472 PART X  •  INFECTIOUS DISORDERS

CHAPTER 91 
SEPSIS AND SEPTIC SHOCK
Elise Mittleman Boller, DVM, DACVECC  •  Cynthia M. Otto, DVM, PhD, DACVECC

Sepsis, severe sepsis, and septic shock are common causes of morbid-
KEY POINTS
ity and mortality: The incidence of severe sepsis in humans in the
• Sepsis is a clinical syndrome of systemic inflammation in United States is high, killing one in four patients or approximately
response to infection. Much of the morbidity and mortality
associated with sepsis is a result of the host’s inflammatory 215,000 people each year.1,2 The incidence of sepsis in veterinary
response. medicine is unknown, but the mortality rates appear to be similar,
• Alterations in the regulation of vasomotor tone, increased vascular ranging from 20% to 68%.3-8 The incidence of sepsis is increasing in
permeability, dysfunctional microcirculation, and coagulation human health care, likely because of advanced and invasive treat-
abnormalities are hallmarks of sepsis. ments, widespread use of antimicrobials, increased incidence of resis-
• Microcirculatory abnormalities are often present in the face of
tant infections, and an increasing number of elderly, debilitated, and
normal macrohemodynamics.
• Treatment should be directed at targeted resuscitation, early immunocompromised patients.9 Recognition, early and aggressive
administration of antimicrobials if bacterial sepsis is suspected, intervention, and intensive supportive care are key to the treatment
and controlling the source of infection. of sepsis and septic shock.
• Untreated sepsis can progress to septic shock, which is
characterized by hypotension, vascular leak, and microvascular
dysfunction. This macrocirculatory and microcirculatory DEFINITIONS AND CLINICAL MANIFESTATIONS
impairment leads to tissue and global oxygen debt, organ failure,
and possibly death. In 2001 the International Sepsis Definitions Conference produced
consensus guidelines for definitions and terminology for syndromes
 CHAPTER 91  •  Sepsis and Septic Shock 473

BOX 91-1  Definitions10,90 Table 91-2  Diagnostic Criteria for Sepsis in People
(Defined as Known or Suspected Infection and Some  
Bacteremia: The presence of live bacterial organisms in the of the Following)10
bloodstream.
Sepsis: The clinical syndrome caused by infection and the host’s Human Parameters
systemic inflammatory response to it; may be of bacterial (gram
positive or gram negative), viral, protozoal, or fungal origin. General Variables
Severe sepsis: Sepsis complicated by dysfunction of one or more Fever Core temperature >38.3° C
organs. Hypothermia Core temperature <36° C
Septic shock: Acute circulatory failure and persistent arterial Heart rate >90/min or >2 SD above the
hypotension (despite volume resuscitation) associated with normal value for age
sepsis. In people, hypotension is defined by a systolic arterial Tachypnea
pressure less than 90 mm Hg, a mean arterial pressure less than Altered mental status
60, or a reduction in systolic pressure of greater than 40 mm Hg Significant edema or positive >20 ml/kg over 24 hrs
from baseline despite adequate volume resuscitation, in the fluid balance
absence of other causes of hypotension.10 Hyperglycemia Plasma glucose >120 mg/dl in
Systemic inflammatory response syndrome (SIRS): The clinical the absence of diabetes
signs of systemic inflammation in response to infectious or
Inflammatory Variables
noninfectious insults (e.g., trauma, pancreatitis, burns,
Leukocytosis WBC count >12,000/µl
snakebites, neoplasia, and heat stroke).
Multiple organ dysfunction syndrome (MODS): Physiologic Leukopenia WBC count <4000/µl
derangements of the endothelial, cardiopulmonary, renal, Normal WBC count with Normal WBC count with >10%
>10% immature forms immature forms
nervous, endocrine, and gastrointestinal (GI) systems associated
with the progression of uncontrolled systemic inflammation and Plasma C-reactive protein >2 SD above the normal value
disseminated intravascular coagulation (DIC). Plasma procalcitonin >2 SD >2 SD above the normal value
above the normal value
Tissue Perfusion Variables
Hyperlactatemia (>1 mmol/L)
Decreased capillary refill or
Table 91-15  Systemic Inflammatory Response mottling
Syndrome Criteria for Dogs and Cats
Other Variables
Species Dogs Cats ScvO2 >70%
Cardiac index >3.5 L/min
Temperature <37.2/99, <37.8/100.4,
(Celsius/Fahrenheit) >39.2/102.5 >40/104 SD, Standard deviation; WBC, white blood cells.

