyalism and bruxism, are typically more orally, but the IV pharmacokinetics of the PPI pantoprazole
common with this diagnosis. have been determined in foals.594 Other treatments include
TABLE 20.11 Drugs Used in the Prophylaxis and Treatment of Gastric Disorders in Foals
Drug Class Drug Dosage (mg/kg) Route Frequency (h)
H2RA Ranitidine 6.6 PO 8
1.5–2.0 IV 6
PPI Omeprazole—treatment 4 PO 24
Omeprazole—prevention 1 PO 24
Pantoprazole 1.5 IV 24
Mucosal protectant Sucralfate 20–80 PO 6–12
Prostaglandin E1 analog Misoprostol 2–5 μg/kg PO 8–12
Antacids Aluminum/magnesium hydroxide 120–240 mL PO 4–8

H2RA, Histamine 2-receptor antagonists; IV, intravenously; PO, orally; PPI, proton pump inhibitor.
mucosal adherents, such as sucralfate, and oral antacids, such treatment of renal dysplasia or hypoplasia is usually unre-
as aluminum hydroxide and magnesium. Sucralfate dissoci- warding if bilateral renal involvement is present.
ates in the acidic environment of the stomach to sucrose octa- Pollakiuria, dysuria, stranguria, and incontinence may be
sulfate and aluminum hydroxide. Sucrose octasulfate binds observed with renal dysplasia/hypoplasia, but these are more
to the ulcerated mucosa and decreases tissue exposure to commonly associated with conditions such as ectopic ure-
hydrochloric acid and may also interfere with the activity of ters.606-608 Ectopic ureters may be associated with urine scald
peptic enzymes.595 Sucralfate appears safe and is well tolerated caused by urinary incontinence. Surgical intervention, while
and likely represents a safer approach for ulcer prevention in often challenging, is the only option for addressing cases of
hospitalized neonatal foals compared with the use of a PPI. ectopic ureter, with relocation of the ureteral opening being
The prostaglandin E1 analog misoprostol has been used in an the primary intervention. Hematuria is uncommonly associ-
effort to enhance ulcer healing by increasing epithelial mucous ated with congenital urogenital disorders but may be pres-
secretion, bicarbonate secretion, and mucosal blood flow.596 ent in association with renal arteriovenous malformations.609
Misoprostol may also enhance epithelial repair via closure Congenital abnormalities of the bladder have been suspected
of tight junctions following epithelial restitution of denuded in some cases of uroperitoneum,610,611 but evidence of a true
regions of the mucosa.597 congenital origin is lacking in horses or other species.612
Umbilical hernias may be present at birth but are usually small
Y UROGENITAL DISORDERS and will resolve without intervention. Larger hernias, typically
over 3 cm in size, may require surgical repair, but there is no
Abnormalities involving the urogenital tract are common in rush to perform this procedure as long as the hernia remains
foals and can be congenital or acquired in nature. Acquired easily reducible. Inguinal hernias may also be present at birth
conditions may occur secondary to infectious, toxic, traumatic, but are also typically small and easily reducible. Conservative
or iatrogenic causes. The presence of urogenital disorders may medical management consisting of frequent, repeated reduc-
represent the primary disease process or may occur second- tion, or bandaging to maintain reduction, is often successful in
ary to other disease processes. In some cases the presenting resolving small hernias. Larger inguinal hernias may allow for
signs may be directly associated with the urogenital disorder, substantial herniation of the small intestine and often require
but often these cases present with nonspecific signs such as surgical repair.
depression and poor body condition. Clinicopathologic evalu-
ation may be normal, but cases involving impaired renal func- Uroperitoneum
tion or urine retention are typically associated with azotemia Accumulations of urine within the peritoneal cavity represent
and electrolyte abnormalities. Azotemia most often presents one of the most common urogenital conditions in young foals,
as an elevation in serum creatinine concentration, but with involving as many as 2.5% of hospitalized neonates.613 Most
more chronic or insidious conditions an elevation in blood cases are observed within the first few days of life and are asso-
urea nitrogen (BUN) may be more prominent. Serum elec- ciated with bladder wall rupture.614,615 The most common site
trolyte abnormalities may include hyponatremia, hypochlore- of bladder wall failure is the dorsal wall, and it is believed that
mia, and hyperkalemia. Metabolic acidosis is also common. most cases occur during parturition. The proposed etiology is
Urinalysis in normal foals will demonstrate hyposthenuria, that the fetus has a very full bladder, which ruptures under the
because they produce dilute urine with a specific gravity 1.010 intense pressures occurring during transit through the birth
or less. Foals with renal dysfunction may have hyposthenu- canal. Obstruction of urine outflow via the urachus during
ric, isosthenuric (specific gravity of 1.010), or concentrated, delivery may contribute to high intravesicular pressures. This
hypersthenuric urine (specific gravity >1.010), depending on theory is supported by anecdotal reports of bladder disten-
the nature of dysfunction. Transient proteinuria is typical at tion identified on fetal ultrasonographic examination in foals
birth, but this should resolve in the first few days of life in nor- that subsequently developed bladder rupture after birth. There
mal foals, and casts should not be present. may be some sex predilection for bladder rupture, with colts
being overrepresented in cases presenting shortly after birth,
Congenital Disorders but in cases developing later there does not seem to be a dif-
Congenital urinary tract disorders are quite rare in foals, but ference between the sexes.612 Not all cases of uroperitoneum
of these renal dysplasia or hypoplasia is the most commonly are associated with primary bladder rupture, however, because
reported.598-604 No familial or breed predisposition has been ureteral tears and urachal rupture can also result in uroperi-
demonstrated for this condition in horses. In utero expo- toneum. Although ureteral tears initially result in urine accu-
sure to therapeutic drugs or toxins may cause renal dyspla- mulation in the retroperitoneal space, this typically progresses
sia, and there are reports of renal dysplasia in foals born to to uroperitoneum after several days. Urachal rupture may be
mares treated for equine protozoal myeloencephalitis with associated with infection and necrosis of the umbilical rem-
pyrimethamine, trimethoprim, sulfonamides, folic acid, and nant, and for this reason these foals may present slightly later
vitamin E.605 Renal dysplasia or hypoplasia may represent an than foals with bladder rupture.
incidental finding in a foal or young adult horse presented for Diagnosis of uroperitoneum is made on the basis of his-
evaluation of other problems. Azotemia is typically not pres- tory, physical examination, clinical pathology, and ultrasound
ent unless renal function has been impaired by at least 65% to examination. The clinical signs associated with uroperito-
75%, because of the substantial reserves of renal function that neum may vary based on the site of leakage, but affected foals
are normally present. Cases with bilateral renal involvement, most often present with depression and weakness and signs
urine retention, or suffering from acute-on-chronic disease of hypovolemia. It can be difficult to differentiate these foals
are more likely to be associated with clinical and clinicopatho- from those suffering from neonatal sepsis, and indeed many
logic findings consistent with renal insufficiency. Patients with affected foals may be suffering from sepsis in addition to uro-
unilateral involvement often remain asymptomatic, whereas peritoneum.613 The rate at which clinical signs develop is often
associated with the size of the defect and the associated rate Definitive confirmation of uroperitoneum requires abdomi-
of urine leakage into the peritoneal space, with small defects nocentesis. Creatinine diffuses poorly across the semipermeable
in the bladder or retroperitoneal ureteral leakage often not peritoneal membrane, so the creatinine concentration in the
becoming clinically obvious for several days to a week post peritoneal fluid will be at least twofold higher than the creatinine
foaling. Some foals with uroperitoneum will present with ven- concentration in the serum. Abdominocentesis is both a diagnos-
tral edema, although this is most dramatic in foals with umbil- tically important technique and a therapeutic technique, because
ical trauma and associated subcutaneous urine leakage. Foals it allows for the drainage of accumulated urine from the perito-
with retroperitoneal urine accumulation may present with neal cavity. Removal of this fluid will aid in controlling hyperka-
stranguria before the development of uroperitoneum, and lemia, and it will minimize further potassium absorption from
foals with urethral defects most often demonstrate substantial the peritoneal cavity. Drainage will also decrease the pressure
subcutaneous edema in the perineal region. Some foals with being exerted on the diaphragm and thoracic cavity, aiding in
uroperitoneum will present with abdominal distention or the resolution of any tachypnea, dyspnea, or respiratory distress.
abdominal discomfort but will otherwise be in good physical Abdominocentesis should be performed with a teat cannula or
condition. Palpation or ballottement of the abdomen may aid stainless bitch catheter or with an indwelling type of catheter such
in detecting fluid accumulation within the peritoneal cavity. as a Foley or mushroom-tip peritoneal catheter. This approach
The classic clinicopathologic presentation of the foal minimizes the risk of trauma to the abdominal viscera and allows
with uroperitoneum is that of azotemia, with increases in for safe manipulation and maintenance of the catheter while the
serum creatinine and (less reliably) BUN. Azotemia is typi- abdomen is being drained. Care should be taken to administer
cally accompanied by hyperkalemia, hyponatremia, hypo- appropriate fluid therapy before and during the drainage of the
chloremia, and metabolic acidosis. Hyperkalemia is caused abdomen to avoid hypovolemia resulting from the removal of
by the reabsorption of substantial amounts of potassium, this third-space fluid. Drainage should be continued until surgi-
whereas hyponatremia and hypochloremia are caused by cal repair is performed, because premature discontinuation will
reabsorption of water from the urine within the abdomen. simply allow for reaccumulation of urine within the abdomen.
These changes are likely more pronounced because of the Although medical management has been described, the
milk-based diet of foals; milk contains relatively high con- treatment of uroperitoneum is primarily surgical because the
centrations of potassium (25 mEq/L) and is relatively low site of urine leakage must be identified and addressed by surgi-
in sodium (12 mEq/L).616 Hyperkalemia is potentially life- cal repair or removal. Correction of hypovolemia and electro-
threatening because of the possibility of fatal bradyarrhyth- lyte disturbances before surgery is important in minimizing
mias. An electrocardiogram (ECG) should be performed in the risk of anesthetic complications. The most critical of these
all foals with uroperitoneum or hyperkalemia of any cause. disturbances is hyperkalemia because of the risk of cardiac
Typical ECG findings in hyperkalemia will progress from disturbances. Hyperkalemia is addressed by the administra-
peaked T waves and a shortened QT interval to lengthening tion of IV fluids that do not contain potassium, and isotonic
PR interval and loss of P waves, followed by widening of the (0.9%) or hypotonic (0.45%) saline solutions are most com-
QRS complex, and potentially leading to cardiac arrest and monly used. Dextrose is typically added to the fluids at a rate of
death.617 Other potential cardiac sequelae associated with 5%, and this will aid in lowering serum potassium concentra-
hyperkalemia include third-degree atrioventricular block, tions by encouraging movement of potassium from the extra-
ventricular fibrillation, and ventricular premature contrac- cellular to the intracellular compartment, but in severe cases
tions. This classic pattern of electrolyte abnormalities is the administration of exogenous insulin (0.1 U/kg) may be
not typically observed, however, in hospitalized foals that necessary to substantially reduce serum potassium concentra-
develop uroperitoneum while being treated with IV fluid tions. Sodium bicarbonate therapy may aid in lowering serum
therapy with balanced electrolyte solutions.612,613 potassium concentrations and may be helpful in addressing
Ultrasonographic examination is the most useful ancillary the concurrent hyponatremic metabolic acidosis.617 Adminis-
diagnostic test in the evaluation of uroperitoneum. Not only tration of calcium gluconate may also be helpful in decreasing
can one confirm the presence of free fluid within the perito- the negative effects of hyperkalemia.617 Recent reports have
neal space, but one can also assess the degree of fluid accumu- suggested that the frequency of anesthetic complications dur-
lation and investigate possible sites of urine leakage. The free ing surgical correction of uroperitoneum is less common than
fluid within the abdomen is typically hypoechoic to mildly previously reported, perhaps because of less severe electrolyte
hyperechoic, and numerous loops of small intestine or other disturbances, better preoperative stabilization, or the use of
intraabdominal structures may be suspended in the free fluid safer inhalant anesthetics (primarily isoflurane).612
contained within the abdomen. The dorsal bladder wall is the The prognosis for survival in foals with uncomplicated uro-
most common site of bladder rupture, and this area should peritoneum secondary to bladder rupture is good, whereas the
be thoroughly investigated because in some cases the free prognosis for foals suffering from ureteral or urethral disor-
margins of the defect can be readily observed. It is important ders is less favorable. Delays in the identification of affected
to remember that there may be more than one site of urine foals and the presence of concurrent disease, especially sepsis,
leakage, however, either from the bladder itself or potentially will result in worsening of the prognosis for survival.612,613
involving the urachus, ureters, or urethra. Although ultra- Umbilical Disorders
sound examination is typically less useful when evaluating
ureteral or urethral defects, it is important to perform a com- The umbilicus represents the primary channel for exchange
plete examination of the urinary tract to detect any defects in of nutrients and oxygen between the dam and the fetus and
the kidneys or ureters that might be missed if only the blad- the primary outlet for fetal urine. The umbilical cord consists
der and urachus are examined. Contrast radiography may be of two arteries carrying poorly oxygenated blood away from
required to identify sites of leakage other than the bladder or the fetal heart and one vein carrying relatively better oxygen-
urachus. ated blood from the placenta toward the fetal heart and the
urachus, which connects the fetal urinary bladder to the allan- ascending migration of bacteria. This is likely true in some
toic cavity.618 Following second-stage parturition the umbili- cases, and for this reason it is important to practice appropri-
cus will narrow and separate at a point 2 to 3 cm from the ate routine cleaning and disinfection of the external remnant.
body wall, typically within about 10 minutes if the mare and Excessive cleansing or treatment with caustic agents may actu-
foal are undisturbed.619 A small amount of neonatal blood loss ally increase the risk of ascending infection, so moderation
may occur normally following separation of the cord, but it is key. It is very possible that bacteremia occurs secondary to
should be of minimal volume and should cease within a few umbilical infections, resulting in seeding of other sites. Infec-
minutes. If the mare stands too soon, then premature sepa- tion of remote structures, especially synovial structures and
ration of the umbilical cord or umbilical cord damage may growth plates, has been frequently associated with the pres-
occur. Subcutaneous rupture of the urachus can result in sub- ence of umbilical remnant infections. Although the umbili-
stantial accumulation of urine in the tissues of the abdominal cal structures may represent the primary site of infection, it is
wall, which will likely require surgical resection of the umbili- also possible that some umbilical remnant infections actually
cal remnants. Following separation from the placenta the develop secondary to systemic illness and bacteremia, rather
umbilical structures immediately become vestigial, and in the than secondary to external contamination.
normal foal the umbilical remnants will atrophy over the first Ultrasonographic examination of the umbilical remnants
few months of life. is well described and can be performed readily with either
One of the most common umbilical disorders is patent a linear or curved probe using a frequency of 5 to 7.5 MHz,
urachus, in which the urachal remnant is open and urine although higher quality imaging can be obtained with a linear
drains to the external environment. Although this may occur 10- to 12-MHz probe.620 All four umbilical structures (ura-
immediately following cord separation, it is more typically chus, vein, and paired arteries) can be readily imaged in the
seen several days after birth and is most often associated with external remnant as it courses out of the body wall. Internally
umbilical infections. Systemic illness and the associated stress the paired umbilical arteries are found ventral and lateral to
of handling involved in the management of sick foals may the urachus and bladder, and they course caudally and deep
also predispose the patient to the resumption of patency. Pat- toward their origins from the iliac arteries. They are thick-
ent urachus may present simply as moistness of the external walled structures and should have a diameter of less than 13
umbilical remnant or may be associated with a streaming flow mm.621 Although the arteries may still be observed to pulsate
of urine. Urine scald of the abdominal wall and the medial in very young foals, they should contract down and be immo-
aspect of the hindlimbs may occur secondarily. It is important bile by 24 hours of age. The lumen may be filled with clotted
that an ultrasound examination be performed in these cases blood in some cases. The urachus extends from the apex of
to determine whether there are internal abnormalities, such the bladder outward to the umbilical stump, and the lumen
as umbilical remnant infections, associated with a patent ura- is typically collapsed and difficult to appreciate. A transverse
chus. Conservative management consisting of topical cleans- view of the urachus and umbilical arteries taken at the apex
ing of the external umbilicus and close monitoring for the of the bladder should normally measure less than 25 mm in
development of infection is often sufficient, although complete total diameter.621 The umbilical vein courses cranially from
resolution may take days to weeks in some cases. If any infec- the site of the external umbilicus to the liver and is located
tious component is suspected then appropriate systemic anti- along the midline very close to the abdominal wall. The vein is
microbial therapy is indicated. Chemical cautery using silver a thin-walled structure and may contain anechoic fluid within
nitrate sticks is often used and may accelerate closure of the its lumen. The vein should measure less than 5 to 10 mm in
urachal remnant, especially in early, mild cases. Excessive use diameter.621 Infection involving these structures will typically
of silver nitrate may result in local tissue necrosis, however, manifest as filling of the lumen with material of variable echo-
and may precipitate the development of infection. If conserva- genicity, thickening of the wall, and an increase in the overall
tive management fails then surgical excision of the umbilical size of the structure.622,623 Thorough assessment is important,
remnants is indicated, but this is rarely a problem that needs to because multiple structures may be involved in the infectious
be addressed urgently, especially in a foal suffering from sys- process.
temic illness or other disease processes. Treatment of umbilical remnant infections can be medi-
Umbilical remnant infections are also common and can cal or surgical in nature. Medical management is generally
take several forms. Affected foals may appear clinically nor- preferred, and treatment with appropriate broad-spectrum
mal or they may exhibit signs of systemic inflammation (fever, antimicrobials is often successful in resolving the infection.
leukocytosis, hyperfibrinogenemia, and elevated SAA). Infec- Prolonged treatment of several weeks’ duration and ongoing
tion of the external umbilical structures will result in local ultrasonographic monitoring is required to ensure complete
abscess formation, which presents as swelling, inflammation, resolution. In cases suffering from a combination of umbilical
and often discharge from the area of the external umbilicus, remnant infection and infections in other sites the clinician
but it can become more locally invasive, involving the body may feel a sense of urgency to surgically remove the umbilical
wall. External umbilical abscesses can often be treated with remnants, but the stress of general anesthesia and abdominal
the establishment of drainage combined with appropriate surgery may be counterproductive. Stabilization of the patient
systemic antimicrobial therapy. Internal umbilical remnant and the institution of antimicrobial therapy before surgery may
infections can occur in all three of the distinct umbilical struc- be beneficial in these cases. Broad-spectrum antimicrobial
tures: the urachus (infection of the urachus is called urachi- therapy is indicated, preferably using oral medications because
tis), the umbilical arteries (infection of the umbilical arteries of the need for prolonged therapy in most cases. The pres-
is called omphaloarteritis), and the umbilical vein (infection of ence of gas within the internal structures on ultrasonographic
the umbilical vein is called omphalophlebitis). It has tradition- examination or a fetid order represents an indication for the
ally been thought that umbilical remnant infections occurred addition of metronidazole to the treatment regimen. In cases
secondary to external contamination of the umbilicus, with refractory to medical therapy, surgical excision of the affected
internal umbilical remnants is indicated. Thorough ultrasono- to evaluate the serum creatinine concentration frequently to
graphic examination preoperatively is helpful in developing assess the response to therapy and detect upward trends as
the surgical plan and may reveal areas of infection deep in the early as possible.
umbilical arteries or vein that may not be able to be surgically Given the limitations of serum creatinine concentration
removed. Continued medical management may be indicated as a marker of renal function, and more specifically glomeru-
in such a situation, but marsupialization of the umbilical vein lar filtration rate (GFR), it may be helpful in some cases to
or arteries can be performed to allow for external drainage and obtain a more accurate assessment of GFR. The exogenous
possible lavage of the infected structures.624-626 marker iohexol has been validated in foals, but iohexol assays
are not readily available.630 Endogenous creatinine clearance
Acute Kidney Injury and Acute Renal Failure is actually fairly simple to perform in foals with an indwell-
Acute kidney injury can occur in foals secondary to sys- ing urinary catheter and urine collection system. This involves
temic disease, toxin exposure, or postrenal obstruction. The obtaining a baseline serum sample for creatinine determina-
most common of these etiologies is systemic disease, which tion and simultaneous emptying of the urine collection bag,
has previously been termed vasomotor nephropathy, although followed by a timed urine collection over at least several hours,
the actual pathophysiology involved in these cases is not but ideally over 24 hours. At the end of that time a second
well understood.627 It appears likely that there is a complex serum sample is obtained for serum creatinine measurement.
interaction among systemic cardiovascular responses, local The volume of urine collected is accurately measured, and a
vasomotor tone, systemic and local inflammatory mediators, representative sample of urine is collected for creatinine deter-
microvascular dysfunction, and local renal tissue responses mination. The endogenous creatinine clearance is calculated
that result in decreased renal function. This decrease in renal using the formula631:
function may represent a self-protective response by the kid-
neys in which decreased energy and oxygen demands within endogenous creatinine clearance (mL/min/kg)
the kidney may help to improve tissue survival and recov- = (urine [creatinine]/plasma [creatinine])
ery.628 The most common toxic causes of renal injury in foals × (urine output [mL]/time [minutes])/body weight [kg]
are iatrogenic in nature—namely, aminoglycoside antimicro-
bials and oxytetracycline (administered as a treatment for ten- Reported values for endogenous creatinine clearance in nor-
don contracture).629 Nonsteroidal-associated renal injury is mal foals are 1.78 to 2.17 mL/min per kilogram.630,632,633
relatively uncommon in foals and is likely because these drugs Urinalysis can be helpful in detecting acute kidney injury,
are not commonly used in foals at this time, although this but interpretation can be challenging because of temporal
may change with increasing use of COX-2–specific NSAIDs changes in the composition of neonatal urine and the influ-
in foals. Other causes of toxin-induced renal injury are hemo- ences of fluid therapy and other treatments on urine con-
globin released because of NI and myoglobin released because stituents. Urine specific gravity is normally hyposthenuric
of myopathies, most commonly white muscle disease. Postre- (<1.010) in foals that are well hydrated and should increase
nal obstruction is very rare in foals and is primarily associated appropriately (>1.012) in foals that are dehydrated. Isosthe-
with congenital abnormalities. nuria (specific gravity of 1.010) may indicate a loss of renal
Diagnosis of acute kidney injury is complicated by the poor function, but serial determination may be required to con-
sensitivity of the commonly used biomarkers of renal func- firm the inability of the kidneys to dilute or concentrate the
tion—namely, serum creatinine and BUN. Because of the urine with changes in hydration status. Proteinuria is nor-
substantial renal reserve, it is likely that substantial injury has mally present in the first 24 hours of life but should then
occurred by the time changes in these markers are detected be absent unless there is renal injury. If the urine is alka-
clinically. BUN is so insensitive that it is of limited use in eval- line, then mild spurious proteinuria (1+) may be observed
uation of acute kidney injury in foals, but one should be con- on dipstick examination. Sick foals often will have acidic
cerned when substantial simultaneous increases in BUN and urine, making this less of an issue of interpretation than in
serum creatinine are observed. Serum creatinine, despite its adults. Examination for enzymuria has been advocated as an
poor sensitivity, remains the best biomarker for renal function early indicator of renal injury in foals, primarily regarding
in foals. Although there is tremendous interest in identify- urine γ-glutamyl transferase (GGT). This is assessed using
ing more sensitive biomarkers of renal function, none has yet the GGT-to-creatinine ratio (urine GGT/urine creatinine ×
been characterized in foals. Interpretation of serum creatinine 100), which corrects for dilutional effects. Elevations of the
concentrations in neonatal foals is complicated by spurious urine GGT:creatinine ratio above 25 are suggestive of proxi-
hypercreatininemia, which can be caused by placental insuffi- mal tubular injury, but this test does not have good specific-
ciency or neonatal hypoxia.166 Although foals presenting with ity. Unfortunately elevations of the GGT:creatinine ratio are
spurious hypercreatininemia had similar elevations of serum to be expected in foals receiving systemic aminoglycoside
creatinine concentration compared with foals presenting with therapy, and the magnitude of the increase is not well cor-
acute renal failure, serum creatinine concentrations in foals related with the degree of renal injury.634
with spurious hypercreatininemia typically decrease by 50% Treatment of acute renal failure is primarily supportive in
within 24 hours of initiation of treatment and normalize by 72 nature. All efforts should be made to remove exposure to the
hours.166 The most effective way of improving the sensitivity of potential initiating cause of acute kidney injury, if possible.
serum creatinine is to become more critical about evaluation Fluid therapy is typically indicated, both to correct any exist-
of changes in the serum concentration. Even though the values ing dehydration or hypovolemia and to induce diuresis. Care-
may remain within the published normal range, an elevation fully monitoring of urine output is indicated to be sure that the
of as little as 0.3 mg/dL above baseline may be indicative of patient is not oliguric or anuric, and placement of a urinary
decreased renal function. Because serum creatinine may be catheter and urine collection system is extremely helpful in
elevated from prerenal causes at presentation, it is important this regard. This may be difficult to achieve in the ambulatory
patient but is readily accomplished in recumbent foals. Urine 19% by 3 months of age).638 Increases in the free cortisol frac-
output in a normal 4-day-old foal is approximately 6 mL/kg per tion can be associated with localized or systemic inflamma-
hour, but this value should increase in response to fluid ther- tion, because bound cortisol can be released from CBG by the
apy.632 Monitoring of “ins” versus “outs” should be routinely neutrophil elastase.639 The concentration of active cortisol is
performed, with the goal of at least two thirds of fluid intake also regulated at the tissue level by the action of two isoforms
being excreted. If this is not achieved, then fluid overload is of the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD).
likely to develop. If urine output is inadequate after restoration 11β-HSD1 primarily generates active cortisol from inactive
of normovolemia and correction of systemic hypotension, cortisone, whereas 11β-HSD2 primarily converts active corti-
then diuretic therapy is indicated. Furosemide appears safe sol to inactive cortisone.640 Unbound cortisol reaches the tis-
and is well tolerated. In addition to its loop diuretic effects, sues by diffusion and enters the cell, in which it binds to the
furosemide may actually lessen renal metabolic demands by intracellular glucocorticoid receptor (GR). The cortisol–GR
suppression of tubuloglomerular feedback. Recommended complex then translocates to the nucleus in which it is able
dosing of furosemide ranges from 0.5 to 1.0 mg/kg IV q 8–12 to exert both genomic (regulation of gene transcription) and
h to 1 to 2 mg/kg every 30 to 120 minutes over 6 hours.185,635 nongenomic (protein–protein) effects.309 In critical illness
CRIs have also been used in foals based on dosing regimens cortisol is important in supporting cardiovascular function,
developed for adult horses, starting with a loading dose of regulating immune responses, and increasing the availability
0.12 mg/kg IV, followed by 0.12 mg/kg per hour CRI.636 If of glucose as an energy source.
furosemide is ineffective, then osmotic diuretics can be used. A variety of approaches has been used to assess the func-
DMSO is commonly administered to foals suspected of suf- tion of the HPA axis in both health and disease. These include
fering from NE, and in addition to its free radical scavenging the determination of neutrophil:lymphocyte ratios, basal
effects it does have some osmotic diuretic effects. Mannitol serum cortisol concentrations, basal serum ACTH concentra-
can be used as a more potent osmotic diuretic, at a dosage of tions, ACTH/cortisol ratios, and ACTH stimulation tests that
0.5 to 1.0 g/kg IV as a 20% solution over 20 minutes.185 If med- measure the ability of the adrenal glands to produce cortisol
ical therapy is not effective, then renal replacement therapy (delta cortisol). There are a number of challenges associated
(dialysis) can be considered. Hemodialysis is the gold stan- with HPA axis assessment, however.641 The first is that the acti-
dard therapy and has been performed in foals, but it is rarely vation and response of the HPA axis are highly dynamic, with
available for equine patients because of the expense and lack rapid changes in a short period of time and substantial varia-
of access to the appropriate equipment.629 Although typically tion even on an hour-to-hour basis. The second challenge is
less effective than hemodialysis, peritoneal dialysis and tho- that measurement of total serum cortisol concentrations does
racic dialysis have been performed in foals and are much more not reflect the biologically active free portion, and determina-
feasible in most clinical settings.635 tion of the active, free cortisol fraction is technically challeng-
ing, time-consuming, and not readily available in the clinical
Y ENDOCRINE DISORDERS setting. The third is that the concentration of cortisol in the
circulation provides no information related to the concentra-
The critically ill foal undergoes severe physiologic stress, and tion of cortisol at the tissue or intracellular levels, in which it is
the body responds to this stress with a complex, integrated active. The fourth challenge is that ACTH stimulation testing,
series of neuroendocrine and humoral adaptations that are either high or low dose, may not represent an accurate assess-
directed toward support of critical hemodynamic, immune, ment of HPA axis function in critical illness. Finally, there
and metabolic functions. The HPA axis, sympathetic-adreno- may be substantial variation among cortisol assays, rendering
medullary axis, hypothalamic-pituitary-thyroid (HPT) axis, it extremely difficult to compare the results of studies using
and the somatotropic axis are all of critical importance in this different assays114 and calling into question the use of specific
response. values of serum cortisol as indicators of HPA axis function or
dysfunction.
The maturation of HPA axis function in the equine fetus
Hypothalamic-Pituitary-Adrenal Axis Function occurs very late in gestation, in the last few days before birth,
and Dysfunction and continues for the first several weeks of life.64,92,93,642 As
Activation of the HPA axis leads to increased secretion of a result, foals delivered prematurely often suffer from inad-
corticotropin-releasing hormone (CRH) and arginine vaso- equate HPA axis function, manifested by inappropriately low
pressin (AVP) from the paraventricular nucleus of the hypo- serum cortisol concentrations despite increased serum ACTH
thalamus. CRH is the primary stimulus for the production concentrations. These findings are indicative of a decreased
and secretion of ACTH by the anterior pituitary, whereas AVP response to ACTH at the level of the adrenal gland, and this
acts synergistically with CRH to increase ACTH secretion. is supported by the fact that these premature foals also show
ACTH is secreted into the systemic circulation and interacts impaired responses to ACTH stimulation testing.64,91,92 The
with the cells of the zona fasciculata of the adrenal glands, neutrophil:lymphocyte ratio was noted by Rossdale et al. to
which subsequently produce cortisol. Cortisol is not stored in be an easily determined surrogate marker for basal corti-
the adrenal glands; it is released into the systemic circulation sol concentration in foals, with a ratio of <1.0 suggestive of
immediately after it is produced. Only the unbound, or “free,” impaired HPA axis function in premature foals, whereas a
cortisol is biologically active, and in the normal adult state the ratio of >2.0 was associated with adequate HPA function in
vast majority of the cortisol in circulation is bound to cortisol term foals.92 Normal term foals also show some evidence of
binding globulin (CBG), with much smaller amounts bound incomplete HPA axis development, however, because they
to albumin.637 Foals have been shown to have a much greater exhibit impaired responses to endogenous ACTH and both
free cortisol fraction (58 ± 8 at birth to 33 ± 6 at 7 days of age) low- and high-dose ACTH stimulation tests, compared with
than adult horses (7 ± 3) or human infants (32% at birth to adult horses.64,642 Following birth the serum cortisol and
ACTH concentrations peak in the first hour of life and then than in healthy foals. Some septic foals in that study exhib-
gradually decline over 6 to 12 hours to levels lower than nor- ited low or normal serum cortisol concentrations despite an
mally seen in adult horses.638,643 increased ACTH concentration, which was considered to be
The correlation between HPA axis dysfunction and equine suggestive of RAI.657 Hart et al. examined a population of
prematurity led to an early interest in this area of equine medi- hospitalized foals and an age-matched population of healthy
cine, but little work was done in this area until the past decade. foals.97 They found that 46% of hospitalized foals had an inap-
This renewal of interest was primarily the result of extensive propriately low baseline cortisol concentration, and 52% had
work done in humans regarding the role of the HPA axis in an inadequate response to high-dose ACTH stimulation. A
critical illness.644 The concept of relative adrenocortical insuf- significant correlation was observed between an inadequate
ficiency (RAI) was developed and defined as an inadequate response to high-dose ACTH stimulation and both shock
cortisol response for the degree of illness.645 RAI is considered and MODS in hospitalized foals as well as a correlation with
