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Article neurology

Treating Hypoxic Ischemic Encephalopathy


With Hypothermia
Jose M. R. Perez, MD,* Educational Gaps
Alexander Feldman, DO,†
1. Candidates for therapeutic hypothermia need to be properly identified.
Gad Alpan, MD, MBA†
2. It is unclear whether the indications for therapeutic hypothermia can be expanded
further.
Author Disclosure 3. The need for careful monitoring during the rewarming phase of therapeutic
Dr Perez has disclosed hypothermia should be recognized.
that he holds a patent
for the Neonatal Abstract
Laminar Flow Unit. Hypoxic-ischemic encephalopathy (HIE) is associated with high rates of morbidity and
mortality, and only recently has an effective treatment been developed to mitigate its se-
Drs Feldman and
quelae. Moderate therapeutic hypothermia (TH) (core temperatures of 33oC–35oC) has
Alpan disclosed no
been found in a number of randomized clinical trials to reduce mortality and improve neu-
financial relationships rodevelopmental outcomes in full-term neonates with moderate or severe HIE. TH can be
relevant to this article. administered using various techniques, but optimal use dictates meticulous control of tar-
This commentary does geted core temperature (usually assessed as rectal temperature), and thus servo-controlled
contain a discussion of devices have an advantage. Treatment is applied for 72 hours, and then gradual rewarming
is performed at a slow rate. Rapid rewarming and hyperthermia should be avoided because
an unapproved/
they may be associated with neuronal damage and reversal of the benefits of TH. Long-
investigative use of
term outcomes, at ages 6 to 8 years, correlate well with the benefits observed at 18- to
a commercial product/ 24-month follow-up. Although better than any alternative therapy currently available,
device. the rates of mortality and morbidity still remain high even when using TH.

Objectives After reading this article, readers should be able to:

1. Appreciate some of the mechanisms whereby hypothermia affects neuroprotection.


2. Gain an overall familiarity with various means used to maintain moderate
hypothermia in the newborn.
3. Learn about the evidence base underlying the clinical use of therapeutic hypothermia.
4. Understand the need for careful monitoring during maintenance of hypothermia and
the rewarming phase of treatment.

Introduction
Hypoxic ischemic encephalopathy (HIE) is estimated to occur in 1 to 2 per 1,000 full-term
live-born neonates. In developing countries, the incidence is significantly higher. For many
years, other than supportive treatment, there was little proven benefit that medicine could
offer these infants, and rates of mortality and impaired neurodevelopmental outcomes re-
mained high. Recently, various clinical trials and meta-analyses have found that treatment
with moderate hypothermia confers a benefit in HIE with reductions in mortality and ad-
verse developmental outcomes in full-term newborns with moderate or severe HIE.

Mechanisms of HIE and Therapeutic Hypothermia


HIE evolves over time with various overlapping pathophysiologic processes. After initial
hypoxic-ischemic and asphyxia insult (primary phase), some neurons die. However, many

*SIBEN - Ibero-American Society of Neonatology, International Neurodevelopment Neonatal Center, São Paulo, Brazil.

The Regional Neonatal Center, Maria Fareri Children’s Hospital at Westchester Medical Center, New York Medical College,
Valhalla, NY.

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neurology / HIE & therapeutic hypothermia