Heart rate (beats/min) >140 <140, >225

Respiratory rate >30 >40
(breaths/min) Table 91-3  Diagnostic Criteria for Severe Sepsis in
People (Defined as Sepsis with Organ Dysfunction)10
WBC × 10 /µl
3
<6, >19 <5, >19
WBC, White blood cells. Organ Dysfunction Variables:
Arterial hypoxemia PaO2/FiO2 <300
Acute oliguria Urine output <0.5 ml/kg/hr or
associated with microbial infection and the subsequent host response 45 mmol/L for at least 2 hours
called systemic inflammatory response syndrome, or SIRS (Box 91-1 Creatinine >2 mg/dl
and Table 91-1; see Chapter 6).5,10 SIRS has been previously described Coagulation abnormalities INR >1.5 or aPTT >60 seconds
in veterinary patients.5 Studies in both human and veterinary medi- Thrombocytopenia Platelet count <100,000/µl
cine are seeking to identify reliable and specific biomarkers of inflam- Hyperbilirubinemia Plasma total bilirubin >2 mg/dl
or 35 mmol/L
mation that can be used to assess the host inflammatory response to
infection. Currently it is more feasible to use deviations in heart rate, aPTT, Activated partial thromboplastin time; INR, international normalized
respiratory rate, body temperature, and white blood cell count as ratio.
markers of systemic inflammation. These clinical parameters are
most valuable for screening sick patients for eligibility to participate
in clinical studies of sepsis. The SIRS criteria lack specificity (many tory failure (in people) is defined as a systolic blood pressure of less
nonseptic patients can fit the criteria) and rarely dictate interventions than 90 mm Hg, mean arterial pressure of less than 60 mm Hg, or a
but can help increase the index of suspicion for sepsis. In human reduction in systolic blood pressure greater than 40 mm Hg from
medicine, sepsis is defined as a documented or suspected infection baseline despite adequate volume.10 In veterinary patients there are
with one or more general or inflammatory variables that suggest the no studies to define critical blood pressures, but it is reasonable to
presence of SIRS (Table 91-2).10 Severe sepsis is defined as a docu- consider that similar blood pressure values are appropriate.11
mented or suspected infection and signs of organ dysfunction such Sepsis is a clinical syndrome characterized by a systemic inflam-
as those listed in Table 91-3.10 Multiple organ dysfunction syndrome matory response to a bacterial, viral, protozoal, or fungal infection.
(MODS) involves the physiologic derangements of the endothelial, Bacteremia, defined by the presence of live organisms in the blood-
cardiopulmonary, renal, nervous, endocrine, microcirculatory, and stream, may be variably present in septic patients. The syndrome of
gastrointestinal systems associated with progression of uncontrolled sepsis includes the continuum of severity from uncomplicated (SIRS
systemic inflammation and disseminated intravascular coagulation with an infection) to severe (where organ failure becomes a compo-
(DIC). Septic shock is defined as acute circulatory failure and persis- nent) to septic shock (the development of hypotension despite
tent arterial hypotension despite volume resuscitation. Acute circula- volume resuscitation). The prognosis for survival decreases with
474 PART X  •  INFECTIOUS DISORDERS

progression along this continuum and the associated progressive species, proteases, lysozymes, lactoferrin, cathepsins, and defensins.
systemic inflammation, organ dysfunction, and ultimately cardio­ Neutrophils produce relatively small amounts of TNF-α, IL-1, and
vascular collapse. Dysregulation of vasomotor tone, increased vascu- platelet-activating factor.
lar permeability, dysfunctional microcirculation, and coagulation A controlled inflammatory response is beneficial to the host.
abnormalities are hallmarks of sepsis. The clinical manifestations and Such a response is localized and represents a balance between activa-
course of disease in patients with sepsis ultimately depend on the tion of the inflammatory cascade and host CARS. An excessive
location of infection; virulence of the organism; size of inoculums; inflammatory response results from disproportionate activation of
host nutritional status, comorbidities, age, immune response, and the proinflammatory mediators or lack of regulatory counterparts.
organ function; and genetic host response, including coding for cyto- On the other extreme, “immune paralysis” results from excessive
kine genes, immune effector molecules, and receptors. After the 2001 antiinflammatory activity. Additionally there may be regional and
International Sepsis Definitions Conference, a concept called PIRO temporal differences in proinflammatory versus antiinflammatory
was adopted to stage sepsis and to describe clinical manifestations of activity.16
the infection and host response to it.10 In this model, PIRO is an
acronym for predisposition, insult or infection, response, and organ LOSS OF HOMEOSTATIC MECHANISMS
dysfunction. This conceptual and clinical framework attempts to IN SEPSIS
incorporate patient factors with the microbial insult in order to stage
the disease process and identify factors that may contribute to mor- Many of the pathophysiologic derangements and subsequent clinical
bidity and mortality. The PIRO approach may employ advanced signs in septic patients are related to derangements of normal
diagnostic techniques not yet available in veterinary medicine, but homeostatic mechanisms responsible for regulating vasomotor tone,
hopefully it can serve as a guideline until similar methods are avail- inflammation, coagulation, endothelial permeability, and microvas-
able and validated. cular perfusion.

