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JAMA. Author manuscript; available in PMC 2018 January 24.
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Published in final edited form as:

JAMA. 2017 October 24; 318(16): 1550–1560. doi:10.1001/jama.2017.14972.

Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age

on Death or Disability Among Newborns With Hypoxic-Ischemic
Encephalopathy:
A Randomized Clinical Trial

Abbot R. Laptook, MD,

Department of Pediatrics, Women & Infants Hospital, Brown University, Providence, Rhode Island
Author Manuscript

Seetha Shankaran, MD,

Department of Pediatrics, Wayne State University, Detroit, Michigan

Jon E. Tyson, MD, MPH,

Department of Pediatrics, McGovern Medical School at the University of Texas Health Science
Center at Houston

Breda Munoz, PhD,

Social, Statistical, and Environmental Sciences Unit, RTI International, Research Triangle Park,
North Carolina

Edward F. Bell, MD,

Department of Pediatrics, University of Iowa, Iowa City
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Ronald N. Goldberg, MD,

Department of Pediatrics, Duke University, Durham, North Carolina

Nehal A. Parikh, DO, MS,

Corresponding Author: Abbot R. Laptook, MD, Women & Infants Hospital of Rhode Island, 101 Dudley St, Providence, RI 02905
(alaptook@wihri.org).
Author Contributions: Ms Munoz and Dr Pedroza had full access to all of the data in the study and take responsibility for the
integrity of the data and the accuracy of the data analysis.
Concept and design: Laptook, Shankaran, Tyson, Bell, Parikh, Ambalavanan, Pedroza, Pappas, Das, Ehrenkranz, Hensman, Chalak,
Frantz, Devaskar, Carlton, Sánchez, Higgins.
Acquisition, analysis, or interpretation of data: Laptook, Shankaran, Munoz, Bell, Goldberg, Parikh, Ambalavanan, Pedroza, Pappas,
Das, Chaudhary, Ehrenkranz, Hensman, Van Meurs, Chalak, Hamrick, Sokol, Walsh, Poindexter, Faix, Watterberg, Frantz, Guillet,
Devaskar, Truog, Chock, Wyckoff, McGowan, Harmon, Brumbaugh, Cotten, Sánchez, Hibbs, Higgins.
Author Manuscript

Drafting of the manuscript: Laptook, Tyson, Munoz, Ambalavanan, Pedroza, Sánchez.

Critical revision of the manuscript for important intellectual content: Laptook, Shankaran, Tyson, Bell, Goldberg, Parikh,
Ambalavanan, Pappas, Das, Chaudhary, Ehrenkranz, Hensman, Van Meurs, Chalak, Hamrick, Sokol, Walsh, Poindexter, Faix,
Watterberg, Frantz, Guillet, Devaskar, Truog, Chock, Wyckoff, McGowan, Carlton, Harmon, Brumbaugh, Cotten, Sánchez, Hibbs,
Higgins.
Statistical analysis: Shankaran, Tyson, Munoz, Pedroza, Das.
Obtained funding: Shankaran, Bell, Ambalavanan, Hensman, Walsh, Faix, Frantz III, Truog, Carlton, Cotten, Sánchez.
Administrative, technical, or material support: Bell, Goldberg, Chaudhary, Hensman, Chalak, Hamrick, Faix, Devaskar, Chock,
Wyckoff, McGowan, Carlton, Hibbs, Higgins.
Supervision: Shankaran, Bell, Goldberg, Das, Hensman, Sokol, Poindexter, Faix, Frantz, Truog, Wyckoff, Carlton, Cotten, Higgins.
Conflict of Interest: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
Disclaimer: The comments and views of the authors do not necessarily represent the views of the NICHD.
Additional Contributions: We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to
take part in this study.
 Laptook et al. Page 2

Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio

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Namasivayam Ambalavanan, MD,

Division of Neonatology, University of Alabama at Birmingham

Claudia Pedroza, PhD,

Department of Pediatrics, McGovern Medical School at the University of Texas Health Science
Center at Houston

Athina Pappas, MD,

Department of Pediatrics, Wayne State University, Detroit, Michigan

Abhik Das, PhD,

Social, Statistical, and Environmental Sciences Unit, RTI International, Rockville, Maryland

Aasma S. Chaudhary, BS, RRT,

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Department of Pediatrics, University of Pennsylvania, Philadelphia

Richard A. Ehrenkranz, MD,

Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut

Angelita M. Hensman, MS, RNC-NIC,

Department of Pediatrics, Women & Infants Hospital, Brown University, Providence, Rhode Island

Krisa P. Van Meurs, MD,

Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University
School of Medicine, Palo Alto, California

Lucile Packard Children’s Hospital, Palo Alto, California

Lina F. Chalak, MD, MSCS,

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Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas

Shannon E. G. Hamrick, MD,

Emory University School of Medicine, Department of Pediatrics, Children’s Healthcare of Atlanta,
Atlanta, Georgia

Gregory M. Sokol, MD,

Department of Pediatrics, Indiana University School of Medicine, Indianapolis

Michele C. Walsh, MD, MS,

Department of Pediatrics, Rainbow Babies & Children’s Hospital, Case Western Reserve
University, Cleveland, Ohio

Brenda B. Poindexter, MD, MS,

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Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio

Department of Pediatrics, Indiana University School of Medicine, Indianapolis

Roger G. Faix, MD,

Department of Pediatrics, Division of Neonatology, University of Utah School of Medicine, Salt
Lake City

Kristi L. Watterberg, MD,

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 Laptook et al. Page 3

University of New Mexico Health Sciences Center, Albuquerque

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Ivan D. Frantz III, MD,

Division of Newborn Medicine, Department of Pediatrics, Floating Hospital for Children, Tufts
Medical Center, Boston, Massachusetts

Ronnie Guillet, MD, PhD,

University of Rochester School of Medicine and Dentistry, Rochester, New York

Uday Devaskar, MD,

Department of Pediatrics, University of California, Los Angeles

William E. Truog, MD,

Department of Pediatrics, Children’s Mercy Hospital, Kansas City, Missouri

University of Missouri Kansas City School of Medicine, Kansas City

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Valerie Y. Chock, MD, MS-Epi,

Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University
School of Medicine, Palo Alto, California

Lucile Packard Children’s Hospital, Palo Alto, California

Myra H. Wyckoff, MD,

Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas

Elisabeth C. McGowan, MD,

Department of Pediatrics, Women & Infants Hospital, Brown University, Providence, Rhode Island

David P. Carlton, MD,

Emory University School of Medicine, Department of Pediatrics, Children’s Healthcare of Atlanta,
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Atlanta, Georgia

Heidi M. Harmon, MD, MS,

Department of Pediatrics, Indiana University School of Medicine, Indianapolis

Jane E. Brumbaugh, MD,

Department of Pediatrics, University of Iowa, Iowa City

C. Michael Cotten, MD, MHS,

Department of Pediatrics, Duke University, Durham, North Carolina

Pablo J. Sánchez, MD,

Department of Pediatrics, Nationwide Children’s Hospital, Columbus, Ohio

Anna Maria Hibbs, MD, and

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Department of Pediatrics, Rainbow Babies & Children’s Hospital, Case Western Reserve
University, Cleveland, Ohio

Rosemary D. Higgins, MD
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National
Institutes of Health, Bethesda, Maryland

for the Eunice Kennedy Shriver National Institute of Child Health and Human Development
Neonatal Research Network

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 Laptook et al. Page 4

Abstract
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IMPORTANCE—Hypothermia initiated at less than 6 hours after birth reduces death or disability
for infants with hypoxic-ischemic encephalopathy at 36 weeks’ or later gestation. To our
knowledge, hypothermia trials have not been performed in infants presenting after 6 hours.

