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com MEDICAL
PROGRESS
Hypoxic-Ischemic Encephalopathy and Therapeutic Hypothermia:
The Hemodynamic Perspective
Regan E. Giesinger, MD, FRCPC1,2, Liane J. Bailey, BScH3, Poorva Deshpande, MBBS, MRCPCH1,2, and
Patrick J. McNamara, MB, BCh, BAO, DCH, MSc, MRCP, MRCPCH1,2,4

H
ypoxic-ischemic encephalopathy (HIE) is a severe to intervention may decrease the effectiveness of neuroprotective
central nervous system injury in neonates secondary strategies by compromising vital organ perfusion and
to perinatal asphyxia. It may cause devastating life- metabolism.
long neurocognitive impairments including cerebral palsy. The
introduction of therapeutic hypothermia (TH) as standard
therapy for neonates >36 weeks gestational age with HIE has Biophysiologic Effects of Asphyxia
improved patient outcomes and is supported by evidence from
both animal studies and large-scale clinical trials in humans. Direct Cardiovascular Effects of Asphyxia
TH has been shown to produce clinically important improve- The cardiovascular consequences of a hypoxic-ischemic insult
ments in both neonatal mortality (number needed to treat = 11) are broad and complex. Both the primary insult and ongoing
and neurodevelopmental impairment in survivors (number central nervous system redistribution of blood flow lead to
needed to treat = 8) in patients with moderate or severe reduced myocardial perfusion and resultant papillary muscle
encephalopathy.1 Although this intervention is the standard and subendocardial tissue ischemia.4 The neonatal heart is
of care in many institutions, the rates of death or uniquely vulnerable to ischemic injury because of relative im-
neurodevelopmental impairment are approximately 45%- maturity of transverse tubular architecture and lack of devel-
55% despite optimal application of TH1; reasons for this opment of the excitation-contraction coupling of the
disparity remain elusive. The relative contribution of hemo- cardiomyocyte.5 In addition, hypoxia upregulates a variety of
dynamic instability or treatment for it to the injurious process molecular pathways that lead to decreased myocardial
remains poorly understood; most clinicians “feel” a compul- contractility.6 Transient myocardial ischemia, which may or may
sion to treat presumed low blood pressure or low cardiac output not be symptomatic, occurs in one-third of asphyxiated neo-
based on traditional viewpoints. Multiorgan dysfunction is nates and represents one of the most common causes of peri-
common2 and cardiovascular dysfunction, defined as either evi- natal myocardial infarction.7-9 Birth asphyxia or associated
dence of transient myocardial ischemia or hypotension re- conditions, such as meconium aspiration syndrome, may limit
quiring an inotrope >24 hours, is noted in 62% of neonates the normal decline in pulmonary vascular resistance after birth
with a diagnosis of HIE.2 leading to acute pulmonary hypertension. The clinical and
The reported incidence of hemodynamic instability in pub- physiological consequences include low pulmonary blood flow
lished clinical trials ranges from 33% to 77% in patients re- and/or right heart dysfunction because of high right ventricu-
ceiving TH and from 25% to 83% in controls3 (Table I; available lar afterload leading to systemic hypotension/low cardiac output
at www.jpeds.com). Though there has been no consistent link state. TH further induces pulmonary vasoconstriction,10 which
between the degree of hemodynamic instability and may aggravate acute pulmonary hypertension necessitating an
neurodevelopmental outcome, the physiology is often complex, escalation of treatment; the impact of such deterioration and
which presents a window of opportunity to individualize treatments for it on brain injury remain unknown.
therapy with a goal of improving outcomes.
The current therapeutic approach to hemodynamic care Interaction between the Cardiovascular System
focuses on improving arbitrary mean arterial pressure thresh- and Central Nervous System Injury
olds and fails to consider the severity of the asphyxial injury, Hypoxic-ischemic injury represents a complex biological dis-
the complexity of the hemodynamic derangement, or the turbance, which may lead to secondary energy failure and cell
impact of both TH and rewarming. In this review, we ap- death by both necrosis and/or apoptosis (Figure 1).6,7,11 Whether
praise the clinical and physiological impact of HIE and TH on there is a direct link between cerebral ischemia and cardiac dys-
neonatal hemodynamics and myocardial performance. It is function in HIE is not yet clear. Stroke victims are known to
plausible that ongoing hemodynamic instability, related either
to the primary insult or the effects of TH, and the approach
From the 1Division of Neonatology, The Hospital for Sick Children, Toronto, Ontario,
Canada; 2Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada;
3
Institute of Medical Science; and 4Department of Physiology, University of Toronto,
HIE Hypoxic-ischemic encephalopathy Toronto, Ontario, Canada
iNO Inhaled nitric oxide The authors declare no conflicts of interest.
MRI Magnetic resonance imaging
TH Therapeutic hypothermia 0022-3476/$ - see front matter. © 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org10.1016/j.jpeds.2016.09.009