to be a transient, reversible condition and has been associated decreased survival in a subset of septic foals. Armengou et al.
with exaggerated proinflammatory responses in conditions reported that nonsurviving septic foals have higher corti-
such as sepsis, ARDS, and severe trauma. Potential mecha- sol concentrations and ACTH/cortisol ratios than surviving
nisms of RAI include suppression of the HPA axis at the level foals.114 Although there are no reports examining the role of
of the hypothalamus, the pituitary, or the adrenal gland.646 RAI peripheral tissue corticosteroid resistance in the development
has been associated in a number of studies with an increase in of CIRCI in foals, a recent study performed in adult horses
the risk of death in critically ill human patients.647 Subsequent with SIRS found that decreased GR binding affinity was asso-
studies using corticosteroid supplementation demonstrated ciated with nonsurvival and a trend toward an increased
a trend toward decreased mortality and improved vasopres- ACTH:cortisol ratio.658 Investigation of the role of peripheral
sor responsiveness, which further supported the concept of tissue corticosteroid resistance in foals may be warranted.
RAI in critical illness.648-650 The diagnosis of RAI remained The variability seen in these equine studies mirrors the chal-
challenging, however, because of the wide range of diagnos- lenges observed in human medicine in applying basal cortisol
tic criteria used in different studies. The most widely accepted concentrations and the results of high- and low-dose ACTH
criteria was a random total serum cortisol of <10 mg/dL or stimulation testing in the diagnosis of RAI. The use of base-
a delta cortisol of <9 mg/dL following ACTH stimulation.651 line cortisol concentrations and ACTH stimulation testing is
Several studies have been performed in healthy foals no longer recommended in human critical care patients.659-661
to characterize normal HPA axis function in this popula- Similarly, there is currently no consensus regarding the appro-
tion.95,642,652 Substantial age-related changes in basal cortisol priate diagnostic features of this condition in foals.662 Because
concentrations were found, and normal age-based ranges were of these difficulties and the increasing appreciation that it is
reported. Unfortunately the rapid changes over time and the not possible to determine the actual activity of cortisol at the
high variability of a single cortisol measurement mean that the tissue level, a new term was developed in human medicine:
application of basal cortisol concentration as a clinical marker CIRCI. CIRCI is inadequate cellular corticosteroid activity for
of RAI cannot be recommended at this time.315 The response the severity of the patient’s illness.309 The current recommen-
to both low- and high-dose ACTH stimulation testing has also dations in human medicine regarding the diagnosis of CIRCI
been examined, and although the dosages of ACTH varied are based on clinical criteria rather than diagnostic testing.
among some studies there was a consistent pattern of age- Patients with hypotension refractory to fluid replacement and
related differences in the response to ACTH, with the most vasopressor therapy should be suspected of suffering from
profound responses observed immediately after birth.95,642,653 CIRCI, and they should be treated with hydrocortisone. The
Age-related reference ranges for both low-dose and paired positive response to hydrocortisone therapy is potentially sup-
low- and high-dose ACTH stimulation testing have been portive of a diagnosis of CIRCI.309,660
reported.95,642 There is very little information available regarding the treat-
Several studies have been performed in clinically ill foals ment of foals that may be suffering from CIRCI. The results
to determine whether RAI occurs in the septic foal. The first of multiple studies in human patients have demonstrated that
report of transient adrenal insufficiency in a septic foal was low-dose corticosteroid therapy in septic shock is associated
published in 1998, and the foal in that report had a low basal with improved hemodynamics and a decreased requirement
serum cortisol concentration and an inadequate response to for vasopressor therapy, but it is not clear that there is a sur-
high-dose ACTH stimulation testing.654 Gold et al. reported vival benefit associated with this intervention.663 Based on
that septic foals had higher mean cortisol and ACTH concen- the experience in human medicine, it appears reasonable to
trations than normal foals, and the septic foals also had higher reserve corticosteroid therapy for those foals in which CIRCI
ACTH/cortisol ratios than normal foals.655 Castagnetti et al. is suspected and that demonstrate fluid-refractory, vasopres-
reported that nonsurviving septic foals had higher ACTH sor-resistant hypotension.190,662,664,665 The potential role of
and ACTH/cortisol ratios at admission than healthy foals or corticosteroid replacement therapy may be supported by the
surviving septic foals.656 Interestingly, Wong et al. reported recent study regarding factors associated with nonsurvival in
no difference in baseline cortisol or ACTH concentrations or foals with NE. This study reported that persistent hypoten-
ACTH/cortisol ratios between normal and clinically ill foals.96 sion requiring vasopressor and/or inotrope therapy was sig-
A small number of foals in that study did exhibit low baseline nificantly associated with nonsurvival.666 Recommendations
cortisol and ACTH concentrations or inadequate responses for corticosteroid therapy in foals are by necessity based pri-
to ACTH stimulation suggestive of RAI, however. Hurcombe marily on the recommendations derived from human medi-
et al. reported that ACTH, cortisol, and AVP concentrations cine, because no specific therapeutic protocols have been
were increased in septic foals, compared with sick, nonseptic investigated in the foal.667 Current human recommendations
foals and normal foals.121 They also found that ACTH, cortisol, are for the use of physiologic dosages of hydrocortisone.
and AVP concentrations were higher in sick, nonseptic foals This approach most closely mimics normal corticosteroid
dynamics rather than using high supraphysiologic dosages alteration in the HPT axis may account for the rapid growth
or long-acting drugs like prednisolone or dexamethasone.315 of foals in the first few months of life and their high neonatal
A 3.5-day course of tapering dosages of hydrocortisone (1.3 thermogenic capacity.669,674
mg/kg/day divided q 4 h IV) in healthy 2- to 6-day-old foals Dysfunction of the HPT axis has been described in neo-
was reported to potentially have beneficial antiinflammatory natal foals and is caused by congenital hypothyroidism,
effects without any apparent adverse effect on innate immu- prematurity, and systemic illness. A syndrome of congeni-
nity.313 The daily endogenous production of cortisol and the tal hypothyroidism and dysmaturity syndrome was first
pharmacokinetics of hydrocortisone have been studied in described in neonatal foals in Western Canada in 1981.676,677
neonatal foals, and it was determined that an appropriate dos- This syndrome is associated with thyroid hyperplasia (goi-
age of hydrocortisone for foals suspected to have CIRCI might ter), increased gestational length, dysmaturity, and numer-
be in the range of 1 to 3 mg/kg per day.314 This is slightly lower ous musculoskeletal abnormalities, including flexural limb
than the 2- to 4-mg/kg-per-day dosage (divided into two to deformities, rupture of the common digital extensor tendon,
four IV boluses per day) currently recommended in human incomplete ossification of the cuboidal bones, mandibu-
medicine,309 and it has since been suggested that a reasonable lar prognathism, and incomplete closure of the abdominal
hydrocortisone dosage for foals may be 1 to 4 mg/kg per day wall.676,678-684 This syndrome is also suspected to be associ-
divided into four to six IV boluses per day.315 The appropriate ated with abortion in some cases.685 Thyroid hormone levels
duration of therapy is unknown in foals, but in humans it has in affected foals may be low or normal, but the response to
been shown that early withdrawal of hydrocortisone therapy is TSH stimulation is consistently decreased.686,687 Although
deleterious, and prolonged treatment (7–10 days) with subse- the etiology is unknown, this syndrome is suspected to be
quent tapering of dosages is recommended.646,668 associated with exposure to some causative agent, and epi-
demiologic investigations have suggested increased dietary
nitrate intake or exposure to mustard plants could be
Hypothalamic-Pituitary-Thyroid Axis Function involved.643,678,682 Other potential risk factors could include
and Dysfunction inadequate iodine or selenium intake.682,688 The prognosis
The production of thyroid hormones is regulated by the hypo- for survival in affected foals is poor, and those that do sur-
thalamus, which releases thyrotropin-releasing hormone vive are likely to suffer a variety of orthopedic abnormalities
(TRH) into the pituitary portal system. TRH then stimulates that render them unsound.680 Congenital hypothyroidism
the thyrotropes of the anterior pituitary to release thyroid- has also been reported in foals whose dams suffered dietary
stimulating hormone (TSH) into the systemic circulation. iodine deficiency or excess, and affected foals typically
TSH regulates the synthesis and release of thyroid hormones exhibit prominent goiter.689-691 In utero exposure of foals to
by the thyroid gland. The thyroid hormones are stored within endophyte (A. coenophialum)-infected fescue has been asso-
the thyroid gland as the precursor thyroglobulin, which is ciated with clinical signs of hypothyroidism after birth and
cleaved to produce triiodothyronine (T3) and thyroxine (T4) with decreased circulating concentrations of T3.32,692
under the influence of TSH. T3 and T4 then enter the systemic Premature foals exhibit hypothyroidism because they
circulation. In the circulation the thyroid hormones are bound have substantially lower thyroid hormone concentrations
to thyroid binding globulin and other proteins, including albu- compared with healthy, full-term foals.82,671 This may be
min. T4 has minimal activity and essentially serves as a prohor- analogous to the syndrome of transient hypothyroxinemia
mone. It is converted to T3, the primary active form of thyroid of prematurity that has been described in premature human
hormone, at the tissue level. Only the unbound, free thyroid infants.693,694 One report described that both premature
hormones can be transported into the cell, in which they bind and term hospitalized foals had lower T3 concentrations
to thyroid hormone receptors in the nucleus and subsequently compared with healthy term foals, whereas the premature
influence gene transcription. The effects of thyroid hormones foals had lower T4 concentrations than either group of term
are extensive but primarily involve increasing metabolic rate, foals.674 The presence of systemic illness is also associated
enhancing cardiovascular function, and thermogenesis.643 with hypothyroidism in both premature and term foals, and
The assessment of HPT function relies primarily on the this has been termed the sick euthyroid syndrome or the non-
measurement of TSH and/or the measurement of basal thy- thyroidal illness syndrome (NTIS). NTIS is well described in
roid hormone concentrations (T3, T4, free T3, free T4, and humans, dogs, and cats, and there is increasing evidence that
reverse T3). This approach is complicated by the age-related it occurs in adult horses and foals.671-674,695,696 NTIS in sick
changes in these hormone concentrations that occur in new- foals is characterized primarily by low T3 concentrations.674
born foals, as well as the myriad of influences of other nonthy- The mechanisms underlying NTIS are thought to be associ-
roidal factors. The measurement of circulating concentrations ated with the proinflammatory state associated with illness,
is also poorly reflective of the activity of these hormones at but they may also be related to decreased feed intake, because
the tissue level. Stimulation testing is difficult because of the fasting induces NTIS in healthy humans.697,698 It has been
lack of ready availability of TRH or TSH and is not practi- proposed that this phenomenon may represent an appropri-
cal in the clinical setting. In newborn foals thyroid hormone ate and beneficial response to critical illness, at least in the
concentrations are substantially higher at birth than in adult acute stages, and may not require any therapeutic interven-
horses.669-674 These elevated concentrations gradually decrease tion beyond addressing the primary disease.697,699
to adult levels over several months’ time. Only a few studies
have measured TSH in neonatal foals, and they found that the Dysfunction of the Somatotropic Axis and
concentrations were not elevated; instead, they were similar
to the levels seen in adult horses.674,675 This suggests that the Energy Regulation
HPT axis is different in foals, perhaps because of increased As previously discussed the maturation of the endocrine
activity of TSH or increased receptor sensitivity to TSH. This system of the foal is incomplete at birth, and development
continues for weeks to months after parturition. This is also the (55.6%).708 A second study, however, found no clinically rele-
case for the systems regulating energy metabolism in foals.700 vant pattern of alteration in blood glucose concentration when
These systems are very complex, involving neuroendocrine comparing septic and sick, nonseptic neonatal foals to healthy
(cortisol, vasopressin, and thyroid hormone), somatotropic controls.114 Septic foals had slightly lower median blood glu-
(growth hormone [GH] and insulin-like growth factor-1 cose concentrations than controls, but this remained within
[IGF-1]), sympathoadrenal (epinephrine and norepineph- the normal reference range. The treatment of hypoglycemia in
rine), and pancreatic (insulin and glucagon) responses, as well sick foals is of critical importance when it is documented and
as signals derived from fat stores (leptin and adiponectin) and should be addressed by the immediate provision of nutritional
the gastrointestinal tract (ghrelin).701 The somatotropic axis support, either enterally and/or parenterally, as is appropriate
is stimulated by hypothalamic release of growth hormone- to the individual case (see the later section Nutritional Sup-
releasing hormone and inhibited by the release of somatosta- port for the Foal).
tin.702 The somatotropic cells of the anterior pituitary respond Hyperglycemia is common in critically ill foals as well,
to these signals by increasing or decreasing the release of GH. with one study reporting that 36.5% of foals demonstrated
The effects of GH are primarily mediated by IGF-1, which is hyperglycemia at admission, which was similar to the rate of
produced by the liver and has similar effects on insulin when hypoglycemia (34.4%).131 That study reported that extreme
regulating blood glucose concentrations by decreasing hepatic hyperglycemia (>180 mg/dL) was associated with an increased
gluconeogenesis and stimulating the uptake, utilization, and risk of nonsurvival, which is similar to the situation reported
storage of glucose.703 The secretion of GH is stimulated by in human neonates and adult horses with acute abdominal
ghrelin and under negative feedback control of IGF-1 and disease.710-713 Interestingly, Barsnick et al. reported different
leptin. findings, because the septic foals with the highest blood glu-
The sympathoadrenal response is stimulated by physiologic cose concentrations (up to 329 mg/dL) in their study all sur-
stress and hypoglycemia, leading to the release of epinephrine vived.709 Insulin resistance may play a role in the development
from the adrenal gland.704 The metabolic effect of epinephrine of hyperglycemia, although there are many other factors that
is to increase energy substrate availability by inhibiting pan- may contribute to the development of hyperglycemia, as dis-
creatic insulin secretion and increasing glucagon secretion, cussed previously. Increased insulin concentrations have been
interfering with the effects of insulin on the tissues, stimulat- associated with mortality in critically ill foals, which might
ing hepatic glycogenolysis, and increasing lipolysis. The pan- be an indication of insulin resistance in the most severely
creatic hormones insulin and glucagon are critical mediators affected individuals.709 Insulin resistance does not appear
of blood glucose concentrations, with insulin being produced to be a common feature of critical illness in foals, however,
by β cells in response to hyperglycemia and glucagon pro- because both sick nonseptic and septic foals have exhibited
duced by α cells in response to hypoglycemia. Insulin has a normal insulin sensitivity in the studies that have investigated
multitude of effects, primarily focused on lowering blood this phenomenon.114,709
glucose concentrations, and these include increasing glu- There has been tremendous interest and debate in human
cose uptake in insulin-dependent tissues such as muscle and medicine regarding therapeutic interventions to control
adipose tissue, increasing glycogen synthesis, increasing fat hyperglycemia in the critically ill. Tight regulation of blood
synthesis, and decreasing gluconeogenesis and lipolysis. Glu- glucose concentrations (between 80 and 110 mg/dL) was ini-
cagon acts in opposition to insulin, primarily functioning to tially advocated in human medicine,714 but this approach has
increase blood glucose concentrations by increasing glycoge- been shown to be deleterious because of frequent hypoglyce-
nolysis and gluconeogenesis, as well as by increasing lipolysis. mia resulting from insulin administration. A more permis-
The adipokine leptin is involved in the control of appetite, with sive approach is now recommended, in which blood glucose
increases seen following ingestion of a meal and with increas- concentrations are maintained between 145 to 180 mg/dL.715
ing total body fat, whereas adiponectin is negatively correlated This approach attempts to avoid the requirement for aggres-
with total body fat and has some activities similar to glucagon. sive insulin therapy, minimizing hypoglycemic episodes,
Ghrelin mainly acts to increase feed intake and to stimulate while also recognizing that stress hyperglycemia is a normal
GH secretion. physiologic response that is important for maximizing energy
Hypoglycemia is a common finding in critically ill equine delivery to noninsulin-dependent tissues, such as the brain,
neonates, perhaps because of limited endogenous energy intestine, red blood cells, and kidney.716,717 The primary goal
stores and decreased enteral intake.131,705,706 Care should be should be the avoidance of severe hypoglycemia that exceeds
taken in interpreting blood glucose concentrations in neonatal the renal threshold, which in foals is likely to be above 180
foals, however, because they typically have relatively low blood mg/dL.718 Insulin therapy may be required to accomplish this
glucose concentrations (50–60% of maternal blood glucose) in goal, and various regimens have been described, including
the immediate postpartum period, especially before their first intermittent bolus administration or continuous rate IV infu-
nursing.707 Hypoglycemia has been repeatedly associated with sions30,643,718-720 (see the later section Nutritional Support for
an increased risk of nonsurvival in critically ill foals, although the Foal). The institution of insulin therapy is not to be taken
different diagnostic criteria have been used to define hypogly- lightly, because it requires frequent monitoring of blood glu-
cemia.118,131,708,709 In the study reported by Hollis et al. there cose concentrations and rapid intervention to avoid hypogly-
was an association between the severity of hypoglycemia and cemia until a stable blood glucose level is achieved, which may
the risk of nonsurvival, with each increase of 18 mg/dL from take several hours of fine-tuning.720
a cutoff of 50 mg/dL being associated with an increase of the Other indicators of alterations of energy regulation that
odds of survival to discharge of 3.4 times (95% CI 2.1–5.4).131 have been investigated in foals include triglycerides (TG), non-
In one study the percentage of survivors was lower among esterified fatty acids (NEFAs), GH, IGF-1, leptin, and gluca-
foals with blood glucose values ≤120 mg/dL (31%) compared gon. Although our understanding of the role of these factors in
with foals with blood glucose concentrations >120 mg/dL equine neonatal critical illness is still developing, these studies
give valuable insight into the complexities involved and pro- time requirement, cost, and ease of implementation.733 Sev-
vide some indication of the potential benefits of assaying these eral studies have indicated that serum globulin concentrations
variables. Barsnick et al. reported that septic foals had higher can be used to estimate the IgG concentration, but it appears
glucagon and TG concentrations than healthy foals but found that the cutoff points must be established in each individual
no difference in leptin concentrations between groups.709 clinical laboratory because of the variations in testing meth-
Lower leptin concentrations were associated with mortality in odology.733,736,737 The enzyme immunoassay test is widely used
that study, however. In a later study Barsnick et al. found that because of its acceptable diagnostic performance as a screen-
septic foals had higher ghrelin, GH, and TG concentrations ing test (high sensitivity), combined with simple performance
and lower IGF-1 and glucose concentrations compared with and rapid results.733 The interpretation of the results of IgG
healthy foals, and these findings are likely related to inanition testing has been the subject of tremendous interest over the
and a negative energy balance.721 Sick, nonseptic foals in that past 40 years and can be a point of confusion because of the
study had higher GH and TG and lower IGF-1 concentrations different diagnostic criteria and different test methodologies
than were observed in healthy foals. The GH:IGF-1 ratio was used over time. A recent report supported the traditional cut-
higher in septic and sick, nonseptic foals than healthy foals off value of >800 mg/dL as indicative of adequate transfer of
and was highest in nonsurvivors. This finding was indicative passive immunity (ATPI) and found that in a large popula-
of somatotropic axis resistance in clinically ill foals.721 Pan- tion of hospitalized foals values <800 mg/dL were proportion-
zani et al. reported that IGF-1 concentrations did not differ ally associated with mortality.165 This study also reported a
between healthy and sick foals but increased over time in all regression equation that could be used to estimate serum IgG
groups, whereas NEFA concentrations were higher in sick concentration from serum TP, albumin, and globulin concen-
foals at some time points.672 Armengou et al. also reported that trations with good diagnostic performance (IgG = −241.4 ×
NEFA concentrations were higher in sick foals than in healthy [albumin] + 462 × [globulin] + 222.8 × [TP] − 370.3).165 This
foals but found no differences in TG concentrations between estimation may be helpful in situations where specific testing
groups.114 Although direct intervention in the somatotropic for serum IgG concentration is not readily available.
axis does not appear to be indicated, 722 these findings support Treatment of FTPI depends to some extent on the clini-
the importance of correcting the negative energy balance that cal status of the foal and the foal’s environment. If the foal is
exists in many critically ill foals. known or suspected to have ingested inadequate amounts of
colostrum, then early enteral administration of maternal or
banked colostrum may be effective; however, such treatment
Y IMMUNOLOGIC DISORDERS should not be assumed to result in ATPI, and monitoring of
serum IgG is still indicated.738 A clinically normal foal exam-
Failure of Transfer of Passive Immunity ined in the home farm environment may not require treatment
The most common type of immunodeficiency disorder in if the IgG value is between 400 and 800 mg/dL (partial FTPI),
horses is FTPI, which is the failure of the foal to ingest or whereas a value of less than 400 mg/dL (complete FTPI) rep-
absorb adequate immunoglobulin from colostrum.723,724 This resents grounds for treatment. If the foal shows any signs of
is critically important because foals are essentially agamma- clinical illness or is being examined in a hospital environment,
globulinemic at birth from the inability of macromolecules then any IgG value of less than 800 mg/dL is an indication for
to transfer across the diffuse epitheliochorial equine placenta treatment. Treatment consists of providing IgG supplementa-
from the dam to the fetus.725 FTPI is regarded as the most tion, which most often is accomplished by IV administration
important risk factor for the development of infection and of equine plasma, because test results are typically not available
death for foals within the first month of life, and the incidence until after the time period in which enteral supplementation
of FTPI has been estimated at 3% to 24%.726 FTPI can occur would likely be effective. The dosage for IV plasma adminis-
by several mechanisms, including failure of the foal to ingest tration is based on the severity of the foal’s deficit, but it is
adequate volumes of colostrum in the early neonatal period, not precise because of the tremendous variability in IgG con-
loss of colostrum before ingestion because of premature lacta- tent in commercial equine plasma.724 In clinical practice the
tion, low colostral immunoglobulin concentration, and inade- administration of 1 L of plasma can reasonably be expected
quate absorption of colostrum by the neonatal gastrointestinal to provide an approximately 200-mg/dL increase in serum
tract.725,727 The timing of colostrum ingestion is critically IgG.739 Unless plasma with a higher IgG concentration is used,
important, because the ability of the neonatal gastrointestinal it can be difficult to administer enough plasma to completely
tract to absorb macromolecules is maximal at birth but rapidly normalize serum IgG in severely affected foals because of the
declines over the first 24 hours of life. risk of volume overload as well as the expense of treatment,
The diagnosis of FTPI cannot be made on clinical grounds so the maximum initial dosage of plasma is typically 2 L.740
and requires determination of the foal’s serum IgG concentra- It is important to monitor the effect of treatment by repeated
tion within the first 18 to 24 hours of life. The gold standard measurement of serum IgG to ensure that further treatment is
assay for the quantification of immunoglobulin quantifica- not required, especially in severely affected clinically ill foals
tion is the single radial immunodiffusion assay, but this test that may have ongoing catabolism of IgG associated with their
requires a prolonged incubation period, rendering it of lit- systemic illness.740
tle utility in the clinical setting. A number of types of rapid
screening tests are available for estimating foal IgG concen- Neonatal Isoerythrolysis
trations, including glutaraldehyde coagulation, zinc sulfate NI is the most common cause of icterus in newborn foals. It is
turbidity, turbidimetric immunoassay, latex agglutination, and an immunogenetic disorder in which the foal’s red blood cells
enzyme immunoassay tests, as well as serum globulin or TP are destroyed by preformed maternal anti–red blood cell anti-
concentrations.727-735 The ultimate decision regarding which bodies ingested in the colostrum. These maternal antibodies
test to use is based on the consideration of each test’s accuracy, are produced in response to exposure of the mare to “foreign”
red blood cell antigens by several possible routes, including by demonstrating the presence of antibodies in the mare’s
placental pathology allowing exposure to fetal red blood cells colostrum or serum directed against the foal’s red blood cell
during gestation, exposure to foal red blood cells during par- antigens. This can be done using agglutination or lytic tests,
turition, or blood transfusions administered to the mare.741 with lytic tests regarded as more reliable.743 The hemolytic
Blood group incompatibilities between the mare and the foal crossmatch of mare serum with foal red blood cells using
are caused by the foal inheriting a blood group antigen from exogenous complement is considered the test of choice. Iden-
the sire that the mare does not possess. These incompatibilities tification of the specific red blood cell factors involved can also
are likely commonly caused by the multitude of equine blood be accomplished by testing panels of red cells that represent all
group antigens, with an estimated incidence of 14%, yet the the known blood groups.741 Despite their limitations, aggluti-
reported incidence of NI is only 1% in Thoroughbreds and 2% nation tests are commonly used because they are more readily
in Standardbreds.122,742,743 This is because the majority of blood performed and provide more rapid results. A crossmatch of
group antigens are not strongly immunogenic under these mare serum with foal red blood cells without the addition of
conditions of exposure. Some blood group factors are strongly exogenous complement has agglutination rather than hemo-
immunogenic, and factor Aa in the A system and factor Qa lysis as the endpoint and is less sensitive than the hemolytic
in the Q system have historically been the factors associated crossmatch. The direct antiglobulin (Coombs) test can be used
with the majority of cases of NI.742 More recent reports have to demonstrate the presence of antibodies on the surface of
documented the involvement of other alloantigens, perhaps as the foal’s red blood cells, but this test can lack sensitivity. The
a result of an enhanced ability to detect these other factors or most readily performed test is the jaundiced foal agglutina-
because of differences in the breed composition of the local tion (JFA) test, which is simple and provides rapid results. The
horse population.119,744 The incidence of NI in mules is much JFA test is performed using red blood cells from the foal and
higher than in horses, with estimates as high as 10% because of colostrum from the mare, with agglutination as the endpoint.
the presence in these foals of a donkey-specific red blood cell Unfortunately the JFA test can lack both sensitivity and speci-
antigen (“donkey factor”) that horses lack.745,746 ficity and is most useful in prevention of NI rather than diag-
Foals affected with NI are typically born clinically normal nosis of an affected foal.
and begin to show clinical signs within 2 to 5 days of birth, The treatment for NI will be dictated by the severity of the
although intervals of as long as 12 days have been reported.119 anemia and the associated clinical signs. Moderately affected
The clinical signs of NI result from anemia and tissue hypoxia foals primarily require supportive care, exercise restriction,
and include progressive lethargy, weakness, tachypnea, and and close monitoring. Stress should be avoided in handling
tachycardia. Affected foals will initially have pale mucous the foal. If the foal presents at less than 24 hours of age then
membranes but subsequently develop icterus, although in per- it should be withheld from nursing until the risk of further
acute cases foals may die before exhibiting icterus.741 As the antibody ingestion has passed. This time interval can be dif-
disease progresses foals will become dyspneic, and seizure- ficult to assess accurately, but it should not exceed 24 hours
like activity may occur, potentially caused by kernicterus in because of waning maternal antibody content in the milk
cases with severe hyperbilirubinemia. Pigmenturia may be and decreased gastrointestinal absorption in the foal. Serial
present, which is caused by severe hemolysis. Affected foals monitoring of the JFA test can be used, if desired, to assess
are anemic, although the magnitude of the anemia may be the decline of maternal alloantibodies in the milk and con-
masked by concurrent hemoconcentration at presentation.119 firm that the introduction of nursing should be safe.748 The
Although most foals will present with hematocrits between foal will need to be provided with nutritional support during
10% and 20%, the anemia can be severe, with hematocrits as this time period, which is most readily performed using an
low as 5% reported.119,741 Thrombocytopenia may be present indwelling feeding tube. IgG supplementation with colostrum
as well, and this finding appears to be more common in mule from another mare or with frozen plasma will be necessary
foals.741,747 Venous blood gas analysis reveals decreased venous to ensure adequate passive transfer. Despite some concerns in
oxygen concentration and saturation caused by increased oxy- the literature, withholding colostrum does not appear to have
gen extraction at the tissue level. There is metabolic acidosis any deleterious effects on gastrointestinal development in
caused by lactic acidosis, which is caused by anaerobic tissue foals.749 IV fluid therapy is helpful in supporting cardiovascu-
metabolism, resulting in increased lactate production. Hyper- lar function and tissue perfusion as well as ensuring diuresis,
bilirubinemia, primarily caused by increased indirect biliru- minimizing the potential nephrotoxic effects of hemoglobin.
bin concentrations, is a consistent feature, although increased Fluid therapy should be administered conservatively, however,
direct bilirubin concentration is seen in some affected animals, to avoid hemodilution, particularly in more severely affected
potentially caused by hepatic injury secondary to hypoxia or foals. Plasma exchange has been successfully used to treat foals
iron toxicity associated with bilirubin accumulation.119,122 affected with severe hyperbilirubinemia secondary to NI.258
Increased SDH concentrations have also been associated Further treatment is indicated if the affected foal shows evi-
with severe anemia (hematocrit <11%) in foals with NI, fur- dence of shock caused by tissue hypoxia, which becomes more
ther supporting that hepatocellular injury occurs in severely likely in foals with profoundly low hematocrits (<10–12%), but
affected foals.119 Hemoglobinemia and hemoglobinuria can it should not be based on the hematocrit reading alone. The
be pronounced, and pigment nephropathy resulting in acute decision to treat in these cases may be supported by findings of
renal failure can occur in severely affected cases. persistent or progressive tachycardia and tachypnea and dem-
Diagnosis is often made based on the signalment, history, onstration of decreased mixed venous oxygen tension.750,751
and clinical signs, but confirmation is important because Treatment in these foals is directed at the restoration of the oxy-
there are other causes of hemolytic anemia in neonatal foals, gen-carrying capacity of the blood and improving tissue oxygen
including DIC associated with sepsis, bacteria-induced delivery. Intranasal oxygen insufflation is readily performed but
hemolysis, and iatrogenic causes such as incompatible trans- may be of limited benefit because oxygen saturation is typically
fusion of blood or plasma.119 A definitive diagnosis is made not adversely affected. The only other way to improve oxygen
delivery is by transfusion of red blood cells that will not be dam- thrombocytopenia, and neutropenia has also been described
aged by the maternal alloantibodies. The transfused red blood in foals.760 It is possible that the incidence of these condi-
cells will likely only persist in the foal’s circulation for a few days, tions is underappreciated, however, because neutropenia
but the goal of the transfusion is to provide support while the and thrombocytopenia are common findings in critically ill
foal produces sufficient red blood cells to support itself. In the patients secondary to a number of other mechanisms.761 The
ideal situation a known Aa and Qa negative “universal” donor pathophysiology of NAIT and NAN is very similar to that
could be used, but these are very difficult to identify and not of NI: affected foals ingest maternal alloantibodies directed
commonly available. In most cases the mare represents the most against antigens on platelets or neutrophils, resulting in their
logical donor, and once her red blood cells have been washed destruction or removal from circulation. Diagnosis of these
to remove the alloantibodies present in her serum they can be conditions is based on the demonstration of persistent throm-
transfused to the foal. The most effective way to wash the mater- bocytopenia or neutropenia in the absence of other disease
nal red blood cells is by centrifugation, but this is often not read- processes that might cause these abnormalities, such as bacte-
ily available. Serial gravity sedimentations of anticoagulated rial sepsis. Foals affected by NAIT may appear clinically nor-
maternal red blood cells using sterile isotonic saline to remove mal or they may exhibit petechial hemorrhages or prolonged
and discard the supernatant is readily performed and reasonably bleeding from venipuncture sites. Foals with NAN are typi-
effective, but it does require a substantial period of time (several cally clinically normal, but they are predisposed to second-
hours) during which the foal’s clinical status may deteriorate. ary bacterial infections that may lead them to exhibit clinical
There are reports of the administration of polymerized bovine signs of local or systemic inflammation. Confirmation of the
hemoglobin (Oxyglobin, Biopure Corporation, Cambridge, clinical diagnosis requires the demonstration of antibodies
MA) as an alternative form of bolstering oxygen transport bound to the patient’s platelets (NAIT) or neutrophils (NAN).
capacity. This is appealing because the product is shelf-stable Direct fluorescent antibody tests, ELISA, immunoradiomet-
and requires no delay in administration.119,750,752 These reports ric tests, and flow cytometry have been used to confirm the
provide some conflicting evidence regarding the potential safety diagnosis.747,755-759,762
of this approach because the administration of bovine hemo- Treatment of NAIT is supportive in most cases, although
globin was associated with poor outcomes in some instances. whole blood or platelet-rich plasma transfusions can be