OBJECTIVE—To estimate the probability that hypothermia initiated at 6 to 24 hours after birth
reduces the risk of death or disability at 18 months among infants with hypoxic-ischemic
encephalopathy.

DESIGN, SETTING, AND PARTICIPANTS—A randomized clinical trial was conducted

between April 2008 and June 2016 among infants at 36 weeks’ or later gestation with moderate or
severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US
Neonatal Research Network centers participated. Bayesian analyses were prespecified given the
anticipated limited sample size.
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INTERVENTIONS—Targeted esophageal temperature was used in 168 infants. Eighty-three

hypothermic infants were maintained at 33.5°C (acceptable range, 33°C–34°C) for 96 hours and
then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range,
36.5°C–37.3°C).

MAIN OUTCOMES AND MEASURES—The composite of death or disability (moderate or

severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization.

RESULTS—Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks’
gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both
groups were acidemic at birth, predominantly transferred to the treating center with moderate
encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic
and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic
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infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95% CI, −1%
to 17%). Bayesian analysis using a neutral prior indicated a 76% posterior probability of reduced
death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio,
0.86; 95% credible interval, 0.58–1.29). The probability that death or disability in cooled infants
was at least 1%, 2%, or 3% less than noncooled infants was 71%, 64%, and 56%, respectively.

CONCLUSIONS AND RELEVANCE—Among term infants with hypoxic-ischemic

encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling
resulted in a 76% probability of any reduction in death or disability, and a 64% probability of at
least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after
birth may have benefit but there is uncertainty in its effectiveness.

TRIAL REGISTRATION—clinicaltrials.gov Identifier: NCT00614744

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Hypoxic-ischemic encephalopathy represents a subset of neonatal encephalopathy, occurring

in approximately 1.5 per 1000 live births.1 It is an important etiology of neonatal mortality
and serious or devastating lifelong cerebral palsy, neurosensory deficits, and cognitive
impairments.2 Therapeutic hypothermia initiated within 6 hours after birth for moderate or
severe hypoxic-ischemic encephalopathy reduced the composite outcome of death or
disability at 18 months in multiple randomized clinical trials3–8 and improved outcomes at 6

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to 7 years.9,10 The American Academy of Pediatrics published a framework to ensure

appropriate use of hypothermia.11
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In all previous neonatal trials, hypothermia was initiated within 6 hours after birth,3–8
reflecting a 6-hour therapeutic window for hypothermia after brain ischemia in fetal sheep.
12–14 However, only 5 fetal sheep were cooled at 8.5 hours after ischemia,14 and the results

could not exclude the possibility of a longer therapeutic window. Initiating hypothermia
before 6 hours after birth can be difficult if infants are born in remote communities and need
to be transferred, or if encephalopathy evolves or is recognized after 6 hours. Initiation of
hypothermia beyond 6 hours is currently without evidence of benefit.15 A definitive trial to
determine benefit or harm cannot be conducted for this uncommon condition because even
large research networks have an insufficient number of patients to achieve high statistical
power in a reasonable time. To provide the most feasible estimate of treatment effect, a
multicenter, randomized clinical trial was conducted over 8 years among infants with
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moderate or severe hypoxic-ischemic encephalopathy treated with hypothermia initiated at

or after 6 hours but before 24 hours of age compared with noncooled infants. Bayesian
analyses were performed to estimate the probability that hypothermia reduced the risk of
death or disability at 18 months.

Methods
Participants
Trial enrollment occurred between April 2008 and July 2014 and follow-up was completed
in June 2016 at 21 centers of the Eunice Kennedy Shriver National Institutes of Child Health
and Human Development Neonatal Research Network located across the United States. The
full trial protocol is available in Supplement 1. Each center received institutional review
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board approval and infants were enrolled after written informed parental consent was
obtained. Newborns with gestational age 36 weeks or later and postnatal age 6 to 24 hours
were screened for eligibility if they were admitted to a participating neonatal intensive care
unit with a diagnosis of encephalopathy, perinatal asphyxia, or neurological depression.
Enrollment until 24 hours of age was based on the variability in the manifestations of
newborn encephalopathy,16 ongoing injurious processes in the hours to days after hypoxia-
ischemia,17 benefit from hypothermia initiated at 12 hours after ischemia in a preclinical
study,18 and the uncertainty in extrapolating from animal to human newborns.

Inclusion criteria were identical to the prior Neonatal Research Network hypothermia trial4
except for postnatal age. Infants who fulfilled biochemical or clinical criteria and were
determined to have seizures or moderate or severe encephalopathy on examination by
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certified examiners were eligible.4 Infants without moderate or severe encephalopathy by

examination but with clinical seizures were classified as having moderate encephalopathy.
Exclusion criteria included a core temperature of less than 34°C for more than 1 hour,
known anomaly, chromosomal aberration, birth weight less than 1800 g, in extremis
condition, and parental or attending physician refusal. Race/ethnicity was obtained by
maternal report using fixed categories to ensure group comparability along with other
demographic variables.

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Randomization
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Infants were stratified by postnatal age (≤12 hours or >12 hours) and stage of
encephalopathy (moderate or severe), and they were randomly assigned by telephone by the
data center to hypothermia or noncooling using a computer-generated permutated block
algorithm with block size of 2 and 4 with a 1:1 ratio.

Intervention
Before randomization, temperature control was per center practices. The hypothermia group
underwent whole-body cooling similar to the Neonatal Research Network hypothermia
trial4,19 to maintain esophageal temperature at 33.5°C (acceptable range, 33.0°C–34.0°C)
using a Hyper-Hypothermia Blanketrol system (Cincinnati Sub-Zero). The duration of
hypothermia was lengthened from 72 hours4 to 96 hours based on preclinical data before
2008 that a longer duration of hypothermia was needed to achieve neuroprotection with
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increasing delays between hypoxia-ischemia and initiation of cooling.18,20 At 96 hours,

rewarming was conducted at 0.5°C per hour using the Blanketrol system and completed
using a radiant warmer to maintain esophageal temperature of 37.0°C over 5 hours.
Temperatures were recorded every 15 minutes during the first 3 hours of cooling, every hour
until 12 hours, and at 4-hour intervals through the remainder of cooling and rewarming. The
noncooled group was treated with an esophageal temperature probe and temperatures
maintained at 37.0°C (acceptable range, 36.5°C–37.3°C). Infants were cared for on radiant
warmers and the control set point for the skin temperature was adjusted to achieve the
desired esophageal temperature. An algorithm was used to correct hyperthermia by ensuring
appropriate thermal care if the esophageal temperature exceeded 37.3°C, and a tepid bath
and/or cooling blanket if the temperature exceeded 37.5°C. Temperatures were recorded
every 4 hours in the noncooled group. At 108 hours, esophageal temperature probes of both
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groups were removed and temperature control was resumed per local practice.