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Figure 1. Theoretical model of concurrent circulatory and neuronal changes after a hypoxic ischemic injury.11-15 Cells may enter
the latent phase at different times because both primary and secondary energy failure may coexist. CBF, cerebral blood flow.

experience electrocardiographic abnormalities and cardiovas- of the latent period varies, and hemodynamic instability after
cular disturbances, similar to HIE, which may lead to death.12 the initial insult may contribute to ongoing injury beyond the
In a rat model, cerebral ischemia directly causes myocardial 6- hour therapeutic window (Figure 1). The duration of po-
dysfunction by disrupting calcium homeostasis.16 This pro- tential exposure to ongoing injury likely relates to the nature
vides biological plausibility for a comparable association in and severity of the initial insult, and the aggressiveness of re-
human neonates. suscitation; therefore, injury may occur over a period of minutes
to hours. Early recognition of low systemic blood flow may
Effects of Asphyxia on Cerebral Blood Flow play a role; however, it is unclear whether cardiovascular therapy
Asphyxia is associated with a variable degree of vasomotor pa- itself may impact the brain’s ability to autoregulate as has been
ralysis, which if moderate or severe, may be associated with suggested in some preterm studies. The relative contribution
impaired autoregulation. This is supported by evidence that of reperfusion to the injurious process is likely to relate to the
hypoperfusion is followed by hyperperfusion over a predict- specific agent used, dosage used, and route of administra-
able time course. The magnitude of this elevation in cerebral tion; rapid augmentation of inotropic agents or potent vaso-
blood flow is associated with the risk of neurocognitive pressors may cause dramatic reperfusion over a period of
impairment17; specifically, the most severely affected infants minutes to hours.24 Current guidelines for initiation of TH are
develop high cerebral blood flow by 12-24 hours of age.18 It based on evidence from animal experimental models where
remains unclear, however, whether this association is a mani- the insult was timed, and on both human and animal studies
festation of the severity of the underlying insult or whether where central nervous system damage occurs during the sec-
reperfusion injury contributes to worse outcome. ondary energy failure stage after a 6- to 15-hour latent period.
The initial injury varies in severity, duration, and timing and It is unclear whether there are groups of neonates who may
has been classically grouped into discrete categories (Table II; benefit from modification of established guidelines for TH or
available at www.jpeds.com)19,20; in reality, neonates with HIE, if tighter control of hemodynamics and cerebral blood flow
particularly the moderate group, represent a heterogeneous may contribute to improved outcomes.
group with variable and overlapping clinical and radiologic
phenotypes.21 At a cellular level in fetal sheep, partial pro- Cardiovascular Impact of TH
longed asphyxia produces cortical hyperexcitability and sen- Though the mechanisms of hypothermic neuroprotection are
sitization to neuronal injury, implying an escalating risk of acute fairly well understood,13,14,25 the effects of TH on other organ
or chronic injury.22 It is biologically plausible that unregu- systems are relatively unknown. Human and animal models
lated changes in cerebral blood flow may have a role in suggest a cardioprotective effect similar to its effect in the central
modulating the severity of injury following the initial insult. nervous system; troponin I levels are reduced in newborn piglets
In near-term fetal sheep, cooling initiated after the start of the and human neonates when TH is used.26 Liu et al26 found that
secondary energy failure stage is not effective.23 In clinical prac- immediate initiation of TH resulted in a 50% reduction in
tice, the exact timing of injury is rarely known, the duration ischemic heart lesions compared with normothermic piglet
2 Giesinger et al

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Figure 2. Interrelationship between contributors to ischemic injury resulting from initial insult, TH, and reperfusion injury on
rewarming.2,28,30,32-34 Both ischemia and reperfusion injury may contribute to the degree of brain injury via modification of car-
diovascular factors. Resumption of cellular activity after transient suppression is a putative source of potentially damaging oxi-
dative radicals.25 HR, heart rate; LV, left ventricle; PBF, pulmonary blood flow; PVR, pulmonary vascular resistance; RV, right
ventricle.

