Blog #16

Hypothermia for Neonatal Encephalopathy in Low and Middle-Income Countries

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

Re-written summaries by: Anuva Gajjar

Date Published: 2/18/2023

Original research links:

https://pubmed.ncbi.nlm.nih.gov/34358491/

Introduction

Neonatal encephalopathy (NE) is a condition that occurs in newborns (approximately 1.5 million newborns every year) due to a lack of oxygen or blood flow to the brain during or before birth. It is a major cause of infant mortality and long-term disability, especially in low-income and middle-income countries (LMICs) where access to healthcare and advanced medical facilities is limited. Hypothermia treatment has been found to be effective in reducing brain damage and improving the outcomes of infants with moderate or severe neonatal encephalopathy in high-income countries. However, there is a lack of data on the effectiveness of hypothermia treatment in low-income and middle-income countries. The Hypothermia for Encephalopathy in Low and Middle-Income Countries (HELIX) consortium aimed to evaluate the effectiveness and feasibility of hypothermia treatment for neonatal encephalopathy in low-income and middle-income countries. 

Methods

The HELIX consortium conducted a multicountry, open-label, randomized controlled trial in seven tertiary neonatal intensive care units in India, Sri Lanka, and Bangladesh. From Aug 15, 2015, to Feb 15, 2019, 2296 infants were screened, and 576 infants were eligible for inclusion. After exclusions, 408 eligible infants were recruited and randomly assigned to either a group receiving whole-body hypothermia (33·5°C) for 72 hours using a servo-controlled cooling device or to usual care (control group) within 6 hours of birth. Infants born at or after 36 weeks of gestation with moderate or severe neonatal encephalopathy and a need for continued resuscitation at 5 minutes of age or an Apgar score of less than 6 at 5 minutes of age (for babies born in a hospital), or both, or an absence of crying by 5 minutes of age (for babies born at home) were enrolled. All recruiting sites had facilities for invasive ventilation, cardiovascular support, and access to 3 Tesla MRI scanners and spectroscopy. Masking of the intervention was not possible, but those involved in the magnetic resonance biomarker analysis and neurodevelopmental outcome assessments were masked to the allocation. The primary outcome was a combined endpoint of death or moderate or severe disability at 18-22 months, assessed by the Bayley Scales of Infant and Toddler Development (third edition) and a detailed neurological examination.

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To summarize this more, the trial enrolled 381 newborns with moderate or severe neonatal encephalopathy, who were randomly assigned to either the hypothermia treatment group or the standard care group. The hypothermia treatment group received whole-body cooling to 33.5°C for 72 hours, followed by slow rewarming to normal body temperature. The standard care group received routine neonatal care. The primary outcome was a composite of death or moderate or severe disability at 18 months of age. Secondary outcomes included mortality, neurodevelopmental impairment, and adverse events. The study enrolled neonates with moderate to severe NE and randomized them to either therapeutic hypothermia or standard care. The primary outcome was death or moderate to severe disability at 18 to 22 months of age, assessed using the Bayley Scales of Infant and Toddler Development, Third Edition. The secondary outcomes included mortality, the incidence of seizures, adverse events, and the prevalence of hypoxic-ischemic encephalopathy.

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Results

Primary outcome data was available for 195 (97%) of the 202 infants in the hypothermia group and 199 (97%) of the 206 control group infants. Of the infants in the hypothermia group, 50% either died or had moderate or severe disability, while 47% of infants in the control group had the same outcome (risk ratio 1·06; 95% CI 0·87-1·30; p=0·55). Among the infants who died, 84 (42%) were from the hypothermia group, and 63 (31%) were from the control group (p=0·022). Of these, 72 (36%) and 49 (24%; p=0·0087) died during neonatal hospitalization. Three serious adverse events occurred in the hypothermia group (one hospital readmission relating to pneumonia), and two occurred in the control group (one sepsis and one respiratory distress).

