Effect of Therapeutic Hypothermia on the Outcome in Term Neonates with Hypoxic Ischemic Encephalopathy—A Randomized Controlled Trial

Abstract

Objective

To assess the effect of therapeutic hypothermia on the outcome in term neonates with hypoxic ischemic encephalopathy (HIE).

Methods

A randomized controlled trial was conducted in a tertiary care teaching hospital in south India. Term infants with moderate to severe HIE were randomized to be treated with normothermia or hypothermia. Mortality, neurological abnormality or normal outcome was recorded at hospital discharge or 28 days of age, whichever was earlier, and at 18 months of age.

Results

The baseline maternal and neonatal characteristics in the two groups were similar. The 78 infants in the hypothermia group had more normal survivors at discharge (38%) than the 84 infants in the normothermia group (30%), ratio 1.29 (95% confidence interval 0.84–1.99), and at 18 months of age (65% vs. 42%), ratio 1.54 (1.13–2.10). When these results were combined with those of a previous randomized trial in the same neonatal unit, there were significantly more normal survivors with hypothermia compared to normothermia at discharge, ratio 1.49 (1.18–1.88) and at 6–18 months of age, ratio 1.37 (1.17–1.60).

Conclusion

In term infants with HIE, therapeutic hypothermia reduced mortality and neurological abnormalities, and resulted in more normal survivors.

LAY SUMMARY

Babies who do not breathe immediately after they are born are likely to die or have brain damage. Previous studies have suggested that cooling these babies after birth might reduce the number who die or have brain damage. In this resource-limited setting, babies who were cooled were less likely to die or survive with brain damage.

INTRODUCTION

One to five neonates per 1000 live births are likely to have encephalopathy due to hypoxia-ischemia [1]. Severe encephalopathy increases the risk of mortality among the affected neonates and also increases the incidence of cerebral palsy and mental retardation among those who survive [2]. A Cochrane review reports evidence for the beneficial effect of cooling of term and late preterm neonates with hypoxic ischemic encephalopathy (HIE); therapeutic hypothermia has also been noted to reduce mortality without increasing major disability among neonates who survive [3]. In developed countries, therapeutic hypothermia is the accepted management for neonates with HIE. However, in low- and middle-income countries including India, there is no consensus regarding the role of hypothermia [4, 5]. Because of the paucity of literature on therapeutic hypothermia in India, we performed a randomized controlled trial (RCT) in term neonates with moderate to severe HIE. A previous RCT in the same neonatal intensive care unit (NICU) had suggested that hypothermia might be beneficial [6].

METHODOLOGY

We conducted this RCT in a level III NICU of a tertiary care institute situated in south India. Institute ethics committee approval was obtained before initiating the study. The RCT was also registered retrospectively with the Clinical Trial Registry of India (CTRI/2018/01/011085). Term babies with moderate or severe encephalopathy according to Sarnat and Sarnat staging were included in the study provided they had a pH ≤7 or base deficit ≥−12 meq in cord blood and also satisfied any two of the following criteria: (i) Apgar score at 10 min ≤6, (ii) any clinical evidence of fetal distress, (iii) requiring assisted ventilation for at least 10 min soon after delivery, and (iv) any evidence of one or more organ dysfunction. Those neonates who could not be randomized within 6 h of delivery and babies delivered outside our hospital were excluded. Neonates with major congenital abnormalities and those neonates who had no spontaneous respiratory efforts by 20 min following delivery were also excluded [6]. Before randomization, informed written consent from parents of the participants was obtained. Eligible neonates were randomized to two groups (normothermia and therapeutic hypothermia) using computer-generated random numbers (Fig. 1). Serially labeled opaque-sealed envelopes were used for allocation concealment. The baseline demographic data and characteristics of mothers and their significant antenatal problems were recorded. Pertinent clinical data of the neonates including gestational age, Apgar scores, birth weight and resuscitation details were also noted in the case report form.

Therapeutic hypothermia in the intervention arm was achieved using phase-changing material (MiraCradle Neonate Cooler. Mfg. Pluss Advanced Technologies Pvt. Ltd, India). A rectal temperature of 33.5 ± 0.5°C was maintained for the neonates in hypothermia group. Rectal probes were used for continuous monitoring of the core temperature. Cooling was started within 6 h of delivery and maintained for a period of 72 h. After the cooling phase, neonates were slowly rewarmed over 10–12 h (0.5°C/h) [7]. The rectal temperature was monitored for a further period of 12 h after completion of rewarming phase. Neonates in the normothermia group were managed as per the standard NICU protocol for HIE. These neonates were placed under radiant warmers in servo-controlled mode and a rectal temperature of 36.5°C was maintained. We observed carefully for any complications including coagulopathy, bleeding, shock, acute kidney injury, arrhythmias and skin changes among the study participants.

