Clinical and experimental implementation of standardized hypothermic treatment for neonatal asphyxia in low-income settings

Background: Hypoxic ischemic encephalopathy (HIE) is a potentially devastating condition caused by birth asphyxia. The standard of care for infants with moderate and severe HIE is therapeutic hypothermia (TH), initiated within six hours after delivery. This intervention improves survival rates and reduces long- term neurological disabilities. Despite its efficacy in high-income countries, the implementation of TH faces significant challenges in low- and middle-income settings, including a lack of evidence supporting its benefits, inadequate high- cost cooling equipment, and insufficient long-term outcome predictive markers and evaluations.

Aims: The overall aim of this thesis was to develop and evaluate novel equipment for counteracting hypoxic-ischemic brain injuries in newborns in low- and middle-income countries. The specific aims included: To evaluate the application of phase changing material (PCM) for induction of TH in infants with moderate- severe HIE in a tertiary setting and during inter-hospital transportation, in order to enhance the therapeutic effects of TH (Studies I & II) and to determine neurological and neurodevelopmental outcomes for infants treated with TH in low- and middle-income settings (Study III). An additional aim was to evaluate early predictors of outcome of asphyxiated newborns transported for TH, by measuring levels of blood lactated dehydrogenase (LDH) activity and monitoring brain function with amplitude-integrated EEG (aEEG) (Study IV).

Materials and methods: One pilot observational study (Study I) and one clinical trial (Studies II-IV) were conducted in Hanoi, Vietnam, between 2014 and 2019. The studies involved neonates born in the northern regions of Vietnam with HIE and requiring TH. The primary outcomes were short-term outcomes of HIE and medium-term outcomes. In study IV, the predictive values of high LDH (>1000 U/L) and severely depressed aEEG were evaluated.

Results: Studies I and II showed that, despite not being a servo-controlled device, the PCM mattress effectively cooled and maintained infantsŐ body temperatures at more than 80% of the 72-hour treatment period with little nursing intervention, a significant advantage in resource-limited settings. When used during inter- hospital transportation, PCM as compared to passive cooling did not improve short-term outcomes. However, PCM was a safe and effective piece of equipment for transport of babies eligible for TH and reduced the time to achieve the target temperature for TH. Follow-up at 18 months showed that infants who received TH 67% survived, and, among the survivors, 60% demonstrated normal development or only mild delays in movement and cognition. The remaining survivors exhibited severe neurological disorders, such as cerebral palsy or epilepsy. Study III showed that these serious sequelae can be identified early in the post-natal period using simple screening tools like the Ages and Stages Questionnaires and the Hammersmith Infant Neurological Examination with high sensitivity and specificity. In Study IV, we also found that biological and imaging markers can predict outcomes early, including lactate dehydrogenase (LDH) and early aEEG.

Conclusion: The studies presented in this PhD thesis demonstrate the effectiveness of a mattress made of PCM as a low-cost cooling method for TH of infants with moderate to severe HIE in low- and middle-income countries. A majority of the infants treated with TH had favorable outcomes, with many surviving and developing normally or with only mild delays. Early identification of neurological sequelae through simple screening tools and early biomarkers aids clinicians in improving prognosis and treatment decisions for HIE babies.

List of scientific papers

I. HANG T T TRAN, Ha T. T. Le, Hanh T. P. Tran, Dung T. K. Khu, Hugo Lagercrantz, Dien M. Tran, Birger Winbladh, Lena Hellstršm-Westas, Tobias AlfvŽn*, Linus Olson*. Hypothermic treatment for neonatal asphyxia in low-resource settings using phase-changing material- An easy to use and low-cost method. Acta Paediatrica. 2021;110:85Đ93. *Shared last authorship.
https://doi.org/10.1111/apa.15331

II. HANG T T TRAN, Dien M Tran, Ha T Le, Lena Hellstršm-Westas, Tobias AlfvŽn*, Linus Olson*. Cooling during transportation of asphyxiated newborns using phase change material mattresses in low-resource settings: a randomized controlled trial in Hanoi, Vietnam. *Shared last authorship.
https://doi.org/10.1186/s12887-024-04987-6

III. HANG T T TRAN, Ha Thi Le, Dien Minh Tran, Giang Thi Huong Nguyen, Lena Hellstršm-Westas, Tobias AlfvŽn*, Linus Olson*. Therapeutic hypothermia after perinatal asphyxia in Vietnam - medium-term outcomes at 18 months: a prospective cohort study. BMJ Paediatr Open. 2024; 8(1): e002208. *Shared last authorship.
https://doi.org/10.1136/bmjpo-2023-002208

IV. HANG T T TRAN, Ha T Le, Dien M Tran, Tobias AlfvŽn, Lena Hellstršm-Westas, Linus Olson. Phase-change material, lactate dehydrogenase and amplitude-integrated EEG (aEEG), and for management of out-born hypothermia-treated newborns in Hanoi, Vietnam. [Manuscript]