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

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

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

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ventricular output alone, however, is not associated with a
greater risk of ischemic MRI changes.30 Further studies are re-
quired to determine clinical relevance of this observation.
Hyperperfusion and associated hyperoxia are putative con-
tributory factors to secondary injury.18 Identification of the ideal
cerebral blood flow to optimize substrate delivery and mini-
mize the risk of reperfusion injury may yield a potential target
of therapy. No clinical intervention aimed at matching cere-
bral demand with supply is presently available; the ideal strat-
egy should take into consideration the theoretical hazards of
isolated hyper- or hypoperfusion or cycling between both. The
optimum ranges for arterial pressure and cardiac output, which
minimize harmful fluxes in cerebral perfusion, remain uncer-
tain and warrant prospective scientific investigation. In
addition, none of the infants in these studies were followed
long-term; therefore, the relationship between cerebral blood
flow and neurodevelopmental impairment remains an area for
study.
The Effects of Rewarming
The physiological consequences of rewarming are likely to in-
fluence both treatment and clinical outcomes, although there
is little published evidence (Figure 2). Known changes include
augmentation of cardiac output and systolic blood pressure
with a concurrent decrease in systemic vascular resistance and
diastolic blood pressure; the net consequence is overall reduc-
tion of mean blood pressure by approximately 8 mm Hg.32 The
pattern of redistribution of cardiac output to the brain, seen
during the cooling phase in infants with adverse outcome,
remains consistent during rewarming.28 These physiologic
changes may have implications for neonates requiring cardio-
vascular support, particularly if there is concomitant dose es-
calation. In addition, changes in temperature affect volume of
distribution, metabolism, and clearance of drugs.5,37 Drugs with
a large volume of distribution are mobilized from seques-
tered tissues and may have an exaggerated effect during
rewarming.
In a cohort of 160 asphyxiated neonates, of whom 9% de-
veloped intraventricular hemorrhage, hemorrhage at the time
of rewarming was associated with a greater degree of hemo-
dynamic instability.38 Therefore, it is plausible that rewarm-
ing represents a particularly vulnerable period for the central
nervous system; it is important to avoid large fluctuations in
cerebral blood flow during this period. Active adjustment of
cardiovascular medications throughout the warming period
may be necessary to avoid iatrogenic hypertension and exces-
sive unregulated cerebral blood flow. Neonates require careful
monitoring during rewarming; for those neonates requiring
significant support, more gradual rewarming may have theo-
retical benefit in achieving a more controlled change in he-
modynamics. Rewarming hemodynamics, however, requires
further study.
Clinical Implications of HIE/TH
Clinical assessment of systemic and central nervous system he-
modynamics in neonates with asphyxia during TH may be dif-
4 Giesinger et al
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Table III. Confounders of assessment of systemic he-
modynamics in patients because of HIE* and/or TH†39
Variables Change Pathophysiology
Heart rate Sinus bradycardia ↓ repolarization at SA node†
Blood pressure ↑ DAP Systemic vasoconstriction†
↓ SAP ↓ cardiac output†
Color Pallor ↓ skin perfusion†
Capillary refill time Prolongation ↓ skin perfusion†
Urinary output Oliguria or anuria Acute renal injury*
Blood gas Metabolic acidosis Residual perinatal acidosis*
Lactate Lactic acidosis Lactate washout after initial
insult*, sequestering†
DAP, diastolic arterial pressure; SA, sinoatrial; SAP, systolic arterial pressure.
*HIE.
†TH.
ficult because of the confounding effects of temperature
(Table III). First, it is the norm for neonates undergoing TH
to have resting bradycardia32; normal heart rate may be falsely
reassuring. Laboratory markers, such as metabolic acidosis and
elevated lactate,40 may reflect the primary hypoxic insult, in-
dependent of cardiovascular status, and may persist for hours
to days after the initial injury, or may relate to a low cardiac
output state.41 A high index of suspicion should be main-
tained for circulatory inadequacy, and clinical variables should
be interpreted cautiously in the context of multiorgan
dysfunction.
Arterial pressure thresholds are commonly used to ap-
praise cardiovascular health but may be difficult to interpret.
Observational studies in healthy, term neonates attempt to as-
certain the reference ranges for the different variables repre-
sented by neonatal arterial pressure. The bulk of neonates have
been studied in small populations via noninvasive upper-
limb measurement on day 1-242,43 or beyond,44,45 with limited
data in the transitional period.46 Arterial pressure is influ-
enced by gestational and chronologic age47,48; some sources
suggest differences related to birth weight48 and sex.46 Based
on limited data, day 1 median (fifth per centile) values for sys-
tolic, diastolic, and mean arterial pressure are 65 mm Hg
(55 mm Hg), 45 mm Hg (30 mm Hg), and 48 mm Hg (40 mm
Hg), respectively.42 High quality, large, prospective cohort studies
that take into consideration sex, racial, and geographic vari-
ability, as well as gestation and size are required. Multiple time
point measurements over the first 24 hours are required to take
variation in transition into account. When assessing the clini-
cal relevance of systemic hypotension, it is important to con-
sider the components of systolic, diastolic, and mean separately.