neurons partially recover after the initial insult (either mediators. Hypothermia attenuates various steps in this
spontaneously or after resuscitative measures) during a la- proinflammatory cascade. Hypothermia attenuates STAT3
tent phase, which may last 6 to 15 hours. After this, there expression, which may also result in a decreased number of
is a secondary phase of neuronal cellular metabolic dete- apoptotic cells. Recent studies have also suggested that hy-
rioration, which may result in further subsequent neuro- pothermia may have an additional, more specific, mecha-
nal death. Neuronal injury during this second phase may nism of action. Although hypothermia is usually associated
be extensive and is responsible for many of the adverse with downregulation of protein synthesis, there is a small
outcomes seen after HIE. It is the goal of treatment(s), in- subset of cold-shock proteins that are induced by hypo-
cluding hypothermia, to mitigate this injury. As outlined thermia (and suppressed by elevated temperature). One
in this sequence of events, there is a therapeutic window such protein is the RBM3. This protein is expressed dur-
of opportunity during which treatment must be given be- ing early stages of brain development, has antiapoptotic
cause, once the secondary phase is well under way, there functions, and can enhance cell proliferation.
is little of benefit that hypothermia can confer. The above is only a selective sketch, necessarily brief, of
The cellular and metabolic processes that underlie the in- the numerous mechanisms that are affected by hypother-
jury after HIE are complex, and the determinants of final mia. The mechanisms of action of hypothermia have been
injury are multifactorial. Excitatory amino acids (eg, gluta- derived from focused animal and in vitro studies; thus, it
mate), free radical (oxygen species and nitric oxide), im- remains unclear which are the key mechanisms that are
paired cellular osmotic regulation and calcium influx, crucial in the human infant. It may well be that the neuro-
mitochondrial impairment, changes in various trophic fac- protective effects of hypothermia are, in fact, attributable
tors and inflammatory cascades, and, importantly, activation to its breadth and multiplicity of actions. An attempt to
of apoptotic mechanisms all play a role. Hypothermia affects classify the relative importance of hypothermia’s various ef-
all these pathways. fects is made in the excellent review by Drury et al. Their
During the initial phase of HIE, one immediately obvi- conclusion is that the most important mechanisms of neu-
ous effect of hypothermia is to reduce tissue metabolic de- roprotection are those that relate to apoptosis, the mitiga-
mands. In an animal model, every 1°C reduction in body tion of secondary inflammation, and possibly the effects of
temperature was associated with a 6% to 10% decrease in hypothermia on glutamate receptor activation.
cerebral metabolism. However, the benefits of hypother-
mia are not restricted to the mere reduction in metabolic Methods of Inducing Hypothermia
demands. Ischemia results in intracellular and extracellular A variety of methods are available to induce and maintain
acidosis, a decrease in adenosine triphosphate, and impair- hypothermia: cooling mattresses, selective head cooling,
ment to various ion channels. In addition to cellular swell- and ice bags or gloves filled with ice. Recently, a new laminar
ing, there is a significant influx of calcium into neuronal flow cooling device has been described. Total-body cooling
cells, which leads to mitochondrial dysfunction. Through (33ºC–34ºC) was achieved by convection using the neona-
activation of a caspase intrinsic pathway, this leads to apo- tal laminar flow unit for 72 hours, with continuous rectal
ptosis. Hypothermia has a beneficial effect on many of temperature servo-control, isolation, and humidification.
these ion pump dysfunctions and reduces cellular calcium With this device, we found that our outcomes are very sim-
influx and thus neurotoxicity. Ischemia reperfusion is also ilar to those reported in previous trials and meta-analyses.
associated with production of free oxygen radicals and ni- The laminar flow unit is effective in maintaining moderate
tric oxide, which further impairs mitochondrial respiration total-body hypothermia under well-controlled conditions.
and leads to apoptosis. This effect is particularly important In selective head cooling, active cooling is applied to
in newborns, whose protective antioxidant mechanisms the cranium only, whereas in the other methods whole-
may be overwhelmed. Free radicals also lead to peroxida- body cooling is achieved. Means of cooling also differ in
tion of lipids, proteins, and nucleic acids. Hypothermia is that in some of them temperature control is maintained
unlikely to completely counter this surge in free radicals, in the desired range using servo-control, whereas in others
but it appears to significantly reduce it, thereby allowing temperature is controlled manually. Core temperature
endogenous antioxidant mechanisms to mitigate damage. (usually measured rectally) was most stable and within
Ischemia reperfusion also stimulates various immune and the desired range when using the whole-body cooling
inflammatory responses, which, when unchecked, can lead mattress with servo-control, and the poorest temperature
to secondary neuronal injury. Thus, ischemia reperfusion maintenance was associated with using water-filled gloves.
triggers release of various proinflammatory cytokines (eg, Overall, servo-control devices afford less variability in
interleukin 6), various chemokines, and proinflammatory temperature maintenance and decrease the likelihood of