Other than the main intervention (therapeutic hypothermia), neonates in both groups were managed similarly. They were given supportive care including anticonvulsant medications, inotropic support and mechanical ventilation according to our NICU protocol. Early outcome including mortality and neurological abnormality at discharge (based on Amiel-Tison examination) were evaluated [8]. Study participants were followed up at 28 days or discharge, whichever was earlier, and at 18 months of age [9]. Neurodevelopmental assessment was done by a trained developmental child therapist blinded to the group allotment. Infants were assessed for neurodevelopmental (motor, cognitive, language and personal social) outcome using Developmental Assessment Scale for Indian Infants. The outcomes in this RCT were combined in a meta-analysis with the outcomes of the previous RCT of hypothermia in this NICU [6].

Sample size was calculated assuming an alpha error of 5%, 80% power and an effect size of d = 0.5; the required sample size was calculated as 77 in each group (G power software version 3.1.9.2). An intention-to-treat analysis was performed. Unpaired t-tests were used for continuous variables and chi-square tests for categorical variables. The normally distributed variables were compared between the two groups using the independent Student’s t-test and the Mann–Whitney test was used to compare non-Gaussian data. p-Values <0.05 were considered significant. Data analysis was done using Strata version 11.0.

RESULTS

Two hundred neonates were assessed for eligibility and 38 were excluded; the remaining 162 neonates were randomized to normothermia and hypothermia groups (Fig. 1). The baseline maternal and neonatal characteristics in both groups were similar (Table 1). After birth, the median time to achieve a rectal temperature <34°C was 8 h (interquartile range 6–9 h, range 3–12 h). The outcomes in the normothermia and hypothermia groups are shown at discharge or 28 days of age whichever occurred earlier (Table 2) and at 18 months of age in this trial and at 6 months of age in the previous trial (Table 3). Figure 2 shows a meta-analysis of the two RCTs for the number of normal survivors in the hypothermia group divided by the number of normal survivors in the normothermia group.

DISCUSSION

Among infants who are born at term, HIE is one of the important causes of mortality and neurodevelopmental sequelae. Neonates with HIE contribute 20% of the perinatal deaths. Among HIE infants who survive, 30% develop neurological deficits, and 60% of neonates with severe encephalopathy have neurodevelopmental abnormalities later [10]. Several mechanisms have been postulated for the neuroprotective effect of therapeutic hypothermia. Therapeutic hypothermia has been noted to reduce mortality without increasing severe disability among survivors [3]. Low-cost cooling devices have been developed which are likely to have a major effect on the management of HIE neonates in resource-restricted settings. A multicentric study by Thomas, et al. [7] involving different neonatal units in India has shown the feasibility of administering therapeutic hypothermia for HIE with the help of a phase change material-based cooling device coupled with a standard treatment protocol, with successful maintenance of hypothermia. The phase change material used in our study is less cumbersome than using cooling gel packs. It is easy to use, safe, lightweight, portable and gives the precise temperature control of 33–34°C for a period of 72 h with minimal manual supervision and no requirement of constant electricity supply. The approximate cost of one cooling device is 1.7 lakhs INR.

In this RCT and the previous RCT [6], compared to the normothermia group, the hypothermia group had more normal survivors, with lower mortality and fewer neurological abnormalities, at both discharge (Table 2) and at 6–18 months of age (Table 3). When the results of the two RCTs were combined in a meta-analysis, a normal outcome was more likely in the hypothermia group with a ratio of 1.49 (1.18–1.88) at discharge and 1.37 (1.17–1.61) at 18 months of age in this trial and 6 months of age in the previous trial (Fig. 2). These results suggest that neonates in India with HIE should be treated with hypothermia.

AUTHOR CONTRIBUTIONS

R.C.C.: helped in data collection. V.B.B.: designed study, supervised study and edited the manuscript. B.A.: helped in designing study, data analysis and drafting the manuscript. S.K.B.: helped in data collection and clinical management. P.C.: helped in data analysis.

FUNDING

This work was supported by the Department of Biotechnology, Government of India [BT/PR8717/MED/97/141/2013].

REFERENCES