PATHOGENESIS OF THE SEPTIC SYSTEMIC Loss of vasomotor tone

INFLAMMATORY RESPONSE In patients with severe sepsis and septic shock, loss of the normal
homeostatic balance between endogenous vasoconstrictors and vaso-
Microbial Factors dilators occurs, resulting in dysregulation of vasomotor tone. Over-
Sources for gram-negative sepsis commonly include the gastrointes- production of nitric oxide (NO) during sepsis is a major contributing
tinal (GI) and genitourinary systems. The gram-negative bacterial factor.17 NO is a powerful vascular smooth muscle relaxant that con-
cell wall contains a potent molecule, lipopolysaccharide (LPS). This tributes to the vasodilatory state of patients with septic shock, leading
pathogen-associated molecular pattern (PAMP) is recognized as one to clinical signs such as hyperemic mucous membranes, short capil-
of the most potent stimuli of the host immune response. Host rec- lary refill time, and tachycardia in dogs and in people.5,17-20 Cats do
ognition and reaction involves binding of LPS to lipopolysaccharide not typically display the hyperemic, hyperdynamic state.20-22 In
binding protein (LBP), followed by the LPS-LBP complex binding to response to stimulation with endotoxin, TNF-α, IL-1, or platelet
membrane-bound CD14 on macrophages.12,13 This binding activates activating factor (PAF), inducible nitric oxide synthase (iNOS) accu-
the macrophage and initiates signaling transduction via the Toll-like mulates and generates high levels of nitric oxide (NO), thereby con-
receptors to the nucleus to start transcription of inflammatory cyto- tributing to signs of vasodilatory shock.17,23 In one prospective,
kines,14 most notably tumor necrosis factor-α (TNF-α), interleukin observational study in dogs, the NO breakdown products nitrate/
(IL) 1, IL-6, IL-8, and interferon γ. In addition to proinflammatory nitrite in plasma were was significantly greater in septic dogs or in
mediators, the response also generates production of counterinflam- dogs with SIRS compared with healthy controls.24
matory mediators (IL-4, IL-10, IL-13, transforming growth factor β,
and glucocorticoids), also referred to as the compensatory antiin- Dysregulation of inflammation and coagulation
flammatory response syndrome, or CARS.13 Bacterial infection and host inflammatory cytokines upregulate
Common sources for gram-positive sepsis include skin, injured tissue factor (TF) levels; TF then combines with factor VIIa to initiate
soft tissue, and intravenous catheters.15 Activation of the inflamma- the coagulation cascade.25 The TF-fVIIa complex and its downstream
tory cascade by gram-positive bacteria occurs in response to cell wall products (i.e., thrombin) can also trigger the elaboration of inflam-
components (lipoteichoic acid, peptidoglycan, peptidoglycan stem matory cytokines and platelet activation.25 Normally, initiation of the
peptides) or bacterial DNA or via elaboration of soluble bacterial coagulant pathway causes a counterregulatory activation of fibrino-
exotoxins. Gram-positive bacterial exotoxins can act as “superanti- lytic and anticoagulant pathways to maintain hemostasis without
gens” and induce widespread activation of T cells, leading to uncon- excessive thrombosis. In septic patients, however, natural anticoagu-
trolled release of inflammatory cytokines such as interferon γ and lant and fibrinolytic processes (as well as other complex processes)
TNF-α.13 In both gram-negative and gram-positive sepsis, interac- are inhibited via downregulation of antithrombin, tissue factor
tion with these PAMPS largely drives the host response and clinical pathway inhibitor, and tissue plasminogen activator (tPA) and
manifestations of sepsis. increased plasminogen activator inhibitor (PAI-1).25 The protein C/S
pathway is also inhibited, leading to a reduction of the normal acti-
Host Response to Bacterial Infection vated protein C anticoagulant and antiinflammatory effects. Platelets
Activation of macrophages initiates the sepsis-induced systemic also play a major role in this procoagulant state. Platelets exacerbate
inflammatory response, and TNF-α production is a key factor in the expression of procoagulant products such as TF, factor Va, and VIIIa;
early phase of sepsis.2 LPS is the most potent stimulus for the release express the fibrinogen receptor; recruit additional platelets; and serve
of TNF-α, which acts as an early central regulator of interactions as part of the support structure of clots.26 The hemostatic balance in
among cytokines. Macrophage-derived cytokines, such as TNF-α, septic patients, therefore, favors the procoagulant and antifibrinolytic
activate other inflammatory cells (i.e., neutrophils, monocytes), and state initially. Progression over time to a hypocoagulable state