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neurology / HIE & therapeutic hypothermia

temperature overshoot. Most of the trials conducted on randomized clinical trials found that TH was associated
therapeutic hypothermia (TH) aimed to maintain core with improvement in the following outcomes: combined
temperature in the range 33ºC to 34oC or 34ºC to 35oC. outcome of death or major neurodevelopmental disability,
This moderate hypothermia is maintained for 72 hours, mortality, major neurodevelopmental disability in survi-
and then a rewarming phase is commenced with a recom- vors, and cerebral palsy. Disability was assessed at ages
mended rewarming rate of 0.5oC per hour. 18 to 24 months. For the combined outcome of death
Excessive rewarming is to be avoided. In the practical or major disability, mean absolute risk reduction and num-
application of TH, the clinician should be familiar with ber needed to treat were 15% and 7, respectively. Five to
the device and protocol used in their unit. 10 infants have to be treated to prevent one death or major
disability. There was also a reduction in blindness, al-
though this was not statistically significant. Do the outcomes
Selection of Infants for TH differ according to the method of cooling (total-body
Newborns with suspected HIE should be screened as to
vs selective head cooling)? In detail, yes, but, overall,
whether they are eligible to receive TH. Although the var-
we think not. For example, for the single outcome of mor-
ious clinical trials of TH differed in detail, they were overall
tality, meta-analyses found an overall reduction and also
similar in their enrollment criteria. In broad outline, these
a reduction in the studies that used whole-body hypother-
consisted of (1) gestational age greater than 35 or
mia. However, although there was also a reduction in
36 weeks, (2) evidence of peripartum compromise (eg, Ap-
mortality in the selective-head-cooling studies, the latter
gar scores <5 at 10 minutes and/or cord pH <7.1 or ini-
reduction was not statistically significant. Of note, the ef-
tial arterial blood pH <7.1 or base deficit of ‡12 mEq/L
fect of hypothermia was consistent, and the issue of con-
[‡12 mmol/L] within 1 hour of birth), (3) clinical evi-
cern is the achievement of statistical significance. Because
dence of encephalopathy, (4) enrollment within 6 hours
statistical significance depends on a number of factors,
of birth, and (5) no evidence of major congenital anoma-
sample size being one of them, we think that the consis-
lies. Some studies also used abnormal amplitude integrated
tency of clinical results should outweigh the formal statis-
EEG as a minor enrollment criterion.
tical analyses in this case. At this stage of knowledge, no
Recent reports have suggested that the eligibility criteria
data support preference for one method of TH over an-
mentioned above should be liberalized. HIE occurs in neo-
other; such data can likely be obtained only by a head-
nates born at 33 to 35 weeks’ gestation at an incidence
to-head comparison of different techniques. Of greater
equal or greater than that in full-term infants. Current data
interest is whether the benefits of hypothermia depend
are that moderate hypothermia is safe, and given the lack of
on severity of the presenting encephalopathy. For both
alternative proven therapies, there is a natural temptation
moderate and severe HIE, there is a reduction in the com-
to extend the application of hypothermia to this lower ges-
bined outcome of mortality or major disability and for the
tational age group. Clinical trials are in progress to address
outcome of mortality alone. However, infants with severe
this. At this stage, however, we would suggest that the cur-
HIE had no reduction in major neurodevelopmental dis-
rent evidence does not support extension of therapeutic
ability, but such a reduction was seen in those with only
hypothermia to an extreme extent because the mechanisms
moderate encephalopathy. This finding raises the question
of cerebral injury in very premature neonates likely differ
of whether treatment with hypothermia in infants with se-
from those of more mature preterm infants. Similarly,
vere HIE increases survival while adding to the burden of
the requirement that treatment be applied within 6 hours
increased disability. Hence, it is reassuring that treatment
of birth is also often relaxed. The requirement that therapy
with hypothermia in newborns with severe HIE had
be given within 6 hours is based on animal studies. The
a mean reduction in incidence of major disabilities, albeit
logic of applying treatment within the therapeutic window
not a statistically significant one: the mean relative risk of
has a solid foundation in physiologic studies. However, no
major disability was 0.75 (95% CI, 0.5–1.12). Had im-
data allow precise timing of that therapeutic window in hu-
proved survival been associated with increased disability,
man neonates. Current trials are under way to study the
we would have expected a different trend.
possible benefits of hypothermia begun after 6 hours.
Long-term outcome data (6–8 years) are available from
some of the large trials of TH. Overall, there was a strong
Outcomes After TH and Adverse Effects correlation between outcomes assessed at 18 to 24 months
Various randomized clinical trials have found significant and those in childhood. In following up infants who re-
benefits of moderate hypothermia in full-term newborns ceived whole-body hypothermia at ages 6 to 7 years, the
with moderate or severe HIE. Meta-analyses of 11 primary outcome assessed was death or IQ of less than

