MANUSCRIPT CITATION

Laptook AR, Shankaran S, Tyson JE, Munoz B, Bell EF, Goldberg RN, et al. Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial. JAMA 2017; 318:1550-60. PMID: 29067428.

REVIEWED BY

Stephanie L. Bourque, MD
Neonatal-Perinatal Fellow
Department of Pediatrics, Section of Neonatology
University of Colorado, Aurora, CO
stephanie.bourque@childrenscolorado.org

Robert M. Dietz, MD, PhD (corresponding author)
Assistant Professor of Pediatrics
Department of Pediatrics, Section of Neonatology
University of Colorado, Aurora, CO
robert.dietz@childrenscolorado.org

TYPE OF INVESTIGATION

Treatment

QUESTION

(P) In infants >36 weeks gestational age with neonatal encephalopathy, who meet criteria for therapeutic hypothermia, (I) does late therapeutic hypothermia initiated between 6-24 hours after birth (C) compared to noncooled infants (O) lead to reduced risk of death or disability at 18 months?

METHODS

• Design: Randomized clinical trial
• Allocation: Concealed by using computer-generated blocked randomization with block sizes of 2 and 4, allocation ratio of 1:1. Randomization was stratified by postnatal age (<12 hours or >12 hours) and stage of encephalopathy (moderate or severe) and was randomly assigned by data center.
• Blinding: Un-blinded intervention; follow-up assessments at 18-22 months done by examiners blinded to intervention.
• Follow-up period: In this study, infants were followed until 18-22 months of age
• Setting: Enrollment at 21 centers in the United States between April 2008 – July 2014
• Patients: Infants >36 weeks gestation age, between 6 and 24-hours old who were identified to have neonatal encephalopathy, perinatal asphyxia or neurologic depression. Inclusion criteria followed previously published Neonatal Research Network (NRN) hypothermia trial criteria. Infants who were already hypothermic (core temperature <34°C for longer than 1 hour), had chromosomal or other anomalies, weighed <1800g or were in extremis were excluded from study consideration.
• Intervention: Infants meeting inclusion criteria were randomized to either the treatment group (therapeutic hypothermia with whole body cooling to 33-34°C) or noncooled group (standard care without therapeutic hypothermia). Infants in the treatment group were re-warmed to goal 37°C after 96 hours of cooling.
• Outcomes:
  • Primary Outcome: Composite outcome of death or moderate-severe disability at 18-22 months
  • Pre-Specified Secondary Outcomes: Death, moderate-severe disability, disability based on level of encephalopathy, seizures, do not resuscitate order (DNR), DNR and support withdrawn, DNR and survival or death, nonbrain organ dysfunction
• Analysis and Sample Size: The study was designed with a predefined sample size of 168 patients, based on the largest feasible sample during the six-year enrollment time period. The anticipated effect size for late therapeutic hypothermia was expected to be smaller than previously published NRN hypothermia trial which had a risk ratio (RR) of 0.72, 95% CI 0.54-0.95. Bayesian analysis was performed using three prior probabilities including a neutral prior (assuming no treatment effect, RR 1.0), enthusiastic prior (assuming 28% reduction in risk of death or disability, RR 0.72 as in the NRN trial), and a skeptical prior (assuming 10% increase in risk of death or disability, RR 1.10). Significance was set to 0.05.
• Patient follow-up: Among the 3088 infants assessed for eligibility, 2920 were excluded, 1324 of which were already hypothermic (<34°C) at time of enrollment. 168 infants were randomized, 83 to the treatment hypothermia group and 85 to the noncooled control group. With minimal loss to follow-up, 78 in the hypothermia group and 79 in the noncooled group were included in the primary analysis and were followed to 18-22 months.

MAIN RESULTS

Highlighted Maternal Demographics

Highlighted Infant Demographics

Highlighted Results

*P-TB – Probability of Treatment Benefit (%)

CONCLUSION

The authors conclude that late therapeutic hypothermia for infants >36 weeks gestational age who initiate cooling at 6 to 24 hours of age have a 76% probability of any reduction of death or moderate-severe disability and a 64% probability of at least a 2% reduction of death or moderate-severe disability at 18-22 months of age.

