COMMENTARY
Hypothermia: A Neuroprotective Therapy for
Neonatal Hypoxic-Ischemic Encephalopathy
Lillian R. Blackmon, MDa, Ann R. Stark, MDb, the Committee on Fetus and Newborn, American Academy of Pediatrics
aDepartment of Pediatrics, Division of Neonatology, University of Maryland School of Medicine, Baltimore, Maryland; bDepartment of Pediatrics, Section of Neonatology,
Baylor College of Medicine, Houston, Texas
The authors have indicated they have no financial relationships relevant to this article to disclose.
I N MAY, 2005, the National Institute of Child Health and
Human Development (NICHD) convened a workshop
to evaluate the status of knowledge regarding the safety
and efficacy of hypothermia as a neuroprotective ther-
apy for neonatal hypoxic-ischemic encephalopathy
(HIE).1 Participants, including the current and past
chairs of the American Academy of Pediatrics Commit-
tee on Fetus and Newborn, reviewed current evidence
and identified gaps in knowledge and clinical implica-
tions. They agreed that current evidence supports the
conclusion that mild to moderate hypothermia holds
promise for the amelioration of neural injury after a
perinatal hypoxic-ischemic insult.
OBJECTIVES
The objectives of this commentary are to review briefly
the background and current knowledge regarding the
therapeutic efficacy and safety of sustained mild to mod-
erate hypothermia to prevent death and severe disability
in neonates who have experienced a significant hypoxic-
ischemic insult and to urge caution and restraint in the
immediate implementation of this therapy before more
corroborating evidence has been published.
BACKGROUND
The lack of a definitive therapeutic approach for HIE
remains one of the unresolved clinical frustrations of
contemporary neonatal medicine. The dismal prognosis
for infants who sustain a severe asphyxial insult in the
perinatal period has altered little despite advances in the
application of diagnostic and multiorgan life-support
techniques to newborns.2–5 In part because the principal
etiologies differ, therapeutic advances in the manage-
ment of encephalopathy in older children and adults
have not proved to be applicable to neonates.6 In addi-
942 BLACKMON, et al
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tion, unlike older patients, the etiology, onset, and du-
ration of perinatal hypoxic-ischemic injury are varied
and often unknown.
Early Studies
In the 1950s and 1960s, Miller and Westin7,8 studied the
physiologic basis for the neuroprotective role of hypo-
thermia in the treatment of “asphyxia neonatorum,”
first in newborn animals and then in human newborns.
They and others demonstrated improved survival with-
out cerebral palsy or mental retardation of apneic
newborns who were cooled rapidly to 23 to 32°C after
delivery when conventional resuscitation techniques
failed.9–13 Despite their results, hypothermia did not be-
come an accepted therapy in neonatal care, in part be-
cause it was never evaluated by randomized, controlled
trials (RCTs).
Hypothermia During Cardiac Surgery
Hypothermic circulatory arrest (core temperature of 18 –
20°C) was introduced in the 1960s to facilitate repair of
complex congenital heart disease.14 This technique al-
lowed earlier definitive repair of complex defects and
thus less cardiac morbidity in infancy and early child-
Abbreviations: NICHD, National Institute of Child Health and Human Development;
HIE, hypoxic-ischemic encephalopathy; RCT, randomized, controlled trial;
NRN, Neonatal Research Network
Opinions expressed in this commentary are those of the author and not necessarily those of
the American Academy of Pediatrics or its Committees.
www.pediatrics.org/cgi/doi/10.1542/peds.2005-2950
doi:10.1542/peds.2005-2950
Accepted for publication Dec 14, 2005
Address correspondence to Lillian R. Blackmon, MD, University of Maryland School of Medicine,
Room N5W68, 22 S Greene St, Baltimore, MD 21201. E-mail: lblackmon@peds.umaryland.edu
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2006 by the
