Key Words

Hypoxia – insufficient levels of blood oxygen required to maintain normal body function

Ischemia – insufficient blood flow required to maintain normal body function

Encephalopathy – a disease affecting brain function or structure

Asphyxiation – oxygen deprivation

Birth can be an anxious period of time, but is a testament to the resilience of both the mother and baby. It is made even more stressful when complications arise during or shortly afterward. In high-income countries, 2 in every 1000 live births will experience encephalopathy due to asphyxiation, whereas 20 in every 1000 live births will be similarly affected in low income countries.

Hypoxic-ischemic encephalopathy is a traumatic brain injury caused by low oxygen in newborns. Hypoxia is associated with rising brain temperatures due to the increased metabolic demands caused by insufficient circulating oxygen. Hypothermia induction is used to decrease the core body temperature, which causes a reduction in metabolic demands, such as the conversion of oxygen to energy. This decrease allows the body to recover. In this manner, therapeutic hypothermia has been used to improve hypoxic-ischemic encephalopathy patient outcomes, but its effectiveness, especially across varying economic statuses, has not yet been established. The following study aims to bridge this gap in knowledge by investigating the efficacy of therapeutic hypothermia in neonates or newborns from upper to lower class countries.

Methods

This study was conducted in Ethiopia and led by Biruk Beletew Abate from the Department of Nursing at Woldia University. The work also features scientists from Addis Ababa University and Debre Tabor University who performed a systematic review and meta-analysis of randomized controlled trials, specifically looking at the mortality rate of induced hypothermia versus no hypothermia treatment in neonatal groups with hypoxic-ischemic encephalopathy [1]. Data from relevant research used for the review were found using keywords including, but not limited to, “neonates”, “therapeutic hypothermia”, and “hypoxic-ischemic.” Key details from the studies included the severity of encephalopathy, the number of deaths across induced hypothermia versus non-induced hypothermia groups, and cooling methods. Two types of cooling were analyzed ‒ selective head cooling, which focuses on decreasing brain temperatures through the use of cooling caps, and whole-body cooling, which lowers core body temperature using cooling blankets and cold gel packs. 

Results

28 randomized controlled trials were analyzed in various countries with the following economies: 15 high-income, 4 upper-middle-income, 7 lower-middle-income, and 2 low-income countries. 11 studies used cold gel packs and 9 studies used cooling blankets for a total of 20 studies employing whole body cooling. The remaining 8 studies used selective head cooling with cooling caps. The overall effect of therapeutic hypothermia in each study can be seen in Figure 1, where the Y-axis represents the relative risk (RR) of mortality, which was measured as a ratio of neonates treated with or without induced therapeutic hypothermia. 

The overall pooled risk of mortality, which combines the results from all of the studies to determine the effect of therapeutic hypothermia, was 0.74. A RR less than 1 indicates a lower risk of death in newborns that undergo therapeutic hypothermia. The lower the RR, the lower the risk.

The mortality rate for neonates exposed to therapeutic hypothermia across low, lower-middle, upper-middle, and higher-income countries were 0.32, 0.5, 0.62, and 0.76, respectively, as shown in Figure 1. Thus, it can be seen that therapeutic hypothermia was more effective in lower-income countries.

When comparing the RR between different treatment methods, the mortality rates in the groups using cooling caps, cooling blankets, and cold gel packs were 0.74, 0.74, and 0.73, respectively, as seen in Figure 2. The graph shows that the rates of mortality were similar across the three cooling methods, meaning all three were similarly effective. 

Discussion

It was found that therapeutic hypothermia was effective at decreasing mortality in moderate to severe hypoxic-ischemic encephalopathy neonates. The RR was found to be 26% lower in the induced-hypothermia groups compared to the groups with no treatment, proving the treatment’s efficacy. 

Lack of oxygen at birth can lead to decreased adenosine triphosphate levels (ATP) levels. ATP is an essential energy source that powers cell function. Low ATP causes dysfunction of neuronal membranes and subsequent brain damage. Therapeutic hypothermia works by slowing cerebral metabolism, which reduces the intensity of cerebral and metabolic demands and minimizes the progression of brain damage in the neonate. Low and lower-middle income countries showed the lowest rate of mortality using therapeutic hypothermia. Although the specific reason behind this result has not been explored, other studies show conflicting evidence regarding the use of therapeutic hypothermia. Pauliah et al. (2013) conducted a meta-analysis in which there was no statistically significant decrease in mortality rates as a result of induced hypothermia [2]. Conversely, Thayyil et al. (2021) performed a randomized control trial study, which found that therapeutic hypothermia treatment groups had an increased rate of mortality and thus, greater number of deaths [3]. Due to the varied results from these studies, it is important to conduct further research into this field in order to find more conclusive and generalizable data. Additionally, while not explicitly investigated in this study, the authors deduced that whole-body cooling may be more effective in inducing hypothermia than cooling caps due to its accessibility and large body surface area coverage. However, the affordability of these cooling mechanisms threatens the feasibility of this therapy.

It is also important to assess the limitations of this research. The study only assessed rates of mortality in the intervention and control groups. Other patient outcomes, such as the presence and severity of subsequent disabilities, were not assessed. 45% of neonates born to hypoxic insults can develop learning and cognitive disabilities while others may exhibit chronic motor and visual deficits. This study is limited in its scope as it only focuses on one aspect of hypoxic-ischemic encephalopathy and not the long-term consequences.

Overall, the data indicates that therapeutic hypothermia is a potentially effective method for decreasing mortality in neonates with moderate-to-severe hypoxic-ischemic encephalopathy, using both whole body and selective head cooling. Lower-income countries show the most potential for benefits from this method, however, safety and affordability in low and lower-middle income countries should be further explored. Due to the prevalence of neonatal deaths as a result of hypoxic-ischemic encephalopathy, it is imperative to focus more research in this field and work on improving the quality of life from its onset.

Works Cited

1. Abate BB, Bimerew M, Gebremichael B, Mengesha Kassie A, Kassaw MW, Gebremeskel T, et al. Effects of therapeutic hypothermia on death among asphyxiated neonates with hypoxic-ischemic encephalopathy: A systematic review and meta-analysis of Randomized Control Trials. PLOS ONE. 2021 Feb 25;16(2). https://doi.org/10.1371/journal.pone.0247229. https://creativecommons.org/licenses/by/4.0/legalcode 
2. Pauliah SS, Shankaran S, Wade A, Cady EB, Thayyil S. Therapeutic hypothermia for neonatal encephalopathy in low- and middle-income countries: A systematic review and meta-analysis. PLoS ONE. 2013;8(3). doi:10.1371/journal.pone.0058834
3. Thayyil S, Pant S, Montaldo P, Shukla D, Oliveira V, Ivain P, et al. Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (helix): A randomised controlled trial in India, Sri Lanka, and Bangladesh. The Lancet Global Health. 2021 Sept;9(9). doi:10.1016/s2214-109x(21)00264-3