It is unclear if this is the result of the product administered or administered to foals exhibiting clinical bleeding diathesis.763
a result of case selection, in which the most severely affected Supportive care is indicated in foals with NAN, although
foals were likely selected to receive this therapy.752 When blood recombinant human granulocyte colony-stimulating fac-
transfusions are used the volume of blood to be administered to tor can be administered in an effort to increase endogenous
the foal should be kept to a minimum; administration of greater neutrophil production.758,759 Foals affected by NAIT and espe-
than 4 L of blood is associated with the development of hepatic cially NAN appear to be at increased risk for secondary bacte-
failure (OR 19.5).122 Reinforcing this concern is the finding that rial infections, so appropriate broad-spectrum antimicrobial
the administration of each additional unit of blood was shown therapy is indicated. Both conditions are ultimately self-
to increase the odds of nonsurvival 8.4 times.122 limiting because the offending alloantibodies are consumed
The most effective treatment for NI is prevention. Blood and eliminated from circulation. The use of immunosuppres-
typing of the mare can be performed before breeding to fully sive therapy has been proposed but does not appear to be indi-
characterize the mare’s blood group, and if the mare lacks fac- cated in these conditions.
tors Aa and/or Qa she would be considered at risk for becom-
ing sensitized in the future.741 Testing to identify the specific Y HEPATIC DISORDERS
alloantibodies produced by a mare that has produced an NI-
affected foal can be used in combination with blood typing of Hepatic disorders are uncommon in foals, but there are a wide
the sire to predict future risk.753 This is rarely done, however, range of possible etiologies. True hepatic failure is rare, and
and it is simpler to perform the JFA test at the time the foal is hepatic dysfunction is the most common disorder. Detec-
born and before the foal is allowed to nurse. When performed tion and diagnosis of hepatic disease in foals are challenging
in this manner the JFA test is reasonably diagnostic, and a because the clinical signs are nonspecific and often related to
negative result supports allowing the foal to nurse.748,754 In the a primary disease process. These nonspecific signs can include
absence of JFA test results, any foal born to a mare that has anorexia, depression, fever, weight loss, and abdominal pain.
had a previous foal affected by NI should be considered at high Icterus may be present but is not specific for hepatic dysfunc-
risk, and the foal should be muzzled at birth and not allowed to tion, and it may be secondary to anorexia, intravascular or
nurse for the first 24 hours of life. Although clinically affected extravascular hemolysis, sepsis, or severe systemic illness.
foals have likely received adequate passive transfer of immu- With more severe hepatic involvement one may observe any
noglobulins, any foals that are deprived of maternal colostrum or all of the following: CNS signs, bleeding disorders, edema,
as a preventive measure must receive immunoglobulins in the ascites, diarrhea, or dermatitis. A definitive diagnosis requires
form of pooled colostrum administered enterally or fresh fro- clinicopathologic examination consisting of serum enzyme
zen plasma administered intravenously. activities and conjugated and unconjugated bilirubin at a
minimum but potentially including serum bile acids, serum
ammonia, and prothrombin time. Additional biochemical
Neonatal Alloimmune Thrombocytopenia abnormalities that may be supportive of, but not specific for,
and Neutropenia hepatic disease include hypoglycemia, metabolic acidosis, low
Neonatal alloimmune thrombocytopenia (NAIT) and neo- BUN, and polycythemia. Ultrasonographic examination also
natal alloimmune neutropenia (NAN) appear to be rare can be very helpful because it allows for the assessment of the
in the equine, but they have been reported in horse and hepatic parenchyma and may allow for the detection of struc-
mule foals.747,755-759 A syndrome of ulcerative dermatitis, tural abnormalities. Hepatic biopsy, although rarely performed
TABLE 20.12 Biochemical Parameters in Foals over the First the onset of clinical signs.770,771 The primary manifestation of
Month of Life this disease is a peracute bacterial hepatitis. This disease is well
described in foals, with numerous cases documented in the
Biochemical Parameters Units 1 Day 7 Days 1 Month United States and other countries over the past 40 years.772-778
Alkaline phosphatase IU/L <2670 <1170 <866 The causative agent of Tyzzer’s disease is C. piliforme, a soil-
γ-Glutamyl transferase IU/L <33 <98 <44 and manure-borne gram-negative, pleomorphic, motile, spore-
Sorbitol dehydroge- IU/L <21 <18 <6 forming, rod-shaped obligate intracellular bacterium.779 The
nase epidemiology is poorly understood, but as the disease does not
affect adult horses it is likely that adult carriers contaminate
Aspartate aminotrans- IU/L <340 <620 <440
the environment with subsequent fecal-oral transmission.770
ferase
Risk factors for this disease include seasonality, with a 7.2 times
Glutamate dehydroge- IU/L <27.5 <17 — greater risk between March 13 and April 13.770 Foals born to
nase young mares (<6 years of age) and nonresident mares are also
Total bilirubin mg/dL <4.5 <3.3 <1.7 at increased risk, possibly because of lack of previous expo-
Direct bilirubin mg/dL <0.35 <0.7 <0.6 sure leading to poor colostral antibody production resulting in
Ammonia μg/dL — <60 — inadequate passive immunity in their foals.770
Bile acids μmol/L <82 <30 <17
Tyzzer’s disease often affects otherwise healthy foals, and
affected individuals, especially younger foals, may simply be
Adapted from Axon JE, Palmer JE. Clinical pathology of the foal. Vet Clin found dead. In foals presenting alive the clinical signs are often
North Am Equine Pract. 2008;24:357-385, vii; Divers TJ, Byars TD: nonspecific, including lethargy, anorexia, dehydration, icterus,
Hepatic disease. In: McKinnon AO, Squires EL, Vaala WE, et al., eds. Equine fever, colic, diarrhea, and seizures followed by the rapid onset
Reproduction. West Sussex, UK: Wiley-Blackwell; 2011:409-415; Barton of recumbency, weakness, coma, and death.771,776 Antemortem
MH, LeRoy BE. Serum bile acids concentrations in healthy and clinically ill
neonatal foals. J Vet Intern Med. 2007;21:508-513; Armengou L, Jose- diagnosis is difficult and is typically based on the signalment,
Cunilleras E, Rios J, et al. Metabolic and endocrine profiles in sick neonatal history, clinical signs, and clinicopathologic findings. PCR
foals are related to survival. J Vet Intern Med. 2013;27:567-575. testing may be useful for early and specific diagnosis,771 but the
results may not be available within a useful time frame because
in foals, may be useful in diagnosis, treatment planning, and of the rapid progression of disease. Clinicopathologic examina-
prognostication. tion typically demonstrates severe leukopenia with a left shift;
The interpretation of the biochemistry profile can be chal- thrombocytopenia; marked hypoglycemia; severe metabolic
lenging in young foals because the activities of some hepatic acidosis; elevated serum fibrinogen; and elevated total, indi-
enzymes and other parameters are substantially different from rect, and direct bilirubin concentrations.771,779 The hepatocel-
those normally seen in adult horses (Table 20.12). Serum alka- lular enzymes AST and SDH are markedly increased, but GGT
line phosphatase (ALP) activity shows the most striking eleva- and ALP are typically within normal limits.768,771 Ultrasono-
tions compared with adults, with values as much as 10-fold graphic examination of the liver reveals marked hepatomeg-
greater in the first week of life. This is primarily caused by bone aly with increased echogenicity of the hepatic parenchyma,
metabolism, which rapidly declines over the first month of life or possibly an enhanced vascular pattern.623,771 Treatment is
and then gradually decreases to the adult range by 6 months of extremely difficult because of the severe, acute nature of the
age.707,764,765 Serum GGT activity transiently increases during disease, and the prognosis should be regarded as grave. There
the second week of life and then returns to the normal adult are, however, reports of successful treatment of three suspected
range by 1 month of age.766,767 AST concentrations increase and one confirmed case of the disease.770,771,780 Treatment con-
slightly after the first week of life but then remain similar to sists of antimicrobial therapy with penicillin or ampicillin in
adult values.707,764 SDH and glutamate dehydrogenase (GLDH) combination with an aminoglycoside, as well as fluid therapy,
values do not differ significantly with age.707,768 Serum bile correction of electrolyte and acid-base disorders, parenteral
acid concentrations are also increased at birth but gradually nutritional support, and appropriate supportive care.771,780
decrease to normal adult ranges over the first 6 weeks of life.769
Neonatal hyperbilirubinemia is well documented in foals and Bacterial Hepatitis
is primarily associated with increased total bilirubin concen- Bacteria other than C. piliforme can cause hepatic disease,
tration.707 This elevation gradually resolves, and values are and are commonly associated with severe systemic inflamma-
typically within normal adult ranges after the first week of life. tion and bacteremia, but these cases do not typically present
Direct bilirubin concentrations are low at birth but increase with primary hepatic disease. These foals typically present as
to normal adult ranges after the first few days of life.769 The septic, critically ill foals, and the finding of hepatic involve-
serum enzymes that are liver specific—namely, SDH, GLDH, ment is secondary.781 Actinobacillus spp. and S. equi subsp.
and GGT—are of greatest utility in evaluating the foal with zooepidemicus have been reported to be involved in acute
hepatic dysfunction compared with the nonspecific enzymes bacterial hepatitis of young foals.768,781 The spirochete Barton-
ALP and AST. GGT is liver and biliary tract specific, whereas ella henselae was recently associated with severe suppurative
SDH and GLDH are of hepatocellular origin. cholangiohepatitis in a foal, which was successfully treated
with trimethoprim-sulfamethoxazole and rifampin along with
S-adenosylmethionine and pentoxifylline for their potential
Acquired Disorders antifibrotic and antioxidant effects.782 Leptospirosis has been
Tyzzer’s Disease associated with jaundice and death in a 10-day-old foal,783 and
Tyzzer’s disease is an enterohepatic syndrome affecting foals Leptospira interrogans serovar Pomona appears to be a rare
from 7 to 42 days of age that is associated with the rapid onset cause of hepatic disease in neonatal foals.784 Ascending chol-
of septic shock and death, usually within 2 to 48 hours from angiohepatitis and bile duct obstruction have been associated
with duodenal stenosis resulting from severe gastroduodenal decrease hepatic iron accumulation in healthy foals receiving
ulcer disease (GDUD).785-787 Effective surgical bypass proce- blood transfusions.794 Although the use of this drug in foals
dures have been described for foals suffering from delayed with NI has not been reported, the results of this study suggest
gastric emptying associated with GDUD, but the prognosis for that the administration of deferoxamine to foals with NI start-
foals with hepatic involvement appears to be guarded.591,787 ing before blood administration may be beneficial in decreas-
ing iron-associated hepatic injury.784,794
Equine Herpesvirus 1
EHV-1 infection of the near-term fetus can result in the Iron Toxicity
delivery of a nonviable foal suffering from hepatic, respi- The oral administration of iron fumarate is a very well-
ratory, and/or gastrointestinal disease.358,788 Most affected described cause of hepatic injury in foals. The greatest risk of
foals will be born premature and will be severely icteric on toxicity is associated with iron administration before the foals
initial examination. Clinicopathologic examination typically first suckle, presumably caused by the presence of protective
demonstrates severe leukopenia caused by neutropenia and factors in colostrum or milk that decrease the hepatotoxicity of
lymphopenia, which may be more severe than seen in septic iron when administered after nursing has begun.795-797 When
foals.183 Hyperbilirubinemia may be present, although the iron is administered at birth and before colostrum ingestion,
magnitude of hyperbilirubinemia may be less than one might clinical signs will typically manifest within 2 to 5 days and are
expect based on the profound icterus observed clinically.183,184 primarily associated with hepatoencephalopathy. Seizures,
No increase is usually observed in the serum activity of the profound depression, head pressing, ataxia, and abnormal
hepatic enzymes, which is surprising given the severity of behavior are common. Icterus is usually present at the time
the hepatic necrosis detected on postmortem examination.183 of onset of neurologic signs. Clinicopathologic examination
Although hepatic involvement is prominent in most affected typically reveals elevated bilirubin, GGT, ALP, and SDH, as
foals, death is usually caused by overwhelming respiratory dis- well as increased ammonia concentrations.
ease within 1 to 5 days of birth.184 Treatment with acyclovir
was associated with an improvement in survival in one report,
although valacyclovir may represent a superior choice given Inherited or Congenital Disorders
the superior bioavailability of that drug in adult horses after Glycogen Storage Disease Type IV
oral administration.184,789 Glycogen storage disease type IV, a fatal recessive inher-
ited deficiency of the glycogen branching enzyme, has been
Hepatic Lipidosis described in Quarter Horse foals.798 The clinical signs asso-
Hepatic lipidosis can occur secondary to hyperlipemia in neo- ciated with this disease are variable, ranging from stillbirth
natal foals, but this appears to be most common in Miniature to progressive weakness, transient flexural limb deformities,
breeds.790-792 Hypertriglyceridemia (>500 mg/dL) typically persistent recumbency, seizures, and respiratory or cardiac
develops as a consequence of a negative energy balance result- failure.798 Affected foals are leukopenic and typically have ele-
ing from inanition or anorexia caused by some other primary vated AST and GGT activities, in addition to elevated creatine
disease process and, if unresolved may progress to hyperlipe- kinase (CK) caused by muscle pathology. The genetic lesion
mia, with characteristic grossly lipemic serum.709,793 Fat accu- is a single base nonsense mutation in the glycogen branching
mulation in the liver can proceed rapidly, resulting in hepatic enzyme encoded by the GBE1 gene.799,800 One study reported
lipidosis. Hepatic enzyme activities may be increased, but this that approximately 2.5% of fetal and early neonatal deaths
is not consistently observed.790,791 Clinical signs of hepatic in Quarter Horse–related breeds were homozygous for the
lipidosis may be referable to the primary disease process but mutant GBE1 allele, suggesting that this syndrome has a clini-
can include severe depression, seizures, blindness, and ventral cally relevant impact on the reproductive efficiency of these
edema.768 Treatment should be directed toward resolving any breeds.801
primary disease process and correction of the negative energy
balance with parenteral nutrition. Insulin therapy is often Persistent Hyperammonemia
critical in facilitating the resolution of the hyperlipemia and Persistent hyperammonemia associated with encephalopathy
allowing for the administration of adequate amounts of par- has been described in Morgan foals 4 to 7 months of age.263,802
enteral nutrition. Affected foals exhibit acute onset of clinical signs shortly after
weaning, which can include coma, blindness, and seizures.
Neonatal Isoerythrolysis Hepatic enzymes may be mildly elevated, but hepatic pathol-
NI is the most common cause of hyperbilirubinemia in foals, ogy is modest. Blood ammonia levels are extremely high in
and hepatic disease may develop because of hepatocellular affected foals (300–600 μmol/L), and this syndrome is thought
injury resulting from excessive bilirubin accumulation, ane- to be related to an inherited disorder of hepatic ammonia
mic hypoxia, and/or iron toxicosis.119,122 Total and direct bili- metabolism and possibly other amino acids.803 The metabolic
rubin, AST, ALP, and SDH activities may be increased in foals defect may resemble HHH syndrome in humans.263 Although
with NI. Foals with the lowest presenting packed cell volumes some foals may survive the first encephalopathic crisis, the
tend to have the highest SDH values, suggesting that hepatic syndrome is considered to be fatal and may end with a termi-
injury was present at the time of presentation.119 One study nal hemolytic crisis.768
reported that foals receiving multiple blood transfusions (4 L
or more) were 19.5 times more likely to develop hepatic fail- Congenital Fibrosis
ure than those receiving smaller volumes of blood products.122 A syndrome of congenital hepatic fibrosis has been described
It is thought that multiple blood transfusions may cause iron in the Swiss Franches-Montagnes and Swiss Frieberger
overload leading to iron toxicity.122,794 The administration of breeds.804,805 The onset of clinical signs is sudden, and affected
deferoxamine mesylate, an iron chelator, has been shown to foals are jaundiced and encephalopathic, with abdominal
distention and colic. Fever and tachypnea are also common. in the Gbe1 gene and results in severe impairment of glucose
Leukocytosis caused by neutrophilia and increased GGT, ALP, homeostasis.800 The clinical presentation is variable, with foals
and serum bile acid values are reported. Histopathology dem- born alive that are weak and hypothermic. Although they often
onstrates diffuse bridging portal fibrosis with numerous small respond positively when assisted to nurse or bottle-feed, inter-
and irregular bile ducts, which are sometimes cystic.805 mittent hypoglycemia and seizures may develop unless they
nurse regularly.823 Other clinical signs can include fever, tachy-
Portosystemic Shunts pnea, and tachycardia, and because of this very nonspecific spec-
Portosystemic shunts are an infrequent congenital anomaly in trum of clinical signs it can be difficult to differentiate these foals
foals that allow for shunting of blood directly from the portal from those suffering from neonatal sepsis.824 Respiratory failure
circulation to the systemic circulation.806-808 The shunts can and sudden death can occur, even with only mild to moderate
be located intra- or extrahepatic and may be single or mul- exercise.823 Clinicopathologic evaluation may reveal leukope-
tiple in number.807 Clinical signs of encephalopathy often do nia; intermittent hypoglycemia; and persistent elevations of CK,
not develop until foals are 6 to 12 weeks of age. The diagno- AST, and GGT activities.822 Despite supportive care the condi-
sis is based on the signalment, particularly age of onset, and tion is ultimately fatal, with most foals succumbing by 6 to 8
presence of encephalopathic signs with normal serum hepatic weeks and no reports of survival beyond 18 weeks of age.822,823 A
enzyme activities but marked elevations of serum ammonia. genetic test is available for diagnosis of this disease.801
Confirmation of the diagnosis may be possible using hepatic
ultrasonography, or by a “bubblegram” study involving the Nutritional Myodegeneration
injection of 10 mL of agitated saline into the spleen while
monitoring for the rapid appearance of bubbles via simulta- (White Muscle Disease)
neous echocardiography.808 CT, positive contrast portography, Nutritional myodegeneration (NMD) is a noninflamma-
and transrectal portoscintigraphy may also be useful in con- tory, degenerative disease primarily seen in foals less than 30
firmation of the diagnosis.784 Successful surgical repair using days of age. It affects skeletal as well as cardiac muscle and is
banding techniques that provide progressive occlusion has associated with low serum selenium and vitamin E concen-
been described.807,808 trations.825-829 The primary deficiency of vitamin E and sele-
nium appears to be in the mare, and for this reason NMD is
most commonly seen in areas with selenium-deficient soils,
Y MUSCULAR DISORDERS forages, and grains.830 These areas include the northeastern,
northwestern, mid-Atlantic, and Great Lakes regions of the
Polysaccharide Storage Myopathy United States. The clinical presentation of NMD can be acute
Polysaccharide storage myopathy (PSSM) was first described or subacute. The subacute form is associated with muscular
in Quarter Horses and related breeds, such as Paint and Appa- weakness, whereas the acute form is associated with rap-
loosa horses, but is now recognized in some draft, Warmblood, idly progressive weakness leading to recumbency and death
and light horse breeds as well.809-813 PSSM is characterized by within a few days.831 Dysphagia is a common finding in the
abnormal glycogen accumulation in skeletal muscle associ- subacute form and is related to involvement of the muscles
ated with muscle damage following exertional exercise. This involved in prehension, mastication, and swallowing. It may
syndrome has been associated with an incompletely pen- contribute to the development of FTPI and aspiration pneu-
etrant autosomal dominant mutation in the GYS1 gene, which monia.828 Severely affected foals typically have involvement
encodes the skeletal muscle glycogen synthase enzyme.814 This of the myocardium and the respiratory musculature, contrib-
mutation has been identified in more than 30 horse breeds, uting to cardiovascular and respiratory failure and leading
although at highly variable frequencies, with Quarter Horses to death.822 Diagnosis of NMD is based on clinical signs in
and Belgians having the highest reported prevalences.814-819 combination with increased muscle enzyme activities (CK and
PSSM is rarely reported in foals because it remains subclini- AST), decreased blood selenium, decreased glutathione per-
cal, especially if foals are stall confined.820 The only indication oxidase activity, and response to vitamin E and selenium treat-
of the presence of the syndrome may be increased serum CK ment.828,830 Profound electrolyte abnormalities may be present,
activity, unless the foals undergo a period of exertional activ- including hyperkalemia, hyponatremia, hypochloremia, and
ity or are affected by concurrent disease. Typically the dis- hypocalcemia, with hyperkalemia potentially contributing to
ease is not recognized until affected individuals are mature cardiac arrest in severely affected foals. Myoglobinuria may
enough to be put into training or work.820 The clinical signs be present, and pigment nephropathy can lead to the develop-
may range from muscle soreness and gait abnormalities in ment of acute renal failure. Muscle biopsies may be supportive
Warmbloods to progressive weakness and muscle atrophy in of NMD, but a more definitive antemortem diagnosis requires
draft breeds, whereas Quarter Horses may suffer from acute assessment of vitamin E and selenium concentration or glu-
exertional rhabdomyolysis.815,821 Diagnosis in adults depends tathione peroxidase activity.828 Postmortem examination con-
on muscle biopsy, but this may not be diagnostically useful in sistently reveals bilaterally symmetric myodegeneration with
foals, and genetic testing is preferred.822 Daily pasture exercise a dry appearance and pale discoloration of affected muscles.
and appropriate feeding of a balanced, low-starch, fat-supple- Treatment requires supportive care, IV fluid therapy for cor-
mented diet to both the foal and its dam will likely be benefi- rection of hypovolemia, electrolyte derangements, metabolic
cial in management of affected foals.822 acidosis, and diuresis. Dysphagic foals will require nutritional
support, either by indwelling nasogastric feeding tube or par-
Glycogen Branching Enzyme Deficiency enterally. Vitamin E and selenium supplementation is essential
Glycogen branching enzyme deficiency represents an important in the treatment of affected foals (Table 20.13). The injectable
cause of stillbirth and early neonatal death in the Quarter Horse form of selenium also contains vitamin E but at an insufficient
and Paint breeds.798,801,822 The syndrome is caused by a mutation concentration, requiring that foals also receive injectable or
TABLE 20.13 Treatments Drugs Used for Nutritional Achieving therapeutic concentrations at the site of infec-
Myodegeneration tion can be challenging, especially when the drug has to cross
an epithelial barrier (CNS, eye, lung, biliary, etc.). Drugs that
Drug Dosage Route Frequency (h) are highly lipid soluble tend to distribute more fully to the tis-
Vitamin E 2–6 IU/kg PO 24 sues, whereas water-soluble drugs tend to distribute primarily
(preferably in within the extracellular water and penetrate epithelia poorly.
the form of dl- The presence of inflammation will allow for increased tissue
alpha-tocopheryl permeability of epithelial barriers; however, the resolution of
acetate) inflammation allows for epithelial restitution. This may limit
Selenium 0.055–0.067 IM (deep) Once the ability of water-soluble drugs to maintain therapeutic
mg/kg respiratory concentrations as healing progresses, and recur-
1 mg total PO 24 rent infections may result.
dose The pharmacodynamic characteristics of the different
antimicrobials also impact decisions regarding the route and
IM, Intramuscularly; IV, intravenously; PO, orally. frequency of administration. The two fundamental classes of
drugs are the time-dependent and the concentration-depen-
dent antimicrobials. Efficacy of time-dependent antimicrobi-
oral vitamin E. Although the initial prognosis is guarded, foals als, such as the β-lactams, require that the concentration at the
that regain the ability to stand have a more favorable progno- site of infection be maintained above the minimum inhibitory
sis.823 Prevention of NMD can be aided by ensuring that mares concentration (MIC) for as much of the treatment interval as
have adequate dietary vitamin E and selenium intake and by possible. Time-dependent drugs benefit from intramuscu-
prophylactic parenteral administration of vitamin E and sele- lar and oral administration because slower absorption yields
nium to newborn foals in endemic areas. lower serum concentrations, but therapeutic concentrations
are typically maintained for longer periods of time. The use of
Y FOAL ANTIMICROBIAL THERAPY CRIs for delivery of time-dependent drugs can yield optimal
pharmacokinetics and is feasible in the hospital environment
The presence of documented focal or systemic bacterial infec- using electronic infusion pumps. The efficacy of concentra-
tion, such as septic arthritis, pneumonia, enterocolitis, meningi- tion-dependent drugs requires high peak serum concentra-
tis, or umbilical remnant infections, represents a clear indication tions for maximal efficacy (greater than 10 times MIC for the
for the use of antimicrobial therapy in the foal. Unfortunately the aminoglycosides) but does not require high concentrations
clinical situation is not always so straightforward. Because of the throughout the treatment interval. These compounds benefit
risk of septicemia in any compromised neonatal foal, it is often from IV or topical administration to achieve high peak con-
better to make the assumption that bacterial infection is present centrations, with prolonged treatment intervals.
rather than risk allowing the patient to deteriorate further while It is also important to remember that foals differ from adult
awaiting confirmation of the diagnosis.194 In those situations in horses in a number of ways that may impact the choice of anti-
which bacterial infection is likely or suspected, aggressive ther- microbial therapy. First, foals have substantially greater total
apy that includes antimicrobials is indicated. Although there body water content than adult horses, typically requiring that
are some risks associated with antimicrobial therapy, primarily the dosage of water-soluble drugs be increased. For example,
AAD, these risks are greatly outweighed by the risks associated doses of aminoglycosides are often increased as much as 100%
with withholding antimicrobial therapy from a patient with sep- in foals, compared with dosing in adults, to compensate for
sis secondary to bacterial infection. Early appropriate empiric this increase in the volume of distribution. Also, neonatal
antimicrobial therapy has been shown to reduce mortality in foals do not have complete maturation of their hepatic and
human patients suffering from septic shock,832 and although renal systems, especially during the first week of life, which
published evidence is lacking, clinical experience in neonatal may result in impaired elimination of certain drugs metabo-
foals supports this conclusion as well.833 lized or eliminated by those routes. Different types of toxicities
When implementing antimicrobial therapy one must con- associated with antimicrobial use in foals must also be con-
sider some basic pharmacologic concepts. The first concept is sidered—for example, the risk of arthropathy associated with
whether the antimicrobial selected is appropriate for the likely the administration of fluoroquinolones (because their rapidly
target of the therapy. To understand this, one must have a con- growing cartilage tissue).
cept of the drug’s mechanism of action and how that relates to There are some advantages in designing foal antimicrobial
the different classes of bacteria and their inherent susceptibili- therapy. Most orally administered antimicrobials are more
ties. Second, how is the drug to be delivered, and is that route effectively absorbed in foals compared with adults, which
of delivery likely to achieve therapeutic concentrations of the allows for wider use of this route. In addition, foals appear to
drug at the affected site? There are key factors that profoundly be at reduced risk of AAD, which is likely because they have
affect our ability to effectively deliver antimicrobials to some not yet fully transitioned to hindgut fermentation. Last, some
sites of infection, and failure to take these into account will antimicrobials used in in foals are cost-prohibitive in adult
preclude effective treatment. The physical and pharmacologic horses because of the total dose required; hence, the cost for
characteristics of the different antimicrobials and their inter- foals is much less.
actions with various tissues will also have a significant influ-
ence on the efficiency and efficacy of the treatment of bacterial Therapeutic Targets
infections. Consideration should also be given to the route of The most common isolates encountered will vary somewhat
administration and frequency of dosing, particularly if treat- based on the specific site of infection and the predisposing fac-
ment is to be administered by lay personnel or owners. tors associated with the infection. However, when looking at
retrospective studies of isolates from bacteremic neonatal foals Penicillin G is the most commonly used β-lactam anti-
some patterns become apparent. Over the past 30 years the microbial in equine medicine, and it exhibits good efficacy
most common bacteria isolated from blood cultures of infected against many gram-positive organisms and anaerobes, but it
foals have been gram-negative organisms.25,123,171 Gram- has a limited gram-negative spectrum. Penicillin G exhibits
positive organisms isolated from infected foals represented good synergy with aminoglycoside antimicrobials, making it a
less than 20% of isolates and were typically present in mixed useful drug in a combination therapy approach. Procaine pen-
infections with gram-negative organisms.25,123 Although some icillin is administered intramuscularly, whereas the aqueous
of the variance in the patterns of bacteria isolated from foals solutions of sodium or potassium penicillin are administered
may result from regional differences, it does appear that more intravenously (Table 20.14). Procaine penicillin G is readily
recently an increase in the percentage of gram-positive isolates available and inexpensive, but the requirement for repeated
has occurred.177 Several studies have reported increased num- intramuscular injections makes it less desirable for use in neo-
bers of gram-positive isolates ranging from 30% to 43% of the natal foals because of their minimal muscle mass. Potassium
total isolates.180,181 This temporal change in patterns of isolates or sodium penicillins are substantially more expensive than
highlights the need to consider the likely pathogens present in procaine penicillin on a daily cost basis but are commonly
the formulation of the initial empiric antimicrobial plan. Based used in hospitalized foals with ready venous access. There
on the most recent reports, E. coli remains the most common are reports of administering potassium or sodium penicillin
isolate followed by Enterococcus spp., Actinobacillus spp., β- as an IV CRI, which can provide favorable pharmacokinetics
hemolytic Streptococci, Staphylococcus spp., and Enterobacter with these time-dependent compounds.833 Toxicity is low for
spp.180,834 Unfortunately there have also been temporal changes the penicillins and is primarily associated with adverse reac-
in the patterns of antimicrobial susceptibility observed in the tions to the inadvertent IV or intraarterial injection of the
bacteria isolated from bacteremic foals. Although there may intramuscular preparation, procaine penicillin G, which likely
be some debate as to the driving force behind these chang- represents adverse reactions to procaine rather than penicillin,
ing patterns of antimicrobial sensitivity, there is no doubt although anaphylactic reactions have been reported.837
that the phenomenon is real. Some earlier reports mentioned Ampicillin and amoxicillin are synthetic penicillins that
the presence of a few isolates that were resistant to multiple exhibit better activity against gram-negative bacteria because
antimicrobials,120,177 but recent reports have demonstrated of improved outer cell wall penetration. They do suffer some
substantial numbers of multidrug-resistant (MDR) organ- loss of efficacy compared with penicillin G regarding suscep-
isms (up to 38% of isolates).180,182 Definitions vary somewhat tible gram-positive bacteria. Ampicillin is widely used as an
among references, but generally speaking, MDR organisms alternative to penicillin in the treatment of neonatal sepsis,
display resistance to three or more of the core antimicrobi- typically in combination with amikacin.177,194,834,838 Other
als in a sensitivity panel. Recent studies in human medicine β-lactam drugs that are occasionally used in foals include
have characterized the most common and problematic of the the antipseudomonal penicillins and the carbapenems. These
MDR organisms as the ESKAPE group, which includes Entero- drugs exhibit a superior gram-negative spectrum of action
coccus faecium, Staphylococcus aureus, Klebsiella pneumoniae, and are primarily used in cases where aminoglycosides cannot
Acinetobacter baumanii, Pseudomonas aeruginosa, and Entero- be administered or in the treatment of pathogens resistant to
bacter spp.835 This group of pathogens is responsible for the aminoglycosides. The use of these drugs should be restricted to
majority of nosocomial infections in human hospitals, and all cases with documented infections involving susceptible MDR
routinely “escape” most currently used antimicrobial drugs.836 organisms. The most commonly used antipseudomonal peni-
The increasing prevalence of MDR organisms will require that cillin is ticarcillin, which is typically combined with clavulanic
antimicrobials are used judiciously and appropriately to limit acid.839,840 Clavulanic acid causes irreversible time-dependent
the further spread of these organisms. The risk associated with inactivation of many of the β-lactamases, enhancing the activ-
these organisms also reinforces the need to perform appropri- ity of ticarcillin against organisms producing these enzymes.
ate culture sampling (blood, synovial fluid, CSF, body cavity Imipenem, a carbapenem antimicrobial, has been used in foals
effusions, etc.) to be sure of the pathogens involved and tailor for the treatment of MDR infections. Imipenem is used in
antimicrobial therapy appropriately. combination with cilastatin, which slows renal elimination of
imipenem and allows for a decreased frequency of dosing.841
Antimicrobials Cephalosporins
β-Lactams Cephalosporins are traditionally grouped into “generations”
β-Lactam antibiotics bind to penicillin binding proteins, inter- according to their order of discovery and their spectrum of
fering with bacterial cell wall synthesis. This leads to the for- action. First-generation drugs exhibit a primarily gram-positive
mation of defective cell walls that are osmotically unstable, and spectrum, whereas subsequent generations have an increasing
cell death usually results from cell lysis. These drugs include gram-negative spectrum and corresponding decreases in the
the penicillins, synthetic penicillins, cephalosporins, and gram-positive spectrum. Fourth-generation drugs are consid-
carbapenems. Modifications of the basic penicillin or cepha- ered to be truly broad spectrum. The primary cephalosporin
losporin molecule confer differences in antimicrobial activity, administered to horses is ceftiofur, which is a third-generation
as seen with the synthetic penicillins and third-generation drug.842 It exhibits a fairly broad spectrum with an empha-
cephalosporins, which exhibit an increased gram-negative sis toward gram-negative coverage. Because of this spectrum
spectrum. Increased stability against β-lactamases may also be of activity ceftiofur has often been used as the sole therapy in
achieved, such as seen in the carbapenems. β-Lactam drugs the initial treatment of foals. The relative safety of ceftiofur in
are time-dependent antimicrobials and must be present in the foals has fostered this approach, because it allows the clinician
tissues at concentrations greater than the MIC throughout to avoid using combined therapy including aminoglycosides.
most, preferably all, of the dosage interval to be effective. Unfortunately some recent studies have documented frequent
TABLE 20.14 Antimicrobial Dosages for Use in Foals