American Academy of Pediatrics
hood. It was widely adopted, although the duration of
ischemia that could be sustained without incurring per-
manent central nervous system injury was not estab-
lished. The heterogeneity of lesions and lack of unifor-
mity of the operative procedures and duration of
circulatory arrest made it difficult to draw conclusions
about safety. Some case series reported poor neurologic
outcomes linked to longer duration of arrest, although
the role of depth of cooling is uncertain.15–17 The Boston
Circulatory Arrest Trial compared deep hypothermia
with either circulatory arrest or low-flow cardiopulmo-
nary bypass in infants with a single lesion. In this study,
all groups have had more neurodevelopmental problems
than expected for their age peers, and more functional
deficits that may impact educational achievement have
been revealed as the children have grown older.18–20
Contemporary Studies
Several groups have demonstrated recently that either
selective or whole-body mild to moderate hypothermia
(33–34°C), applied within hours of an acute asphyxial
event, is neuroprotective in various animal models.21–26
In addition, the pathogenesis of neural injury from a
hypoxic-ischemic insult has been defined better,27,28 and
technically applicable mechanisms for cooling neonates
have been developed.29,30
After pilot studies to identify technical and safety
issues (⬃104 infants subjected to various regimens of
hypothermia),29–35 RCTs were initiated to test hypother-
mia in near-term and term human neonates (ⱖ35–36
weeks’ gestation) with HIE. To date, only 3 trials have
been reported, with a total of 250 hypothermia-treated
infants and 257 routine-thermal-support controls. These
trials include those by Eicher et al,36,37 who used whole-
body cooling with surface ice packs and cooling blankets,
Gluckman et al,38 who used an experimental head-cool-
ing device (Cool Cap), and the Neonatal Research Net-
work (NRN) (Shankaran et al39), who used whole-body
cooling with cooling blankets. These trials assessed the
primary composite outcome of death or neurodevelop-
mental disability at 12 months37 or 18 months38,39 of age.
Characteristics of the trials and the various outcomes are
summarized in Tables 1 and 2. The 3 reported studies
differ considerably in methodology, entry criteria, and
follow-up evaluation. Three additional RCTs—the TOBY
trial,40 the Infant Cooling Evaluation trial,41 and a trial by
Simbruner and the neo.nEuro.network42—are under-
way and share some similarities to the published reports
in entry criteria, methodology, and outcomes that may
make meta-analysis possible.
DISCUSSION
The question of sufficient efficacy has not been an-
swered adequately. Because the trials vary in method-
ology and results, comparisons are difficult. The im-
provement in the composite primary outcome of death
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or moderate and severe disability at 18 months of age
was statistically significant in only 1 trial (NRN).39 In that
trial, blood gas entry criteria were less stringent than in
the others, and the primary outcome included moderate
as well as severe disability. Neither survival nor survival
without disability was independently significantly im-
proved. The influence of the initial severity of clinical
status on the ultimate outcome is uncertain, because
none of the studies were designed to demonstrate a
relationship between clinical severity at entry and the
final outcomes. Infants with less severe manifestations of
HIE may be at lower risk for a severe outcome. However,
including moderate disability as a component of the
primary study outcome could decrease the likelihood of
showing a significant difference between treatment and
control groups.
Safety was addressed in both the initial pilot trials and
the RCTs, although more comprehensively in some.29–39
Cold-injury syndrome, a potential complication of ther-
apeutic hypothermia, can result in sclerema, multisys-