controls. Sinus bradycardia, however, is a well-established as- nates with a more severe or prolonged hypoxia are at greater
sociation of TH. It occurs because of slowed diastolic repo- risk of impaired transition eventually leading to persistent pul-
larization in the sino-atrial node and diminished influence of monary hypertension of the newborn. Specifically, reduced pul-
the sympathetic autonomic nervous system on heart rate.5 In monary blood flow leads to lower preductal cardiac output
controlled hypothermia for out-of-hospital patients with cardiac which, combined with systemic hypoxemia, may further
arrest, resting bradycardia is associated with a significant re- magnify the ischemic insult.31 On the other hand, the use of
duction in mortality and improved neurologic outcome.27 The rapidly acting pulmonary vasodilators, such as inhaled nitric
mechanism behind this association is unclear, likely multifac- oxide (iNO), leads to increased pulmonary venous return and
torial, and may reflect both cause and effect. Relative brady- augmentation of preductal cardiac output, which may con-
cardia may result in an overall reduction in myocardial substrate tribute to reperfusion injury (Figure 2). During rewarming,
requirement and, therefore, may be protective against ongoing these changes are likely to be further amplified. Concurrent
ischemic stress, whereas the use of chronotropic cardiovascu- exposure to high concentrations of oxygen35 and exogenous
lar treatments may increase metabolic requirements and the nitric oxide36 promotes the production of reactive oxygen
risk of cell death. Alternatively, normal heart rate despite low species, which may cause further injury to the brain.
temperature may reflect subclinical systemic hypoperfusion and The impact of abnormal hemodynamics on cerebral blood
may contribute to ongoing brain injury (Figure 1). The re- flow is relevant to short-term clinical outcomes. In 24 neo-
duction in heart rate after initiation of TH leads to a 60%- nates, normal brain MRI was associated with lower cerebral
70% decrease in left ventricular output compared with blood flow, which further declined in those undergoing TH
normothermic controls.28 These changes are generally well tol- compared with neonates with poor radiologic outcome who
erated, and although cardiac output is lower, it is likely to meet had a higher baseline and progressive rise in cerebral blood
the metabolic needs of the asphyxiated newborn, particu- flow despite TH.17 In addition, neonates with abnormal brain
larly in the context of TH where metabolic activity is further MRI demonstrate significant redistribution of left ventricu-
reduced. TH alone is not associated with an increased risk of lar output toward the central nervous system. This is evi-
hypotension, 1 and in the absence of cardiovascular denced by a 57% reduction in left ventricular output with
comorbidities, most neonates have normal or slightly in- preserved superior vena cava flow during TH in asphyxiated
creased blood pressure related to hypothermia induced vaso- neonates with abnormal day 3-4 MRI compared with healthy
constriction and normal myocardial performance.29 term controls studied at a comparable age. Neonates with
Severity of brain injury may be associated with dysregulation normal postrewarming MRI have a proportional reduction in
of vascular tone in the pulmonary vascular bed. Neonates with both left ventricular output and superior vena cava flow during
concurrent pulmonary hypertension and HIE are more likely TH.28 It is not known whether this redistribution reflects brain-
to have an abnormal brain magnetic resonance imaging (MRI) sparing physiological adaptation, or whether it is pathologic
despite TH.30 This may reflect greater disease severity as neo- and represents impaired cerebral autoregulation. Low left
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ventricular output alone, however, is not associated with a

Table III. Confounders of assessment of systemic he-
greater risk of ischemic MRI changes.30 Further studies are re-
modynamics in patients because of HIE* and/or TH†39
quired to determine clinical relevance of this observation.
Hyperperfusion and associated hyperoxia are putative con- Variables Change Pathophysiology
tributory factors to secondary injury.18 Identification of the ideal Heart rate Sinus bradycardia ↓ repolarization at SA node†
cerebral blood flow to optimize substrate delivery and mini- Blood pressure ↑ DAP Systemic vasoconstriction†
↓ SAP ↓ cardiac output†
mize the risk of reperfusion injury may yield a potential target Color Pallor ↓ skin perfusion†
of therapy. No clinical intervention aimed at matching cere- Capillary refill time Prolongation ↓ skin perfusion†
bral demand with supply is presently available; the ideal strat- Urinary output Oliguria or anuria Acute renal injury*
Blood gas Metabolic acidosis Residual perinatal acidosis*
egy should take into consideration the theoretical hazards of Lactate Lactic acidosis Lactate washout after initial
isolated hyper- or hypoperfusion or cycling between both. The insult*, sequestering†
optimum ranges for arterial pressure and cardiac output, which DAP, diastolic arterial pressure; SA, sinoatrial; SAP, systolic arterial pressure.
minimize harmful fluxes in cerebral perfusion, remain uncer- *HIE.
tain and warrant prospective scientific investigation. In †TH.