Drug Dosage Route Frequency (hours)
Acyclovir 16–20 mg/kg PO 8
Amikacin 25–30 mg/kg (neonates) IV 24
20–25 mg/kg (2–4 weeks)
7–14.5 mg/kg (weanlings)
Amikacin 8 mg/kg Aerosol 24
Ampicillin sodium 10–20 mg/kg IV, IM 8
Amoxicillin trihydrate 10–20 mg/kg IM 8
20–30 mg/kg PO 6–8
Azithromycin 10 mg/kg PO 24 h for 5 days,
then every 48 h
Cefazolin 25 mg/kg IM 6–8
Cefepime 11 mg/kg IV, IM 8
Cefpodoxime proxetil 10 mg/kg PO 6–12
Ceftiofur sodium 5 mg/kg IV 12
2.2 mg/kg IM 12–24
1.5 mg/kg/h IV CRI
2.2 mg/kg Aerosol 24
Ceftiofur crystalline-free acid 6.6 mg/kg IM 96 (two doses)
Cefotaxime 50–100 mg/kg IV 6
Cephalexin 30 mg/kg PO 8
Ceftriaxone 25 mg/kg IV 12
Chloramphenicol 50 mg/kg PO 6
Clarithromycin 7.5 mg/kg PO 12
Doxycycline 10 mg/kg PO 12
Erythromycin 25 mg/kg PO 6–8
Fluconazole 8 mg/kg (loading) PO Once
4 mg/kg (maintenance) PO 12
Gentamicin 11–13 mg/kg (neonates) IV, IM 24
6.6 mg/kg (weanlings)
Gentamicin 2.2 mg/kg as a 50-mg/mL solution Aerosol 24
Imipenem/cilastatin 5–10 mg/kg IM 12
10–20 mg/kg IV 6
Metronidazole 10 mg/kg (neonates) PO 12
15 mg/kg (10–12 day old) PO 12
15 mg/kg (over 2 weeks) PO 8
Minocycline 4 mg/kg PO 12
Penicillin G 20,000 IU IM (procaine penicillin) 12 (IM)
IV (K or Na penicillin) 6 (IV)
Rifampin 5–10 mg/kg PO 12–24
Sulfadiazine-trimethoprim 30 mg/kg PO 12
Ticarcillin 44 mg/kg IV 6
Valacyclovir 27 mg/kg (loading) PO 8
18 mg/kg (maintenance) PO 12