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neurology / HIE & therapeutic hypothermia

70. Secondary outcomes were death, severe disability, var- of error should be allowed so that infants receiving TH
ious components of disability, and cognitive function. TH are not exposed to hypocarbia, which is associated with
was found to confer benefit in the outcomes of death or impaired neurologic outcome in itself.
IQ of less than 70, mortality, and the combined outcomes TH affects many organ systems. One should not as-
of death or severe disability, death or IQ of less than 55, sume that the usual pharmacokinetic data obtained in eu-
and death or cerebral palsy. For the single outcome of IQ thermic infants necessarily holds. Although the data
of less than 70 or the single outcome of cerebral palsy, appear to be conflicting, TH may be associated with al-
there were reduced rates in the group receiving TH, but tered gentamycin kinetics, and a reduced clearance of
these were not statistically significant. There was no differ- morphine, with elevated levels, has been found in neo-
ence between TH and control children in incidence of low nates receiving TH. Until further data become available,
attention and executive function scores or low visuospatial it may be wise to monitor drug levels, when relevant,
scores. more closely during TH. Sedation is highly recommen-
TH appears remarkably safe when used with strict atten- ded during TH because stress increases metabolic de-
tion to details. The most common adverse effect noted is mand and, likely, neural activity. Temperature control
sinus bradycardia. Increased incidence of leukopenia and is also easier in sedated infants.
neutropenia was noted when using whole-body cooling, The rewarming phase of TH is associated with various
and an increased incidence of thrombocytopenia was noted dangers of its own, in addition to those mentioned above.
when using selective head cooling. No adverse clinical out- Rewarming should proceed slowly, at a rate not greater
comes were associated with these findings; specifically, than 0.5oC per hour. More rapid rates, or overshooting
there was no increase in the incidence of sepsis or in the into a hyperthermic range, are associated with adverse neu-
incidence of clinical coagulopathy. Furthermore, treatment rologic outcomes or seizures. Studies in animals have sug-
with TH compared with euthermic controls was not asso- gested that there is an increase in apoptosis and reversal of
ciated with a differential incidence of arrhythmias (other previous benefits from hypothermia, when rewarming at
than the bradycardia mentioned above), hypotension, need a fast pace (4oC per hour) compared with a slower pace
for vasopressor drugs, anemia or requirement for transfu- (0.5oC per hour).
sions, coagulopathy, renal failure or impaired urine output,
sepsis, pulmonary hypertension, or hepatic dysfunction. Open Questions and Adjunct Therapies
We have previously mentioned issues surrounding the lib-
Further Considerations During TH: Supportive eralization of criteria deemed appropriate for administra-
Care, Medications, and the Rewarming Phase tion of TH. Similarly, the core temperatures used and
HIE may be associated with significant dysfunction of the duration of TH should not be seen as cast in stone.
other organ systems; hence, attempts should be made to Many of the pathophysiologic processes mentioned above
optimize general supportive care. Appropriate interven- overlap and likely exhibit some variability. Patients are also
tions are called for to ensure adequate blood flow, venti- likely to exhibit significant heterogeneity even within the
lation, and oxygenation. Hypothermia is associated with common coarse classification of moderate or severe en-
a decrease in cardiac output, heart rate, and mean arterial cephalopathy. It would thus seem unreasonable to expect
blood pressure, with an increase in peripheral vascular re- a “one size fits all” protocol to achieve maximal benefits.
sistance and no change in stroke volume. The decrease in Thus, ongoing trials are in progress to study the effects of
metabolic rate is equal to or greater than the decrease in mildly extending either the extent or duration of hypother-
cardiac output; hence, changes in oxygen delivery are mia in patients with HIE. An intriguing recent study sug-
not usually of great concern. These changes are essentially gested that current protocols are insufficient for newborns
reversed during rewarming; hence, the rewarming phase of with severe HIE. Magnetic resonance spectroscopy was
TH is associated with a decrease in arterial blood pressure, used to determine regional brain temperatures during
and one should monitor for significant hypotension or im- TH. It was found that, when cooled to the same rectal
paired perfusion and treat accordingly. In theory, the he- temperature, brain temperatures were higher in infants
modynamic changes associated with hypothermia may with severe HIE compared with those with moderate
mask cardiac dysfunction, which may become apparent HIE. It is thus possible that improved outcomes in pa-
on rewarming; this has been confirmed in animal models. tients with severe HIE might be achieved if they were se-
There is debate about whether measured arterial lectively cooled to a greater extent.
blood gas values, in particular PCO2, should be corrected Various trials are under way to study the benefits of
for core temperature during TH. In any event, a margin TH together with various allied therapies, with somewhat

