Therapeutic hypothermia (TH) is an effective therapy for neonatal encephalopathy when the likelihood of a hypoxic-ischemic origin is high. Multiple randomized trials have demonstrated that relatively small reductions in core temperature either alone, or in combination with reduced head temperature, reduced death or disability at 18 months.1–6 The Cochrane metaanalysis indicates that TH reduced death or major neurodevelopmental disability in survivors from 61% in noncooled infants compared with 46% in infants treated with hypothermia, yielding a risk ratio of 0.75 (95% confidence interval [CI] 0.68–0.83), along with decreased death from 34% to 25% (risk ratio 0.75, 95% CI 0.64–0.88), and decreased long term disability from 24.9% to 19.2% (risk ratio 0.77, 95% CI 0.63–0.94).⁷ Neuroprotective effects of TH persisted even at 6 to 7 years.^8,9 Given the beneficial effects of hypothermia, the Committee on the Fetus and Newborn of the American Academy of Pediatrics has provided an overview of the available data and expectations for centers that provide this therapy.¹¹ The importance of this therapy extends beyond the benefits provided to infants and their families; it signifies that hypoxic-ischemic brain injury is modifiable (Fig. 7.1) and has accelerated testing other potential neuroprotective interventions either with or without TH.¹⁰

Hypothermia regimens have multiple components: induction, maintenance, and rewarming. Induction represents the time from initiation of cooling to reaching target temperature; maintenance represents the duration of keeping the infant at the target temperature; and rewarming represents the reestablishment of a normothermic temperature. The initial trials of hypothermia1–6 used remarkably similar cooling regimens. Specifically, the age of initiation was always less than 6 hours after birth, the extent of temperature reduction was 33.5°C for whole-body cooling and 34.5°C for head combined with body cooling, the duration of cooling was 72 hours, and the rate of rewarming was 0.5°C/hr. The similarity in hypothermia regimens facilitated metaanalyses of multiple trials to provide more accurate estimates of patient outcomes.⁷ The only major component of cooling regimens that differed among the initial trials was the mode of cooling: whole-body versus head with body cooling. Metaanalysis indicated that outcomes are similar irrespective of the mode of cooling.⁷

There are several justifications to perform further studies of hypothermia.1–6 First, the Cochrane metaanalysis indicated that 46% of infants treated with hypothermia continue to either die or are diagnosed with moderate or severe disability.⁷ Data from the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN), Optimizing Cooling Trial enrolled a more recent cohort of infants with moderate to severe hypoxic-ischemic encephalopathy (HIE) and reported that death or disability occurred in 29%.¹ Even though clinicians and NICUs have more experience caring for infants with HIE, care practices continue to evolve and outcomes have improved over the last decade, there is still much room for improvement in outcomes.² Clearly, further investigations of hypothermia are needed in that it was studied in a specific group of newborns—that is, those with a diagnosis of presumed hypoxia-ischemia presenting at less than 6 hours of age and with a gestational age of at least 36 weeks in high-income countries. These trials did not address other cohorts of newborns (preterm, mild encephalopathy, or cooling in low-resource countries).^3,54–56

This chapter addresses important gaps concerning the use of TH for HIE. Some of the gaps have been addressed, some are currently under study, and some remain to be investigated.

The depth of temperature reduction used in the first series of hypothermia trials1–6 was extrapolated from preclinical investigation and pilot studies in newborns. Recognition that small changes in brain temperature modified the extent of hypoxic-ischemic brain injury in adult animals¹³ prompted perinatal animal investigations to examine the effects of depth and duration of “modest hypothermia” at varying times after brain hypoxia-ischemia. Modest hypothermia encompassed a range of temperature reductions from as little as 2°C to as much as 5°C using newborn swine, rat pups, and fetal sheep.^14–18 This range reflected concerns regarding a possible trade-off between the potential benefit of lower temperature and adverse effects of hypothermia, which increase with greater reductions in core temperature.¹⁹ The optimal temperature to use for hypothermic intervention in clinical trials was not known but was guided by existing animal data and the assessment of incremental reductions in core temperature in pilot human studies of head cooling combined with body cooling^20,21 and whole-body cooling.²² Based on this body of work, clinical trials of head cooling combined with body cooling and whole-body cooling alone were conducted at a rectal temperature of 34.5°C and an esophageal temperature of 33.5°C, respectively.^1,2