An adequate diastolic arterial pressure is generally main-
tained in neonates receiving TH by hypothermia induced pe-
ripheral vasoconstriction.32 In contrast, systolic arterial pressure
is usually in the low normal range but is likely to be suffi-
cient to maintain adequate organ perfusion.32 Dramatic in-
creases in systolic arterial pressure are theoretically harmful
by increasing the risk of reperfusion hemorrhage; cautious use
of pharmacologic support in otherwise stable neonates is there-
fore recommended. Over reliance on mean arterial pressure,49
however, may also result in late identification of major drops
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
Low SAP, normal LV/RV systolic dysfunction (+) Inotropy
oxygenation
Low SAP, impaired PPHN Pulmonary vasodilation and
oxygenation ↑SBF
LV dysfunction + PPHN (+) inotropy, maintain R
→ L ductal shunt to support
SBF
RV dysfunction + PPHN (+) Inotropy, reduce RV
afterload, maintain adequate
RV preload
PGE1, prostaglandin E1; SBF, systemic blood flow.
Electrocardiogram and cardiac enzymes are widely used to
identify myocardial ischemia in adult patients.50 Electrographic
changes (Table IV; available at www.jpeds.com)51 and marked
cardiac enzyme increase51,52 also have been associated with tran-
sient myocardial ischemia in neonates with HIE. The sensi-
tivity and specificity of the electrocardiogram for the detection
of transient myocardial ischemia are not known, though as-
phyxiated neonates more frequently demonstrate abnormali-
ties of the ST segment and Q waves than healthy controls.53
Alterations in the amplitude and axis of the T wave alone may
be associated with ischemia after 24 hours of life.54 Further study
is required to define the prognostic value of the electrocar-
diogram; if early ischemic changes can be reliably detected, the
electrocardiogram may aid in identification of neonates who
may benefit from echocardiography. Creatine kinase MB
isozyme is significantly elevated in neonates with moderate to
severe encephalopathy and begins to rise within 4-8 hours of
injury.9 Furthermore, it has been suggested that cardiac tro-
ponin I level at 24 hours of age, often not measured as part
of routine clinical practice, is a useful prognostic marker of
neurologic outcome 18-22 months in both cooled and
noncooled infants.55
Targeted neonatal echocardiography is a bedside tool, used
to assess cardiovascular health and refine therapeutic inter-
ventions in this high-risk population (Table V). Assessment
by an experienced operator may enhance the precision of di-
agnosis and clinical appropriateness of therapeutic interven-
tions by delineating actual pathophysiology of hemodynamic
instability, rather than relying on clinical estimation. In neo-
nates who are sick and have HIE, assessment by pediatric car-
diology may be beneficial. A high index of suspicion is
important, particularly in infants of mothers with diabetes, for
associated congenital heart disease or hypertrophic obstruc-
tive cardiomyopathy. In the absence of targeted neonatal
echocardiography, echocardiography by pediatric cardiology
may provide insight into hemodynamics, depending on local
practice. Left ventricular systolic function may be assessed using
conventional methods (fractional shortening or ejection frac-
tion), or tissue Doppler imaging of the anterior/septal walls
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Suggested management
1st line: dobutamine
2nd line: epinephrine
- Hydrocortisone (if refractory)
1st line: iNO, optimum ventilation
2nd line: vasopressin or norepinephrine
- PGE1 (if restrictive DA)
- Hydrocortisone (if refractory)
1st line: dobutamine, PGE1 (if
restrictive DA)
2nd line: epinephrine (caution if severe oxygenation failure)
- Hydrocortisone (if refractory)
1st line: dobutamine, iNO
2nd line: PGE1 (if restrictive DA) 3rd line: vasopressin or norepinephrine
- Hydrocortisone (if refractory)
of the mitral valve leaflet.9 The assessment of right ventricu-
lar function was previously limited to subjective assessment;
however, this method has been shown to be inaccurate.56 Recent
studies of healthy newborn infants have shown that calcula-
tion of right ventricular fractional area change, the displace-
ment of the tricuspid annulus (tricuspid annular plane systolic
excursion), or use of deformation/tissue Doppler methods are
feasible for evaluation of right ventricular systolic performance.57
Left and right ventricular output may be calculated as surro-
gate markers of systolic performance. Where available, tar-
geted neonatal echocardiography offers an advantage in the
ability to perform longitudinal assessments and assess treat-
ment response; with increasing training of neonatologists in
the skill, focused assessment will be more widely available.