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different mechanisms of actions, to determine whether Hoque N, Chakkarapani E, Liu X, Thoresen M. A comparison of
combined treatment improves outcomes beyond those cooling methods used in therapeutic hypothermia for perinatal
asphyxia. Pediatrics. 2010;126(1):e124–e130
achieved by TH alone. Three such treatments are combi-
Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis
nations of TH with erythropoietin, inhaled xenon, or PG. Cooling for newborns with hypoxic ischaemic encephalop-
topiramate. The success of TH has indicated that out- athy. Cochrane Database Syst Rev. 2013;1(1):CD003311
comes of infants with HIE can be improved. This success Olsen SL, Dejonge M, Kline A, et al. Optimizing therapeutic
has encouraged the search for further treatments because hypothermia for neonatal encephalopathy. Pediatrics. 2013;131
(2):e591–e603
the outcomes after TH, although better than the alterna-
Papile LA, Baley JE, Benitz W, et al; Committee on Fetus and
tive, still leave much room for improvement. Newborn. Hypothermia and neonatal encephalopathy. Pediat-
rics. 2014;133(6):1146–1150
Perez JMR, Golombek SG, Fajardo C, Sola A. A laminar flow unit
Conclusions for the care of critically ill newborn infants. Med Devices (Auckl).
TH confers benefit in full-term neonates with HIE: it is as- 2013;6:163–167
sociated with reduced mortality and improved neurodevel- Róka A, Melinda KT, Vásárhelyi B, Machay T, Azzopardi D, Szabó
opmental outcomes. When using TH, there should be M. Elevated morphine concentrations in neonates treated with
attentive monitoring of adherence to maintenance tempera- morphine and prolonged hypothermia for hypoxic ischemic
encephalopathy. Pediatrics. 2008;121(4):e844–e849
tures, and monitoring is particularly important during the re-
Saliba E. Should we extend the indications for therapeutic
warming phase, where excessively rapid temperature increase hypothermia? Acta Paediatr. 2015;104(2):114–115
or temperature overshoot should be avoided. Temperature Scaravilli V, Bonacina D, Citerio G. Rewarming: facts and myths from
servo-control is highly recommended. While receiving the systemic perspective. Crit Care. 2012;16(suppl 2):35–38
TH, infants should be given adequate ventilatory and he- Schmitt KRL, Tong G, Berger F. Mechanisms of hypothermia-