Outcomes
The primary outcome was death or disability, either moderate or severe, at 18 to 22 months
of age. Certified examiners trained to reliability21 and masked to treatment assignment
conducted a neurological examination and psychometric testing, assessed growth, and
reviewed vision and hearing with the family. The Bayley Scales of Infant Development III
were used to obtain cognitive, language, and motor scores (reported mean [SD] score, 100
[15]; range, 55–145).22 The Gross Motor Function Classification Score (GMFCS; range, 0
[normal] to 5 [worst]) was used to classify motor findings.23 Severe disability was defined as
any of the following: a cognitive score less than 70, a GMFCS level of 3 to 5, and blindness
or hearing impairment with inability to follow commands despite amplification. Moderate
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disability was defined as a cognitive score between 70 and 84 and any of the following: a
GMFCS level of 2, an active seizure disorder (antiepileptic drugs in use), or a hearing deficit
with the ability to follow commands after amplification.4 Infants who did not meet the
primary outcome were categorized as either mild disability or normal. Mild disability was
defined by a cognitive score of 70 to 84 alone or a cognitive score of 85 or greater, and any
of the following: a GMFCS level of 1 or 2, a seizure disorder (without medication), or a
hearing deficit with the ability to follow commands without amplification.

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Prespecified secondary outcomes were the frequency of death alone, moderate-severe

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disability alone, disability (severe, moderate, and mild), disability based on level of
encephalopathy, seizures (with or without electroencephalograms), do not resuscitate order
(DNR), DNR and support withdrawn, DNR and survival or death, and nonbrain organ
dysfunction. The latter 2 are not reported. Outcomes not pre-specified were adverse events,
in-hospital organ system morbidities, components of disability, normal infants (cognitive
score of ≥85, a normal GMFCS level, no neurosensory deficits, and no seizures), and growth
parameters at follow-up.

Sample Size and Statistical Analyses

The effect size was expected to be smaller than the prior Neonatal Research Network
hypothermia trial (risk ratio [RR], 0.72; 95% CI, 0.54–0.95).4 A sample size of 168 was
predefined and represented the largest sample that could be attained in a feasible time
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interval (6-year enrollment). A Bayesian analysis was prespecified to estimate the

probability of treatment benefit based on recommendations for trials of rare conditions with
limited sample size and power in frequentist analyses to identify conclusive treatment
effects.24

In Bayesian analyses, the probability of treatment effect (posterior probability) is estimated

after the trial and incorporates the prior probability estimated from the best data from
previous studies (clinical trials or pilot trials).25 Judgment of the prior probability may vary
and be neutral, enthusiastic, or skeptical. Therefore, analyses were performed using 3
different prior probabilities: (1) a neutral prior, assuming no treatment effect (RR, 1.0); (2)
an enthusiastic prior, assuming a 28% reduction in the risk of death or disability as in the
earlier Neonatal Research Network trial4 (RR, 0.72); and (3) a skeptical prior, assuming a
10% increase in the risk of death or disability (RR, 1.10). Whether neutral, enthusiastic, or
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skeptical, assessments of prior probability involve uncertainty about the minimum and
maximum likely treatment effects. To reflect this uncertainty in each analysis, a probability
distribution for the treatment effect with the 95% credible intervals that ranged from half to
twice the assumed RR (SD, 0.35 in the log scale) was used. For example, the probability
distribution for the neutral prior was centered at an RR of 1.0 (mean of 0 in the log scale)
with a 50% prior probability of a better outcome, a 50% prior probability of a worse
outcome, and a 95% credible interval for the RR of 0.5 to 2.0 (eAppendix in Supplement 2).
The RR of 0.5 to 2.0 includes treatment effects for major clinical outcomes of the size
observed in almost all large clinical trials.26 For adequately powered trials, differences
between neutral, enthusiastic, and skeptical priors have almost no effect on the posterior
probability. However, for smaller trials, Bayesian analyses allow assessment of how much
the estimated probability of a treatment effect is affected by differing assessments of the
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prior evidence.

All analyses followed the intention-to-treat principle. A binomial model was used with a log
link to estimate the posterior RR for different binary outcomes for the hypothermia group
compared with the noncooled group. The model to obtain the adjusted RR (aRR) included 3
main effects: treatment (hypothermia or noncooling), age at time of randomization (≤12
hours or >12 hours), and level of encephalopathy (moderate or severe). Center was not

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included because models did not converge with center as a covariate. The original analysis
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plan specified a logistic model. This represented an oversight as the intent was to present
adjusted relative risks to quantify the treatment effect. The decision to use a log binomial
model was made prior to the derivation of the primary outcome and all analyses.

Interactions of treatment with age at enrollment, level of encephalopathy at randomization,

and sex on the primary outcome were assessed with a log-linear model. Bayesian analyses
were used to determine probabilities for the absolute risk difference (binomial model) and
adjusted cognitive scores (linear regression). P values from parallel frequentist analyses are
provided for outcomes not pre-specified, using 2-sided χ2, Fisher exact, Wilcoxon, and t
tests; 1-sided t tests were used for absolute differences. A P < .05 was considered significant
and was not adjusted for multiple comparisons. Statistical software for Bayesian analysis
was JAGS version 4.6 and OpenBUGS version 3.2.3., and for frequentist analysis was SAS
version 9.3 (SAS Institute). The data safety monitoring committee reviewed safety after
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every 20 infants and effectiveness at 33%, 50%, and 75% of outcome accrual.

Results
There were 168 participants and 83 were randomly assigned to hypothermia and 85 to
noncooling (Figure 1). Hypothermic and noncooled infants were term (mean [SD], 39 [2]
and 39 [1] weeks’ gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were
male, respectively. Emergency cesarean delivery was performed for 99 of 168 infants (59%),
of whom 146 (87%) were transferred to the treating center (Table 1). At birth, intubation
was performed in 92 of 168 infants (55%) and chest compressions were performed in 44 of
168 infants (26%). Hypothermic and noncooled infants were randomized at a mean (SD) of
16 (5) and 15 (5) hours, respectively. Enrollment beyond 12 hours after birth occurred in 114
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of 168 infants (68%) and moderate encephalopathy was found in 151 of 168 infants (90%).
Ten infants in each group were enrolled based on clinical seizures without moderate or
severe encephalopathy. Infants with incomplete or no follow-up (n = 11) were similar to
those with a known outcome (eTable 1 in Supplement 2).

Following hypothermia induction, mean (SD) esophageal temperature was maintained at

33.3 (0.3)°C between 3 and 96 hours (eFigure in Supplement 2). The mean (SD) esophageal
temperature for the noncooled group during the intervention was 36.8 (0.5)°C. In the
noncooled group, the median number of esophageal temperatures per infant below 36.5°C
was 1 (interquartile range [IQR], 0–3) and the mean of these values was 36.2°C (IQR,
35.9°C–36.4°C). The median number of esophageal temperatures per infant greater than
37.3°C was 1 (IQR, 0–4) and the mean of these values was 37.5°C (IQR, 37.4°C–37.7°C).
Interventions to reduce elevated temperature were performed in 27 of 85 infants (32%) in the
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noncooled group; 24 infants (28%) received a tepid bath and 7 infants (8%) were treated
with a cooling blanket.

During the intervention and rewarming, unmasked observers recorded 13 and 6 adverse
events in the hypothermia and noncooled groups, respectively (Table 2). One infant
(hypothermia) developed subcutaneous fat necrosis and 1 infant (noncooled) developed
diabetes insipidus, both remote from the intervention. There were no group differences in

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organ system morbidities or need for extracorporeal membrane oxygenation. A blood

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glucose concentration greater than 150 mg/dL occurred more frequently in the hypothermia
than the noncooled group (to convert glucose to millimoles per liter, multiply by 0.0555).