chemokines serve to attract other cells to the affected area. Neutro- depends on host protein synthesis, effectiveness of natural coagula-
phil responses to cytokine signaling can result in extensive host tissue tion inhibitors, virulence of the invading organism, and resolution
damage secondary to the release of products such as reactive oxygen of the inflammatory source.
 CHAPTER 91  •  Sepsis and Septic Shock 475
26,27
Hemostatic dysfunction has been reported in septic dogs. One edema on physical examination, dogs that had markedly elevated
study showed that septic dogs had significantly lower protein C levels VEGF levels were less likely to survive.37 Increased vascular perme-
and antithrombin (AT) activities and higher prothrombin time, ability causes efflux of water, proteins and solutes into the interstitial
partial thromboplastin time, d-dimer, and fibrin(ogen) degradation space, thereby causing an increased distance from the red blood cells
products than did controls.4 In a study of dogs with septic peritonitis, within the capillaries to the target cell mitochondria, and conse-
coagulation abnormalities, lower AT activity, lower protein C, higher quently impairment of oxygen transport and delivery to the mito-
fibrinogen, and less hypercoagulable thromboelastograms were asso- chondria.35 One can think of the endothelium itself as an “organ,”
ciated with poor outcomes.28 Dogs with naturally occurring parvo- subject to dysfunction and failure in sepsis, just as the heart, kidneys
viral enteritis had decreased AT activity and increased maximum and brain (and others) can become dysfunctional. There are likely
amplitude on the thromboelastogram, consistent with hypercoagu- regional and temporal differences in microcirculatory function and
lability (see Chapter 104).29 Commonly available laboratory testing dysfunction. Areas that are very dysfunctional contribute to arterio-
may elucidate these hematologic and hemostatic changes (see venous shunting as a result of functional and mechanical obstruc-
Table 91-2).18,26,30 tion; the associated tissue suffers from a hypoxic insult. The
dysfunctional endothelium has been proposed as the “motor” of
Endothelial, microcirculatory, MODS. New technology such as sidestream darkfield imaging
and mitochondrial abnormalities enables visualization and assessment of microcirculatory derange-
Alterations in the endothelium, increased vascular permeability, and ments during sepsis and in response to therapy.
microcirculatory derangements can be caused by many different and Even if the microcirculation is functional, mitochondrial changes
complicated mechanisms, including endothelial dysfunction,31 alter- still occur secondary to sepsis.35 Mitochondria themselves can
ations and damage to the endothelial glycocalyx layer,32 rheologic become dysfunctional in septic patients (termed cytopathic hypoxia),
changes to red blood cells,33 leukocyte activation, microthrombosis, which contributes further to heterogenous hypoxic tissue beds.33,38 In
and loss of vascular smooth muscle autoregulation.34 The overall addition to their critical role in oxidative phosphorylation, mito-
regulation of vascular permeability is complicated (see Chapter 11). chondria are also involved in apoptotic pathways and cell death.
The decreased functional capillary density, increased diffusional dis-
tance for oxygen, and heterogenous microvascular blood flow all lead EPIDEMIOLOGY
to alterations in tissue oxygen extraction and tissue hypoxia.35-37
Importantly, serious microcirculatory disturbances can occur despite Septic Foci, Diseases, and Pathogens Associated
normal macrohemodynamic variables (e.g., blood pressure); this dis- with Sepsis
connect between systemic hemodynamics and microcirculatory per- The available epidemiologic information describing the septic
fusion, also known as cryptic shock, is characteristic of both septic foci and common pathogens in small animals can be found in
human and canine patients.35,36 Table 91-4. Although there are numerous possible septic sources
One prospective observational study in critically ill dogs evalu- (see Table 91-4 and Chapters 23, 97 to 102, 117, 122, and 126),
ated vascular endothelial growth factor (VEGF) levels and edema septic peritonitis is a common cause of sepsis, particularly in dogs.
formation in critically ill dogs. VEGF is a hypoxia-responsive angio- Leakage of contents from the GI tract occurs secondary to GI neo-
genic factor that is also associated with increasing vascular permea- plasia, ingestion of foreign bodies (and subsequent perforation),
bility. Although VEGF levels were not correlated to presence of dehiscence of biopsy sites, enterotomies or resected intestine,