addition, none of the infants in these studies were followed

long-term; therefore, the relationship between cerebral blood ficult because of the confounding effects of temperature
flow and neurodevelopmental impairment remains an area for (Table III). First, it is the norm for neonates undergoing TH
study. to have resting bradycardia32; normal heart rate may be falsely
reassuring. Laboratory markers, such as metabolic acidosis and
The Effects of Rewarming elevated lactate,40 may reflect the primary hypoxic insult, in-
The physiological consequences of rewarming are likely to in- dependent of cardiovascular status, and may persist for hours
fluence both treatment and clinical outcomes, although there to days after the initial injury, or may relate to a low cardiac
is little published evidence (Figure 2). Known changes include output state.41 A high index of suspicion should be main-
augmentation of cardiac output and systolic blood pressure tained for circulatory inadequacy, and clinical variables should
with a concurrent decrease in systemic vascular resistance and be interpreted cautiously in the context of multiorgan
diastolic blood pressure; the net consequence is overall reduc- dysfunction.
tion of mean blood pressure by approximately 8 mm Hg.32 The Arterial pressure thresholds are commonly used to ap-
pattern of redistribution of cardiac output to the brain, seen praise cardiovascular health but may be difficult to interpret.
during the cooling phase in infants with adverse outcome, Observational studies in healthy, term neonates attempt to as-
remains consistent during rewarming.28 These physiologic certain the reference ranges for the different variables repre-
changes may have implications for neonates requiring cardio- sented by neonatal arterial pressure. The bulk of neonates have
vascular support, particularly if there is concomitant dose es- been studied in small populations via noninvasive upper-
calation. In addition, changes in temperature affect volume of limb measurement on day 1-242,43 or beyond,44,45 with limited
distribution, metabolism, and clearance of drugs.5,37 Drugs with data in the transitional period.46 Arterial pressure is influ-
a large volume of distribution are mobilized from seques- enced by gestational and chronologic age47,48; some sources
tered tissues and may have an exaggerated effect during suggest differences related to birth weight48 and sex.46 Based
rewarming. on limited data, day 1 median (fifth per centile) values for sys-
In a cohort of 160 asphyxiated neonates, of whom 9% de- tolic, diastolic, and mean arterial pressure are 65 mm Hg
veloped intraventricular hemorrhage, hemorrhage at the time (55 mm Hg), 45 mm Hg (30 mm Hg), and 48 mm Hg (40 mm
of rewarming was associated with a greater degree of hemo- Hg), respectively.42 High quality, large, prospective cohort studies
dynamic instability.38 Therefore, it is plausible that rewarm- that take into consideration sex, racial, and geographic vari-
ing represents a particularly vulnerable period for the central ability, as well as gestation and size are required. Multiple time
nervous system; it is important to avoid large fluctuations in point measurements over the first 24 hours are required to take
cerebral blood flow during this period. Active adjustment of variation in transition into account. When assessing the clini-
cardiovascular medications throughout the warming period cal relevance of systemic hypotension, it is important to con-
may be necessary to avoid iatrogenic hypertension and exces- sider the components of systolic, diastolic, and mean separately.
sive unregulated cerebral blood flow. Neonates require careful An adequate diastolic arterial pressure is generally main-
monitoring during rewarming; for those neonates requiring tained in neonates receiving TH by hypothermia induced pe-
significant support, more gradual rewarming may have theo- ripheral vasoconstriction.32 In contrast, systolic arterial pressure
retical benefit in achieving a more controlled change in he- is usually in the low normal range but is likely to be suffi-
modynamics. Rewarming hemodynamics, however, requires cient to maintain adequate organ perfusion.32 Dramatic in-
further study. creases in systolic arterial pressure are theoretically harmful
by increasing the risk of reperfusion hemorrhage; cautious use
Clinical Implications of HIE/TH of pharmacologic support in otherwise stable neonates is there-
fore recommended. Over reliance on mean arterial pressure,49
Clinical assessment of systemic and central nervous system he- however, may also result in late identification of major drops
modynamics in neonates with asphyxia during TH may be dif- in systolic arterial pressure.
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Table V. Echocardiography findings, pathophysiology, and suggested therapy in neonates with HIE and hemodynamic
instability39
Clinical presentation Echocardiography findings Management principles Suggested management
Low SAP, normal LV/RV systolic dysfunction (+) Inotropy 1st line: dobutamine
oxygenation 2nd line: epinephrine
- Hydrocortisone (if refractory)
Low SAP, impaired PPHN Pulmonary vasodilation and 1st line: iNO, optimum ventilation
oxygenation ↑SBF 2nd line: vasopressin or norepinephrine
- PGE1 (if restrictive DA)
- Hydrocortisone (if refractory)
LV dysfunction + PPHN (+) inotropy, maintain R 1st line: dobutamine, PGE1 (if
→ L ductal shunt to support restrictive DA)
SBF 2nd line: epinephrine (caution if severe oxygenation failure)
- Hydrocortisone (if refractory)
RV dysfunction + PPHN (+) Inotropy, reduce RV 1st line: dobutamine, iNO
afterload, maintain adequate 2nd line: PGE1 (if restrictive DA) 3rd line: vasopressin or norepinephrine
RV preload - Hydrocortisone (if refractory)

PGE1, prostaglandin E1; SBF, systemic blood flow.