Conclusion​

The results of this study suggest that therapeutic hypothermia did not result in a significant difference in death or moderate or severe disability at 18-22 months in infants with neonatal encephalopathy in low- and middle-income countries, although a higher number of infants in the hypothermia group died compared to the control group. The study adds to the evidence on the feasibility and safety of therapeutic hypothermia in low- and middle-income countries. Further research may be needed to identify and address barriers to implementation of therapeutic hypothermia in these settings. The study's findings indicate that it is not enough to transfer interventions that have been successful in high-income countries to low- and middle-income countries without considering the unique needs and challenges of these settings.

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Helpful Definitions:

• Hypothermia: A medical treatment that involves lowering a person's body temperature to reduce damage caused by lack of oxygen to the brain or other organs.

• Neonatal encephalopathy: A condition in which a newborn baby experiences brain dysfunction due to a lack of oxygen or blood flow to the brain before or during birth.

• Randomized controlled trial: A type of study in which participants are randomly assigned to one of two or more groups, with one group receiving a treatment or intervention and the other(s) serving as a control group. This type of study is used to determine the effectiveness of a treatment or intervention by comparing the outcomes of the different groups.

• Low- and middle-income countries: Countries that have lower levels of economic development and per capita income compared to high-income countries.

• Lancet Global Health: A medical journal that publishes research on global health issues.

• Erratum: A correction or retraction issued by a journal for an error in a published article.

• Enrolment: The process of recruiting and registering participants in a study.

• Inclusion and exclusion criteria: The specific characteristics that are required or not allowed for participants in a study. These criteria are used to ensure that the participants are similar in important ways and that the study results are valid.

• Blinding: A technique used in a study to prevent participants, researchers, or both from knowing which treatment or intervention each participant is receiving. This is done to reduce bias in the study results.

• Placebo: An inactive substance or treatment that is given to the control group in a study to ensure that the effects seen in the treatment group are due to the treatment and not some other factor, such as the placebo effect.

• Clinical outcomes: The effects of a treatment or intervention on a patient's health or well-being, such as survival, quality of life, or symptoms.

• Adverse events: Negative side effects or complications that occur during a treatment or intervention.

• Subgroup analysis: An analysis of the study results that focuses on a specific subgroup of participants, such as those with a certain characteristic or those who received a certain treatment.

• Intention-to-treat analysis: An analysis of the study results that includes all participants who were randomly assigned to a treatment group, regardless of whether they completed the treatment or not. This type of analysis is used to avoid bias caused by participants dropping out of the study or not following the assigned treatment.

• Study: a research project designed to answer specific questions

• Retrospective study: a study that looks back in time to analyze data

• Cohort study: a type of observational study that follows a group of people over time

• Mortality rate: the measure of the number of deaths in a given population over a specified period of time

• Incidence rate: the measure of the number of new cases of a disease in a given population over a specified period of time

• Hazard ratio: the measure of the likelihood of an event occurring in one group compared to another group

• multivariable analysis: a statistical technique used to evaluate the relationship between multiple variables and an outcome of interest

• Adjusted: a statistical method used to control for confounding factors that may influence the relationship between two variables

• Confounding factors: variables that can affect the relationship between two other variables

• Comorbidities: the presence of one or more additional health conditions in a patient

• Risk factors: characteristics or exposures that increase the likelihood of developing a particular disease or condition

• Odds ratio: a measure of the strength of association between an exposure and an outcome in case-control studies

• P-value: a statistical measure that helps determine the likelihood that a study's results occurred by chance

• Statistical significance: a measure of the likelihood that a study's findings are not due to chance alone.

• Neonate: a newly born infant, typically up to 4 weeks old. It is a medical term used to describe the first 28 days of a baby's life.

• Gestation: the period of time during which a fetus develops inside the uterus of a pregnant mammal, starting from fertilization of the egg to the birth of the offspring. It is also known as the pregnancy period. The length of gestation varies between species, but for humans, it typically lasts about 40 weeks or 9 months.