Table 91-4  Septic Foci in Cats and Dogs and Pathogens Involved4,19,21,22,40-45,89-92
Site Disease Examples Dogs (%) Cats (%) Pathogens
2,4,8 10
Peritoneal GI perforation 35%-36% 47% Coagulase-negative Staphylococcus spp,
cavity Enterococcus spp, B-hemolytic
Streptococcus spp, Escherichia coli,
Klebsiella spp, Enterobacter spp,
Pasteurella spp, Corynebacterium
spp4,40,42,43
Pulmonary Pneumonia 20%4,41 24% (pyothorax) + 14% B-hemolytic Streptococcus spp, E. coli,
parenchymal, (pneumonia)21 Bordetella bronchiseptica, Staphylococcus
pleural spp, E. coli, Klebsiella spp, Pseudomonas
spp, Enterococcus faecalis, Acinetobacter
spp, Pasteurella spp4,44
Gastrointestinal Enteritis, bacterial 4% 5%21 E. coli 21
translocation
Reproductive Pyometra 25%4,6 Group G Streptococcus spp, Enterococcus
Prostatitis spp, B-hemolytic Streptococcus spp,
E. coli, Klebsiella spp4
Urinary tract Pyelonephritis 4%-10%4 8%,22 7%21 B-hemolytic Streptococcus spp, E. coli,
Bacterial cystitis Acinetobacter spp, Enterococcus spp4,22
Soft tissue, Trauma, osteomyelitis, 29% 16%,22 3% (osteomyelitis) + 3% E. coli, Enterobacter spp4
bone bite wounds (bite wounds21; 3%-50%6,21,22
Cardiovascular Endocarditis 14%21 Staphylococcus lugdunensis, Bartonella spp,
S. aureus, E. faecalis, Granulicatella spp,
Streptococcus spp, Brucella spp45
476 PART X  •  INFECTIOUS DISORDERS