Electrocardiogram and cardiac enzymes are widely used to of the mitral valve leaflet.9 The assessment of right ventricu-
identify myocardial ischemia in adult patients.50 Electrographic lar function was previously limited to subjective assessment;
changes (Table IV; available at www.jpeds.com)51 and marked however, this method has been shown to be inaccurate.56 Recent
cardiac enzyme increase51,52 also have been associated with tran- studies of healthy newborn infants have shown that calcula-
sient myocardial ischemia in neonates with HIE. The sensi- tion of right ventricular fractional area change, the displace-
tivity and specificity of the electrocardiogram for the detection ment of the tricuspid annulus (tricuspid annular plane systolic
of transient myocardial ischemia are not known, though as- excursion), or use of deformation/tissue Doppler methods are
phyxiated neonates more frequently demonstrate abnormali- feasible for evaluation of right ventricular systolic performance.57
ties of the ST segment and Q waves than healthy controls.53 Left and right ventricular output may be calculated as surro-
Alterations in the amplitude and axis of the T wave alone may gate markers of systolic performance. Where available, tar-
be associated with ischemia after 24 hours of life.54 Further study geted neonatal echocardiography offers an advantage in the
is required to define the prognostic value of the electrocar- ability to perform longitudinal assessments and assess treat-
diogram; if early ischemic changes can be reliably detected, the ment response; with increasing training of neonatologists in
electrocardiogram may aid in identification of neonates who the skill, focused assessment will be more widely available.
may benefit from echocardiography. Creatine kinase MB Novel technologies may allow the assessment of the direct
isozyme is significantly elevated in neonates with moderate to impact of cardiovascular change on brain health. Near-
severe encephalopathy and begins to rise within 4-8 hours of infrared spectroscopy is a bedside tool that indirectly evalu-
injury.9 Furthermore, it has been suggested that cardiac tro- ates cerebral blood flow by measuring real-time regional mixed
ponin I level at 24 hours of age, often not measured as part venous saturation (rScO2), reflecting the oxygen supply/
of routine clinical practice, is a useful prognostic marker of demand ratio. There is some evidence that it could be used
neurologic outcome 18-22 months in both cooled and to predict adverse outcome in the setting of HIE/TH58 and has
noncooled infants.55 been used to assess cerebral autoregulation.59 These studies have
Targeted neonatal echocardiography is a bedside tool, used limitations including small sample sizes and the lack of cor-
to assess cardiovascular health and refine therapeutic inter- relation with a clinical gold standard method. Longitudinal
ventions in this high-risk population (Table V). Assessment studies of combined targeted neonatal echocardiography and
by an experienced operator may enhance the precision of di- near infrared spectroscopy may allow further delineation of
agnosis and clinical appropriateness of therapeutic interven- abnormal physiology and the impact of treatment. Heart rate
tions by delineating actual pathophysiology of hemodynamic variability is a well-validated surrogate of fetal well-being in
instability, rather than relying on clinical estimation. In neo- obstetrical literature; specifically, reduced beat-to-beat vari-
nates who are sick and have HIE, assessment by pediatric car- ability and superimposed decelerations are associated with acute
diology may be beneficial. A high index of suspicion is fetal asphyxia.60 Recent literature has examined the predic-
important, particularly in infants of mothers with diabetes, for tive role of heart rate variability in staging of HIE and outcome
associated congenital heart disease or hypertrophic obstruc- prognostication. Preliminary data suggests that lower heart rate
tive cardiomyopathy. In the absence of targeted neonatal variability in the first 24 hours of life is associated with more
echocardiography, echocardiography by pediatric cardiology severe HIE as measured by electroencephalogram and MRI.60
may provide insight into hemodynamics, depending on local Heart rate variability is, however, ineffective for predicting
practice. Left ventricular systolic function may be assessed using seizures,61 and it remains to be seen whether this modality will
conventional methods (fractional shortening or ejection frac- provide additional or earlier information than established
tion), or tissue Doppler imaging of the anterior/septal walls methods.
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Approach to Cardiovascular Care in HIE/TH hypertension,65 and it has been shown to improve systemic he-
modynamics in animal models of asphyxia66,67; its effects in neo-
The approach to cardiovascular care should consider actual nates with HIE, particularly those with left ventricular
pathophysiology, phase of intervention (eg, during TH or re- dysfunction, remain unknown. Of note, the administration of
warming), and impact of concomitant treatments.39 Most neo- milrinone to neonates undergoing TH for HIE is not recom-
nates with isolated transient myocardial ischemia are mended as drug clearance is lower, which may lead to toxic
asymptomatic and improve over time. Given the association drug levels and extreme hypotension because of potent sys-
between increased cerebral blood flow and poor outcome, ag- temic vasodilation.63 There is limited evidence for the use of
gressive volume resuscitation should be avoided except when norepinephrine, an endogenous systemic vasoconstrictor; it is
there is direct evidence of acute hypovolemia. Blood transfu- a potent a agonist with some activity at the b1 receptor. Both
sion for anemia should be considered in pulmonary hyper- animal data68,69 and small trials in human neonates70 suggest
tension to optimize oxygen carrying capacity. Myocardial that norepinephrine may have some pulmonary vasodilator
ischemia may affect either ventricle or both. Left ventricular effects; b1 activity provides some positive inotropy. Adrenal