Complete follow-up at a mean (SD) of 21 (3) months was achieved among 69 of 74 (93%)
and 72 of 78 (92%) hypothermia and noncooled survivors to discharge, respectively. There
were 9 deaths in each group. There were minimal missing data for the components of
disability among survivors, which did not prevent assignment of a primary outcome except
for 2 infants with incomplete follow-up evaluations (Figure 1). Death or disability (moderate
or severe) at follow-up was known for 157 infants (93.5%) and occurred in 19 of 78 (24.4%)
of the hypothermia group and 22 of 79 (27.9%) of the noncooled group (absolute difference,
3.5%; 95% CI, −1% to 17%; Table 3). Bayesian analysis using a neutral prior indicated a
76% posterior probability of reduced death or disability with a posterior aRR of 0.86 (95%
credible interval, 0.58–1.29) (Figure 2). The corresponding frequentist aRR was 0.81 (95%
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CI, 0.44–1.51). Further, 73% and 68% probabilities were identified for reduction in death
and in moderate-severe disability, respectively, under the neutral prior. Expressed as an
absolute risk difference, the posterior probability that death or disability for hypothermia
using a neutral prior was at least 1%, 2%, or 3% less compared with noncooled treatment
was 71%, 64%, and 56%, respectively. A 2% absolute risk difference was associated with a
3.2-times (64%/20%) higher probability of reduced compared with increased death or
disability among hypothermia relative to noncooled infants, assuming a range of risk
differences viewed as equivalent (Figure 2). Using an enthusiastic prior, the posterior
probability that death or disability was at least 1%, 2%, or 3% less compared with noncooled
increased to 86%, 80%, and 74%, respectively. Death or moderate-severe disability did not
differ by age at randomization: 6 of 25 infants (24.0%) and 7 of 26 infants (26.9%) when
randomized at 12 hours or less, and 13 of 53 infants (24.5%) and 15 of 53 infants (28.3%)
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when randomized between 12 and 24 hours in the hypothermia and noncooled groups,
respectively. There were no interactions between treatment and age at randomization, level
of encephalopathy, or sex for the primary outcome (Bayesian probability of an interaction,
46%, 38%, and 22%, respectively).

Other prespecified and exploratory outcomes did not differ between groups (eTable 2 in
Supplement 2). Although Bayley cognitive scores did not differ, they contributed to the
extent of disability within each group; a post-hoc Bayesian analysis (neutral prior) indicated
a 97% probability of higher scores among hypothermia infants. A post-hoc aRR for survival
of infants with a normal outcome was 0.98 (95% credible intervals, 0.76–1.26; neutral
prior).
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Discussion
Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24
hours after birth resulted in a 76% probability of any reduction in death or disability using a
Bayesian analysis with a neutral prior. The probability that death or disability was at least
2% less in hypothermia compared with noncooled infants was 64%. Enrolled infants met
criteria for hypothermia of the earlier Neonatal Research Network trial.4 Death or disability

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(moderate or severe) was known for 93.5% of enrollees and follow-up assessments were
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performed by examiners blinded to the intervention.

It can be difficult to study therapies for rare diseases or uncommon features of previously
studied disease processes. Extrapolation from animal studies has limitations.27 The
therapeutic window during which hypothermia may modify hypoxic-ischemic brain injury
may differ between preclinical studies and human newborns owing to species maturation,
methods to induce hypoxia-ischemia, and outcomes studied. Randomized clinical trials are
unlikely to have sufficient power to identify clinically important treatment effects in
traditional frequentist analysis. This is especially pertinent to a trial of hypothermia initiated
after 6 hours of age as it addresses a small subset of infants with moderate-severe
encephalopathy. Furthermore, based on preclinical studies,12–14 hypothermia started after 6
hours was anticipated to provide less neuroprotection than hypothermia started before 6
hours, making it even less feasible to achieve high power even in the Neonatal Research
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Network, with 21 centers serving large delivery cohorts and referral bases throughout the
United States. However, the high rates of potentially catastrophic outcomes associated with
hypoxic-ischemic encephalopathy, and reports of initiating hypothermia after 6 hours in a
subset of infants with moderate-severe encephalopathy without any systematic study,
provided justification to undertake this trial.

With the sample size studied, traditional frequentist analysis identified no significant
difference for death or disability between the hypothermic and noncooled groups. A
frequentist analysis of an underpowered trial would provide little help for clinicians treating
infants with encephalopathy who present beyond 6 hours. However, frequentist analyses do
not allow calculation of the probability of a specified benefit while Bayesian methods allow
for direct assessment of the probability of treatment effect based on the trial results.24,25,28 A
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series of absolute risk differences in death or disability were provided to assess effect size.
An absolute risk reduction of 1% or 2% in death or moderate-severe disability may be
viewed as clinically important given the seriousness of the outcome. Perinatal and adult
therapies have been recommended at a similar low absolute risk reduction for major adverse
outcomes. A risk reduction of 1.6% for cerebral palsy has been reported among preterm
newborns whose mothers were treated with magnesium sulfate,29 a treatment now widely
used in obstetrics.30 Statins have been recommended in adults with a cardiovascular disease
risk of 10% but without cardiovascular disease31 based on absolute risk reductions of 0.4%
and 1.4% for all-cause and composite cardiovascular mortality, respectively.32

The reduction in death or disability for hypothermic compared with noncooled infants is
suggestive but not conclusive. No evidence of commensurate harm was found. Adverse
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events, prespecified and those not prespecified, occurred in more hypothermic than
noncooled infants but did not differ by frequentist analysis. The number of deaths per group
was the same, but the Bayesian analysis indicated the aRR favored hypothermia and the
posterior probability of reduced death was 73% under a neutral prior. A decision to use
hypothermia at 6 to 24 hours will need to consider the probability of benefit, the frequency
of adverse events, and the availability of evidence-based alternative treatments.

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In all neonatal trials, hypothermia initiated at less than 6 hours reduced death or disability,33
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and therefore a prior based on an RR between 1.0 (no benefit) and 0.72 (the benefit
identified in the previous Neonatal Research Network hypothermia trial4) might be
considered appropriate. If so, the estimated probabilities for any reduction or a greater than
1% or greater than 2% absolute reduction in death or disability would be somewhat higher
and intermediate between the estimates using a neutral prior and those using an enthusiastic
prior. Given these considerations, estimated probabilities based on a neutral prior could be
considered conservative. Since the initiation of this trial, there is little new information on
late hypothermia treatment to provide an estimate of treatment effect. A trial from China
randomized 93 newborns within 10 hours of birth to hypothermia or normothermia; only 9
infants received hypothermia between 6 and 10 hours.34 Single-center and registry data
reported initiation of hypothermia after 6 hours but did not provide treatment effect.15,35

Hypoxic-ischemic encephalopathy resulting in moderate or severe disability is a devastating

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outcome. The results of this trial should not change the priority of early identification of
infants with hypoxic-ischemic encephalopathy and initiation of hypothermia at less than 6
hours. This trial provides an approach to estimate the treatment effect for uncommon
diseases in the largest feasible clinical trial and avoid the biases inherent in observational
studies.