nonsteroidal antiinflammatory drug (NSAID)–associated ulcers, cultures are positive in 30% to 50% of patients with severe sepsis or
perforation of megacolon, and severe colitis. Other reported causes septic shock.1,48 In veterinary medicine, blood cultures may be less
of septic peritonitis include contamination from the urinary bladder, routinely performed. In one study, however, 49% of critically ill dogs
gallbladder, or uterine rupture; GI disease such as salmonellosis or and cats had positive blood cultures.64 Another study reported that
parvoviral enteritis; and hepatic, pancreatic, splenic, and mesenteric 43% of dogs with gastric dilation and volvulus developed positive
lymph node abscess formation.6,22,40 Aside from septic peritonitis, blood cultures. The importance of obtaining samples for culture to
other less common causes of sepsis include pyelonephritis, pneumo- aid in selection (and deescalation) of antimicrobials cannot be over-
nia, septic arthritis, deep pyoderma, bacterial endocarditis, tick- emphasized; however, obtaining the samples should not cause a delay
borne diseases, vasculitis, septic meningitis, pyothorax, trauma, bite in initiating resuscitation nor put the patient at risk.
wounds, osteomyelitis, septic prostatitis, and immune suppression.*
Gram-negative enteric bacteria are the most commonly impli- Bundle Element: Early Source Control
cated organisms in sepsis in dogs and cats; however, mixed infections and Early Antibiotic Administration
and gram-positive infections are also described.4,22,40,42-45 Culture of (see Chapters 175 to 182)
infected tissue should be obtained whenever possible (i.e., safe for Of paramount importance in treating the septic patient is the iden-
the patient) because early and appropriate antimicrobial selection is tification and removal of the septic focus (“source control”) and early
essential for preventing bacterial replication and reducing the host administration of antimicrobials. In human patients with septic
inflammatory response to infection. Knowledge of common isolates shock, elapsed time from shock recognition and qualification for
and the hospital antibiogram may help guide empiric antimicrobial early goal-directed therapy to appropriate antimicrobial therapy is a
selection (see Chapter 175). primary determinant of mortality; there is no reason to think that
the same is not true in veterinary patients.65-67 Early antimicrobial
RESUSCITATION AND TREATMENT OF SEPSIS, therapy is now conceptually “bundled” with more traditional aspects
SEVERE SEPSIS, AND SEPTIC SHOCK of sepsis resuscitation such as hemodynamic stabilization.68 Empiric
selection of appropriate antimicrobials can be challenging and
Introduction to the Bundle Concept should consider the location of the infection (and the ability of the
Major improvements in outcome in septic human patients have been antibiotic to penetrate the site), the suspected bacterial flora, com-
accomplished through use of sepsis treatment “bundles.” A bundle of munity versus nosocomial source, duration of hospitalization, and
care refers to a group of therapies that, when instituted together, previous exposure to antimicrobials (see Chapter 175). Bactericidal
result in better outcomes than if each individual component were to rather than bacteriostatic antimicrobials are preferred. In both vet-
be implemented alone.46 For sepsis, evidence-based guidelines for erinary and human studies, administration of inappropriate antimi-
sepsis management are published in the Surviving Sepsis campaign crobials is associated with increased mortality.6,67 In patients who
international guidelines. Hospitals47 that have implemented the have been hospitalized for some time, the chances of infection with
guidelines report decreased mortality rates.48-50 Bundle recommenda- multidrug-resistant bacteria increase, so careful consideration of
tions and the current guidelines were born out of earlier landmark hospital antibiograms should be employed when choosing empiric
studies in early goal-directed resuscitation.51 Although there is still antimicrobials therapy.69 In some patients, sample collection may be
controversy regarding the best individual bundle components, impossible because of cardiopulmonary instability or coagulopathy;
numerous studies have since shown that implementation of a sepsis however, the inability to gather samples for culture and susceptibility
bundle reduces mortality.52 Enthusiasm remains for the bundle testing should never cause a delay in the administration of antimi-
approach (even in veterinary medicine), and it stands to reason that crobials to patients with sepsis, severe sepsis, or septic shock. Septic
the same approach may improve outcomes in veterinary patients.† patients require a broad-spectrum bactericidal antimicrobial regimen
that is administered via the intravenous route (see Chapters 175 and
Bundle Element: Lactate 182). Following are some examples of four-quadrant therapy (i.e.,
Lactate production is a result of anaerobic metabolism, most com- therapies that are effective against gram-positive and gram-negative
monly as a result of hypoperfusion. High initial lactate levels are aerobes and anaerobes). All dosages are listed for the intravenous
associated with poorer outcomes, particularly if the hyperlactatemia route, except when indicated otherwise:
persists and if accompanied by hypotension.55-62 However, lactate • Ampicillin (22 mg/kg q8h) and enrofloxacin (10 to 20 mg/kg
clearance as it relates to traditional (e.g., blood pressure) and more q24h; 5 mg/kg q24h in cats)
recent (e.g., ScvO2) parameters remain unclear. Lactate kinetics in the • Ampicillin (22 mg/kg q8h) and amikacin (15 mg/kg q24h [dog],
individual patient probably depends on the phase of sepsis; lactate 10 mg/kg q24h [cat])
together with ScvO2 may provide complementary information about • Ampicillin (22 mg/kg q8h) and gentamicin (10 mg/kg q24h [dog],
the efficacy of resuscitation (see Chapter 183).58,63 The Surviving 6 mg/kg q24h [cat])
Sepsis campaign guidelines recommend measuring lactate within the • Cefazolin (22 mg/kg q8h) and amikacin (15 mg/kg q24h [dog],
first 6 hours of admission and promptly initiating fluid resuscitation 10 mg/kg q24h [cat])
for patients with lactate concentrations 4 mmol/L or greater.38 The • Cefazolin (22 mg/kg q8h) and gentamicin (10 mg/kg q24h [dog],
available veterinary literature supports this recommendation (see 6 mg/kg q24h [cat])
Chapter 56).36,53,55 • Ampicillin (22 mg/kg q8h) and cefoxitin (15 to 30 mg/kg q4-6h)

Bundle Element: Samples for Culture

• Ampicillin (22 mg/kg q8h) and cefotaxime (25 to 50 mg/kg q4-6h)

(Blood, Tissue, or Fluid Cultures)

• Ampicillin (22 mg/kg q8h) and ceftazidime (30 to 50 mg/kg
q6-8h)
In human health care, obtaining blood cultures in patients with • Clindamycin (8 to 10 mg/kg q8-12h) and enrofloxacin (5 to
sepsis or suspected sepsis is very much the standard of care and blood 20 mg/kg q24h; 5 mg/kg q24h in cats)
• Clindamycin (8 to 10 mg/kg q8-12h) and amikacin (15 mg/kg
q24h [dog], 10 mg/kg q24h [cat])
*References 4, 6, 21, 22, 29, 41. • Clindamycin (8 to 10 mg/kg q8-12h) and gentamicin (10 mg/kg
†
References 18, 36, 48, 50, 53, 54. q24h [dog], 6 mg/kg q24h [cat])
 CHAPTER 91  •  Sepsis and Septic Shock 477