tem organ damage (especially pulmonary hemorrhage,
renal failure, and disseminated intravascular coagulopa-
thy), hypovolemia, glucose instability, and pulmonary
hypertension.43,44 However, no serious adverse safety is-
sues have been reported to date, although all 3 RCTs
noted reversible cardiovascular effects, specifically sinus
bradycardia and hypotension. Thoresen and Whitelaw45
reported that some concurrent medications exacerbated
adverse cardiovascular effects during both cooling and
rewarming in an early pilot study. Gluckman et al38
reported elevated liver enzymes and Eicher et al36 noted
an increase in late coagulopathy (several days after re-
warming) and more persistent pulmonary hypertension
that required inhaled nitric-oxide treatment in the hy-
pothermia-treated infants. Reported causes of death in-
cluded multiorgan failure; however, it is uncertain
whether this resulted from the initial hypoxic-ischemic
insult or from that resulting from the hypothermia treat-
ment.37–39 Excessive warming after a hypoxic-ischemic
insult may be deleterious and magnify any difference in
outcome between treatment groups.46,47 In the NRN trial,
41 infants in the control group experienced hyperther-
mia (core temperatures of ⬎38°C) at least once during
the study period.39 Eicher et al36 reported elevated core
temperatures during both the study period and later in
the first week in treated and control infants.
The NICHD conference identified many significant
questions that remain to be answered before universal
implementation can be encouraged. These questions in-
clude:
1. What is the most effective technique— head cooling
with or without deep body cooling or deep body
cooling?
2. What is the most effective and safest duration of
cooling— 48 hours, 72 hours, or longer?
PEDIATRICS Volume 117, Number 3, March 2006 943
 944
BLACKMON, et al
TABLE 1 Comparison of Study Methodology of RCTs
Study Entry Subject No. Infant Criteria Diagnostic Criteria Hypothermia Management
Dates
Eicher et al36,37 (7 sites, 6 follow- 1998–2001 H, 32; C, 33 ⱖ35 wk GA, ⱖ2 kg BW; exclusions: One of: UA pH ⱕ7; UA BD ⱖ13; 10-min Ice packs initially to head and body, circulating
up) maternal chorioamnionitis, sepsis at Apgar ⱕ5; resuscitation for ⱖ5 min; cold-water blanket for maintenance; target
birth, BW or HC ⬍10%, OR presumed HR ⬍80 for ⱖ15 min; OR postnatal O2 T: rectal 33 ⫾ 0.5°C enrollment age: 3.1–4.6
chromosomal abnormality saturation ⱕ70% or PaO2 ⱕ35 for 20 h; mean time to target T ⬃ 120 min;
min and evidence of ischemia; AND 2 duration: 48 h; rewarming: 0.5°C per h
of: abnormal tone, reflexes, state of
consciousness, seizures, posturing,
autonomic dysfunction
Gluckman et al38 (25 sites) 1999–2002 H, 116; C, 118 ⱖ36 wk GA, ⱖ1.8 kg BW; exclusions: 10-min Apgar ⱕ5 AND resuscitation for Head: cooled with circulating water coil cap at
prophylactic anticonvulsant, major ⱖ10 min; OR UCB pH ⱕ7 or UCB BD 8–12°C; body: servo-controlled radiant
congenital anomaly, traumatic ⱖ16 OR ⱕ60-min postnatal blood pH warmer; target T: head, not reported; rectal,
intracranial hemorrhage, severe IUGR, ⱕ7 OR BD ⱖ16; AND: lethargy, 34–35°C; enrollment age: mean 4.8 h; time
HC ⬍ mean ⫺ 2 SD, moribund stupor, or coma AND 1 or more of: to target: within 2 h; duration: 72 h;
hypotonia, abnormal reflexes, absent rewarming: 0.5°C per h
or weak suck; OR clinical seizures
Shankaran et al39 (NRN) (15 sites) 2000–2003 H, 102; C, 106 ⱖ36 wk GA, ⱖ1.8 kg BW; exclusions: UCB or ⱕ60-min postnatal blood pH ⱕ7 Whole-body cooling with circulating cold-
major congenital anomaly, severe or BD ⱖ16; OR pH 7.01–7.15, or BD water blanket(s); target T: esophageal.
IUGR, moribund 10–15.9; OR if no blood gas THEN an 33.5°C; enrollment age: 4.3 ⫾ 1.3 h; time to
acute perinatal event AND either target: ⱕ90 min; duration: 72 h; rewarming:
Apgar ⱕ5 at 10 min or ventilation for 0.5°C per h
10 min; AND seizure OR 1 abnormal
neurologic sign in at least 3 categories
of: level of consciousness,
spontaneous activity, posture, tone,