dysfunction results in reduced stroke volume and low cardiac insufficiency may occur independently or in combination with
output; right ventricular dysfunction may lead to both hy- other causes of hypotension, presenting with refractory hy-
poxemia and systemic hypotension via reduced pulmonary potension despite catecholamine therapy and potentially as-
blood flow, reduced left ventricular preload, and, therefore, low sociated with hyponatremia and hypoglycemia. Hydrocortisone
left ventricular output. Ventricular dysfunction may mani- is indicated in refractory hypotension, especially if adrenal injury
fest as systolic or severe hypotension with mild or moderate is suspected.
hypoxemia. Optimal thresholds for intervention are poorly Although the neurologic benefits of TH are clear, exposure
defined; clinicians need to weigh the impact of cardiovascu- to lower core body temperature increases the degree of pul-
lar treatments for impaired myocardial function and low cardiac monary vasoconstriction.10 Though there was no statistically
output against the consequences of reperfusion injury. significant increase in clinically detectable pulmonary hyper-
Dobutamine is the most appropriate first line agent for iso- tension identified in randomized controlled trials, the trials were
lated hypotension, particularly in neonates with low systolic not powered to detect differences in illness severity and from
blood pressure and evidence of end organ hypoperfusion, to some trials (eg, Infant Cooling Evaluation, Neo.nEURO.network
increase stroke volume and cardiac output (Table V). It acts Trial) the most hemodynamically unstable infants were
through a1 and b1 receptors in the myocardium to increase excluded71,72 (Table I). In a subpopulation with preexisting pul-
in cardiac contractility and heart rate. The peripheral effects monary hypertension, TH may further impair oxygenation73;
include both vasoconstriction and vasodilation resulting in a judicious increases in target temperature may improve
net neutral effect.62 oxygenation.74 The approach to management in neonates with
In the setting of high afterload because of persistent pul- moderate hypoxemia should focus on strategies to maximize
monary hypertension, any degree of right ventricular dys- pulmonary vasodilation, in an effort to allow continuation of
function may be poorly tolerated. Even with normal right TH. It has been our anecdotal clinical experience that in pa-
ventricular function, pulmonary hypertension may lead to low tients where pulmonary vasodilator treatments fails, modifi-
pulmonary blood flow, impaired oxygenation, and low cardiac cations of target temperature by small increments (0.5-1 degree)
output. In the setting of pulmonary hypertension and HIE, may improve oxygenation; rarely, TH may need to be discon-
conventional therapies including sedation, muscle relax- tinued. Although there may be advantages to attaining target
ation, and ventilation are indicated. Though a poor response temperature as early as is feasible, it is important to remem-
is seen in 40% of neonates,63 iNO remains the first line pul- ber that TH is a postresuscitation intervention; hence, medical
monary vasodilator. In neonates without concurrent pulmo- stabilization of oxygenation failure in the immediate period
nary parenchymal disease (eg, meconium aspiration syndrome), after birth should precede the initiation of TH.
care must be taken to avoid excess mean airway pressure as Moderate to severe left ventricular systolic dysfunction may
this can further impair pulmonary venous return (Table V). lead to pulmonary venous hypertension because of diastolic
For neonates with systemic hypotension and pulmonary hy- impairment. This manifests clinically as respiratory insuffi-
pertension, intravenous infusion of dobutamine is an appro- ciency and hypoxemia, which may mimic persistent pulmo-
priate choice as it will improve cardiac output and may offer nary hypertension of the newborn.
some improvement to pulmonary blood flow. Vasopressin is Diagnostic clues may include pulmonary edema on chest
a drug with dichotomous properties. In vascular smooth muscle radiography or left to right atrial shunting in the presence of
such as the skin, skeletal muscle, and splanchnic circulation, a right to left ductal shunt in the setting of left ventricular sys-
it produces potent vasoconstriction. In the pulmonary vas- tolic dysfunction on echocardiography.75 Neonates with severe
culature, vasopressin activates endothelial receptors, which result left ventricular dysfunction may have critically low left ven-
in stimulation of the nitric oxide pathway and vasodilation of tricular output and require the support of agents with inotropy,
select vessels.64 Vasopressin may be physiologically advanta- especially as hypothermia induced vasoconstriction may cause
geous in neonates with systemic hypotension and oxygen- left ventricular wall stress and exacerbate dysfunction 76
ation failure where there is unrestrictive right-left flow. There (Table V). The clinical picture may functionally mimic criti-
is evidence of benefit in neonates with pulmonary cal aortic stenosis requiring intravenous prostaglandin infu-
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sion to maintain ductal patency and augment postductal cardiac 8. Martin-Ancel A, Garcia-Alix A, Gaya F, Cabanas F, Burgueros M, Quero
output. Therapies with pulmonary vasodilator effects (eg, J. Multiple organ involvement in perinatal asphyxia. J Pediatr 1995;127:786-
93.
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1977;42:56-8.
In severe cases, retrograde flow in the aortic arch may augment 11. Vannucci RC, Towfighi J, Vannucci SJ. Secondary energy failure after ce-
cerebral perfusion. Neonates with severe right ventricular sys- rebral hypoxia-ischemia in the immature rat. J Cereb Blood Flow Metab
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importance. Int J Clin Pract 2004;58:436-40.
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though TH has transformed the care of this population and 17. Kumagai T, Higuchi R, Higa A, Tsuno Y, Hiramatsu C, Sugimoto T, et al.
led to improved neurodevelopmental outcomes, refinement of Correlation between echocardiographic superior vena cava flow and short-