Table 91-5  Circulatory Support in Severe Sepsis and Septic Shock20

Fluid Therapy Indications Dose Comments

Isotonic crystalloids Intravascular volume replacement Dog: Up to 60 to 90 ml/kg* May precipitate interstitial edema
Interstitial fluid deficits Cat: Up to 40 to 60 ml/kg* in patients with capillary leak or
Maintenance a low colloid osmotic pressure
Synthetic colloids (e.g., Volume replacement Dog: 5 to 20 ml/kg* Dose-related coagulopathies and
hydroxyethyl starch) Colloid osmotic support Cat: 5 to 10 ml/kg* acute kidney injury (humans)
have been documented
An arbitrary recommendation is
≤20 ml/kg q24h
Human albumin Colloid osmotic pressure support 2 ml/kg/hr of 25% HSA for 1 to Doses extrapolated from human
solution (HSA) Volume replacement 2 hours followed by 0.1 to literature
Albumin supplementation 0.2 ml/kg/hr × 10 hours Monitor closely for reactions
Or, calculate albumin deficit: Alb
deficit (in grams) = 10 × (desired
Alb – patient Alb) × wt (kg) × 0.3
and replace over 4 to 6 hours
Fresh frozen plasma Coagulopathies 10 to 15 ml/kg as needed Not effective at increasing
Factor deficiencies albumin concentration
Supplemental volume and colloid
osmotic support
Packed red blood cells Anemia 10 to 15 ml/kg will raise PCV by —
~10%
Fresh whole blood Anemia 20 ml/kg will raise PCV by ~10% —
Thrombocytopenia
Coagulopathies and factor
deficiencies
Volume
replacement
Alb, Albumin; HSA, human albumin serum; PCV, packed cell volume.
*Listed intravenous fluid doses are “shock doses.” Generally, a fraction of the listed dose is given (e.g., one fourth to one half) and response is assessed; the
dose is repeated as necessary or until fluid tolerance is reached. Cats seem to have a poor pulmonary tolerance to volume resuscitation; therefore smaller
doses may be tried first.

• Ticarcillin and clavulanic acid (50 mg/kg q6h) and enrofloxacin resistance can induce an increase in urinary output in the presence
(10 to 20 mg/kg q24h; 5 mg/kg q24h in cats) of renal hypoperfusion.
• Imipenem (5 to 10 mg/kg q6-8h) Fluid choice
• Meropenem (24 mg/kg q24h or 12 mg/kg SC q8-12h)
• Chloramphenicol (25 to 50 mg/kg q8h; 12.5 to 20 mg/kg q12h The first line of resuscitation in septic patients is fluid therapy. Iso-
in cats) tonic crystalloids, hypertonic crystalloid solutions, synthetic colloids,
and blood component therapy may be used for fluid therapy in the
Bundle Element: Treat Hypotension with Fluids septic patient (Table 91-5). The choice of fluids depends on the
and Possibly Vasopressors overall clinical and clinicopathologic picture (see Chapters 58 and
Assessment of volume status and responsiveness 60). Recent studies in human septic patients have called into question
Because septic shock patients are, by definition, in circulatory col- the safety of synthetic colloids, specifically hydroxyethyl starches,
lapse despite volume resuscitation, cardiovascular support is of key which now have a black box warning for this population of human
importance. Fluid therapy is essential to maintain adequate tissue patients.72,73 Synthetic colloids have been a staple of fluid resuscita-
oxygen delivery and to prevent the development of MODS and death tion in veterinary medicine; however, human studies have shown that
(see Chapter 60). Assessment of volume status and the potential for resuscitation with these fluids in people is associated with an
volume responsiveness can be difficult. Traditionally, static measures increased incidence of acute kidney injury and need for renal replace-
to indirectly measure preload, such as pulmonary artery occlusion ment therapy and, in the case of the Perner et al study, an increased
pressure (PAOP) and central venous pressure (CVP), have been used. risk of death at day 90. The results of other studies regarding the
However, they can be cumbersome (PAOP) and not predictive of safety of synthetic colloids were mixed, and no safety studies to date
volume responsiveness (CVP).70 Dynamic measures of fluid respon- are available in veterinary patients.74-76 The current recommendation
siveness may include echocardiographic evaluation of cardiac func- in human critical care is to avoid synthetic colloids in septic patients,
tion and arterial waveform variation in ventilated patients. More especially when other fluid therapy options such as albumin, plasma,
simple yet still dynamic measures may include administering serial or crystalloids are available, or until more rigorous data on the safety
small fluid boluses or (in people) passive leg elevation and evaluation of synthetic colloids are published.52
of the hemodynamic response.52,71 Accurate monitoring of body Patients with severe sepsis and septic shock are very often hypo-
weight and urine output via an indwelling urinary catheter is also albuminemic.77,78 Unfortunately, large volumes of fresh frozen plasma
helpful in assessing total fluid balance as well as monitoring for oli- are required for albumin replacement (i.e., 22 ml/kg of plasma to
goanuric renal failure. It should be noted, however, that urinary raise the albumin concentration by 0.5 g/dl).78 Fresh frozen plasma
output is a result of the balance between preglomerular and postglo- is therefore generally only used to prevent a further decline in
merular resistance. Thus a marked increase in postglomerular albumin in severely hypoalbuminemic patients and for correction of
478 PART X  •  INFECTIOUS DISORDERS