Limitations
This study has several limitations. During this trial, the Neonatal Research Network initiated
the Optimizing Cooling trial to study longer (120 hours) or deeper (32°C) cooling initiated
at less than 6 hours of age.36,37 The Optimizing Cooling trial was stopped early partly owing
to safety concerns for increased in-hospital mortality among infants cooled for 120 rather
than 72 hours. Whether the current trial results would differ if the intervention was shortened
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to 72 hours cannot be answered. Elevated esophageal temperature occurred among

noncooled infants and such temperatures have been associated with a greater risk of death or
disability in prior trials.38–40 The algorithm used in noncooled infants largely mitigated the
extent and duration of esophageal temperatures greater than 37.3°C compared with the
earlier Neonatal Research Network hypothermia trial.4 Also, the reason for presentation at
or beyond 6 hours was not always known.

Conclusions
Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24
hours after birth compared with noncooling resulted in a 76% probability of any reduction in
death or disability, and a 64% probability of at least 2% less death or disability at 18 to 22
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months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is
uncertainty in its effectiveness.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

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 Laptook et al. Page 12

Acknowledgments
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Disclosures: Drs Laptook, Pedroza, Walsh, Faix, and Frantz reported receiving grants from the Eunice Kennedy
Shriver National Institute of Child Health and Human Development (NICHD). Drs Das and Ehrenkranz reported
receiving grants from the NICHD and the National Institutes of Health. Dr Sokol reports receiving grants from the
National Institutes of Health. Dr Brumbaugh reported that the University of Iowa received grant funding from the
NICHD as a member of the Neonatal Research Network. Drs Cotten and Sánchez reported receiving grants from
the NICHD Neonatal Research Network. No other disclosures were reported.

Funding/Support: The National Institutes of Health, the NICHD, the National Center for Research Resources, and
the National Center for Advancing Translational Sciences provided grant support for the Neonatal Research
Network through cooperative agreements.

Role of the Funder/Sponsor: NICHD staff participated in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; preparation, review and approval of the manuscript; and the
decision to submit the manuscript for publication. The National Center for Research Resources and the National
Center for Advancing Translational Sciences provided funding for infrastructure support for the Neonatal Research
Network but did not participate in the design and conduct of the study; collection, management, analysis, and
interpretation of the data; preparation, review and approval of the manuscript; and the decision to submit the
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manuscript for publication.

Group Information
The following investigators, in addition to those listed as authors, participated in this study:
NRN Steering Committee Chairs: Alan H. Jobe, MD, PhD, University of Cincinnati (2003–
2006); Michael S. Caplan, MD, University of Chicago, Pritzker School of Medicine (2006–
2011); and Richard A. Polin, MD, Division of Neonatology, College of Physicians and
Surgeons, Columbia University, (2011-present). Alpert Medical School of Brown University
and Women & Infants Hospital of Rhode Island: Martin Keszler, MD; William Oh, MD;
Betty R. Vohr, MD; Barbara Alksninis, RNC, PNP; Kristin Basso, MaT, RN; Joseph Bliss,
MD, PhD; Carmena Bishop; Robert T. Burke, MD, MPH; William Cashore, MD; Melinda
Caskey, MD; Dan Gingras, RRT; Nicholas Guerina, MD, PhD; Hussnain Mirza, MD;
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Katharine Johnson, MD; Mary Lenore Keszler, MD; Andrea M. Knoll; Theresa M. Leach,
MEd, CAES; Martha R. Leonard, BA, BS; Emilee Little, RN, BSN; Ross Sommers, MD;
Birju A. Shah, MD, MPH; Bonnie E. Stephens, MD; Suzy Ventura; Elisa Vieira, RN, BSN;
and Victoria E. Watson, MS, CAS. Case Western Reserve University, Rainbow Babies &
Children’s Hospital: Deanne E. Wilson-Costello, MD; Nancy S. Newman, RN; Beau Batton,
MD; Monika Bhola, MD; Juliann M. Di Fiore, BSEE; Harriet G. Friedman, MA; Bonnie S.
Siner, RN; Eileen K. Stork, MD; Gulgun Yalcinkaya, MD; and Arlene Zadell, RN.
Children’s Mercy Hospital, University of Missouri Kansas City School of Medicine:
Eugenia K. Pallotto, MD, MSCE; Howard W. Kilbride, MD; Cheri Gauldin, RN, BS,
CCRC; Anne Holmes, RN, MSN, MBA-HCM, CCRC; Kathy Johnson, RN, CRC; and
Allison Knutson, BSN, RNC-NIC. Cincinnati Children’s Hospital Medical Center,
University of Cincinnati Medical Center, and Good Samaritan Hospital: Kurt Schibler, MD;
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Suhas G. Kallapur, MD; Kimberly Yolton, PhD; Cathy Grisby, BSN, CCRC; Barbara
Alexander, RN; Estelle E. Fischer, MHSA, MBA; Teresa L. Gratton, PA; Jody Hessling,
MSN, RN; Lenora Jackson, CRC; Kristin Kirker, CRC; Stephanie Merhar, MD, MS; Holly
L. Mincey, MS, RN, BSN; Greg Muthig, BA; and Sandra Wuertz, RN, BSN, CLC. Duke
University School of Medicine, University Hospital, University of North Carolina, and Duke
Regional Hospital: Kimberley A. Fisher, PhD, FNP-BC, IBCLC; Sandra Grimes, RN, BSN;
Joanne Finkle, RN, JD; Ricki F. Goldstein, MD; Kathryn E. Gustafson, PhD; William F.

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 Laptook et al. Page 13

Malcolm, MD; Patricia L. Ashley, MD, PhD; Kathy J. Auten, MSHS; Melody B. Lohmeyer,
Author Manuscript

RN, MSN; Matthew M. Laughon, MD, MPH; Carl L. Bose, MD; Janice Bernhardt, MS, RN;
Cindy Clark, RN; Diane D. Warner, MD, MPH; Janice Wereszcsak, CPNP; and Sofia
Aliaga, MD, MPH. Emory University, Children’s Healthcare of Atlanta, Grady Memorial
Hospital, and Emory University Hospital Midtown: Barbara J. Stoll, MD; Ellen C. Hale, RN,
BS, CCRC; Yvonne Loggins, RN; Diane I. Bottcher, MSN, RN; Colleen Mackie, BS, RT;
Maureen Mulligan LaRossa, RN; Ira Adams-Chapman, MD; Lynn C. Wineski, RN, MS; and
Sheena L. Carter, PhD. Eunice Kennedy Shriver National Institute of Child Health and
Human Development: Stephanie Wilson Archer, MA. Indiana University, University
Hospital, Methodist Hospital, Riley Hospital for Children at Indiana University Health, and
Eskenazi Health: Lu-Ann Papile, MD; Jessica Bissey, PsyD, HSPP; Lon G. Bohnke, MS;
Ann B. Cook, MS; Anna M. Dusick, MD (deceased); Susan Gunn, NNP-BC, CCRC; Dianne
E. Herron, RN, CCRC; Abbey C. Hines, PsyD; Darlene Kardatzke, MD (deceased); Carolyn
Author Manuscript