cardiovascular care may provide additional benefit. Cur- term outcome in infants with asphyxia. Early Hum Dev 2013;89:307-10.
18. Ilves P, Lintrop M, Metsvaht T, Vaher U, Talvik T. Cerebral blood-flow
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asphyxia in the term infant. Pediatr Neurol 1998;18:391-8.
decision-making. Individualization of therapy may present an
21. Shankaran S, McDonald SA, Laptook AR, Hintz SR, Barnes PD, Das A,
opportunity for improved outcomes. ■ et al. Neonatal magnetic resonance imaging pattern of brain injury as a
biomarker of childhood outcomes following a trial of hypothermia for
Submitted for publication May 5, 2016; last revision received Jul 13, 2016; neonatal hypoxic-ischemic encephalopathy. J Pediatr 2015;167:987-93, e3.
accepted Sep 7, 2016 22. Mallard EC, Williams CE, Gunn AJ, Gunning MI, Gluckman PD. Fre-
Reprint requests: Patrick J. McNamara MB, MSC, Division of Neonatology, quent episodes of brief ischemia sensitize the fetal sheep brain to neu-
The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada ronal loss and induce striatal injury. Pediatr Res 1993;33:61-5.
M5G 1X8. E-mail: patrick.mcnamara@sickkids.ca 23. Gunn AJ, Bennet L, Gunning MI, Gluckman PD, Gunn TR. Cerebral hy-
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Table I. Summary of enrollment criteria for randomized controlled trials of TH for HIE
Hemodynamic variables
Trials Inclusion Exclusion (definition) Outcome variables
Authors Year
TOBY3 2009 • ≥36 wk • ≥6 h of age • Hypotension (MAP < 40 mm • Composite outcome‡:
Whole body TH • Apgar ≤5 at 10 min • Major anomalies Hg) 77% TH vs 83% 45% TH vs 53%
• Resuscitation at 10 min • Surgical disorder control (NS) control (NS)
• Acidosis* cord or <60 min • PPHN (not defined) 10% TH vs
• Encephalopathy† or abnormal aEEG 6% control (NS)
neoEURO72 2010 • ≥36 wk • ≥5.5 h of age • Hypotension (MAP < 40 mm • Composite outcome‡:
Whole body TH • Apgar ≤5 at 10 min • High dose anticonvulsants Hg) 53% TH vs 44% 51% TH vs 83%
• Resuscitation at 10 min • IUGR (<1.8 kg) control (NS) control (P = .001)
• Acidosis* cord or <60 min • Major anomalies • PPHN (need for iNO) 7% TH, • Died during intervention
• Encephalopathy† or abnormal aEEG • Deemed in “extremis” by 16% control (NS) period 8% TH vs 13
neonatologist control (NS)
ICE71 2011 • ≥35 wk • ≥6 h of age • Hypotension (treated with • Composite outcome‡:
Whole body TH • Apgar ≤5 at 10 min • IUGR (<2 kg) inotropes) 46% TH vs 47% 51% TH vs 66%
• Mechanical ventilation at 10 min • Major anomalies control (NS) control (P = .03)
• Acidosis cord or <60 min (pH < 7.0, BD >12) • Active bleeding • PPHN (FiO2 1.0) excluded • Died: 25% TH vs 39%
• Encephalopathy† • FiO2 >80% control (P = .04)
• Refractory hypotension
• Unresponsive acidosis
Zhou et al77 2010 • ≥37 wk • ≥6 h of age • Hypotension (refractory • Composite outcome‡:
Selective head TH + • Apgar ≤3 at 1, ≤5 at 5 • Weight <2.5 kg MAP <40 mm Hg) 33% TH vs 49%
mild systemic TH • Resuscitation at 5 min • Major abnormalities frequency not reported; control (P = .01)
• Acidosis* • Clinical chorioamnionitis difference reported as NS
• Encephalopathy† • Other cause of encephalopathy
• Hb < 120
NICHD78 2005 • ≥36 wk • ≥6 h of age • Hypotension (need for • Composite outcome‡:
Total body cooling • Apgar ≤5 at 10 min • Major anomalies inotropes) 33% TH vs 25% 44% TH vs 62%
• Ventilation at 10 min • IUGR (<1.8 kg) control (NS) control (P = .01)
• Acidosis* (or pH 7.01-7.15 & BD 10- • Moribund • PPHN (not defined) 25% TH vs • Died: 24% TH vs 37%
15.9 + sentinel event) 22% control (NS) control (NS)
• Encephalopathy†
Lin et al79 2006 • ≥ 37 wk • Major anomalies • Hypotension (not defined) • Primary end point of
Selective head TH • Apgar ≤5 at 5 min • Severe PH (not defined) maintained with dopamine improved d 5-7 CT
• Acidosis on first ABG (pH <7.1 or BD >15) • PPHN not reported findings (P < .01)
• Encephalopathy† • Neonatal Behavioral
Neurologic assessment
d 7-10 (P < .01)
Gunn et al74 1998 • ≥37 wk • Major anomalies • Hypotension (MAP < 40 mm
Whole body TH • Acidosis (UA pH ≤ 7.09) • Metabolic diseases Hg) 0% TH vs 0% control
• Apgar ≤6 at 5 min • PPHN (needing iNO) 50%
• Encephalopathy† “minimal TH” vs 0% “mild
TH” vs 20% control
CoolCap80 2005 • ≥36 wk • ≥5.5 h of age • Hypotension (MAP < 40 mm • Composite outcome‡:
Selective head TH + • Apgar ≤5 at 10 min • Prophylactic anticonvulsants Hg) 55% TH vs 52% 55% TH vs 66%
mild systemic TH • Resuscitation at 10 min • Major anomalies control (NS) control (P = .01)
• Acidosis* cord or <60 min • Intracranial hemorrhage • PPHN not reported • Died: 33% TH vs 38%
• Encephalopathy† • IUGR (1.8 kg) • Respiratory distress (need for control (P = .05)
• Illness acuity deemed too high ventilation, CPAP or ECMO)
(neonatologist) 84% TH vs 78% control
Akisu et al81 2003 • ≥37 wk • ≥6 h of age • Hypotension (MAP < 45 mm • Primary outcome: CSF
Selective head TH + • Apgar ≤5 at 5 min • Metabolic disorders Hg) 0% TH vs 0% control platelet-activating
mild systemic TH • Acidosis cord or first ABG (pH <7.1 or BD >10) • Congenital or chromosomal (NS) factor.
• Encephalopathy† disorders • PPHN not reported
• Congenital infection
• Transitory drug depression
Shankaran et al82 2002 • ≥36 wk • ≥6 h of age • Hypotension (need for • Died: 22% TH vs 30%
Whole body TH • Apgar ≤5 at 10 min • Chromosomal/ congenital vasopressor) 56% TH vs control
• Ventilation at 10 min anomaly 30% control • Abnormal MRI 33% TH vs
• Acidosis* cord or <60 min (or pH 7.01-7.15 or • Severe IUGR ( < 1.8 kg) • PPHN (not defined) 33% TH vs 30% control
BD 10-15.9 + sentinel event) • Unlikely to survive 20% control
• Encephalopathy† • Neonatologist deemed
inappropriate to consent
Eicher et al83 2005 • ≥35 wk and 2000g • ≥6 h of age • Hypotension (d on inotropes) 5 • Neurologic outcomes not
Whole body TH • Encephalopathy† • Clinical sepsis, chorioamnionitis TH vs 2 control (P = .02) reported.
• Plus 2 of: • IUGR (<10th percentile) • PPHN (not defined) 29% TH vs
• Apgar ≤5 at 10 min • Congenital anomalies 16% control (NS)
• Resuscitation at 10 min • PPHN requiring iNO 16% TH
• Acidosis cord ≤7.0 or BD ≥13 (first pH <7.1) vs 3% control (P = .01)
• Fetal bradycardia, postnatal hypoxemia, or
hypotension