to 3%, in part because of the high metabolic rate of the brain and
Table 91-6  Commonly Used Constant Rate Infusion cranial half of the body and also because of the contribution of
Vasopressor Therapy vascular circuits that use blood for nonoxidative phosphorylation
Vasopressor Dose rate needs in the caudal half of the body (e.g., the renal blood flow).84 In
shock states the relationship between central and mixed saturation
Norepinephrine 0.1-2 mcg/kg/min IV can reverse; ScvO2 can be much higher than SvO2; this likely is
Vasopressin 0.5-5 mU/kg/min IV due to redistribution of blood flow from the splanchnic circulation
to the coronary and cerebral vascular beds.85-87 Consensus and the
Dopamine 5-15 mcg/kg/min IV
international guidelines state that measuring ScvO2 in lieu of SvO2
(because it technically easier) can be used successfully during sepsis
coagulopathies and factor deficiencies. Human serum albumin (5% resuscitation.48
or 25%) is still in the early stages of clinical use in veterinary medi- In health much more oxygen is delivered than is extracted;
cine and research is ongoing. The 25% human serum albumin solu- however, when delivery decreases to a critical threshold, extraction
tion is hyperoncotic (colloid osmotic pressure = 100 mm Hg) and decreases in concert and the patient experiences oxygen debt and
should be used judiciously in patients with limited fluid tolerance lactic acidosis. Monitoring venous oxygen saturation and using it as
(see Chapter 58 for further details). Although it does seem effective a therapeutic target is a recommendation in the Surviving Sepsis
in raising albumin concentration, questions regarding its safety guidelines.48 The few veterinary studies that have evaluated ScvO2 as
exist.79-81 Coagulopathies, anemia, and thrombocytopenia may a therapeutic goal suggest its potential value in resuscitating septic
prompt the use of blood component therapy (e.g., fresh frozen and critically ill veterinary patients.53,88 In both studies, ScvO2 was
plasma, packed red blood cells, fresh whole blood, respectively). associated with prognosis.53,88 These veterinary studies mirror a large
body of work in human medicine that resulted in a recommendation
Hypotension despite volume resuscitation in the Surviving Sepsis campaign to resuscitate to an ScvO2 of 70%
(septic shock) or greater or an SvO2 65% or greater.48
Hypotension that persists after restoration of intravascular volume is
an indication for vasopressors or inotropic agents to support flow to CONCLUSION
tissues (see Chapters 8, 157, and 158). The decision to use a vasopres-
sor or cardiotonic drug depends on the clinical presentation and Sepsis is an important and very common problem in both veterinary
objective information obtained from the septic patient (e.g., assess- and human health care. Hallmark pathophysiologic changes include
ment of cardiac contractility). Vasopressors such as norepinephrine, widespread endothelial disruption, microcirculatory failure, progres-
vasopressin, dopamine, and phenylephrine are most commonly used sive inflammation or immune paralysis, and activation of the coagu-
in patients with peripheral vasodilation (Table 91-6). Norepineph- lation cascade. Throughout the progression from sepsis to septic
rine is preferred to dopamine in septic human patients, and vasopres- shock, there is extensive interplay between the coagulation and
sin is also considered a reasonable first-line vasopressor.52,82,83 Studies immune systems. Ultimately, circulatory collapse (both macro- and
in septic veterinary patients are ongoing. Although vasopressors may micro-) leads to hypoperfusion, tissue ischemia, organ failure,
maintain arterial blood pressure, they can also result in excessive and death. Treatment of septic patients critically depends on early
vasoconstriction, particularly to the splanchnic and renal circulation, recognition, early antimicrobial therapy, and aggressive hemody-
thereby causing GI and renal ischemia. Particularly in the dog, namic support. Bundled care appears to be very effective in human
splanchnic vasoconstriction may exacerbate the septic state by pro- septic patients, and studies in veterinary medicine are starting to
moting loss of gut barrier function and bacterial translocation of suggest the same.
bacteria to the bloodstream.
Positive inotropic agents such as dobutamine are generally used
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