The optimal duration of hypothermia was also uncertain when the first series of clinical trials of hypothermia were undertaken in newborn infants.^1–6 Available data were derived primarily from adult animals and indicated that increasing the duration of hypothermia reduced brain injury compared with shorter cooling intervals.^23–25 Although not studied as extensively in newborn animals, 21-day-old rat pups subjected to hypoxia-ischemia had reduced brain injury when cooling was extended to 72 hours compared with 6 hours.²⁶ In preparation for clinical trials, pilot studies of hypothermia after brain ischemia in fetal sheep by Gunn et al. indicated rebound epileptiform activity when cooling was stopped after 48 hours but not if cooling was continued for 72 hours.¹⁷ Based on these studies, clinical trials of head cooling with mild body cooling and whole-body cooling used a 72-hour cooling intervention.^27,28

In response to these knowledge gaps, the NICHD NRN conducted a randomized clinical trial of cooling to a lower temperature and for a longer duration (Optimizing Cooling Trial, NCT 01192776).²⁹ The Optimizing Cooling Trial was a randomized 2 × 2 factorial design performed at 18 centers to determine if longer cooling (120 hours), deeper cooling (32.0°C), or both initiated before 6 hours of age are superior to cooling at 33.5°C for 72 hours among infants of at least 36 weeks’ gestation with moderate or severe HIE. The esophageal profiles of each group are plotted in Fig. 7.2 demonstrating the different interventions. The primary outcome was death or disability at 18 to 22 months adjusted for center and level of encephalopathy. The trial was closed to patient enrollment after 364 of a planned 726 infants were enrolled based on recommendations of an independent Data Safety Monitoring Committee due to a trend of higher deaths with longer and deeper cooling and futility. In-hospital mortality rates for cooling of 72 compared with 120 hours’ duration were 11% and 16%, respectively (adjusted risk ratio [aRR] 1.37, 95% CI 0.92–2.04). In-hospital mortality rates for cooling at 33.5°C compared with 32.0°C were 12% and 16%, respectively (aRR 1.24, 95% CI 0.69–2.25). Although not statistically different, the risk ratio and boundary of the 95% CI suggest that longer cooling maybe associated with an increase in mortality. Cooling for 120 hours was associated with more arrhythmias, anuria, and a longer length of hospital stay compared with 72 hours of cooling, whereas cooling to 32.0°C was associated with a higher use of inhaled nitric oxide, extracorporeal membrane oxygenation, longer use of supplemental oxygen, and a higher incidence of bradycardia compared with cooling to 33.5°C. The results at 18-month follow-up confirmed the concern for futility; specifically, death or disability occurred in 32% of infants cooled for 72 hours and 32% for infants cooled for 120 hours (aRR 0.92, 95% CI 0.68–1.25), and 32% of infants cooled to 33.5°C and 31% for infants cooled to 32.0°C (aRR 0.92, 95% CI 0.68–1.26).³⁰

Does rewarming affect neuroprotection?¹²

The clinical guidelines and all trials to date recommend that infants be rewarmed at a rate of 0.5°C per hour, but this is not based on strong evidence.⁴ The effect of rewarming on seizures and neurodevelopmental outcome has not been well studied. There are no randomized controlled trials investigating the optimal rate of rewarming after TH for infants with HIE. The rewarming regimen was uniformly set in all neonatal hypothermia trials to increase the core body temperature by 0.5°C per hour until normothermia is achieved despite the absence of data to support such a regimen.^5,6 The importance of monitoring for seizures during rewarming is underscored by studies demonstrating that even brief increases in brain temperature following ischemia increase neuronal injury.^7,8 Rebound electrical seizures during rewarming after 72 hours of hypothermia have been reported in clinical practice.^9–11

The Systematic Monitoring of EEG in Asphyxiated Newborns during Rewarming after Hypothermia Therapy (SMaRT) study is a nested cohort of the Optimizing Cooling trial. SMaRT used continuous recordings of amplitude-integrated electroencephalogram (aEEG) with a validated raw EEG method of visual confirmation to assess the frequency of electrographic seizures before and during rewarming initiated at 72 hours versus 120 hours.¹² Key study findings were twice higher odds of electrographic seizures during rewarming after 72 hours of TH which was associated with a significantly higher risk of the composite outcome of death or moderate to severe disability at 18 to 22 months of age.¹²

The study showed that 23% of infants had seizures during rewarming and that a longer duration of cooling to 120 hours did not reduce the incidence of seizures. Most concerning was the increased relative risk of abnormal 18 to 22 months outcomes in infants who had seizures during rewarming even after adjusting for baseline severity of encephalopathy, as well as for center. These observations along with other studies^13,14 point to the need to monitor and treat seizures that occur during rewarming.