CRI, Continuous rate infusion; IM, intramuscularly; IV, intravenously; PO, orally.
resistance to ceftiofur in organisms isolated from foals, and in foals.844 Self-limiting diarrhea was reported in 66% of the
there does appear to be a trend toward increasing resistance foals treated with CCFA, but this does not appear to be a clini-
over time, especially among gram-negative enteric bacte- cal problem associated with this drug. Repeated subcutane-
ria.180,834 The use of ceftiofur sodium as a CRI has also been ous dosing of CCFA (13.2 mg/kg) at 48-hour intervals for four
investigated and appears to yield suitable pharmacokinetics.843 doses has been reported to maintain appropriate therapeutic
Ceftiofur is also available in a sustained-release form, which concentrations in foals.845 Other cephalosporins may have
contains CCFA. Subcutaneous administration of CCFA yields utility in foals, such as cefquinome, ceftriaxone, cefpodoxime
appropriate pharmacokinetics for highly susceptible bacteria proxetil, cefotaxime, ceftazidime, and cefepime. Cefquinome
is a fourth-generation cephalosporin that is labeled in Europe can allow for estimation of drug clearance in a more timely
for the treatment of foal septicemia caused by E. coli, but it is manner, allowing for more rapid adjustment of the therapeutic
not available in the United States at this time.846 Cefquinome protocol.634
is dosed at 1 mg/kg IV or intramuscularly every 12 hours, for
very susceptible pathogens, but a higher dose of 4.5 mg/kg Potentiated Sulfonamides
IV every 12 hours is indicated when dealing with pathogens Potentiated sulfa compounds are very common in equine
with higher MIC values.847 Cefpodoxime proxetil is a third- medicine because of their broad spectrum, oral route of
generation drug that is administered orally, but unfortunately administration, and affordability. These drugs exhibit time-
the expense of this drug renders it of limited utility in most dependent pharmacodynamics, and their effects are consid-
cases.833 Cefepime is a fourth-generation drug that can be use- ered to be bactericidal. The potentiated sulfas distribute well
ful in the management of MDR infections.848 to the tissues. Toxicity is most commonly associated with dis-
turbance of gastrointestinal flora associated with the develop-
Aminoglycosides ment of colitis. Although these drugs are not appropriate for
The aminoglycosides continue to constitute a major compo- initial therapy of septic foals, when organisms are documented
nent of the equine clinician’s armamentarium, despite their to be susceptible they can be used quite effectively.
well-described potential for nephrotoxicity. The primary rea-
sons for this are that the aminoglycosides are bactericidal, Tetracyclines
exhibit primarily a gram-negative spectrum, and demonstrate Tetracyclines are bacteriostatic and broad spectrum, possess-
good synergy with β-lactam antimicrobials.634 The bacterial ing activity against a wide variety of bacteria and protozoa as
penetration of aminoglycosides is in part an oxygen-depen- well as Mycoplasma and Rickettsia. These compounds are time
dent transport process and partially accomplished by passive dependent in nature. The most commonly used compounds are
diffusion. This dependence on oxygen-driven transport ren- oxytetracycline and minocycline. Toxicity has been reported
ders anaerobes resistant to the aminoglycosides. The role of from the disturbance of gastrointestinal flora in adults, but
passive diffusion leads to a dependence on high tissue con- this appears to be rare in foals. Because the tetracyclines are
centrations of the drug to achieve high intracellular concen- primarily eliminated via the urinary tract, there is the risk for
trations. Routes of administration and/or dosage schedules toxicity in animals with renal insufficiency. Very large dosages
associated with high peak concentrations at the site of infec- of oxytetracycline are administered to foals suffering from ten-
tion, such as extended-interval dosing, are associated with don contracture, and repeated or injudicious administration
improved clinical responses.849 Prolonged treatment intervals has been associated with nephrotoxicity.629 Rapid IV injection
decrease the risk of nephrotoxicity while still demonstrating of oxytetracycline has been associated with collapse in horses,
clinical efficacy caused by the prolongation of bacterial killing, perhaps caused by chelation of calcium in the blood. For this
even after the aminoglycoside concentration drops below the reason oxytetracycline is administered at 6 to 8 mg/kg slowly
MIC for the targeted organism. This phenomenon is termed IV twice daily, usually diluted in 0.5 to 1 L of normal saline and
the postantibiotic effect. The use of extended interval dosing administered over 30 minutes. Doxycycline is no longer widely
also has been demonstrated to lessen the development of used because of decreased availability and increased expense.
both acquired and adaptive antimicrobial resistance, which Minocycline has come into widespread use in horses because
are caused by the high peak concentrations achieved and the of superior pharmacokinetics compared with doxycycline and
period of time during which the drug is below the MIC.634 a much more reasonable cost of treatment. Although no phar-
Neonatal foals have reduced rates of drug clearance, which macokinetic studies have been performed in foals, minocy-
necessitates prolonged treatment intervals, but their clearance cline is empirically administered at adult dosages.851
increases to adult levels within the first few weeks of life.634
They also have greater volumes of distribution, compared Macrolides
with adults, which necessitates substantially higher dosages Macrolides (erythromycin, azithromycin, and clarithromycin)
to achieve the desired peak serum concentrations. A recent are considered to be bacteriostatic; have a broad spectrum of
study examining the pharmacokinetics of gentamicin in foals action; and accumulate in tissues, particularly the lungs.852
indicated that gentamicin should be dosed at 12 mg/kg IV Their primary application is for the treatment of rhodococ-
every 36 hours in foals less than 2 weeks of age, whereas a cal pneumonia in foals. Macrolides are eliminated by hepatic
lower dose of 6.6 mg/kg IV every 24 hours was estimated to metabolism and can affect the pharmacokinetics of other
be adequate in foals 2 weeks of age or older.850 Because of the drugs metabolized by the P450 system. Erythromycin admin-
unpredictability of aminoglycoside pharmacokinetics in sick istration in foals with rhodococcal pneumonia has been asso-
foals, it is recommended that therapeutic drug monitoring be ciated with frequent hyperthermia and diarrhea, and this drug
performed to ensure that both an adequate peak serum con- is no longer used for this purpose in most areas of the United
centration is achieved as well as appropriate trough concentra- States. Azithromycin and clarithromycin are the most com-
tions. Peak serum concentrations are typically monitored at 30 monly used macrolides in foals at this time. Rifampin therapy
minutes after administration of the IV dose, and trough con- is typically administered in conjunction with the macrolides
centrations are monitored immediately before the subsequent in the treatment of rhodococcal pneumonia because of its
dose. This approach is effective but may lack sensitivity in potential synergistic effects. The combination of clarithro-
detecting impaired clearance of the drug. In addition, because mycin-rifampin has been shown to be more effective than
of the timing of the sample collection the results of the assay erythromycin-rifampin or azithromycin-rifampin in the treat-
will not be available until after the administration of the next ment of rhodococcal pneumonia.441 Despite decades of clini-
dose, which may delay adjustment of the dosage or interval, if cal experience supporting the efficacy of the combination of
indicated. An alternative approach is to obtain serum samples macrolides and rifampin, there is recent evidence that coad-
at 30 minutes and 8 hours after drug administration, which ministration of rifampin with macrolides substantially inhibits
macrolide absorption.444,445 Current recommendations sup- be safe, although no controlled studies have been performed
port the continued use of macrolide-rifampin combinations in to confirm this clinical impression.833,857
the treatment of rhodococcal pneumonia in foals.349 There has
been recent interest in the use of the macrolide gamithromy- Metronidazole
cin in foals because this drug exhibits favorable pharmacoki- Metronidazole is a nitroimidazole antimicrobial that is highly
netics in foals following once-weekly intramuscular injections. effective against anaerobic organisms. Because of the limited
It also has been shown to be noninferior to the combination anaerobic spectrum of most other antimicrobials used in foals,
of azithromycin and rifampin in the treatment of rhodococcal metronidazole is commonly used when anaerobic involve-
pneumonia in foals.435,443 ment is suspected or confirmed in foals. A recent pharmaco-
kinetic study found that there were age-dependent influences
Rifamycins on metronidazole kinetics in foals and suggested a range of
Rifampin is a macrocyclic antibiotic and is used primarily in dosages over the course of the first 2 weeks of life.551
foals as an adjunct therapy to the macrolides for treatment of
rhodococcal pneumonia. It can be combined with other anti- Aerosol Administration
biotics for treatment of abscesses, but it should never be used Aerosol administration of antimicrobials has been demon-
alone because of the risk of rapidly developing antimicrobial strated to achieve high concentrations of antimicrobials at the
resistance. In addition to using rifampin in the treatment of respiratory mucosal surface while minimizing the development
rhodococcal infections, it has been reported to be effective for of systemic side effects. Other potential advantages to deliver-
the treatment of staphylococcal infections. ing medications to the lower respiratory tract by aerosolization
include a decrease in the total dose administered, avoidance
Chloramphenicol of systemic side effects, and a rapid onset of action.463 The
Chloramphenicol is widely distributed to the tissues and has administration of antimicrobials by aerosolization does have
a wide spectrum of action including both gram-positive and limitations, however, including potential problems with drug
gram-negative bacteria, as well as Rickettsia, Mycoplasma, and delivery and pulmonary irritation, as well as the expense of
anaerobes. The half-life of chloramphenicol is short, and it is a the required equipment and the time required for administra-
time-dependent drug, requiring frequent dosing (6-hour inter- tion. Several antimicrobials have been investigated for aerosol
vals).853 Human health concerns regarding possible chloram- administration in horses, including gentamicin, ceftiofur, cef-
phenicol-associated nondose-dependent fatal aplastic anemia quinome, and marbofloxacin. Both gentamicin and ceftiofur
made it illegal to use this drug in food animals over the past are well tolerated and can be administered as aerosols.459,466
50 to 60 years. As a result of the minimal use of the drug there
are low levels of resistance to chloramphenicol in many types Y FLUID THERAPY IN THE FOAL
of bacteria, which has created a potentially important role for
chloramphenicol in the treatment of MDR organisms. Intrigu- One of the fundamental dilemmas facing a clinician when eval-
ingly, the usage of chloramphenicol has been proposed for uating a sick foal is whether or not fluid therapy is indicated. To
human patients infected with MDR organisms, despite the risk determine the answer to that question one must consider the
of aplastic anemia.854 Regardless, the potential risk of aplas- variety of indications for fluid therapy. The most common indi-
tic anemia to humans handling chloramphenicol necessitates cation is for the correction of volume depletion or dehydration.
thorough client education when dispensing this drug (avoid Other indications for fluid therapy can be the correction of spe-
contact with aerosolized drug or direct contact with mucous cific electrolyte imbalances, the provision of colloidal support,
membranes). Animal toxicity appears to be rare and is associ- correction of acid-base disorders, restoration of oxygen-carry-
ated with reversible or irreversible bone marrow suppression. ing capacity, and provision of immunoglobulins. In many cases
Florfenicol is closely related to chloramphenicol but has not more than one of these indications is present, and one must
been associated with aplastic anemia in humans and is labeled be careful in assessing the patient because changes in clinical
for use in food animals. Administration of florfenicol to adult status over time may result in one or more new indications for
horses has been associated with acute colitis and is contraindi- fluid therapy arising, even as others may have been resolved.
cated, but this has not been reported in foals. There are anec- The next question regarding fluid therapy is what type of
dotal reports of successful clinical use of florfenicol in foals at fluid does this patient need. The choice of fluid composition
24- to 48-hour dosing intervals; however, a recent pharmaco- will depend on multiple variables, which include the primary
kinetic study suggested that a shorter treatment interval of 10 goal of fluid therapy as well as patient-specific, route-specific,
hours may be appropriate.833,855 and practical considerations. The clinician must then deter-
mine the most appropriate route for administration of fluid
Fluoroquinolones therapy in the individual patient, and this may also factor into
Fluoroquinolones have a relatively broad spectrum, with the decision-making process regarding the types of fluids to be
excellent activity against gram-negative organisms but mini- administered. The amount of fluid therapy to be administered
mal activity against streptococci. They are bactericidal and must also be determined, primarily based on the patient’s fluid
exhibit excellent tissue penetration. The fluoroquinolones deficit and need for maintenance and replacement of ongo-
exhibit peak concentration-dependent bactericidal effects ing losses. The anticipated duration of therapy can be more
and prolonged postantibiotic effects, which is similar to the difficult to assess in the formulation of a treatment plan, but
aminoglycosides. As a result they can be given at relatively this represents an important factor in deciding how fluids will
high doses at a decreased frequency. Enrofloxacin is the most be administered and the potential costs to the client for fluid
widely used fluoroquinolone in horses, but its use is contrain- therapy. Finally, the clinician must develop a plan for moni-
dicated in foals because of adverse effects on cartilage matura- toring ongoing fluid therapy and for determining when fluid
tion.856 Marbofloxacin has been used in foals and appears to therapy is no longer required.
Patient Requirement for Fluid Therapy into three broad categories: crystalloids, colloids, and oxygen-
The first challenge in patient evaluation is the accurate assess- carrying solutions. Crystalloid solutions contain electrolytes
ment of hydration status. The typical parameters used in and nonelectrolytes (such as dextrose) that are capable of dif-
assessing clinical hydration during a physical examination are fusing through the capillary wall into the interstitium, whereas
mucous membrane color, capillary refill time, jugular refill colloid solutions contain larger molecules that do not readily
time, pulse quality, the temperature of the extremities, mental diffuse and tend to remain within the vascular lumen. Oxy-
status, and urine production. Fundamentally these represent gen-carrying solutions contain either red blood cells or other
indicators of perfusion, rather than hydration, which is an substances capable of delivering oxygen from the lungs to the
important distinction given that there are situations, such as tissues. In the majority of situations the most appropriate fluid
cardiogenic or vasodilatory shock, in which a well-hydrated will be a crystalloid solution. These solutions are classified
patient can present with extremely poor perfusion. The term based on their tonicity relative to normal plasma and are iso-
dehydration actually refers to situations in which there is a tonic, hypertonic, or hypotonic.
total body deficit of pure water. The clinical signs most com- Isotonic electrolyte-containing fluids will have little influ-
monly used for the assessment of dehydration are increased ence on the ICF volume but will expand the ECF volume,
skin turgor, tacky mucous membranes, and sunken eyes. expanding the circulating blood volume. Because these fluids
Unfortunately skin turgor is difficult to assess in foals, and a contain large amounts of sodium, a substantial amount of the
recent study in adult horses indicated that it was also not a fluid will be retained in the body unless the kidneys excrete
reliable estimator of clinical hydration status in that popula- the sodium and water together. Sodium overload can result
tion.858 Further insight into hydration status can be gained by in hypernatremia, which has been associated with increased
the measurement of urine specific gravity, which in the prop- mortality and severity of illness in human patients.861 In addi-
erly hydrated foal should be in the range of 1.010 to 1.001. Val- tion to the substantial sodium content of the isotonic electro-
ues greater than 1.010 indicate that the foal is retaining water lyte solutions, there is typically a substantial chloride content
and is likely not adequately hydrated. Urine output is another as well. This is most pronounced with isotonic saline (0.9%),
useful parameter, but it can be hard to gauge in foals that are which contains 154 mEq/L of both sodium and chloride (Table
not continuously monitored. The normal foal should urinate 20.15). Although the sodium content is only slightly supra-
at least once every 2 hours. More accurate assessment of urine physiologic, the chloride content is dramatically greater than
output is only possible in foals that have a urinary catheter in that present normally in the plasma. In some patients renal
place, allowing for urine collection and measurement. Urine elimination of chloride is impaired and is not adequate to deal
output should be greater than approximately two thirds of the with this high chloride load.862 Excessive chloride adminis-
total fluid intake including all IV infusions and any enteral tration is associated with the development of hyperchloremic
fluids or feeding. Hypotension, considered a mean arterial metabolic acidosis, inflammation, hypotension, and adverse
pressure (MAP) less than 60 mm Hg, may be an indication of renal outcomes in human patients.861 More physiologic fluids,
hypovolemia but can also result from decreased cardiac out- such as lactated Ringer’s solution (LRS), Plasma-Lyte A, and
put or excessive venous capacitance. If the hypotensive patient Normosol-R, contain lower concentrations of chloride more
does not respond to volume replacement then additional ther- closely mimicking normal serum concentrations. Dextrose
apy in the form of vasopressors and/or inotropes is indicated 5% in water is an exception to these rules, because it is an iso-
(see the later section Inotrope and Vasopressor Therapy). tonic crystalloid fluid that does not contain any electrolytes
When attempting to determine whether hypovolemia and/ and is primarily used to replace total body water deficits.
or dehydration are present it is helpful to consider how fluid is Hypertonic crystalloid fluids have higher electrolyte con-
distributed within the body. Neonatal foals have substantially centrations than plasma and have fewer indications for their
higher total body water (TBW) content than adult horses, at use. The most commonly used hypertonic crystalloid is hyper-
75% and 67%, respectively.859 TBW is present in two primary tonic saline, which is primarily used to expand the circulating
compartments, the intracellular fluid (ICF) and ECF, with blood volume. This effect results from the shift of fluid from
the ECF subdivided into the interstitial fluid and the plasma the interstitial space into the circulation, but it is very tran-
volume. In neonatal foals the ECF and ICF each represent sient because of the rapid diffusion of the sodium load from
approximately half of the TBW, and the plasma volume rep- the circulation into the interstitium. The other commonly
resents approximately one fourth of the ECF.859 TBW is pri- used hypertonic crystalloid is hypertonic sodium bicarbonate,
marily determined by the total body sodium content, which which is typically administered to correct metabolic acidosis.
is closely related to the sodium concentration within the ECF By providing sodium without any accompanying chloride this
compartment and regulated by the ingestion or elimination solution directly addresses strong ion acidosis, such as hypona-
of sodium.860 Decreases in the plasma sodium concentration tremic metabolic acidosis. It is less useful in addressing other
(hyponatremia) are indicative of a relative excess of free water types of metabolic acidosis, such as lactic acidosis, and care
and/or decreases in total body sodium content. The kidneys must be taken when administering this solution to foals with
will respond by eliminating water while retaining sodium, depressed ventilation because it will increase carbon dioxide
restoring normal sodium concentration and TBW content. production and potentially worsen respiratory acidosis.
Increases in the plasma sodium concentration represent a loss Hypotonic crystalloid solutions contain much less sodium
of free water and will stimulate thirst, leading to water inges- and chloride than the isotonic replacement fluids. This can
tion and correction of the TBW deficit. be very helpful, because the lower sodium load decreases the
risk of water retention and edema formation, and the lower
Types of Fluids chloride load decreases the risk of hyperchloremic metabolic
Having determined that the patient needs fluids, the next acidosis. For these reasons hypotonic crystalloid solutions are
challenge is determining the types of fluids that should be most useful for maintenance fluid therapy, in which there is
administered. There are many choices of fluids, and they fall less need for electrolyte replacement and more need for the
TABLE 20.15 Composition of Intravenous Fluid Solutions Commonly Administered to Foals