induced cell protection in the brain. Mol Cell Pediatr. 2014;1:7
modynamic support, if needed, because the consequences
Shankaran S. Current status of hypothermia for hypoxemic ischemia
of respiratory or cardiovascular impairment may be more of the newborn. Indian J Pediatr. 2014;81(6):578–584
severe with less margin for error. Pharmacologic treatment Shankaran S. Outcomes of hypoxic-ischemic encephalopathy in
should be monitored with drug levels when applicable. neonates treated with hypothermia. Clin Perinatol. 2014;41(1):
149–159
Shankaran S. Therapeutic hypothermia for neonatal encephalopa-
thy. Curr Opin Pediatr. 2015;27(2):152–157
American Board of Pediatrics Neonatal–Perinatal Shankaran S. Therapeutic hypothermia for neonatal encephalopa-
thy. Curr Treat Options Neurol. 2012;14(6):608–619
Content Specifications
Smit E, Liu X, Jary S, Cowan F, Thoresen M. Cooling neonates
• Know the clinical features, diagnosis, and who do not fulfil the standard cooling criteria - short- and long-
management of perinatal hypoxic ischemic term outcomes. Acta Paediatr. 2015;104(2):138–145
encephalopathy. Tagin MA, Woolcott CG, Vincer MJ, Whyte RK, Stinson DA.
• Know the management of perinatal Hypothermia for neonatal hypoxic ischemic encephalopathy: an
asphyxia, including neural protective updated systematic review and meta-analysis. Arch Pediatr
strategies. Adolesc Med. 2012;166(6):558–566
Thoresen M, Whitelaw A. Cardiovascular changes during mild
therapeutic hypothermia and rewarming in infants with
hypoxic-ischemic encephalopathy. Pediatrics. 2000;106(1, pt
Suggested Reading 1):92–99
Austin T, Shanmugalingam S, Clarke P. To cool or not to cool? Wang B, Armstrong JS, Lee J-H, et al. Rewarming from therapeutic
hypothermia treatment outside trial criteria Arch Dis Child Fetal hypothermia induces cortical neuron apoptosis in a swine model
Neonatal Ed. 2013;98(5):F451–F453 of neonatal hypoxic-ischemic encephalopathy. J Cerebr Blood
Bhat BV, Adhisivam B. Therapeutic hypothermia in hypoxic-ischemic Flow Metab. 2015:1–13
encephalopathy. Indian J Pediatr. 2015;82(2):105–106 Wu T-W, McLean C, Friedlich P, et al. Brain temperature in
Drury PP, Gunn ER, Bennet L, Gunn AJ. Mechanisms of hypothermic neonates with hypoxic-ischemic encephalopathy during thera-
neuroprotection. Clin Perinatol. 2014;41(1):161–175 peutic hypothermia. J Pediatr. 2014;165(6):1129–1134