Lytle, MD, MPH; Heike M. Minnich, PsyD, HSPP; Leslie Richard, RN; Lucy C. Smiley,
CCRC; and Leslie Dawn Wilson, BSN CCRC. McGovern Medical School at the University
of Texas Health Science Center at Houston, Children’s Memorial Hermann Hospital:
Kathleen A. Kennedy, MD, MPH; Julie Arldt-McAlister, MSN, APRN; Katrina Burson, RN,
BSN; Allison G. Dempsey, PhD; Andrea F. Duncan, MD, MSClinRes; Patricia W. Evans,
MD; Carmen Garcia, RN, BSN; Margarita Jimenez, MD, MPH; Janice John, CPNP; Patrick
M. Jones, MD, MA; M. Layne Lillie, RN, BSN; Karen Martin, RN; Sara C. Martin, RN,
BSN; Georgia E. McDavid, RN; Patti L. Pierce Tate, RCP; Shawna Rodgers, RN, BSN;
Saba Khan Siddiki, MD; Daniel K. Sperry, RN; and Sharon L. Wright, MT (ASCP).
Nationwide Children’s Hospital and the Ohio State University Wexner Medical Center: Leif
D. Nelin, MD; Sudarshan R. Jadcherla, MD; Patricia Luzader, RN; and Christine A. Fortney,
PhD, RN. RTI International: Dennis Wallace, PhD; Marie G. Gantz, PhD; Kristin M.
Zaterka-Baxter, RN, BSN, CCRP; Margaret M. Crawford, BS, CCRP; Jenna Gabrio, BS,
Author Manuscript

CCRP; Scott A. McDonald, BS; Jamie E. Newman, PhD, MPH; Jeanette O’Donnell Auman,
BS; Carolyn M. Petrie Huitema, MS, CCRP; and James W. Pickett II, BS. Stanford
University and Lucile Packard Children’s Hospital: David K. Stevenson, MD; Susan R.
Hintz, MD, MS-Epi; M. Bethany Ball, BS, CCRC; Elizabeth F. Bruno, PhD; Maria Elena
DeAnda, PhD; Anne M. DeBattista, RN, PNP, PhD; Lynne C. Huffman, MD; Casey E.
Krueger, PhD; Melinda S. Proud, RCP; Nicholas H. St. John, PhD; and Hali E. Weiss, MD.
Tufts Medical Center, Floating Hospital for Children: Elisabeth C. McGowan, MD; John M.
Fiascone, MD; Brenda L. MacKinnon, RNC; Ana Brussa, MS, OTR/L; Anne Furey, MPH;
Brian Gilchrist, MD; Juliette C. Madan, MD, MS; Ellen Nylen, RN, BSN; and Cecelia
Sibley, PT, MHA. University of Alabama at Birmingham Health System and Children’s
Hospital of Alabama: Waldemar A. Carlo, MD; Myriam Peralta-Carcelen, MD, MPH;
Monica V. Collins, RN, BSN, MaEd; Shirley S. Cosby, RN, BSN; Vivien A. Phillips, RN,
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BSN; Richard V. Rector, PhD; and Sally Whitley, MA, OTR-L, FAOTA. University of
California–Los Angeles, Mattel Children’s Hospital, Santa Monica Hospital, Los Robles
Hospital and Medical Center, and Olive View Medical Center: Meena Garg, MD; Isabell B.
Purdy, PhD, CPNP; Teresa Chanlaw, MPH; and Rachel Geller, RN, BSN. University of Iowa
and Mercy Medical Center: Tarah T. Colaizy, MD, MPH; Karen J. Johnson, RN, BSN;
Diane L. Eastman, RN, CPNP, MA; Michael J. Acarregui, MD, MBA; Jacky R. Walker, RN;
Claire A. Lindauer, RN; Jonathan M. Klein, MD; Nancy J. Krutzfield, RN, MA; Jeffrey L.

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 Laptook et al. Page 14

Segar, MD; John M. Dagle, MD, PhD; Julie B. Lindower, MD, MPH; Steven J. McElroy,
Author Manuscript

MD; Glenda K. Rabe, MD, MME; Robert D. Roghair, MD; Lauritz R. Meyer, MD; Dan L.
Ellsbury, MD; Donia B. Campbell, RNC-NIC; Cary R. Murphy, MD; and Vipinchandra
Bhavsar, MB, BS. University of New Mexico Health Sciences Center: Robin K. Ohls, MD;
Conra Backstrom Lacy, RN; Sandra Sundquist Beauman, MSN, RNC; Sandra Brown, BSN;
Erika Fernandez, MD; Andrea Freeman Duncan, MD; Janell Fuller, MD; Carol
Hartenberger, BSN, MPH; and Jean R. Lowe, PhD. University of Pennsylvania, Hospital of
the University of Pennsylvania, Pennsylvania Hospital, and Children’s Hospital of
Philadelphia: Barbara Schmidt, MD, MSc; Haresh Kirpalani, MB, MSc; Sara B. DeMauro,
MD, MSCE; Kevin C. Dysart, MD; Soraya Abbasi, MD; Toni Mancini, RN, BSN, CCRC;
Dara M. Cucinotta, RN; Judy C. Bernbaum, MD; Marsha Gerdes, PhD; and Hallam Hurt,
MD. University of Rochester Medical Center, Golisano Children’s Hospital, and the
University of Buffalo Women’s and Children’s Hospital of Buffalo: Carl D’Angio, MD;
Author Manuscript

Satyan Lakshminrusimha, MD; Nirupama Laroia, MD; Gary J. Myers, MD; Kelley Yost,
PhD; Stephanie Guilford, BS; Rosemary L. Jensen; Karen Wynn, NNP, RN; Osman Farooq,
MD; Anne Marie Reynolds, MD, MPH; Michael G. Sacilowski, MAT; Holly I. M. Wadkins,
MA; Ashley Williams, MS Ed; Joan Merzbach, LMSW; Patrick Conway, MS; and Melissa
Bowman, MSN. University of Texas Southwestern Medical Center, Parkland Health &
Hospital System, and Children’s Medical Center Dallas: Luc P. Brion, MD; Roy J. Heyne,
MD; Lijun Chen, PhD, RN; Diana M. Vasil, MSN, BSN, RNC-NIC; Sally S. Adams, MS,
RN, CPNP; Catherine Twell Boatman, MS, CIMI; Alicia Guzman; Elizabeth T. Heyne, MS,
MA, PA-C, PsyD; Lizette E. Lee, RN; Melissa H. Leps, RN; Linda A. Madden, BSN, RN,
CPNP; Nancy A. Miller, RN; and Emma Ramon, RNC-NIC, RN, BSN. University of Utah
Medical Center, Intermountain Medical Center, LDS Hospital, and Primary Children’s
Medical Center: Bradley A. Yoder, MD; Anna Bodnar, MD; Karen A. Osborne, RN, BSN,
CCRC; Cynthia Spencer, RNC; R. Edison Steele, RN; Mike Steffen, PhD; Karena Strong,
Author Manuscript

RN, BSN; Kimberlee Weaver-Lewis, RN, BSN; Shawna Baker, RN; Sarah Winter, MD;
Karie Bird, RN, BSN; and Jill Burnett, RNC, BSN. Wayne State University, University of
Michigan, Hutzel Women’s Hospital, and Children’s Hospital of Michigan: Beena G. Sood,
MD, MS; Rebecca Bara, RN, BSN; Kirsten Childs, RN, BSN; Lilia C. De Jesus, MD;
Bogdan Panaitescu, MD; Sanjay Chawla, MD; Jeannette E. Prentice, MD; Laura A.
Goldston, MA; Eunice Hinz Woldt, RN, MSN; Girija Natarajan, MD; Monika Bajaj, MD;
John Barks, MD; Mary Christensen, RT; and Stephanie A. Wiggins, MS. Yale–New Haven
Children’s Hospital: Monica Konstantino, RN, BSN; Matthew Bizzarro, MD; Nancy Close,
PhD; JoAnn Poulsen, RN; Elaine Romano, MSN; and Janet Taft, RN, BSN.