Fluid Types
Plasma-Lyte 56/
0.9% Lactated Plasma-Lyte Normosol-M with 5% Dextrose 50% Dextrose 7.2%
Components Plasma Saline Ringer’s Solution A/Normosol-R 5% dextrose in Water in water Saline
Na+ (mEq/L) 140 154 131 140 40 — — 1232
Cl− (mEq/L) 104 154 111 98 40 — — 1232
K+ (mEq/L) 5 — 5.4 5 13 — — —
Mg2+ (mEq/L) 1 — 1 3 3 — — —
Ca2+ (mEq/L) 2.2 — 2 — — — — —
Dextrose (g/L) — — — — 50 50 500 —
Bicarbonate (mEq/L) 25 — — — — — — —
Lactate (mEq/L) 1 — 29 — — — — —
Gluconate (mEq/L) — — — 23 — — — —
Acetate (mEq/L) — — — 27 16 — — —
Osmolarity (mOsm/L) 285 309 278 295 363 253 2525 —

provision of water. The use of resuscitation fluids, such as LRS hemoglobin. This product has colloidal effects, but they are
and Normosol-R/Plasma-Lyte A, for maintenance therapy in not the primary reason that this product would be used.
foals has been associated with the development of hyperna- Polymerized hemoglobin has been used with apparent clinical
tremia and hyperchloremia, which reinforces this concern.863 efficacy in foals and horses at doses of 2 to 5 mL/kg.750,752 This
Because patients on maintenance fluid therapy often have product is not currently available in the United States, but it is
reduced dietary intake, there is an increased need for potas- available in Europe (Oxyglobin, Dechra Veterinary Products,
sium supplementation, and maintenance fluids have accord- Shrewsbury, UK).
ingly higher concentrations of potassium. There are concerns Synthetic colloids, such as hetastarch and pentastarch, are
that the administration of hypotonic fluids could cause red shelf-stable and do not require collection or thawing before
blood cell lysis, and for this reason maintenance fluids often administration, making them very useful in the critically ill
have dextrose added to bring the tonicity of the solution into patient. The synthetic colloids are typically less expensive
a more appropriate physiologic range. Following administra- than frozen equine plasma and also may provide a more
tion the dextrose is metabolized and has no impact on fluid long-lasting colloidal effect than albumin. There are concerns
shifts within the body. The use of 5% dextrose in water (D5W) that synthetic colloids, especially hetastarch, may interfere
represents an alternative to hypotonic crystalloid fluids for with coagulation, especially in patients with severe systemic
maintenance therapy in foals; this solution will not contrib- inflammation that may already be suffering from subclinical
ute any sodium load because there are no electrolytes. This is coagulative dysfunction. New-generation hetastarch prepara-
problematic because there is an ongoing need for electrolytes tions have lower molecular weight and lower degrees of molar
caused by renal, gastrointestinal, and insensible losses. For this substitution and may have improved safety profiles.864 Of even
reason D5W should not be used alone and is typically com- greater concern is the recent evidence from human medicine
bined with isotonic polyionic crystalloid solutions to provide that resuscitation with hetastarch solutions may be associated
for replacement of any electrolyte deficits as well as ongoing with an increased risk of acute kidney injury and mortality.865
losses. Although there are no studies addressing these concerns, in
Colloids are fluids containing relatively large molecules veterinary patients it is recommended that hetastarch solu-
less readily able to diffuse across the capillary membrane. This tions should only be used in patients with a demonstrated
allows them to exert colloid oncotic pressure within the circu- need for colloid therapy, and potentially in combination with
lation, resulting in fluid shifts from the interstitium into the equine plasma, rather than as the primary resuscitation fluid
vasculature and expanding circulating blood volume. Colloids or the sole colloid. Hetastarch solutions should not be admin-
will also aid in retaining fluids that have been administered istered in doses of more than 5 to 10 mL/kg, and cumulative
within the vasculature for a longer period of time than would dosing should be restricted to no more than 20 mL/kg.
be possible with crystalloids alone. The most commonly used
colloid solution is fresh frozen equine plasma, which contains Route of Administration
albumin as the primary colloid. Albumin, while the most The next challenge is determining the route by which fluids
physiologic colloid, also has a relatively small size and will dif- will be administered to the patient. The most physiologic route
fuse into the interstitial fluid space in which it will then exert is the enteral route, but it can be easy to overlook the utility of
a colloidal effect, potentially exacerbating the development of this route, especially in hospitalized patients. Generally, if the
edema. Blood is another natural colloid. In addition to the col- gut is working it should be used for at least whatever compo-
loidal effect of the albumin that it contains, blood has the ben- nent of the fluid therapy is appropriate. Enteral administration
efit of providing red blood cells to improve oxygen-carrying will be limited in both the volume that can be delivered and the
capacity and tissue oxygen delivery. Another solution with rate at which the fluid will be absorbed, rendering it of limited
oxygen-carrying capacity is ultrapurified polymerized bovine utility in the critically ill patient, but it may be very useful in
delivering maintenance fluid therapy. Enteral therapy may also to administer are the volume needed for maintenance of nor-
be less expensive and more practical in the field setting when mal bodily function, the magnitude of the existing fluid deficit,
treating the less severely compromised patient. IV administra- and the ongoing losses potentially associated with the dis-
tion will achieve the most rapid results because it allows for ease process (diarrhea, reflux) as well as any insensible losses
the rapid administration of large amounts of fluids and is the (sweat). When designing the fluid therapy plan it is important
most commonly used route of administration in critically ill to consider the maintenance fluid plan as separate from the
patients. IV access is associated with some risks, primarily replacement fluid plan, which includes both replacement of
catheter-associated complications such as thrombophlebitis existing deficits and ongoing losses. The types of fluids used
and air embolus aspiration. Neither subcutaneous nor intra- for these purposes are typically different, and inadvertent use
peritoneal fluid administration is well tolerated in equine of maintenance fluids for replacement, or vice versa, can be
patients, and these routes of administration are rarely used. deleterious to the patient. The calculation of maintenance fluid
Practical considerations related to the ability to administer requirements in the foal can be approached in two ways. The
fluid therapy may impact all of these decisions. IV access can traditional approach is based on the accepted value of 3 to 5
be challenging to establish in the sick neonatal foal, especially mL/kg per hour (75–120 mL/kg/day) as the maintenance fluid
in a field setting. Although over-the-stylet catheters are com- requirement. The primary problem with this approach is that
monly used, they can be difficult to place in hypotensive foals it represents a very broad range of fluid rates and may result in
and are susceptible to kinking or displacement caused by foal fluid overload if not closely monitored. A second approach to
movement and frequent handling. These catheters are best used the determination of maintenance fluid requirements has been
for short-term fluid administration in normotensive foals. The proposed, based on the Holliday–Segar formula, which pro-
most commonly used over-the-stylet catheters are made of Tef- vides a “drier,” more conservative rate of fluid administration.
lon, which can be more irritating to the vein than other materi- The calculation is as follows: for the first 10 kg of body weight,
als, but polyurethane over-the-stylet catheters also are available 100 mL/kg per day of fluids are administered, then 50 mL/kg
(MILA International, Inc., Erlanger, KY; Arrow, Teleflex Inc., per day for each kilogram from 11 to 20 kg body weight, and
Wayne, PA). Over-the-wire catheters, although slightly more then 25 mL/kg per day for each kilogram of body weight >20
complex regarding placement, are easier to use in hypotensive kg.190,866 In a 50-kg foal this calculation yields a maintenance
patients and are easier to maintain for longer periods of time. rate of 2250 mL/day, or 94 mL/h, which equates to 1.9 mL/kg
These catheters are typically made of polyurethane, which is per hour.866 When formulating the fluid plan do not forget to
less thrombogenic than Teflon. Silicone over-the-wire cath- incorporate other fluid sources that may be administered to
eters are the least thrombogenic and are rarely used in foals. the foal, which includes any enteral feedings, as well as fluids
Over-the-wire catheters are also available in longer lengths (20 given as drug infusions or parenteral nutrition. It is easy to
cm) than over-the-stylet catheters (13 cm), which is helpful in overlook these additional sources, yet they may constitute a
critically ill foals because they can be placed almost as deep as significant proportion of the daily fluid intake.
a central venous line, potentially decreasing the risk of vascu- The other consideration in the design of the maintenance
lar irritation associated with delivery of hypertonic solutions fluid regimen is the ongoing need for electrolytes, particularly
or irritating medications. Multiple-lumen over-the-wire cath- sodium and potassium. If isotonic replacement solutions are
eters are available that can be helpful in critically ill patients administered for maintenance purposes, then hypernatre-
because they allow for parenteral nutrition or medications to mia and hyperchloremia are likely complications.863 Those
be delivered through a separate catheter lumen than the one solutions also contain inadequate amounts of potassium for
used for IV fluid administration. The downside to these multi- maintenance. The use of hypotonic crystalloid maintenance
lumen catheters is primarily their large outer diameter, which solutions is, therefore, more appropriate. The recommended
can make them more challenging to place and may increase the daily rate of sodium supplementation in foals is less than 3
risk of catheter site or vascular complications. mEq/kg, unless they have increased renal sodium losses.866
Enteral administration of fluids can be achieved using a Administration of a maintenance solution such as Plasma-Lyte
nasogastric tube, but this approach is primarily useful for 56 at 1.9 mL/kg per hour will provide approximately 2 mEq/kg
administration of a few doses of fluids, after which the require- per day of sodium. It is important to remember that the foal
ment to repeatedly pass the tube may represent a very stress- will likely be receiving other sources of sodium in the form
ful intervention. Leaving the nasogastric tube in place is also of drug infusions and catheter flushes and in solutions such
problematic because of local irritation within the pharynx and as parenteral nutrition, plasma, or synthetic colloids. Regard-
interference with voluntary drinking and eating. If repeated ing potassium, the daily maintenance requirements are quite
enteral administration is anticipated, then serious consid- substantial in foals that are not nursing because milk contains
eration should be given to the placement of an indwelling high levels of potassium. Supplementation of potassium at
enteral feeding tube (14 Fr × 125 cm, MILA International, Inc., 1 to 3 mEq/kg per day is a reasonable starting point. Hypo-
Erlanger, KY). The small outer diameter of these tubes allows tonic maintenance solutions, such as Plasma-Lyte 56, contain
for ongoing voluntary intake of feed or water. Having one of substantially more potassium than replacement solutions (13
these tubes in place makes it very simple to administer multi- mEq/L vs. 5 mEq/L, respectively), but this is still insufficient
ple small boluses of enteral fluids or milk with minimal patient for the neonatal foal, and supplementation will be required.
stress. Further discussion of enteral feeding can be found in the The addition of potassium chloride at 20 to 40 mEq/L to a
section Nutritional Support for the Foal later in this chapter. hypotonic maintenance solution is a reasonable starting point
for supplementation. Care should be taken not to administer
Dosage a fluid with that amount of potassium supplementation at a
The clinician must also determine the volume of fluids to be high rate, however, because administration of potassium at a
administered and the duration of fluid therapy. The factors rate greater than 0.5 mEq/kg per hour may result in cardiac
that must be considered in determining the amount of fluids complications caused by hyperkalemia.
TABLE 20.16 Clinical Assessment of Hydration Status TABLE 20.17 Clinical and Physiologic Parameters Useful in the
Assessment and Monitoring of Hydration Status
Degree of Mucous
Dehydration Skin Tenting Capillary Refill Time Membranes Parameters Overhydrated Ideal Underhydrated
<5% 1–3 sec <2 sec Slightly tacky Heart rate — 80–120 >140
5–10% 3–5 sec 2–3 sec Tacky Respiratory Upward <56 —
>10% >5 sec >3 sec Dry rate/effort trend
Hematocrit 20 35–45 >45 (increas-
ing)
Total protein <3 5–8 >8
Using the clinical perfusion indicators mentioned previ-
(g/dL)
ously (mucous membrane color, capillary refill time, jugular
refill time, heart rate, and pulse quality) one can derive a rough Urine output >2 1–2 <0.5
estimate of the degree of clinical dehydration (Table 20.16). (mL/kg/h)
This approach yields estimates of dehydration ranging from Urine specific — 1.005–1.010 >1.012
5% to >10%, and these values can be used when calculating the gravity
estimated fluid deficit. For example, a 50-kg foal with a clinical Plasma lactate — <2 >5 (neonate)
estimate of 5% dehydration will require 2.5 L of fluids (50 kg × (mmol/L) >2.5 (over 4
0.05 = 2.5 kg of fluid) to replace their deficit. Clinicopathologic days)
testing can aid in refining the estimate of the fluid deficit, with Peripheral Obvious May be seen —
variables such as packed cell volume, total plasma protein con- edema signs in some
centration, urine specific gravity, BUN concentration, serum foals
creatinine concentration, and serum lactate concentration all Central venous >8–12 3–8 Negative to 5
potentially providing useful insight (Table 20.17). The packed pressure (cm
cell volume will be increased with hypovolemia but may show H2O)
less marked elevations with dehydration. Total protein con-
centration will typically increase with hypovolemia and dehy- BUN/creatinine — Normal Increasing

dration as well, but this marker may lack sensitivity in patients BUN, Blood urea nitrogen.
with hypoalbuminemia and/or hypoglobulinemia. Urine spe-
cific gravity is a fairly sensitive marker of dehydration and is
very clinically useful. BUN and creatinine concentrations are reassess the patient’s status and determine whether further
indicators of hypovolemia and decreased perfusion rather than boluses are required. Some foals may require more than replace-
dehydration. Both BUN and creatinine are relatively insensi- ment of their calculated deficit, but care should be taken not to
tive markers of decreased perfusion, especially BUN, and only exceed a 60-mL/kg total dose unless there are compelling clini-
begin to increase with substantial decreases in GFR. Serum cal reasons that this is indicated, such as ongoing losses. Exces-
lactate concentration may be a more sensitive marker of per- sive administration of bolus fluid therapy has been associated
fusion but can also be elevated in response to impaired tissue with worsened outcomes in human patients.867,868 If greater
oxygen utilization or decreased hepatic lactate clearance. Mea- than 60 to 80 mL/kg of fluid replacement is required and the
surement of central venous pressure (CVP) can be very useful patient remains hypotensive, then they should be considered
in assessing the foal’s fluid status. This technique is somewhat nonresponsive to fluid therapy, and the initiation of inotrope
technically challenging but is feasible with limited equipment. and/or vasopressor therapy should be seriously considered
If the foal has been catheterized with an over-the-wire 20-cm (see the next section Inotrope and Vasopressor Therapy). Reas-
catheter, then the placement of the catheter tip will be fairly sessment of the patient’s hydration status and response to fluid
central, and this catheter can be used for the determination therapy involves the use of all the parameters discussed earlier,
of an approximate CVP. With the foal in lateral recumbency with serial measurements being critical to this process.
all ingoing fluid therapy is stopped while the measurement is Replacement therapy is intended to address the patient’s
taken. A water manometer or electronic pressure transducer ongoing fluid losses, and determination of the magnitude of
can be used, and the zero position on the manometer should these losses is more art than science because they are diffi-
be set at approximately the height of the base of the heart. cult to measure. In many clinical situations the foal does not
The manometer is primed with sterile heparinized saline and have a urinary catheter in place, so assessment of renal losses
then opened to the IV catheter. Slight fluctuations of pressure is entirely empiric based on frequency of urination and per-
should be observed with respirations, and the measurement ceived volume. The assessment of gastrointestinal losses is
taken is the approximate mean of this range. similar in nature, whereas the losses caused by sweating are
Once a determination of the existing fluid deficit has been extremely difficult to estimate. The fluids used for replacement
made, a deficit fluid replacement plan can be formulated. Use of of losses should be isotonic balanced replacement solutions,
an isotonic replacement fluid (LRS, Normosol-R, and Plasma- because the fluids lost by these routes will be accompanied by
Lyte A) is appropriate for this purpose, as previously discussed; electrolyte losses as well. If foals appear to be urinating and
remember that deficit therapy is given in addition to the ongo- defecating normally and are not obviously sweating, then addi-
ing maintenance fluid support described earlier. Rather than tional replacement fluids are not indicated. In those foals with
simply dividing up the calculated fluid deficit and administer- increased losses associated with these systems one can add
ing it over a set period of time (i.e., 2.5 L over 12 hours), it is intermittent boluses of 10 to 20 mL/kg of replacement-type flu-
more useful to administer boluses of replacement fluids at 20 ids to address the estimated loss. Monitoring of ongoing fluid
mL/kg (e.g., 1 L to a 50-kg foal) over 10 to 30 minutes and then therapy is very important and requires frequent assessment to
ensure that the goals for fluid therapy in the individual patient TABLE 20.18 Dosages of Inotrope and Vasopressor Agents
are being achieved and to avoid the development of adverse
outcomes such as fluid overload. Repeated assessment of the Agent Dosage Range
clinical indicators of hydration status and perfusion is readily Dopamine 3–20 μg/kg/min
performed and extremely valuable in monitoring fluid therapy Dobutamine 1–20 μg/kg/min
because normalization of these parameters is evidence of ther- Norepinephrine 0.1–2 μg/kg/min
apeutic efficacy.
Vasopressin 0.1–2 mU/kg/min
Epinephrine 0.2–2 μg/kg/min
Y INOTROPE AND VASOPRESSOR Adapted from Palmer J. Update on the management of neonatal sepsis in
THERAPY horses. Vet Clin North Am Equine Pract. 2014;30:317-336, vii; Dickey EJ,
McKenzie H 3rd, Johnson A, et al. Use of pressor therapy in 34 hypotensive
Hemodynamic factors, such as volume depletion, low cardiac critically ill neonatal foals. Aust Vet J. 2010;88:472-477; Tennent-Brown,
output, or inappropriate vasodilation, lead to systemic hypo- BS, Seahorn, JL. Inotrope and vasopressor therapy. In: Southwood LL,
Wilkins PA, eds. Equine Emergency and Critical Care Medicine. Boca
tension, which may result in organ hypoperfusion through Raton, FL: CRC Press; 2015:675-684.
reductions in perfusion pressure with potentially deleterious
consequences for the gastrointestinal and renal systems.869 Tis- TABLE 20.19 Target Sites of Action of Inotropes and
sue perfusion can be supported by the provision of IV fluids to Vasopressors
address hypovolemia and improve venous return to the heart,
providing adequate preload to support cardiac output, and fluid Dopami- Vaso-
repletion is always the first intervention to be used in affected Agent α1 β1 β2 nergic pressin-1
foals. Although many foals suffering from hypotension will Dopamine +++ ++++ ++ +++++ 0
respond well to IV fluid administration, a subset of these cases
Dobutamine + +++++ +++ 0 0
will be nonresponsive to fluids and will require additional blood
pressure support. Treatment with inotropes and vasopressors Norepineph- +++++ +++ ++ 0 0
may be indicated in these cases to increase cardiac contractil- rine
ity and afterload, respectively. Administration of these agents Vasopressin 0 0 0 0 +++++
requires that the foal be in a hospital environment with close Epinephrine +++++ ++++ +++ 0 0
monitoring of hemodynamic function and the availability Phenylephrine +++++ 0 0 0 0
of electronic infusion pumps that can provide accurate CRIs.
Blood pressure monitoring is absolutely essential, and this can 0 = no significant affinity; + through +++++ = minimal to maximal affinity.
be accomplished by direct (arterial catheter) or indirect (oscillo- Adapted from Pollard S, Edwin SB, Alaniz C. Vasopressor and inotropic
metric tail cuff) means. In most situations the indirect approach management of patients with septic shock. P T. 2015;40:438-450.
will be used because the placement and maintenance of arterial
catheters in foals can be extremely challenging. Although the assessed quickly, often in as little as 10 to 15 minutes, reinforc-
data obtained from direct measurement are superior, the tech- ing the need for continual patient reevaluation.
nical challenges render this approach impractical. Indirect tech- Dobutamine is a positive inotrope commonly used to treat
niques are not ideal because they can be affected by tail cuff size hypotension in neonatal foals, and it often represents the first-
and placement and can be inaccurate, but they provide accept- line drug of choice30,875 (Table 20.19). The β-adrenoceptor ago-
able accuracy for clinical use, particularly in the monitoring of nist increases myocardial contractility, and therefore cardiac
trends in MAP over time.870,871 output, via its action on β1-receptors. Concurrent stimulation
It can be challenging to determine the point at which a of β2-receptors may also produce peripheral and splanchnic
patient requires additional blood pressure support. In human vasodilation. This vasodilatory effect may be unproductive
patients, exceeding the critical lower level for MAP, which because it can result in decreases in systemic vascular resis-
is regarded as 60 to 65 mm Hg, is vital to maintain cerebral, tance and MAP, which means that dobutamine may not be the
coronary, and renal blood flow.872 A major goal in the man- ideal choice as a single agent in the treatment of fluid-refrac-
agement of critically ill foals, therefore, is to maintain the tory hypotension.876 For this reason dobutamine is normally
MAP above 60 mm Hg, although this level does not neces- used in combination with a vasopressor in human patients.877
sarily indicate adequate tissue perfusion.130,873,874 There is no The positive benefit of the vasodilatory effect of dobutamine is
apparent advantage to achieving higher MAP, and doing so that it may improve splanchnic perfusion when used concur-
may actually be deleterious because of altered distribution rently with vasopressors.876 By increasing myocardial contrac-
of blood flow resulting in decreased perfusion of some tis- tility dobutamine also increases myocardial oxygen demand,
sues.718,872 It is critical to use other indicators of tissue perfu- which can be problematic in the patient with already impaired
sion, including heart rate, mentation, central venous oxygen oxygen delivery. The other concern with dobutamine is that
tension, urine output, acid-base status, and trends in blood because of its stimulation of β1-receptors it can cause tachycar-
lactate concentration, because it has been suggested that neo- dia and arrhythmias, especially at higher doses.877
natal foals may have a different physiologic response to hypo- Dopamine was traditionally used as a first-line agent in
tension than adult horses.873 When implementing inotrope or human and veterinary medicine because it exhibits dose-
vasopressor therapy it is advised to start at the lowest end of dependent stimulation of a wide variety of receptors, with
the dosage range (Table 20.18) and to monitor the response to dopaminergic activity at low doses, β1 and β2 activity at mod-
therapy before increasing the dosage because it is impossible erate doses, and α1 activity at high doses. Through the stimula-
to predict the response of an individual patient. The short half- tion of dopaminergic receptors low-dose dopamine increases
life of these agents means that the response to therapy can be renal and splanchnic perfusion, although this has not
proven to be beneficial in preventing organ failure in human choice as a vasopressor in patients not exhibiting a positive
patients.878 At higher doses dopamine increases cardiac con- response to norepinephrine therapy.877
tractility, vasoconstriction, and heart rate, all of which tend There are a few anecdotal reports of the use of vasopres-
to increase MAP.877 Unfortunately the vasopressor response sin as a second-line vasopressor in equine critical care, with
to dopamine is less pronounced and less consistent than that one reference, by Collins et al., indicating that vasopressin has
achieved with norepinephrine.879 When the inotropic effects begun to be used as the first-line therapy for foals with fluid-
of dopamine were compared with dobutamine in hypoten- refractory hypotension.30,718,888 At this time there is only one
sive human neonates, dopamine was less effective in restor- published report regarding vasopressin therapy in clinically ill
ing blood flow.880 At high doses (greater than 20 μg/kg/min) foals.889 In that report the effects of norepinephrine or vaso-
dopamine can cause pulmonary venous vasoconstriction and pressin on cardiovascular responses and fluid balance were
reduced splanchnic perfusion.30 For all of these reasons dopa- compared in a group of 34 foals with hypotension refractory
mine is now much less commonly used in human or equine to both fluid therapy and dobutamine. Eighteen foals were
critical care. treated with vasopressin, whereas 16 foals received norepi-
Norepinephrine is primarily an α-adrenergic receptor nephrine. Six of the foals in the vasopressin group had failed
agonist, but it also has some limited β1 and β2 effects. Norepi- to respond to norepinephrine therapy, which was withdrawn
nephrine induces arterial and venous vasoconstriction, result- before initiation of vasopressin therapy. The severity of illness
ing in increases in MAP, effective circulating blood volume, was pronounced and similar between groups, with a mean lac-
and venous return and preload, with minimal increase of heart tate of 10.5 ± 4.4 mmol/L in the vasopressin group and 9.6 ±
rate or stroke volume.881 Despite historic concerns regarding 4.6 mmol/L in the norepinephrine group. The two groups also
potential splanchnic hypoperfusion, norepinephrine is now had similar sepsis scores at admission, with a mean of 15.9
regarded as the first-line pressor agent in hypotensive human ± 6.1 in the vasopressin group and 16.1 ± 4.5 in the norepi-
patients.877 Current human guidelines recommended the nephrine group. Vasopressin administration was associated
administration of norepinephrine as a sole agent initially, with with a significant increase in MAP and in urine output as well
dobutamine added if hypoperfusion persists despite adequate as a significant decrease in heart rate, whereas norepineph-
MAP.175 Norepinephrine has been reported to be effective in rine administration was associated with a significant increase
increasing MAP and urine output in hypotensive foals that in MAP. The overall survival rate in this study was only 38%,
were nonresponsive to both fluid administration and dobu- likely reflecting the severe systemic disease present in this
tamine therapy.130 Another study compared the effects of nor- population of foals evidenced by their admission sepsis scores
epinephrine alone and the combination of norepinephrine and lactate concentrations, and was consistent with a previous
and dobutamine with a control treatment of saline infusion.882 report from the same institution, in which the survival rate
Both norepinephrine and norepinephrine-dobutamine for foals presenting with lactate concentrations greater than
increased arterial blood pressure and systemic vascular resis- 6 mmol/L was reported to be only 40%.126 The authors of this
tance and decreased heart rate and cardiac index compared report also describe increased use of vasopressin as a first-line
with saline, but no effect was observed on renal function. therapy for foals with refractory hypotension.889
Norepinephrine-dobutamine did result in higher arterial pres- Other pressor agents include epinephrine and phenyleph-
sures than norepinephrine alone. This combination therapy rine, both of which are strong adrenergic receptor agonists
approach is now commonly used for the treatment of foals and can have negative effects on splanchnic and renal per-
with refractory hypotension. fusion.890 Epinephrine is a catecholamine with potent activ-
In recent years in human medicine, AVP (antidiuretic ity at β-adrenergic and α-adrenergic receptors. Epinephrine
hormone) has gained popularity in managing vasodilatory increases MAP by increasing cardiac output and vascular tone,
shock and cardiac arrest despite concerns regarding potential and in human patients it is regarded as the first alternative to
splanchnic hypoperfusion at higher dosages.883 This concern the combination of norepinephrine and dobutamine.877 How-
regarding splanchnic hypoperfusion deserves consideration ever, epinephrine has been associated with hyperglycemia,
because this effect was observed at high doses of vasopressin hypokalemia, lipolysis, tachycardia, decreased splanchnic per-
in a study that examined the effects of dobutamine, norepi- fusion, increased lactate concentration, and increased platelet
nephrine, and vasopressin in healthy anesthetized foals with aggregation.30,877 Phenylephrine has potent α1 activity but has
induced hypotension.875 Although vasopressin has a myriad of no cardiac effects, mediating its effects through the constric-
effects involving numerous receptors and pathways, it controls tion of the peripheral arterial vasculature.877 Phenylephrine is
blood pressure primarily by vasoconstriction via its actions on primarily of utility in patients with arrhythmias resulting from
the vasopressin-1 receptor.884 Vasopressin has stronger vaso- dobutamine and/or norepinephrine administration and has
constrictive effects on large arterioles than norepinephrine, little application in equine neonatal critical care.
which may explain its effectiveness even in patients refractory Although not a vasopressor per se, low-dose hydrocorti-
to standard catecholamine therapy.885 Vasopressin also has sone therapy has been shown to improve the response to vaso-
been shown to have a positive interaction with hydrocortisone pressors and shorten the duration of vasopressor therapy in
therapy in the treatment of refractory shock in humans.175 human shock patients.891,892 The mechanisms responsible for
When used as a treatment for vasodilatory shock vasopressin this effect are unclear, but do not appear to be associated with
has been shown to decrease heart rate, improve overall hemo- primary corticosteroid insufficiency. Rather, it appears that
dynamics, and lead to a reduction in inotrope requirement.886 corticosteroid therapy directly results in improved vasopressor
A recent human meta-analysis determined that vasopressin responsiveness of peripheral vessels, because hydrocortisone
therapy in human patients in septic shock was safe, useful in raises blood volume, increases vascular tone, and enhances
weaning patients off of catecholamines, and associated with endothelial reactivity to vasopressors.893 A thorough discus-
decreased mortality.887 The consensus in human medicine sion of hydrocortisone replacement therapy can be found in
appears to be that vasopressin is a reasonable second-line the previous section Endocrine Disorders.
Y ANTIINFLAMMATORY AND The mostly highly COX-2–specific NSAIDs that have