COMMENTARY

Hypoxic-ischemic encephalopathy (HIE), also known as neonatal encephalopathy, affects an estimated 1-3 term infants per 1000 live births and leads to significant long-term morbidity and mortality(1). Several clinical trials evaluating the use of therapeutic hypothermia (TH), cooling the core body temperature to 33-34°C for 72 hours, initiated within 6 hours of birth, have demonstrated benefit with decreased moderate-severe disability or death at 18-22 months(2). As such, TH for infants with HIE has become standard of care. While animal studies have demonstrated superior treatment effect with early cooling initiated prior to 6 hours of age(3), not all eligible infants undergo initiation of TH within this ideal timeframe.

This randomized clinical trial by Laptook and colleagues enrolled infants who met clinical or laboratory criteria for TH, but who were between 6 and 24 hours of age at time of randomization(4). Infants underwent whole body cooling to a goal core temperature of 33.5°C (range 33-34°C) for 96 hours. This longer cooling time, compared to the standard 72 hours, was chosen due to previous data suggesting that longer hypothermia was necessary for neuroprotection, although this has been recently refuted(5). The results of this study suggest that the benefit of beginning hypothermia >6 hours of age is much less than starting it earlier which is supported by preclinical data. However, despite most of the patients being >12 hours of age at randomization, there was still a small benefit to TH, indicated by Bayesian analysis, despite an increased seizure burden in the TH group at randomization. Combined with the lack of increased serious in-hospital adverse effects in the treatment group (no difference in hypotension, coagulopathy or seizures, though possible increase in hypoglycemia in TH group), and the significant risk for moderate-severe neurodevelopmental disability after HIE, the small potential benefit purported by this trial should prompt NICUs to consider initiation of TH beyond 6 hours of age. It is important to note that reasons for lack of initiation of early TH are many and while not specifically stated in this population, may include prolonged transport distance from referring hospital to a tertiary care center capable of cooling and under recognition of clinical encephalopathy after birth, among others(6).

The difficulty in translating preclinical pharmacologic interventions for neonatal ischemia has prompted a discussion to expand the inclusion criteria for hypothermia after HIE. Among these groups are infants initiated beyond 6 hours of life, mild encephalopathy, preemies, and neonatal stroke(7).  While others have evaluated non-standard therapeutic hypothermia(7), this is the only randomized clinical trial to date to evaluate the effectiveness of this practice. While trials such as that reviewed here may be difficult to design and fund, it is certainly the better course of action to let randomly controlled clinical trials guide clinical care than to practice medicine by anecdote or trial and error. Much hope remains though that new therapeutic options to augment TH are on the horizon(8). Hence, the concerted efforts of researchers and funding agencies to discover novel strategies to treat acquired neonatal brain injury must continue in earnest.

REFERENCES

1. Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365:663-70.
2. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013; 1:CD003311.
3. Gunn AJ, Gunn TR, Gunning MI, Williams CE, Gluckman PD. Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep. Pediatrics 1998; 102:1098-106.
4. Laptook AR, Shankaran S, Tyson JE, Munoz B, Bell EF, Goldberg RN, et al. Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial. JAMA 2017; 318:1550-60.
5. Shankaran S, Laptook AR, Pappas A, McDonald SA, Das A, Tyson JE, et al. Effect of Depth and Duration of Cooling on Death or Disability at Age 18 Months Among Neonates With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial. JAMA 2017; 318:57-67.
6. Bourque SL, Meier SA, Palmer C, Melara DL, Grover TR, Delaney CA. A Quality Initiative for Optimal Therapeutic Hypothermia during Transport for Neonates with Neonatal Encephalopathy. Pediatric Quality & Safety 2018; 3:056.
7. Smit E, Liu X, Jary S, Cowan F, Thoresen M. Cooling neonates who do not fulfil the standard cooling criteria – short- and long-term outcomes. Acta Paediatr 2015; 104:138-45.
8. McAdams RM, Juul SE. Neonatal Encephalopathy: Update on Therapeutic Hypothermia and Other Novel Therapeutics. Clin Perinatol 2016; 43:485-500.