ABG, arterial blood gas; aEEG, amplitude integrated electroencephalogram; BD, base deficit; CPAP, continuous positive airway pressure; CSF, cerebrospinal fluid; ECMO, extracorporeal membrane oxygenation;
FiO2, fraction of inspired oxygen; IUGR, intrauterine growth restriction; ICE, Infant Cooling Evaluation; MAP, mean arterial pressure; NS, normal saline; PPHN, persistent pulmonary hypertension of the newborn;
UA, umbilical artery.
*Acidosis: pH <7 and/or base deficit >16 mmol/L unless otherwise specified.
†Encephalopathy: Moderate or severe on the basis of Sarnat Score.
‡Composite outcome: Death or severe neurodevelopmental impairment.

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Table II. Comparison of types of asphyxial injury and their characteristics19,20

Acute near-total asphyxia Partial prolonged asphyxia
Type of injury Single catastrophic event Repeated moderate exposure
Pattern of injury Subcortical nuclei in the thalamus and brainstem Cerebral white matter and non-CNS organs
Pathophysiology Acute damage to areas with highest metabolic requirements Gradual redistribution of blood to deep brain structures at the expense of other areas

CNS, central nervous system.

Table IV. Electrocardiogram grading of transient myo-

cardial ischemia51
Grade Severity Electrocardiogram finding
I Equivocal Flat or inverted T wave in 1 lead only
II Suggestive Flat or inverted T wave in several leads + abnormal Q
wave in any lead
III Moderate Flat or inverted T wave in several leads or bundle branch
block + abnormal Q + abnormal ST segments
IV Severe Classic segmental infarction pattern with abnormal Q
waves + markedly elevated ST segments

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