Potentially, rewarming could reactivate inflammatory responses that have been suppressed during hypothermia. Alternatively, rewarming could also lead to reversal of hypothermic suppression of oxidative stress and excitotoxin release.^15,16 There is no data, however, to demonstrate that rewarming at a slower rate may modify the increase in seizures noted with rewarming at 0.5°C/hr. Furthermore, there is no consensus among studies on what constitutes a “rapid” or “slow” rate of rewarming in preclinical models which largely depends on the species, their baseline temperature and cooling.⁴ Future clinical translational studies following the recent SMaRT publication¹² should evaluate the effects of different rates of rewarming.

The time of initiation of hypothermia represents the component of a hypothermia regimen studied in the most systematic fashion in preclinical investigations. Gunn et al. performed a series of fetal sheep studies where 30 minutes of brain ischemia was followed by 72 hours of hypothermia (cooling cap positioned on the fetal head in utero) initiated at 1.5, 5.5, and 8.5 hours following ischemia.^17,31,32 A neuronal loss score in different brain regions was assessed at 48 hours after completion of hypothermia and demonstrated that the extent of neuroprotection was time sensitive. Earlier cooling was neuroprotective (initiation at 1.5 more so than 5.5 hours) but later cooling (initiation at 8.5 hours) was not. These experiments provided the rationale for initiation of cooling within 6 hours of birth in the first series of human cooling trials.^1–6 These trials, however, could not determine if initiation of cooling earlier in the 6-hour window is more effective since the vast majority of enrolled infants had hypothermia initiated between 4 and 5 hours. In the TOBY trial, there was a trend for a reduction in the primary outcome (survival with neurodevelopmental disability) among infants randomized prior to 4 hours (relative risk 0.77, 95% CI 0.44–1.04) in contrast to infants randomized between 4 and 6 hours after birth (relative risk 0.95, 95% CI 0.72–1.25).¹⁷ A more recent single-center retrospective cohort analysis of hypothermia reported that initiation of cooling at 3 hours or earlier is associated with higher psychomotor developmental scores using the Bayley II Scales of Infant Development compared with cooling initiated after 3 hours.³³ Despite the lack of direct evidence from clinical trials, many embrace the goal of initiating TH as early as possible after birth for optimal effectiveness.¹⁸

Although these data suggest that studying initiation of hypothermia after 6 hours of age would be of lesser benefit, there is strong biologic and clinical rationale for further investigation. Even when cooling was initiated at 8.5 hours after ischemia in fetal sheep, a time when seizures occur in this model, there are areas of the brain that have reduced neuronal loss with hypothermia.¹⁹ Furthermore, data from animal models may not be readily extrapolated to newborns. Specifically, a well-defined hypoxic-ischemia event in terms of severity, duration, and timing relative to an intervention in a laboratory setting, may be considerably different from scenarios encountered in neonatal intensive care units. A therapeutic window of 6 hours in fetal sheep is established, but there is no information of the duration of the therapeutic window in newborns with HIE because all cooling trials initiated hypothermia by 6 hours.⁷ Whether in utero preconditioning events prolong the therapeutic window is unknown.^34,35 Enrollment in clinical trials of hypothermia at less than 6 hours of age assumes that hypoxic-ischemic events occur proximate to delivery. However, precise timing of hypoxic-ischemia in utero among newborns with HIE may be inaccurate in the absence of a sentinel event, and prior trials likely enrolled infants beyond 6 hours from hypoxia-ischemia. Other important considerations are births in rural communities remote from centers that provide hypothermia, evolution of encephalopathy after 6 hours of age, and late recognition of encephalopathy. All these variables may limit application of hypothermia within a putative narrow therapeutic window of 6 hours following birth.

Given the knowledge gap concerning initiation of hypothermia beyond 6 hours, the NRN has conducted a randomized trial to obtain an unbiased estimate of the probability of benefit or harm from “late” initiation of hypothermia. https://clinicaltrials.gov/ct2/show/NCT00614744 (Fig. 7.3).⁶⁷

Related posts:

Intraventricular hemorrhage in the premature infant General supportive management of the term infant with neonatal encephalopathy following intrapartum hypoxia-ischemia Posthemorrhagic hydrocephalus management strategies Neonatal herpes simplex vi rus, congenital cytomegalovirus, congenital Zika, and congenital and neonatal SARS-CoV-2 virus infections Neonatal hypotonia and neuromuscular disorders Amplitude-integrated EEG and its potential role in improving neonatal care within the NICU

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