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primitive reflexes, autonomic system
H indicates hypothermia; C, control; GA, gestational age; BW, birth weight; HC, head circumference; UA, umbilical artery; UCB, umbilical cord blood; BD, base deficit; T, temperature; IUGR, intrauterine growth restriction.
 TABLE 2 Comparison of Severity and Outcomes of RCTs
Study Neurologic Status at Entry Primary Outcomes Follow-up Status Deaths Cognitive Motor Function Neurologic Status Other
Function
Eicher et al36,37 Sarnat stage III: H, 25 (78%); Motor function, Bayley PDI Withdrawn before H, 10 (31%); C, 14 (42%); Severe (MDI ⬍70): Severe (PDI ⬍70): H, 4 (24%); Spastic quadriplegia: Hearing loss: H, 2; C, 3;
C, 25 (76%); Sarnat stage ⱖ2 SD below mean ⫽ study completion: support withdrawn: H, 4 (24%); C, 5 C, 7 (64%); moderate (PDI 2 (group not cortical blindness:
II: H, 5; C, 5 ⬍70 OR death at 12 mo H, 2; lost or H, 9; C, 9; late (52%); moderate 70–84): H, 5 (29%); C, 0 reported); C, 1; cortical visual
incomplete data: deathsa: C, 1 (MDI 70–84): H, seizures: H, 1 defects: H, 2;
H, 5; C, 8 2 (11%); C, 1 corrective lens: H, 2;
(8%) C, 1
Gluckman et al38 Severe aEEG: H, 47 (36%); C, Bayley MDI ⬍70, GMF Lost to follow-up: H, 36 (33%); C, 42 (38%); Bayley MDI ⬍70: H, Bayley PDI ⬍70: H, 21; C, 23 GMF 3–5: H, 14; C, Bilateral cortical visual
32 (27%); moderate level 3–5, or bilateral H, 8; C, 8 support withdrawn: 21 (30%); C, 24 21; epilepsy: H, impairment: H, 7
aEEG: H, 63 (54%); C, 76 cortical visual not reported; late (39%) 11; C, 11 (10%); C, 11 (17%);
(64%); seizures: H, 68 impairment OR death deathsb: H, 9; C, 16 bilateral
(59%); C, 75 (75%) at 18 mo sensorineural
hearing loss: H, 5; C,
3; multiple
disability: H, 15
(21%); C, 20 (32%)
Shankaran et al39 Severe: H, 32 (32%); C, 40 Moderate disability, Bayley Lost to Follow-up: H, 24 (24%); C, 38 (36%); Bayley MDI ⬍70c: Bayley PDI ⬍70: H, 20 (27%); Disabling cerebral Blindness: H, 5 (7%); C,
(NRN) (38%); moderate: H, 69 MDI 70–84 AND GMF C, 3 support withdrawn: H, 19 (25%); C, C, 22 (35%); Bayley PDI palsy: H, 15 (19%); 9 (14%); severe
(68%); C, 66 (62%); level 2 OR hearing loss, H, 12; C, 27; late 24 (34%); Bayley 70–84: H, 8 (11%); C, 6 C, 19 (30%) hearing
seizures: H, 44 (43%); C, no aids OR seizures; OR deathsd: H, 5; C, 9 MDI 70–84: H, (10%) impairment: H, 3
51 (48%) severe disability: Bayley 17 (23%); C, 13 (4%); C, 4 (6%)
MDI ⬍70, GMF level (21%)
3–5, hearing loss with
aids OR blindness; OR
death at 18 mo
H indicates hypothermia; C, control; GMF, Gross Motor Function Classification System; aEEG, amplitude-integrated electroencephalography; MDI, Mental Developmental Index; PDI, Psychomotor Developmental Index. Percents are reported as published.