been studied in horses and foals are meloxicam and firocoxib,
ANALGESIC THERAPY with firocoxib demonstrating the greatest degree of COX-2
The indications for antiinflammatory therapy in the foal are specificity. Firocoxib has favorable pharmacokinetics and is
numerous. Most often these compounds are used to regulate reported to be safe in foals when administered by the oral or
fever and local inflammation, reducing patient discomfort, IV routes.905,906 Firocoxib has been demonstrated to be effec-
but there are situations in which they are required for the tive for musculoskeletal and visceral pain in horses,907,908 but
control of systemic inflammation as well. The primary class the analgesic efficacy of firocoxib has not been assessed in
of antiinflammatories used in foals is NSAIDs, which con- foals. Anecdotally it seems that firocoxib may be more effec-
sists of drugs inhibiting arachidonic acid synthesis via COX tive for musculoskeletal pain than for visceral pain, but this has
inhibition. These drugs typically exhibit antipyretic, antiin- not been scientifically evaluated. Meloxicam is marketed for
flammatory, and analgesic effects.894 There are also several equine use in Europe but is currently only labeled for small-
drugs in the NSAID group that have effects on pathways animal use in the United States. Meloxicam pharmacokinetics
other than arachidonic acid metabolism. The second class and safety have been evaluated in foals,909 and no evidence
of antiinflammatory drugs is the corticosteroids (steroidal of gastrointestinal or renal toxicity was detected. Interestingly,
antiinflammatory drugs [SAIDs]). These drugs have potent meloxicam was eliminated more rapidly in foals than in adult
dose-dependent antiinflammatory and immunosuppressive horses, which is quite different from what has been found with
effects, but typically have little antipyretic or analgesic activ- other NSAIDs. For that reason the authors of that study rec-
ity.665 In situations where the primary goal is analgesia one ommended that meloxicam be dosed every 12 hours in foals,
can use NSAIDs, but opioid drugs provide analgesia with- rather than 24 hours.909
out the concerns regarding gastrointestinal and renal toxic- In addition to the COX inhibitors there are several antiin-
ity associated with many NSAIDs. Although not commonly flammatory drugs that have been used in foals and may have
used in very young foals, alternative analgesics such as ket- some application. Dipyrone (metamizole) has been widely used
amine and lidocaine may be beneficial in managing older in horses as an analgesic, antipyretic, and antispasmodic drug
foals with severe, refractory pain. and clinically appears to be safe when used as a single dose in
The NSAIDs include nonspecific COX inhibitors such foals with abdominal pain. Acetaminophen has been used very
as phenylbutazone and flunixin meglumine, more selective little in horses because of concerns about the potential for hepa-
COX-2 inhibitors such as ketoprofen, and COX-2–specific totoxicity, but recent reports suggest that this drug may be both
drugs like meloxicam and firocoxib. Nonspecific COX inhi- safe and effective as an analgesic.910 Although dipyrone and
bition can be associated with side effects including gastroin- acetaminophen have some COX inhibitory effects, that path-
testinal ulceration and renal injury.895 Phenylbutazone has way is not considered to be primarily responsible for the drugs’
been associated experimentally and clinically with toxicity in therapeutic effects.911,912 The current hypothesis is that these
foals895,896 and appears to have a narrow therapeutic index in drugs act primarily through other pathways, including the sero-
this population. In addition, it can be difficult to administer tonergic, opioid, and cannabinoid systems.913,914 Dipyrone or
appropriate dosages of phenylbutazone to foals because of acetaminophen are sometimes combined with more traditional
their small size and the composition of the forms of phenyl- NSAIDs to achieve enhanced analgesic effects,915 but there are
butazone that are available. For all of these reasons phenylbu- limited reports regarding this approach in the horse.912
tazone is rarely used in foals. Flunixin meglumine, however, In addition to the NSAIDs there are other drugs that may
when given parenterally at appropriate dosages, has been exhibit antiinflammatory effects, such as pentoxifylline and
demonstrated to be safe in foals, even when administered for DMSO. Pentoxifylline is a phosphodiesterase inhibitor that
several weeks,897,898 and this is supported by clinical experi- has been shown to have wide-ranging antiinflammatory effects
ence. Flunixin meglumine is primarily used in foals with and is frequently used in adult horses suffering from severe
severe systemic inflammation, severe discomfort, or persis- systemic inflammation.916 Although the pharmacokinetics of
tent fevers. It is important to note that the metabolism and pentoxifylline are not known in foals, it has been used in foals
elimination of NSAIDs can be impaired in neonatal foals, at adult dosages.185 DMSO is a free radical scavenger that is
potentially requiring increases in dosing or prolongation of widely used in horses and foals suffering from severe localized
the dosing interval.899-901 For these reasons it is recommended or systemic inflammation, despite a relative lack of evidence
that the nonspecific COX inhibitors be used with caution in of efficacy.917 When administered intravenously at an appro-
the clinically ill neonatal foal, particularly in foals with severe priate dilution DMSO appears to be safe and is frequently
systemic inflammation, hypovolemia, or the potential for gas- administered to foals suspected to be suffering from NE.185
tric ulceration. Although not a traditional antiinflammatory, the antimediator
In theory, drugs like ketoprofen and carprofen should be polymyxin B is sometimes used in foals with SIRS because it
safer for use in foals because they are more COX-2 selec- has the capability of binding circulating endotoxin and inhib-
tive than phenylbutazone and flunixin. Although there is no iting the upregulation of the inflammatory response.917,918 A
peer-reviewed evidence to support the claim of reduced toxic- recent study performed in healthy foals with experimentally
ity, both of these drugs have been used in foals with appar- induced endotoxemia found that administration of polymyxin
ent safety.902,903 The pharmacokinetics of ketoprofen has been B at 6000 U/kg IV every 8 hours attenuated some of the clini-
studied in foals, and the dosage and treatment intervals rec- cal and clinicopathologic effects of endotoxemia.919 Polymyxin
ommended in that report are both greater than those for adult B is potentially nephrotoxic, however, so caution is indicated
horses899 (Table 20.20). Ibuprofen has also been studied in when considering the utilization of this therapy in the criti-
foals and was found to be safe when administered for up to 6 cally ill, hypovolemic foal.
days.904 There are no published reports of the pharmacokinet- The administration of SAIDs to foals is not frequently
ics of carprofen in foals. indicated and should be restricted to clinical syndromes in
TABLE 20.20 Dosages of Antiinflammatory and Analgesic Medications Used in Foals

Drug Dosage Route Frequency (h)
Aspirin 10–100 mg/kg PO 24
Butorphanol 0.1 mg/kg (up to 8 weeks of age) IV, IM PRN
Carprofen 0.7 mg/kg (adults) PO 24
Dexamethasone 0.01–0.02 mg/kg IM, IV, PO 24–48
0.05–0.2 mg/kg
Dimethyl sulfoxide 0.5–1.0 mg/kg as a 10% solution over 30–60 min IV 12–24
Firocoxib 0.1 mg/kg PO 24
0.09 mg/kg IV
Flunixin 0.25–0.5 mg/kg IV, PO 8
1.0 mg/kg 12–24
Hydrocortisone 0.17–0.67 mg/kg (total dose 1–4 mg/kg/day) IV 4–6
Ibuprofen 25 mg/kg PO 12
Ketamine 0.4–1.2 mg/kg/h IV CRI
Ketoprofen 2.2 mg/kg IV 24
3.3 mg/kg (<24 h)
Lidocaine 1.3 mg/kg loading IV CRI
0.05 mg/kg/min CRI
Meloxicam 0.6 mg/kg PO 12
Methylprednisolone sodium succinate 1 mg/kg IM, IV (slow) 12–24
Phenylbutazone 1.1–2.2 mg/kg IV, PO 12–24
Polymyxin B 6000 U/kg in saline IV 8
Prednisolone sodium succinate 0.25–2.5 mg/kg IV 6, PRN
0.8–5.0 mg/kg
Prednisolone 1–2.2 mg/kg PO 12–24
Pentoxifylline 10 mg/kg (adults) PO 12
Tramadol 3 mg/kg IV Not defined

CRI, Continuous rate infusion; IM, intramuscularly; IV, intravenously; PO, orally; PRN, as needed.
which overwhelming localized or systemic inflammation of time when given as a bolus. Administering butorphanol as
must be controlled. In foals with interstitial pneumonia, ALI, a CRI allows for a much more stable analgesic effect and may
or ARDS, SAID therapy is critical in the downregulation of lessen the sedative effects. Opioid agonists, such as tramadol
pulmonary inflammation and restoration of pulmonary func- and fentanyl, are rarely used in foals but could have utility in
tion and represents the primary pharmacologic therapy for managing chronic, severe musculoskeletal pain.921,922 Lido-
these conditions.324 This syndrome is discussed in detail in the caine is a local anesthetic, but when administered systemi-
previous section Respiratory Disorders. Severely ill foals can cally as a CRI it can provide effective analgesia, especially for
suffer from CIRCI, which is associated with poor clinical out- visceral pain. It is not associated with sedative effects but can
comes.667 This syndrome is discussed in detail in the previous cause neurologic signs if given at an excessive rate. In a recent
section Immunologic Disorders. Cortisol replacement therapy study lidocaine administration to foals achieved lower sys-
using small doses of hydrocortisone administered frequently temic concentrations than in adult horses but appeared to be
may provide antiinflammatory and physiologic benefits in safe and clinically effective.923 Ketamine is a dissociative agent
CIRCI-affected foals and does not appear to interfere with the most commonly used for induction and/or maintenance of
functioning of the innate immune system.313,315 general anesthesia, but it has been reported to have analgesic
If the primary goal of therapy is analgesia independent of effects when administered at lower doses as a CRI.920
antiinflammatory effects there are a number of alternative
therapies available. For short-term analgesia the α2-adrenergic Y NUTRITIONAL SUPPORT OF THE FOAL
agonists, such as xylazine and detomidine, are commonly
used because they are very effective in controlling severe Developing an appropriate nutritional plan when treating a
pain. The limitations of the α2 drugs are profound sedation sick foal can be challenging because one must ensure that the
and decreases in gastrointestinal motility.920 Alternatively, one foal has adequate energy and nutrients for basal metabolism
could consider the use of an opioid agonist or agonist/antago- and immune function and ideally for growth as well. This
nist. Butorphanol, an opioid agonist/antagonist, is the most should be a straightforward process in which the number of
commonly used drug because it is readily available and safe to calories required by the foal is calculated, followed by a deter-
administer. The limitations of butorphanol are primarily that mination of the volume of the appropriate nutrient-containing
it causes substantial sedation and only lasts for a short period solution and the administration of this nutritional source by
the appropriate route. Unfortunately the energy requirements been shown that normal newborn pony foals demonstrated
for sick foals are not well understood and will vary among impaired glucose clearance following the administration of
patients. Additionally, the ability of the foal to appropriately exogenous glucose on the first day of life, suggesting a degree
metabolize the nutrients provided is not guaranteed because of insulin resistance.928 By 10 days of age foals demonstrate
both age and degree of illness impact the foal’s ability to pro- increased rates of glucose clearance, but this response remains
duce metabolic hormones as well as the ability of the tissues lower than that seen in normal adult equines. This gradual
to respond to hormonal stimulation. Another difficulty arises maturation may be an appropriate response to changes in the
because the energy content of mare’s milk cannot be easily composition of mare’s milk, because colostrum contains little
determined, and the exact formulation of substitutes such as lactose, and in the volume of milk ingested, which is less on
artificial milk replacer is not always known. Ultimately the the first day of life than on subsequent days.924,928
burden falls on the clinician to formulate the best plan pos- Starting as early as the second day of life foals will begin
sible with the information at hand and to ensure that the foal ingesting small amounts of hay, grass, and grain while at the
is closely monitored. This will ensure that the goals of the same time they are ingesting maternal feces, which likely pro-
nutritional plan are met while the risk of complications is vides the initial microbial flora required to support digestion
minimized. of these feeds. It is unlikely that grain and roughage are thor-
The foal’s nutritional requirements and dietary composi- oughly digested until several weeks of age, at which point the
tion change substantially during the transition from neonate to foal begins the gradual transition from a milk-based diet to a
weanling, requiring careful consideration of the foal’s stage of forage-based diet. The amount of milk produced by the mare
growth when formulating a nutritional plan. At birth the foal peaks at around 2 months of lactation and then begins a steady
transitions from a continuous supply of nutrients provided by decline, which continues until the time of weaning, necessitat-
the dam via the placenta to intermittent absorption of ingested ing that the foal begin relying on ingestion of solid food for
nutrients. At the same time the metabolism of the neonate is an increasing proportion of its nutritional requirements. At
no longer able to depend on the maternal glucose concentra- the same time, the foal’s hindgut function is increasing and
tion to maintain normoglycemia, and the pancreas assumes is likely fully functional by around 3 to 4 months of age. By
responsibility for regulating glucose homeostasis. These dra- the age of 6 months the foal is receiving less than 30% of the
matic alterations in energy metabolism do not always occur total nutritional requirement in the form of milk, which allows
smoothly, and the foal possesses limited energy reserves in for a fairly easy dietary transition when weaning occurs. As
the form of glycogen and fat. The result is that hypoglycemia the foal’s hindgut function increases, there is a corollary shift
occurs frequently in even the normal neonatal foal, and clini- in the primary energy substrate from carbohydrates absorbed
cally ill foals are at risk of profound hypoglycemia if deprived in the small intestine to volatile fatty acids absorbed from the
of energy intake for even a few hours. large intestine.
The caloric requirements of the normal foal are sizable; When evaluating the sick neonatal foal one must always
they need to support not only their high basal metabolic needs remember that the disease processes at work in the foal may
but also maintain a rate of growth of as much as 2.5% of body have had their origins in utero. Maternal illness, maternal mal-
weight per day in the neonatal period. This means that the nutrition, maternal toxin exposure, placentitis, and placental
neonates caloric requirement is as great as 150 kilocalories per insufficiency all have the potential to profoundly influence
kg body weight per day (kcal/kg/day) but decreases gradually the development and maturation of fetal metabolism. Studies
to around 120 kcal/kg per day at 3 weeks of age and then to 80 investigating the role of a “restricted” uterine environment on
to 100 kcal/kg per day by 1 to 2 months of age.924,925 A more fetal development have demonstrated lifelong impairment of
recent study has suggested that actual energy requirements of growth and development in affected foals.929 Conversely, the
foals from 2 to 6 months of age may be 10% to 20% less than provision of a “luxurious” in utero environment can lead to
these values.926 Because these measurements are given in terms enhanced growth rates out to 3 years of age.929 The influence
of foal body weight, it is important to realize that as the energy of maternal diet is important, because a diet high in soluble
requirement per kilogram is decreasing the foal’s body weight carbohydrates fed to the mare in late gestation contributed
is increasing; thus, the total caloric requirement increases with to a decrease in insulin sensitivity of the foals at 160 days of
age. The initial energy source for the foal is mare’s milk, which age.930 It is clear that there is a potential for lifelong effects
has substantially greater lactose content than cow’s milk, with on metabolic function secondary to this “prenatal program-
lower milk fat content. On a dry matter basis, mare’s milk aver- ming” effect, potentially contributing to the development of
ages about 64%, 22%, and 13% sugar, protein, and fat, respec- metabolic disease later in life.931 This prenatal programming
tively, compared with 38%, 26%, and 30% sugar, protein, and may affect the neonatal foal’s ability to appropriately metabo-
fat, respectively, for cow’s milk. Mare’s milk therefore derives lize nutrients in the clinical setting, with foals from a com-
most of its energy content from carbohydrates, and an appro- promised placental environment potentially exhibiting insulin
priate endogenous production of insulin by the pancreatic β resistance and carbohydrate intolerance.
cells is required for the foal to metabolize and utilize these car- As previously discussed the late gestation rise in fetal cor-
bohydrates appropriately. tisol is critical in the final maturation of energy metabolism,
Maturation of pancreatic β-cell function occurs very late and many foals delivered prematurely fail to undergo this rise
in gestation in the fetal foal and is dependent on the normal in fetal cortisol concentration; therefore, they are unable to
rise in fetal circulating cortisol concentration, which occurs in respond normally to the changes in metabolism that occur
the final days of gestation.927 This preparturient cortisol rise is after birth. Hypoglycemia, complicated by decreased endog-
critical for many aspects of readying the foal for birth, both in enous energy reserves and the impairment of nursing caused
terms of endocrine function as well as respiratory and cardio- by concurrent weakness, depression, and/or difficulty stand-
vascular function. Following birth there is a gradual matura- ing, is a common problem in these foals. Following the suc-
tion of the endocrine response to ingested carbohydrates. It has cessful delivery of nutrients by the enteral or parenteral routes
these foals are likely to be intolerant of carbohydrates, which is gastrointestinal dysfunction, such as gastric reflux, bowel dis-
caused by impaired endogenous insulin production, and they tention, increased bowel wall thickness, and ileus, are unlikely
may suffer profound hyperglycemia. Foals suffering from sys- to tolerate enteral feeding. A conservative approach to enteral
temic inflammation, such as that associated with septicemia, feeding is also indicated for premature or immature foals in
may also exhibit hyperglycemia caused by insulin resistance which there may be incomplete development of the gastroin-
and carbohydrate intolerance. Management of these foals may testinal tract. Foals with perinatal asphyxia syndrome may be
require lipid-containing parenteral nutrition solutions and/or intolerant of enteral feeding caused by ileus and dysfunction
the administration of exogenous insulin to achieve adequate as a result of intestinal ischemic injury.
caloric input. Mare’s milk is the preferred substrate for enteral feeding. It
Attempting to determine the true caloric needs of the is highly digestible and obviously provides the correct balance
clinically ill foal is one of the greatest challenges in designing of nutrients for normal growth and development. Commercial
a nutritional strategy. Historically it was believed that criti- mare’s milk replacers can be used, but it should be recognized
cal illness created a “hypermetabolic” situation in which the that these products are bovine in origin and have lower digest-
patient had increased energy needs caused by increased tis- ibility compared with mare’s milk. This increases the risk of
sue energy consumption. The energy requirements of the sick intestinal dysfunction associated with enteral feeding. Semis-
foal do not appear to be as great as once was thought,932 how- kimmed (2% fat) cow’s milk to which 20 g/L dextrose (equiv-
ever, because there is a reduction in the overall metabolic rate alent to 40 mL of 50% dextrose solution per liter) has been
from a decrease in activity level in combination with a tempo- added can be used if mare’s milk or mare’s milk replacer is
rary reduction in growth rate. Indirect calorimetry testing of unavailable. Foals that are unable to nurse the mare may be fed
clinically ill neonatal foals has shown that their resting energy through a bottle, bowl, or nasogastric feeding tube. Many sick,
requirement is only 45 to 50 kcal/kg per day, which is one recumbent foals have a weak and/or uncoordinated suckle
third of the energy requirement for growing, active, normal reflex, and therefore, milk should be administered through a
foals.933,934 As these foals recover, their energy requirements feeding tube.
gradually increase to approximately 65 to 70 kcal/kg per day, Use of a small-bore, indwelling tube and feeding of small
which is similar to the energy requirements of age-matched volumes at frequent intervals (e.g., every 20 minutes) is pre-
control foals.934 ferred over repeated passage of a nasogastric tube at 1- to
When managing the critically ill neonatal foal it may be 2-hour intervals. Large-bolus feedings may overwhelm diges-
preferable to pursue a hypocaloric approach in which one tive capacity, and repeated passage of a stomach tube is an
endeavors to prevent the foal from entering a severely cata- unnecessary stress on the foal. Another advantage of small-
bolic state while accepting that all of the nutritional needs of bore indwelling tubes is that they do not interfere with volun-
the patient may not be met.935,936 This approach addresses the tary feed and water intake. Therefore the tube may be left in
fact that aggressive nutritional support can result in overfeed- place as the foal is transitioned to feeding from the mare. The
ing, the risks of which may easily outweigh the possible ben- feeding tube should be inserted with the foal in sternal recum-
efits of providing nutritional support. Excessive carbohydrate bency, and correct placement within the esophagus should
administration will lead to an increased generation of carbon be confirmed by radiography or endoscopy. The tube may be
dioxide and can worsen hypercapnia in foals with compro- fastened to the external nares by sutures. At each feeding, it
mised respiratory function. Excessive carbohydrate delivery is important to check that the tube is still in place and that
will also cause hyperglycemia, which is considered to be a there is no reflux. The foal should be in sternal recumbency or
proinflammatory stimulus and has been associated with wors- standing when it is fed. Milk should be administered by grav-
ening of outcome in human critical illness.937,938 Overfeeding ity flow followed by a small amount of clean water to flush the
of protein will result in increased protein catabolism and can tube. The tube should be capped between feedings to prevent
result in the potentiation and/or development of azotemia.938 aspiration of air. Feeding tubes should be replaced every 1 to 2
The excessive administration of lipids may result in hypertri- days to reduce risk of gastrointestinal tract infection.
glyceridemia.719 In contrast to the risks of overfeeding, there is A suggested initial rate of milk delivery is 2 to 3 mL/kg
little evidence in human patients that short-term (several days) body weight per hour, or 100 to 150 mL/h for a 50-kg foal
hypocaloric nutritional support results in worsened outcomes (Table 20.21). This will provide 2.4 to 3.6 L of milk to a 50-kg
compared with regimens designed to meet the patient’s meta- foal during the first 24 hours of enteral support. Dextrose-
bolic needs.935,936 There is some evidence to suggest that this containing fluids can be administered IV to provide addi-
approach, especially regarding the maintenance of appropriate tional calories during the transition to an adequate level of
control of blood glucose levels, is associated with decreased enteral feeding. The feeding rate can be gradually increased
rates of complications and improved outcomes.937 over the next 2 to 3 days (e.g., increase to 4–5 mL/kg/h on day
The first step in the development of a nutritional plan 1 and then to 6–8 mL/kg/h on day 3), which represents a total
involves selection of the route of nutrient delivery. Providing daily intake of 10% to 15% of body weight. Simultaneously,
nutritional support by the enteral route is generally preferred IV caloric support (dextrose) can be gradually withdrawn.
for two reasons. First, this is the most natural and physiologi- This feeding level will likely meet the resting energy require-
cally sound means of nutrient delivery. Second, the intestinal ments of hospitalized foals. Depending on the rate of clinical
mucosa is partially dependent on the products of digestion improvement and the length of hospitalization, it may be pos-
for energy and nutrients. A thorough evaluation of gastro- sible to increase the volume of feeding to 20% to 22% body
intestinal function is needed before the institution of enteral weight per day, which approximates the milk intake of healthy
nutritional support. This will include abdominal auscultation, neonatal foals. Clinical monitoring should include frequent
checking for gastric reflux, and possibly abdominal radio- assessments of gastrointestinal function, including gastric
graphs and ultrasonographic examination for the evaluation reflux, intestinal sounds, abdominal distention, and quantity
of bowel dimensions and motility. Foals with evidence of and quality of feces. Gastric reflux, bloating, colic, diarrhea,
TABLE 20.21 Feeding Recommendations for Neonatal and Growing Foals