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Key Points
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Question
Does initiation of hypothermia at 6 to 24 hours after birth reduce the risk of death or
disability at 18 months among term newborns with hypoxic-ischemic encephalopathy?

Findings
In this Bayesian analysis of a randomized clinical trial of 168 newborns with hypoxic-
ischemic encephalopathy, treatment with hypothermia initiated at 6 to 24 hours after birth
compared with noncooling resulted in a 76% probability of any reduced death or
disability, and a 64% probability of at least 2% less death or disability at 18 to 22 months.

Meaning
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Hypothermia treatment initiated at 6 to 24 hours for newborns with hypoxic-ischemic

encephalopathy may reduce death or disability but there is uncertainty in its effectiveness.
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Figure 1.
Flow Diagram of Neonates With Hypoxic-Ischemic Encephalopathy Through a Trial of
Hypothermia Initiated at 6 to 24 Hours After Birth
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 Laptook et al. Page 19
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Figure 2. Posterior Probability of Death or Disability With Hypothermia Initiated at 6 to 24

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Hours After Birth vs Noncooling

A, The probability density describes the frequency distribution of observed values and is
unit-less. The curves are scaled so that the total area under the curve is 1, and the area
between any 2 values on the x-axis equals the probability of observing a value in that range.
The blue line plots a neutral prior distribution centered at a risk ratio of 1.0 and indicates an
equal number of infants would be expected to benefit by either temperature management
group, hypothermia or noncooled. The posterior probability of treatment effect is derived by
combining the prior distribution with the trial results. The distribution is shifted to the left of
a risk ratio of 1.0 with a point estimate of 0.86. The area under the curve that is less than a
risk ratio of 1.0 (light blue) represents the posterior probability of any reduction in death or
disability (76% for this trial). The area under the curve that is greater than a risk ratio of 1.0
(dark blue) represents the posterior probability of an increase in death or disability (24% for
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this trial). B, The light blue portion indicates a 64% probability that death or disability in
infants treated with hypothermia is at least 2% less than noncooled infants (benefit). The
pale blue area (near zero) is an arbitrary zone of indifference to illustrate the probability of
risk differences where hypothermia and noncooling may be viewed as equivalent. The dark
blue indicates the probability of death or disability among infants treated with hypothermia
is higher than for noncooled infants (harm). In this example, a 2% absolute risk difference

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 Laptook et al. Page 20

was associated with a 3.2-times (64%/20%) higher probability of reduced compared with
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increased death or disability risk among hypothermia relative to noncooled infants.

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Table 1

Maternal and Neonatal Characteristicsa

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Hypothermia Group Noncooled Group

Characteristic (n = 83) (n = 85)

Maternal
Age, mean (SD), y 27 (6) 26 (6)

Married, No. (%) 54 (65) 43 (50.6)

Race/ethnicity, No. (%)

Black 13 (16.1) 21 (25)

White 61 (75.3) 60 (71.4)

Otherb 7 (8.6) 3 (3.6)

Gravida, median (IQR) 2 (1–3) 2 (1.3)

Parity, median (IQR) 1 (1–2) 1 (1–2)

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Education, No. (%)

≤ High school 36 (45.6) 34 (42.5)

Any college or beyond 43 (54.4) 46 (57.5)

Pregnancy complications, No. (%)

Hypertension or pre-eclampsia 13 (15.7) 17 (20.2)

Antepartum hemorrhage 3 (3.6) 7 (8.2)

Thyroid dysfunction 2 (2.4) 3 (3.6)

Diabetes 7 (8.4) 9 (10.7)

Intrapartum complications, No. (%)

Fetal decelerations 59 (72) 60 (70.6)

Cord mishap (prolapse, rupture) 9 (10.8) 13 (15.3)

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Uterine rupture 2 (2.4) 2 (2.4)

Maternal pyrexia (≥37.6°C) 10 (12.1) 9 (10.8)

Placental problems (abruptio, previa) 9 (10.8) 10 (11.8)

Maternal trauma, CPR 2 (2.4) 7 (8.2)

Shoulder dystocia 8 (9.8) 4 (4.7)

Rupture of membranes, median (IQR), h 3.2 (0.02–11.9) 5.5 (0.03–15.5)

Chorioamnionitis, clinical 5 (6.1) 7 (8.5)

Chorioamnionitis, histologic, No./total No. (%)c 13/30 (43.3) 8/22 (36.4)

Emergency cesarean delivery 47 (56.6) 52 (61.2)

Infant
Gestational age, mean (SD), wk 39 (2) 39 (1)
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Birth weight, mean (SD), g 3379 (528) 3303 (553)

Length, mean (SD), cm 51 (3) 51 (3)

Head circumference, mean (SD), cm 34 (2) 34 (2)

Male, No. (%) 47 (56.6) 55 (64.7)

Transferred to treating center, No. (%) 71 (85.5) 75 (88.2)

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 Laptook et al. Page 22

Hypothermia Group Noncooled Group

Characteristic (n = 83) (n = 85)
Delivery room, No. (%)
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Intubation 47 (58.0) 45 (52.9)

Chest compressions 19 (23.5) 25 (29.4)

Medication 9 (11.1) 11 (12.9)

Time to spontaneous respirations >10 min 24 (30.0) 34 (41.0)

Apgar score <5, No. (%)

At 5 min 42 (50.6) 43 (50.6)

At 10 mind 18 (28.6) 20 (26.0)

Cord blood, mean (SD)

pH 6.96 (0.16) 6.99 (0.16)

Base deficit 14.8 (5.8) 13.9 (5.3)

At randomization
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Age, mean (SD), h 16 (5) 15 (5)

≥6 to ≤12 h, No. (%) 26 (31.3) 28 (32.9)

>12 to 24 h, No. (%) 57 (68.7) 57 (67.1)

Level of encephalopathy, No. (%)

Moderate encephalopathy 73 (88.0) 78 (91.8)

Severe encephalopathy 10 (12.1) 7 (8.2)

Clinical seizures at randomization, No. (%) 63 (75.9) 56 (65.9)

Anticonvulsants at randomization, No. (%) 56 (72.7) 48 (67.1)

Inotropic support at randomization, No. (%) 17 (21.0) 16 (18.8)

Abbreviations: CPR, cardiopulmonary resuscitation; IQR, interquartile range.

a
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Percentages are based on the number of mothers and infants for whom data were available. Missing data: maternal education (9 missing), race/
ethnicity (3 missing), rupture of membrane (8 missing), hypertension/pre-eclampsia (1 missing), fetal decelerations (1 missing), cord mishap (1
missing), fetal decelerations (2 missing), shoulder dystocia (1 missing), length (2 missing), head circumference (3 missing), intubation (2 missing),
chest compression (2 missing), medication (2 missing), time to spontaneous respiration (5 missing), Apgar score at 10 min (79 missing), pH (42
missing), base deficit (65 missing), anticonvulsants at randomization (21 missing), and inotropic support at randomization (3 missing).
b
Other race/ethnicity includes American Indian or Alaskan Native, Asian, Native Hawaiian or other Pacific Islander, and multiracial.
c
Percentage based on the number of mothers with placental pathology performed (n = 30 in the hypothermia group and n = 22 in the noncooled
group).
d
The number of infants with an Apgar score at 10 minutes was 63 in the hypothermia group and 77 in the noncooled group.
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Table 2