Novel technologies may allow the assessment of the direct
impact of cardiovascular change on brain health. Near-
infrared spectroscopy is a bedside tool that indirectly evalu-
ates cerebral blood flow by measuring real-time regional mixed
venous saturation (rScO2), reflecting the oxygen supply/
demand ratio. There is some evidence that it could be used
to predict adverse outcome in the setting of HIE/TH58 and has
been used to assess cerebral autoregulation.59 These studies have
limitations including small sample sizes and the lack of cor-
relation with a clinical gold standard method. Longitudinal
studies of combined targeted neonatal echocardiography and
near infrared spectroscopy may allow further delineation of
abnormal physiology and the impact of treatment. Heart rate
variability is a well-validated surrogate of fetal well-being in
obstetrical literature; specifically, reduced beat-to-beat vari-
ability and superimposed decelerations are associated with acute
fetal asphyxia.60 Recent literature has examined the predic-
tive role of heart rate variability in staging of HIE and outcome
prognostication. Preliminary data suggests that lower heart rate
variability in the first 24 hours of life is associated with more
severe HIE as measured by electroencephalogram and MRI.60
Heart rate variability is, however, ineffective for predicting
seizures,61 and it remains to be seen whether this modality will
provide additional or earlier information than established
methods.
5
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Approach to Cardiovascular Care in HIE/TH
The approach to cardiovascular care should consider actual
pathophysiology, phase of intervention (eg, during TH or re-
warming), and impact of concomitant treatments.39 Most neo-
nates with isolated transient myocardial ischemia are
asymptomatic and improve over time. Given the association
between increased cerebral blood flow and poor outcome, ag-
gressive volume resuscitation should be avoided except when
there is direct evidence of acute hypovolemia. Blood transfu-
sion for anemia should be considered in pulmonary hyper-
tension to optimize oxygen carrying capacity. Myocardial
ischemia may affect either ventricle or both. Left ventricular
dysfunction results in reduced stroke volume and low cardiac
output; right ventricular dysfunction may lead to both hy-
poxemia and systemic hypotension via reduced pulmonary
blood flow, reduced left ventricular preload, and, therefore, low
left ventricular output. Ventricular dysfunction may mani-
fest as systolic or severe hypotension with mild or moderate
hypoxemia. Optimal thresholds for intervention are poorly
defined; clinicians need to weigh the impact of cardiovascu-
lar treatments for impaired myocardial function and low cardiac
output against the consequences of reperfusion injury.
Dobutamine is the most appropriate first line agent for iso-
lated hypotension, particularly in neonates with low systolic
blood pressure and evidence of end organ hypoperfusion, to
increase stroke volume and cardiac output (Table V). It acts
through a1 and b1 receptors in the myocardium to increase
in cardiac contractility and heart rate. The peripheral effects
include both vasoconstriction and vasodilation resulting in a
net neutral effect.62
In the setting of high afterload because of persistent pul-
monary hypertension, any degree of right ventricular dys-
function may be poorly tolerated. Even with normal right
ventricular function, pulmonary hypertension may lead to low
pulmonary blood flow, impaired oxygenation, and low cardiac
output. In the setting of pulmonary hypertension and HIE,
conventional therapies including sedation, muscle relax-
ation, and ventilation are indicated. Though a poor response
is seen in 40% of neonates,63 iNO remains the first line pul-
monary vasodilator. In neonates without concurrent pulmo-
nary parenchymal disease (eg, meconium aspiration syndrome),
care must be taken to avoid excess mean airway pressure as
this can further impair pulmonary venous return (Table V).