Foal Age (Days) Energy Requirement Volume of Mare’s Milk or Milk Replacer Percentage of Body Weight Fed
0–1 50–150 kcal/kg/day 2–3 mL/kg/h 5–7%
2–3 100–150 kcal/kg/day 4–5 mL/kg/h 10–12%
4–7 150 kcal/kg/day 6–8 mL/kg/h 14–20%
8–30 120 kcal/kg/day 9–10 mL/kg/h 22%
30 to weaning 80–100 kcal/kg/day Gradually decreasing and replaced with solid feed —

or constipation can indicate intolerance to enteral feeding and Carbohydrate-containing solutions represent the simplest
the need for adjustments to the feeding program. This may means of providing IV caloric support to foals. A solution con-
involve a decrease in the volume or frequency of enteral feed- taining 5% dextrose can be used, and there are several options
ings. In some situations there may be concerns regarding the available including D5W, LRS with 5% dextrose, 0.45% saline
ability of the foal’s gastrointestinal tract to digest and absorb with 5% dextrose, Normosol-M with 5% dextrose (Hospira,
lactose, as in rotaviral infections during which production of Lake Forest, IL), and Plasma-Lyte 56 with 5% dextrose (Bax-
lactase by the enterocytes is likely impaired. In these situa- ter Healthcare Corp., Deerfield, IL). Fluids containing dex-
tions lactase enzyme can be added to the milk or milk replacer trose should not be used for initial fluid resuscitation because
before feeding at the rate of 9000 U (one tablet) per feeding. this will almost certainly result in the delivery of excessive
Additional volumes of enteral fluid may be required in foals amounts of dextrose to a foal with any degree of dehydration,
with diarrhea, and a simple balanced isotonic enteral solution resulting in profound hyperglycemia. Following initial fluid
can be formulated by adding 5.6 g of table salt (NaCl), 0.6 g resuscitation, solutions containing electrolytes as well as dex-
of Lite Salt (50% NaCl, 50% KCl), and 3.4 g of baking soda trose (0.45% saline with 5% dextrose, Normosol-M with 5%
(NaHCO3) per liter of water.939 dextrose, and Plasma-Lyte 56 with 5% dextrose) may be used
It is generally preferred to support foals via the enteral as the primary fluids for maintenance therapy in foals with
route,940,941 both because this is the most natural and physi- minimal ongoing fluid losses. D5W is not an ideal choice as
ologically desirable route and because the epithelial cells lining a maintenance solution because of the absence of electrolytes
the intestine are partially dependent on the products of diges- and is primarily useful in providing free water to patients suf-
tion for energy and nutrients. Unfortunately there are a variety fering from hyperosmolar conditions. The caloric content of a
of situations in which a foal may be unable to receive enteral 5% dextrose solution is 0.17 kcal/mL, so an infusion rate of 10
nutrition or is unable to tolerate the volume of enteral nutri- mL/kg per hour would be required to deliver approximately 40
tion required to support basal metabolism and growth. These kcal/kg per day (0.17 kcal/kg/h × 24 h/day = 41 kcal/kg/day).
range from the critically ill neonate with gastrointestinal com- This rate of infusion is over twice that considered to be a main-
plications to the suckling foal with severe enterocolitis. The tenance rate for a neonatal foal. In addition, care must always
rapid institution of parenteral nutrition can aid in preventing be taken when adjusting the infusion rates of 5% dextrose-
the development of protein/calorie malnutrition and substan- containing solutions in response to changes in the patient’s
tial energy deficits. The limitations of parenteral nutritional fluid status to ensure that excessive amounts of dextrose are
support are primarily caused by the expense of this therapy not infused, especially in premature or very sick foals that are
and the risk of secondary complications. These complications likely to be poorly tolerant of dextrose infusions.
may include hyperglycemia, hypertriglyceridemia, thrombo- Alternatively, a 50% dextrose solution can be delivered
phlebitis, and an increased risk of bloodstream infections. without further dilution using an infusion pump, as long as
The primary goal of parenteral nutrition, as with any type additional isotonic fluids are being administered concurrently
of nutritional support, is to ensure that the patient is sup- to provide dilution and avoid endothelial injury caused by
plied with adequate calories to support basal metabolism at a the hypertonic nature of this solution. Use of 50% dextrose
minimum and ideally to provide additional support to allow solution should be avoided if an infusion pump is not avail-
for ongoing growth. A reasonable initial goal for parenteral able because it is very easy to inadvertently administer an
nutrition administration in the foal is 30 to 40 kcal/kg per day. excessive amount of dextrose, leading to hyperglycemia. The
Although this level of caloric support does not fully meet the caloric content of 50% dextrose solution is 1.7 kcal/mL, so an
theoretic energy requirements of the healthy neonate, it comes infusion rate of 1 mL/kg per hour of this solution will deliver
close to meeting the resting energy requirement in hospital- approximately 40 kcal/kg per day (1.7 kcal/kg/h × 24 h/day =
ized foals.924,933 In this situation parenteral nutrition is used 41 kcal/kg/day). This low rate of infusion means that the pri-
purely as a temporary support to prevent the foal from enter- mary fluid needs of the patient can be met with a dextrose-
ing into a severely catabolic state, in which protein catabolism free isotonic electrolyte-containing fluid, the infusion rate of
would increase and use amino acids for energy produc- which can be altered in response to changes in patient fluid
tion.720,924,942 Failure to provide adequate nutritional support status without concerns related to the requirements of the
may also have a substantial negative influence on the immune nutritional plan. At the end of the first 24 hours of treatment
response.942-944 Short-term parenteral supplementation (less the fluid therapy plan and nutritional plan should be revisited
than 24 hours) may consist of IV carbohydrate solutions and to determine whether the patient can begin to rely on enteral
does not require the patient to receive a balanced nutritional fluid and nutritional intake or if continued parenteral therapy
source consisting of carbohydrates, amino acids, and lipids, is required. Because dextrose-containing fluids are a very
but if parenteral nutrition is expected to be administered for a incomplete nutritional source, they should not be used as the
longer period then a more complete formula should be used. primary nutritional source for more than 24 hours. Continued
parenteral nutritional support will require the formulation of TABLE 20.22 Formulation of Parenteral Nutrition Solutions
a more complete solution that provides amino acids and pos-
sibly lipids. Caloric Density Nonprotein
One important aspect of providing longer term (over 24 Formula Composition (kcal/mL) Calories/gN
hours) parenteral nutrition to foals is the inclusion of a pro- 1 1500 mL 50% 1.02 125
tein source. The metabolic response to injury and sepsis is to dextrose, 1500 mL
increase protein degradation in muscle tissue. This catabolic 8.5% amino acids
response can be reduced by supplying a source of nitrogen or 2 1500 mL 50% dex- 1.08 131
by increasing energy intake. The recommended ratio for non- trose, 500 mL 20%
protein calories to nitrogen is 100 to 200 nonprotein calories lipids, 2000 mL
per gram of nitrogen.945 The inclusion of lipids in the paren- 8.5% amino acids
teral nutrition formulation allows for the provision of a larger
number of calories per unit volume compared with solutions

containing only dextrose. Another advantage of lipid emul-
sions is that they are isotonic, so they moderate the hyperto- An electronic infusion pump should always be used when
nicity of the parenteral nutrition formulation and potentially administering parenteral nutrition solutions, because the rate
decrease the risk of thrombophlebitis. Unfortunately, formu- must be tightly controlled and adjustments to the infusion rate
lating parenteral nutrition solutions with lipids increases the must be made easily and accurately. Excessive rates of admin-
cost of the solution and may increase the risk of complica- istration can easily induce profound hyperglycemia, which has
tions.946 Hyperlipidemia can occur in association with lipid been shown in other species to be associated with severe com-
administration to foals but does not appear to result in adverse plications and increased risk of death.947 The solutions used
effects.719,946 Lipid emulsions are prone to contamination and for parenteral nutrition are all hypertonic and can cause injury
promote bacterial growth. Because of these risks the IV lines to the vascular endothelium, increasing the risk of thrombo-
through which lipid-containing solutions are administered phlebitis. For this reason it is recommended that parenteral
should be changed daily, substantially increasing client costs. nutrition solutions be administered through a 20-cm-long
In a recent report the use of lipid-containing parenteral nutri- polyurethane long-term catheter placed in the jugular vein,
tion solutions allowed for the provision of 40 to 92 kcal/kg per because this provides a “central” line in most foals. The use of a
day (mean = 63 kcal/kg/day) to foals, as opposed to only 25 to multiple-lumen catheter allows for one lumen to be dedicated
66 kcal/kg per day (mean = 41 kcal/kg/day) with a dextrose- to infusion of the parenteral nutrition solution, minimizing
based solution.719 the risks of contamination. Catheter management is extremely
There are two basic approaches to the formulation of important when foals are receiving parenteral nutrition, and
parenteral nutrition to foals. The first approach involves the the catheter site and vein should be monitored at least twice
exact determination of the anticipated metabolic needs of daily for heat, swelling, or exudation. Increased resistance to
the patient, followed by the development of a formulation fluid flow in the catheter may be an indication of thrombosis
that will meet all of these needs in a fairly precise manner, deeper within the vasculature and will often necessitate the
using a mixture of dextrose, amino acids, and lipids. This placement of a catheter in an alternative site, such as the oppo-
approach is fairly complex and is best performed using a site jugular vein, a cephalic vein, or a lateral thoracic vein.
computerized spreadsheet to aid in performing the various All components of parenteral nutrition solutions must
calculations. The second approach is more practical and con- be mixed in a sterile manner before administration. The bag
sists of using two basic parenteral nutrition formulas (Table containing the final parenteral nutrition composition should
20.22). One of these solutions is intended for short-term use be covered with a brown plastic bag during administration
and consists only of 50% dextrose and 8.5% amino acid solu- to protect it from light, which can degrade the amino acids
tions (Solution I). The second solution incorporates a lipid within the solution. The rate of infusion (in mL/h) is calcu-
energy source and is preferred for long-term administra- lated based on the desired kcal/kg per day to be administered.
tion or for administration to foals that are poorly tolerant of A reasonable initial goal is 40 to 60 kcal/kg per day. The initial
infused dextrose (Solution II). Solution I is formulated using infusion rate of parenteral nutrition solutions should be 25%
2000 mL of 50% dextrose (Dextrose 50%, Baxter Healthcare of the calculated final rate, and the rate should be gradually
Corp., Clintec Nutrition Division, Deerfield, IL) and 2000 increased every 1 to 3 hours following monitoring of the blood
mL of 8.5% amino acids (Travasol 8.5%, Baxter Healthcare glucose concentration to ensure that hyperglycemia (blood
Corp., Clintec Nutrition Division, Deerfield, IL), whereas glucose >150 mg/dL) is not present. If the patient tolerates
Solution II is formulated with 1500 mL of 50% dextrose, 500 parenteral nutrition well and maintains blood glucose con-
mL of 20% lipids (Intralipid 20%, Baxter Healthcare Corp., centrations at or near normal levels, then consideration can
Clintec Nutrition Division, Deerfield, IL), and 2000 mL of be given to increasing the parenteral nutrition administration
8.5% amino acids.719 The caloric density of these solutions is rate to a maximum of 50 to 60 kcal/kg per day.948 When par-
1.02 kcal/mL for Solution I and 1.08 kcal/mL for Solution II. enteral nutrition is to be discontinued it is recommended that
The ratio of nonprotein calories to nitrogen is 125 nonpro- the infusion rate gradually be reduced, decreasing the infusion
tein calories per gram of nitrogen (NPC/gN) for Solution I rate in 25% to 50% increments every 4 to 6 hours while gradu-
and 131 NPC/gN for Solution II. An easy-to-use, shelf-stable ally introducing enteral feeding. It is important that blood glu-
multichamber bag preparation identical to Solution I is man- cose monitoring is continued during this weaning process to
ufactured for human use, and it is cost-effective and practical detect or prevent the development of hypoglycemia.
for use in foals (Clinimix 4.25/25 sulfite-free [4.25% amino The foal must be frequently monitored, especially during
acid in 25% dextrose] injection, Baxter Healthcare Corp., the initial phase of parenteral nutrition therapy. This monitor-
Clintec Nutrition Division, Deerfield, IL). ing should include a general physical examination, with close
attention to neurologic status and respiratory function. Rectal changing the rate of insulin infusion. An initial insulin infu-
temperature should also be closely monitored because fever sion rate of 0.07 IU/kg per hour of regular insulin has been
is a common early manifestation of systemic infection. Blood reported to be well tolerated and may represent a reasonable
glucose concentrations should be frequently monitored, ini- starting point in foals intolerant of parenteral nutrition.720,951
tially on an hourly basis until the patient has stabilized with This dosage was derived from a retrospective study of foals
the appropriate rate of parenteral nutrition infusion, followed treated with parenteral nutrition, which reported initial
by monitoring every 3 to 6 hours for the first day of therapy. insulin doses ranging from 0.014 to 0.2 IU/kg per hour, with
The frequency of blood glucose monitoring is dependent on a mean of 0.065 IU/kg per hour.719 Interestingly, in that study
the stability of the patient and may need to be more frequent the final insulin dose ranges remained very similar, from
in the critically ill, but it may not need to be monitored beyond 0.015 to 0.2 IU/kg per hour, with a mean of 0.07 IU/kg per
every 12 hours in the stable patient. Monitoring of urine out- hour. Some advocate starting at lower dosages in foals, such
put and urine glucose concentration may aid in the detection as 0.01 IU/kg per hour.952 This conservative approach is very
of hyperglycemia. Although the actual renal threshold for safe, with less risk of hypoglycemia than the higher dosage
glucose is not well described in foals, glucosuria and diuresis rate, but may require a longer period of time before the dose
are typically seen when blood glucose levels exceed 180 mg/ is titrated to a high enough level to control hyperglycemia.
dL. Additional clinicopathologic monitoring should consist Even lower dosage rates of insulin have been reported, with
of daily complete blood counts and serum chemistry profiles a recent retrospective report describing insulin infusions at
in the critical case, whereas these can be performed every 48 dosages of 0.0016 to 0.018 IU/kg per hour.949
to 72 hours in more stable patients. Serum electrolytes should Therefore an initial insulin infusion rate of 0.01 to 0.07
be monitored at least twice daily. Particular attention should IU/kg per hour represents a reasonable starting point. When
be paid to serum potassium concentrations because they can “fine-tuning” insulin therapy it is best to avoid simultaneous
decrease rapidly, especially in foals receiving insulin therapy. alterations in both the insulin infusion rate and the paren-
Urine output should be monitored continuously, in combina- teral nutrition infusion rate, because this can lead to a “roller-
tion with intermittent monitoring of urine glucose concentra- coaster ride” in which the blood glucose concentration rises
tion, because of the risk of hyperglycemia-induced diuresis and falls wildly because of the delay in the body’s response to
and glucosuria. Ideally body weight should be assessed on a these changes720 (Box 20.6). Blood glucose monitoring should
daily basis to ensure that the foal is at least maintaining its be performed at least hourly for the first 2 to 3 hours after ini-
body weight while on parenteral nutrition. Foals receiving tiation of the insulin CRI, and if hyperglycemia (blood glucose
parenteral nutrition solutions containing lipids should be >150 mg/dL) is persistent beyond the first 2 hours of insulin
monitored for the development of hypertriglyceridemia.719,949 therapy, then the insulin infusion rate may be increased by
50%, followed by hourly blood glucose monitoring for a fur-
Insulin Therapy ther 2 to 3 hours. This procedure for increasing the insulin
The critically ill foal will often demonstrate carbohydrate infusion rate may be repeated if hyperglycemia persists. Con-
intolerance, and this can make it very difficult to achieve even versely, if hypoglycemia (blood glucose <60 mg/dL) is noted
a conservative rate of administration of IV nutrition. This situ- then a bolus of 0.25 to 0.5 mL/kg of 50% dextrose solution
ation can be addressed by the use of a lipid-containing paren- should be administered intravenously over 3 to 5 minutes. The
teral nutrition solution, but if this is ineffective then the only blood glucose level should then be reassessed every 30 min-
alternative is administration of exogenous insulin. The admin- utes for at least 90 minutes ensure that hypoglycemia does not
istration of insulin to the neonatal foal is not to be undertaken recur. If hypoglycemia does recur, then a second bolus of dex-
lightly because this therapy places additional demands on trose is administered and the insulin infusion rate is decreased
both the clinician and nursing staff to ensure that profound by 50%. Close monitoring will then be required for a further
hypoglycemia does not occur. Intermittent dosing of subcu- 60 to 90 minutes to ensure that hypoglycemia does not recur
taneous insulin may offer some advantages in terms of sim- and that hyperglycemia does not develop. Further changes
plicity of administration, expense, and moderation of effects, to the insulin infusion rate are not usually necessary once a
but this route of administration does not allow for changes steady state has been achieved in which the blood glucose level
in dosage over the short term. One recommended dosage for is stable and the desired rate of parenteral nutrition adminis-
subcutaneous insulin in foals is 0.1 to 0.5 IU of regular insu- tration has been achieved. Patient reassessment is indicated if
lin every 12 hours.950 A retrospective report of foal parenteral one finds that the foal has become even more insulin resis-
nutrition described subcutaneous insulin dosage rates 0.02 to tant (requiring additional insulin administration to avoid
0.1 IU/kg given every 6 to 24 hours.949 This approach is not hyperglycemia) as there may be an overall deterioration in
recommended because the risks of hypoglycemia and hyper- the patient’s condition accompanied by increasing systemic
glycemia are greater than with CRIs, and it can be much more inflammation. When insulin therapy is to be discontinued
challenging to achieve homeostasis in terms of blood glucose the insulin administration rate should be gradually titrated
concentrations when using intermittent bolus insulin therapy. downward in parallel with the parenteral nutrition rate, but
The use of CRI for the administration of insulin allows there can be a substantial lag between changes in the insulin
for a fairly rapid onset of action while providing a simple infusion rate and the patient’s response to this change. Some
and timely means of adjustment of the dosage. Because of the time should be allowed to account for this lag. It is critical that
gradual saturation of the cellular insulin receptors, the maxi- foals being weaned from insulin infusions receive some form
mal effect of CRI insulin is not typically seen until roughly of enteral nutrition during this time period. It may be wise to
90 minutes after initiation of the infusion. The response to wean them from parenteral nutrition and insulin over longer
the alteration of the rate of infusion occurs over a similar periods of time (24–36 hours) than would be required for a
time frame, so one should take care to avoid altering the rate foal receiving parenteral nutrition alone to prevent glucose
of infusion of parenteral nutrition solutions too soon after derangements.
BOX 20.6
Protocol for the Monitoring and Regulation of Insulin When Administered as a Continuous Rate Infusion to Foals
Initiate insulin infusion at 0.01-0.07 IU/kg/hr
Monitor blood glucose hourly
If hyperglycemia (blood glucose >150 If hypoglycemia (blood glucose <60 mg/

mg/dL) persists for 2 hours then dL) develops then administer a bolus of
increase insulin infusion rate by 50% 0.25-0.5 mL/kg of 50% dextrose
Monitor blood glucose every hour for Monitor blood glucose every 30 minutes
2-3 hours for 90 minutes
If hypoglycemia recurs then administer

In hyperglycemia (blood glucose >150 a bolus of 0.25-0.5 mL/kg of 50%
mg/dL) persists for 2 hours then dextrose and decrease insulin
increase insulin infusion rate by 50% infusion rate by 50%
Adapted from McKenzie HC 3rd, Geor RJ. Feeding management of sick neonatal foals. Vet Clin North Am Equine Pract. 2009;25:109-119, vii.
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C HA P T E R 20

Basic Life Support

Heart rate >50 bpm or >40

Cardiac arrest – pulseless electrical

Initiate chest compressions – 100/min

Establish venous access

Epinephrine 0.01 mg/kg every 3-5 min

Rhythm check every 2-3 minutes

Asystole Perfusing rhythm

Stop compressions and

Defibrillate 2 J/kg Success – Provide

Resume chest compressions

Bpm, beats per minute; EtCO2, end-tidal CO2.

MODS, multiple organ dysfunction syndrome; SIRS, systemic inflammatory

Other insults: Trauma, Hypoxia

Proinflammatory Proinflammatory cytokines

Endothelial activation and

Systemic hemostatic Refractory hypotension

and, subsequently, to establish neuroanatomic localization of

TABLE 20.6 Neuroanatomic Localization Based on Results of the Neurologic Examination

Avoidance, visual Cranial nerve II, thalamus, cerebral cortex Blindness

there is no definitive test for HIE, so diagnosis is typically Seizure Disorders

much of the damage occurring in the CNS in meningitis is Tetanus

TABLE 20.7 Drugs Used for the Control of Seizures in Foals

CRI, Continuous rate infusion; IV, intravenously; PO, orally.

TABLE 20.9 Normal Arterial Blood Gas Values for Foalsa

MDI, Metered dose inhaler; Neb, nebulization.

TABLE 20.14 Antimicrobial Dosages for Use in Foals

TABLE 20.15 Composition of Intravenous Fluid Solutions Commonly Administered to Foals

Y ANTIINFLAMMATORY AND The mostly highly COX-2–specific NSAIDs that have

TABLE 20.20 Dosages of Antiinflammatory and Analgesic Medications Used in Foals

TABLE 20.21 Feeding Recommendations for Neonatal and Growing Foals

number of calories per unit volume compared with solutions

Initiate insulin infusion at 0.01-0.07 IU/kg/hr

Monitor blood glucose hourly

If hyperglycemia (blood glucose >150 If hypoglycemia (blood glucose <60 mg/

If hypoglycemia recurs then administer

REFERENCES 13. Rossdale PD. Measurements of pulmonary ventilation in nor-

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REFERENCES 13. Rossdale PD. Measurements of pulmonary ventilation in nor-