Neonatal Adverse Events and Hospital Outcomesa

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No. (%)

Hypothermia Noncooled Absolute Differences

Event or Outcome (n = 83) (n = 85) P Value (95% CI)

Adverse Eventsb

Arrhythmia needing treatment 0 0

Persistent metabolic acidosis 0 0

Thrombosis 0 0

Bleeding 4 (4.8) 1(1.2) .21 0.04 (−0.02 to 0.09)

Altered skin integrity 1(1.2) 0 (0) 0.01 (−0.01 to 0.04)

Death 6(7.2) 5 (5.9) .76 0.01 (−0.06 to 0.09)

Otherc 2 (2.4) 0 0.02 (−0.01 to 0.06)

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Neonatal Outcomes in the Hospital

Meconium aspiration syndrome 23 (27.7) 20 (23.5) .60 0.04 (−0.09 to 0.17)

Pulmonary artery hypertension 20 (24.1) 13 (15.3) .18 0.09 (−0.03 to 0.21)

Inhaled nitric oxide use 14 (16.9) 15 (17.7) >.99 0.01 (−0.11 to 0.12)

ECMO 3(3.6) 2 (2.4) .68 0.01 (−0.04 to 0.06)

Ventilation during 96-h intervention 49 (59.0) 44 (51.8) .34 0.07 (−0.08 to 0.22)

Cardiac ischemiad 14 (16.9) 13 (15.5) .84 0.02 (−0.1 to 0.13)

Hypotension treated with vasopressors 28 (33.7) 24 (28.2) .51 0.05 (−0.08 to 0.19)

Oliguria 19 (23.0) 18 (21.2) .85 0.02 (−0.11 to 0.14)

Hepatic dysfunction 19 (22.9) 24 (28.2) .48 0.05 (−0.08 to 0.19)

Disseminated intravascular coagulation 9 (10.8) 4 (4.7) .16 0.06 (−0.02 to 0.14)

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Bacteremia 2 (2.4) 1 (1.2) .62 0.01 (−0.03 to 0.05)

Clinical seizures (any time) 64 (77.1) 64 (75.3) .86 0.02 (−0.11 to 0.15)

EEG recording 69 (83.1) 70 (82.4) >.99 0.01 (−0.11 to 0.12)

Electrographic seizurese 26 (37.7) 25 (34.7) .86 0.02 (−0.14 to 0.18)

Abnormal EEG backgrounde 49 (71.0) 48 (68.6) .85 0.02 (−0.13 to 0.18)

Glucose concentration <40 mg/dL 5 (6.0) 6 (7.1) >.99 0.01 (−0.06 to 0.09)

Glucose concentration >150 mg/dL 33 (39.8) 14 (16.7) .001 0.23 (0.1 to 0.36)

Analgesics during 96-h intervention 41 (50.0) 30 (35.6) .055 0.15 (0.0 to 0.30)

DNR order 7 (8.4) 8 (9.4) >.99 0.01 (−0.08 to 0.1)

DNR order and support withdrawn 6 (7.2) 8 (9.4) .47 0.02 (−0.06 to 0.11)

Gastrostomy tube or gavage feed at discharge 1 (1.4) 1 (1.3) >.99 0 (−0.03 to 0.03)
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Death prior to discharge 9 (10.8) 7 (8.2) .61 0.04 (−0.09 to 0.17)

Abbreviations: DNR, do not resuscitate; ECMO, extracorporeal membrane oxygenation; EEG, electroencephalogram.

SI conversion factor: To convert glucose to millimoles per liter, multiply by 0.0555.

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a
Percentages are based on the number of infants for whom data were available. Hospital outcomes reflect the number of infants experiencing the
outcome. Multiple adverse events occurred in 3 hypothermic infants and 1 control infant.
b
Adverse events during the 96-h intervention and the interval of rewarming.
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c
Other indicates adverse events not prespecified. This was persistent pulmonary artery hypertension with induction of hypothermia in one infant
and during hypothermia in a second infant.
d
Cardiac ischemia was defined as elevation of cardiac enzymes or troponin or electrocardiographic changes
e
Denominator is the number of infants who had an EEG recording.
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Table 3

Primary and Secondary Outcomes: aRRs and Posterior Probability of Treatment Effecta

Enthusiastic Prior Neutral Prior Skeptical Prior

No. (%) (RR, 0.72) (RR, 1.0) (RR, 1.10)
Laptook et al.

Hypothermia Noncooled aRR (95% Credible aRR (95% Credible aRR (95% Credible
Outcome (n = 78) (n = 79) Interval) P-TB,% Interval) P-TB, % Interval) P-TB, %

Primary Outcome
Death or moderate-severe disability 19 (24.4) 22 (27.9) 0.78 (0.52–1.15) 90 0.86 (0.58–1.29) 76 0.89 (0.60–1.32) 73

Secondary Outcomes

Deathb 9 (11.5) 9 (11.4) 0.74 (0.45–1.21) 89 0.86 (0.54–1.44) 73 0.90 (0.56–1.52) 67

Moderate or severe disabilityc 10 (12.8) 13 (16.5) 0.74 (0.44–1.24) 87 0.89 (0.54–1.48) 68 0.93 (0.56–1.55) 61

Severe disabilityc 9 (11.5) 12 (15.2) 0.73 (0.43–1.23) 88 0.88 (0.53–1.50) 68 0.93 (0.55–1.55) 61

Moderate disabilityc,d 1 (1.3) 1 (1.3)

Mild disabilityc 16 (20.5) 12 (15.2) 1.0 (0.62–1.62) 50 1.18 (0.73–1.91) 25 1.23 (0.76–2.0) 20

Abbreviations: aRR, adjusted risk ratio; P-TB, posterior probability of treatment benefit (risk ratio <1.0); RR, risk ratio.
a
Reference for the aRR is the noncooled group and the aRR is adjusted for level of encephalopathy (moderate, severe) and age at randomization (≤12 h, >12 h). Variables in the adjusted analyses were
outcome, treatment, level of encephalopathy at randomization, and age at randomization.
b
Causes of death in the hypothermia group were asphyxia brain injury (n = 5), multiorgan failure (n = 1), persistent pulmonary hypertension (n = 1), respiratory failure associated with intractable seizures (n
= 1), and intracranial hemorrhage (n = 1). Causes of death in the noncooled group were asphyxia brain injury (n = 5), multiorgan failure (n = 1), and meconium aspiration syndrome (n = 1), and 2 were
without an assigned cause (after discharge).
c
Disability categories were defined as follows: severe included any of the following: a cognitive score less than 70, a Gross Motor Function Classification Score (GMFCS) level of 3 to 5, or blindness or

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hearing impairment with inability to follow commands despite amplification; moderate included a cognitive score between 70 and 84 and any of the following: a GMFCS level of 2, an active seizure
disorder (antiepileptic drugs in use), or a hearing deficit with the ability to follow commands after amplification; and mild included a cognitive score between 70 and 84 or a cognitive score of 85 or greater
with any of the following: a GMFCS level of 1 or 2, seizure disorder (without medication), or a hearing deficit with the ability to follow commands without amplification.
d
Analyses could not be performed with 1 infant in each group.
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