For neonates with systemic hypotension and pulmonary hy-
pertension, intravenous infusion of dobutamine is an appro-
priate choice as it will improve cardiac output and may offer
some improvement to pulmonary blood flow. Vasopressin is
a drug with dichotomous properties. In vascular smooth muscle
such as the skin, skeletal muscle, and splanchnic circulation,
it produces potent vasoconstriction. In the pulmonary vas-
culature, vasopressin activates endothelial receptors, which result
in stimulation of the nitric oxide pathway and vasodilation of
select vessels.64 Vasopressin may be physiologically advanta-
geous in neonates with systemic hypotension and oxygen-
ation failure where there is unrestrictive right-left flow. There
is evidence of benefit in neonates with pulmonary
6 Giesinger et al
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hypertension,65 and it has been shown to improve systemic he-
modynamics in animal models of asphyxia66,67; its effects in neo-
nates with HIE, particularly those with left ventricular
dysfunction, remain unknown. Of note, the administration of
milrinone to neonates undergoing TH for HIE is not recom-
mended as drug clearance is lower, which may lead to toxic
drug levels and extreme hypotension because of potent sys-
temic vasodilation.63 There is limited evidence for the use of
norepinephrine, an endogenous systemic vasoconstrictor; it is
a potent a agonist with some activity at the b1 receptor. Both
animal data68,69 and small trials in human neonates70 suggest
that norepinephrine may have some pulmonary vasodilator
effects; b1 activity provides some positive inotropy. Adrenal
insufficiency may occur independently or in combination with
other causes of hypotension, presenting with refractory hy-
potension despite catecholamine therapy and potentially as-
sociated with hyponatremia and hypoglycemia. Hydrocortisone
is indicated in refractory hypotension, especially if adrenal injury
is suspected.
Although the neurologic benefits of TH are clear, exposure
to lower core body temperature increases the degree of pul-
monary vasoconstriction.10 Though there was no statistically
significant increase in clinically detectable pulmonary hyper-
tension identified in randomized controlled trials, the trials were
not powered to detect differences in illness severity and from
some trials (eg, Infant Cooling Evaluation, Neo.nEURO.network
Trial) the most hemodynamically unstable infants were
excluded71,72 (Table I). In a subpopulation with preexisting pul-
monary hypertension, TH may further impair oxygenation73;
judicious increases in target temperature may improve
oxygenation.74 The approach to management in neonates with
moderate hypoxemia should focus on strategies to maximize
pulmonary vasodilation, in an effort to allow continuation of
TH. It has been our anecdotal clinical experience that in pa-
tients where pulmonary vasodilator treatments fails, modifi-
cations of target temperature by small increments (0.5-1 degree)
may improve oxygenation; rarely, TH may need to be discon-
tinued. Although there may be advantages to attaining target
temperature as early as is feasible, it is important to remem-
ber that TH is a postresuscitation intervention; hence, medical
stabilization of oxygenation failure in the immediate period
after birth should precede the initiation of TH.
Moderate to severe left ventricular systolic dysfunction may
lead to pulmonary venous hypertension because of diastolic
impairment. This manifests clinically as respiratory insuffi-
ciency and hypoxemia, which may mimic persistent pulmo-
nary hypertension of the newborn.
Diagnostic clues may include pulmonary edema on chest
radiography or left to right atrial shunting in the presence of
a right to left ductal shunt in the setting of left ventricular sys-
tolic dysfunction on echocardiography.75 Neonates with severe
left ventricular dysfunction may have critically low left ven-
tricular output and require the support of agents with inotropy,
especially as hypothermia induced vasoconstriction may cause
left ventricular wall stress and exacerbate dysfunction 76
(Table V). The clinical picture may functionally mimic criti-
cal aortic stenosis requiring intravenous prostaglandin infu-
■■ 2016
sion to maintain ductal patency and augment postductal cardiac
output. Therapies with pulmonary vasodilator effects (eg,
oxygen, iNO) should be used with caution, as they either may
be of no benefit or may precipitate cardiogenic shock. Strat-
egies to increase pulmonary vascular resistance (eg, permis-
sive hypercapnia, lower oxygen saturation targets) and promote
right-left shunt are required to augment systemic blood flow.
In severe cases, retrograde flow in the aortic arch may augment
cerebral perfusion. Neonates with severe right ventricular sys-
tolic dysfunction may benefit from afterload reduction with
pulmonary vasodilator therapy. In addition, as the pulmo-
nary circulation becomes pressure passive, maintaining
adequate right ventricular preload is essential (Table V). In
some centers, targeted neonatal echocardiography may provide
pathophysiologic information, which may enhance the care of
neonates with severe or refractory hypotension and/or
hypoxemia.
Conclusions
Neonates with asphyxia represent a vulnerable population. Al-
though TH has transformed the care of this population and
led to improved neurodevelopmental outcomes, refinement of
cardiovascular care may provide additional benefit. Cur-
rently, the relationship between altered hemodynamics and
brain health remains poorly understood. A comprehensive un-
derstanding of the physiological mechanisms of disease and
therapy and real-time bedside assessment tools, such as tar-
geted neonatal echocardiography, may be invaluable aids to
decision-making. Individualization of therapy may present an
opportunity for improved outcomes. ■
Submitted for publication May 5, 2016; last revision received Jul 13, 2016;
accepted Sep 7, 2016
Reprint requests: Patrick J. McNamara MB, MSC, Division of Neonatology,
The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada
M5G 1X8. E-mail: patrick.mcnamara@sickkids.ca
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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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