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a Deaths occurring after the first week.

b A. J. Gunn, MB, ChB, PhD, personal communication, October 2005.

c Data unavailable: H, 3; C, 6.

d Deaths occurring after discharge.

945 PEDIATRICS Volume 117, Number 3, March 2006

3. What is the most appropriate target temperature—33,
33.5, 34, or 34.5°C or another temperature?
4. What is the most important central nervous system
anatomic target—superficial cortical or deep cortical/
brainstem?
5. Which infants are most likely to benefit, and what is
the best way to identify them— gestational age, pre-
disposing history, or clinical criteria or objective mea-
sures such as electroencephalography or diagnostic
imaging?
6. What is the optimal age from birth to institute hypo-
thermia, and how late is too late?
7. What is the safest timing and method of rewarming?
8. How does the incidence and spectrum of adverse
neurodevelopmental outcomes change at 4 years of
age, 8 years of age, and beyond?
RECOMMENDATIONS
NICHD workshop participants concluded that therapeu-
tic hypothermia, at present, should be considered an
evolving therapy for which long-term safety and efficacy
have not been established.1 They noted that given the
heterogeneity of etiology and pathogenesis of HIE, no
single intervention is likely to result in a favorable out-
come in all infants treated.
Based on a review of the 3 published RCTs,37–40 the
Committee on Fetus and Newborn concludes that:
1. Therapeutic hypothermia is a promising therapy that
should be considered investigational until the short-
term safety and efficacy have been confirmed in the
additional human trials underway. Long-term safety
and efficacy remain to be defined.
2. Completion of the 3 large RCTs in progress41–43 should
be supported so that projected enrollment is accom-
plished.
3. Additional trials are needed that would define the
most effective cooling strategies.
4. Registries of infants with perinatal encephalopathies
should be established to facilitate data collection re-
garding diagnoses, treatments, and outcomes.
5. If therapeutic hypothermia is to be implemented out-
side of an RCT, clinicians should follow published
protocols, ensure systematic follow-up of survivors
validated neurodevelopmental tests, and submit pa-
tient data to national or international registries as
they are established. Parents should be informed of
the current status of hypothermia therapy and con-
sent for the procedure obtained.
6. Longer-term follow-up at least through early school
age is essential
946 BLACKMON, et al
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CONCLUSIONS
Substantial uncertainties exist regarding mild to moder-
ate hypothermia as a safe and effective neuroprotective
intervention for newborns who have sustained a perinatal
hypoxic-ischemic insult resulting in encephalopathy. Com-
pletion of ongoing trials and long-term follow-up of survi-
vors is essential. Thus, widespread implementation outside
the limits of controlled trials is premature.
COMMITTEE ON FETUS AND NEWBORN, 2005–2006
Ann R. Stark, MD, Chairperson
David H. Adamkin, MD
Daniel G. Batton, MD
Edward F. Bell, MD
Susan E. Denson, MD
William A. Engle, MD
Gilbert I. Martin, MD
Lillian R. Blackmon, MD, Immediate Past Chairperson
Vinod K. Bhutani, MD
LIAISONS
Keith J. Barrington, MD
Canadian Paediatric Society, Committee on Fetus
and Newborn Chairman
Gary Hankins, MD
American College of Obstetricians and
Gynecologists, Committee on Obstetric Practice
Chairman
Kay M. Tomashek, MD, MPH
Centers for Disease Control and Prevention
Carol Wallman, MSN, RNC, NNP
National Association of Neonatal Nurses,
Association of Women’s Health, Obstetric and
Neonatal Nurses
Tonse N. K. Raju, MD, DCH
Pregnancy and Perinatology Branch, National
Institutes of Child Health and Human Development
STAFF
James Couto, MA
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J Cereb Blood Flow Metab. 1992;12:380 –389

GLOBAL TREND: MORE SCIENCE, MORE FRAUD

“The South Korean scandal that shook the world of science . . . is just one sign
of a global explosion in research that is outstripping the mechanisms meant
to guard against error and fraud. . . . Experts now say that the explosive
growth of science around the globe has made the problem far worse, because
most countries have yet to institute the extra measures that the United States
has put in place. That imbalance is at least partly responsible for a rise in
scientific scandals in other countries, they say. . . . Contributing to the prob-
lem is a drastic rise in the number of scientific journals published around the
world: more than 54,000, according to Ulrich’s Periodicals Directory. This glut
can confuse researchers, overwhelm quality-control systems, encourage
fraud and distort the public perception of findings. ‘Foreign scientific journals
have gone through the roof,’ said Shawn Chen, a senior associate editor at
Ulrich’s, nearly doubling to 29,098 in 2005 from 15,300 in 1980. ‘We’re
having a hard time keeping up.’ While millions of articles are never read or
cited, and some are written simply to pad resumes, others enter the pressure
cooker of scientific and biomedical promotion, becoming lucrative elements
or companies’ business strategies.”
Altman LK, Broad WJ. New York Times. December 20, 2005
Noted by JFL, MD

948 BLACKMON, et al
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 Hypothermia: A Neuroprotective Therapy for Neonatal Hypoxic-Ischemic
Encephalopathy
Lillian R. Blackmon and Ann R. Stark
Pediatrics 2006;117;942
DOI: 10.1542/peds.2005-2950

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 Hypothermia: A Neuroprotective Therapy for Neonatal Hypoxic-Ischemic
Encephalopathy
Lillian R. Blackmon and Ann R. Stark
Pediatrics 2006;117;942
DOI: 10.1542/peds.2005-2950

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/117/3/942

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since 1948. Pediatrics is owned, published, and trademarked by
the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2006 by the American Academy of Pediatrics. All rights reserved. Print ISSN:
1073-0397.

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