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1. A newborn infant requires extensive resuscitation at birth and is diagnosed as having hypoxic-ischemic
encephalopathy (HIE). There is not a clear origin, but the mother reports that there may have been decreased
fetal movement during the past day. Which of the following statements correctly describes the mechanism of
brain injury in HIE?
A. In contrast to older pediatric and adult patients, fetal and neonatal neurons do not have the capacity to
recover after an ischemic insult.
B. The latent phase after an initial ischemic insult lasts 6 to 15 hours.
C. The secondary phase of neuronal injury is typically very mild and does not add significantly to the primary
injury.
D. The greatest neuronal injury occurs at the third phase of injury, which is typically 24 to 72 hours after
delivery.
E. Although apoptosis has been implicated in brain injury of preterm infants, it does not appear to have a role
in term infants with HIE.

2. The patient is placed on a protocol for therapeutic hypothermia (TH). Which of the following statements
regarding mechanism of action of TH for HIE is correct?
A. Hypothermia decreases metabolic activity of the heart and lungs but increases the metabolic activity of the
brain, leading to improved neuronal reparative efforts.
B. Hypothermia reduces calcium influx into neuronal cells, potentially reducing the degree of mitochondrial
dysfunction.
C. Hypothermia increases the production of free oxygen and nitric oxide in cerebral blood vessels.
D. Hypothermia leads to increased release and activity of interleukin 6 and other cytokines, which can help to
prevent neuronal secondary injury.
E. Hypothermia increases STAT3 expression, which is a cellular protection mechanism against reperfusion
injury.

3. The patient is placed on a cooling mattress. The father of the child asks why the whole body is being cooled if
the brain is the target of treatment. Which of the following statements regarding method of cooling newborns
is correct?
A. Laminar flow cooling devices have been unsuccessful in achieving target cooling temperatures.
B. Core temperature is most stable and within the desired range when using whole-body cooling mattress
with servo-control.
C. The use of water-filled plastic gloves has been evaluated and found to be just as effective at maintaining
target temperature and reducing variability compared with any of the other established methods.
D. Most of the trials conducted on therapeutic hypothermia for newborns have targeted a core body
temperature of 35˚C to 36˚C.
E. In selective head cooling, active cooling is applied to the cranium and a vest over the upper chest to cool
the heart.

4. The father asks about the likelihood of his daughter having a good outcome after receiving hypothermia.
Which of the following statements about long-term outcomes after therapeutic hypothermia for HIE is true?
A. One caveat in considering outcomes is that although survival is improved with hypothermia, those who
receive hypothermia and survive are more likely to have severe disability compared with survivors who did
not receive hypothermia.

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neurology / HIE & therapeutic hypothermia

B. A combined analysis of all the trials to date found clear superiority of selective head cooling compared with
whole-body hypothermia.
C. The long-term outcomes of the randomized clinical trials to date have only reached outcomes at age
12 months.
D. Meta-analyses of randomized clinical trials found that therapeutic hypothermia is associated with
improvement in the combined outcome of death or major neurodevelopmental disability, mortality, major
neurodevelopmental disability in survivors, and cerebral palsy.
E. The number needed to treat for the combined outcome of death or major disability is 20 to 25 patients.

5. The infant is receiving the third day of treatment with hypothermia, and the team prepares to rewarm. Which
of the following is appropriate for rewarming this patient?
A. Rewarming should take place at a rate not greater than 0.5˚C per hour.
B. Some degree of hyperthermia during the rewarming phase is likely and even desirable because it is
associated with decreased incidence of seizures.
C. Rewarming is often associated with hypertension as cardiac output increases, and low-dose prophylactic
hydralazine is recommended for term patients.
D. An effort should be made to induce a mild to moderate hypocarbia to prevent respiratory deterioration.
E. Sedation with drugs such as morphine should be avoided during initiation and maintenance of
hypothermia therapy, as well as the rewarming phase.

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Treating Hypoxic Ischemic Encephalopathy With Hypothermia
Jose M. R. Perez, Alexander Feldman and Gad Alpan
NeoReviews 2015;16;e413
DOI: 10.1542/neo.16-7-e413

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Treating Hypoxic Ischemic Encephalopathy With Hypothermia
Jose M. R. Perez, Alexander Feldman and Gad Alpan
NeoReviews 2015;16;e413
DOI: 10.1542/neo.16-7-e413

The online version of this article, along with updated information and services, is
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60007. Copyright © 2015 by the American Academy of Pediatrics. All rights reserved. Online
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