The feasibility of Telemedicine in Implementation of Therapeutic Hypothermia for Management of Neonatal Hypoxic-Ischemic Encephalopathy in Resource-Limited Areas.

Background: Telemedicine is widely used in neonatal services in developed countries. Lack of expertise and/or facilities, however, limited its use in developing countries and around areas of military conflicts. To our knowledge, no reports are demonstrating the feasibility of administering therapeutic hypothermia (TH) through telemedicine to neonates with hypoxic-ischemic encephalopathy (HIE) in resource-limited areas.Methodology: This is a retrospective study, evaluating 22 patients who received TH, guided by telemedicine, through a mobile app (Telegram®). We assessed the feasibility of utilizing Telemedicine in guiding the application of TH to infants affected with HIE in the North-West of Syria between July 2020 and July 2021.Results: Out of 5,545 newborn infants delivered during the study period, 22 patients were eligible for TH guided by Telemedicine. Patients were referred for consultation at a median (IQR) of 137 (35-165) minutes of life. A median (IQR) of 12 (3-18) minutes elapsed between the call for a consultation and the consultant response, and a median (IQR) of 30 (0-42) minutes elapsed between seeking the consultation and the initiation of cooling therapy. Eighteen patients completed cooling for 72 hours. The patients' temperatures were within the target range (33-34°C) most of the time (84.1%).Conclusion: Telemedicine is a feasible method to guide the implementation TH for HIE in resource-limited areas. The short-term success rate is relatively high; however, further studies with a larger population are needed to confirm these findings.

Using a Human Circulation Mathematical Model to Simulate the Effects of Hemodialysis and Therapeutic Hypothermia

Background: We developed a hemodynamic mathematical model of human circulation coupled to a virtual hemodialyzer. The model was used to explore mechanisms underlying our clinical observations involving hemodialysis. Methods: The model consists of whole body human circulation, baroreflex feedback control, and a hemodialyzer. Four model populations encompassing baseline, dialysed, therapeutic hypothermia treated, and simultaneous dialysed with hypothermia were generated. In all populations atrial fibrillation and renal failure as co-morbidities, and exercise as a treatment were simulated. Clinically relevant measurables were used to quantify the effects of each in silico experiment. Sensitivity analysis was used to uncover the most relevant parameters. Results: Relative to baseline, the modelled dialysis increased the population mean diastolic blood pressure by 5%, large vessel wall shear stress by 6%, and heart rate by 20%. Therapeutic hypothermia increased systolic blood pressure by 3%, reduced large vessel shear stress by 15%, and did not affect heart rate. Therapeutic hypothermia reduced wall shear stress by 15% in the aorta and 6% in the kidneys, suggesting a potential anti-inflammatory benefit. Therapeutic hypothermia reduced cardiac output under atrial fibrillation by 12% and under renal failure by 20%. Therapeutic hypothermia and exercise did not affect dialyser function, but increased water removal by approximately 40%. Conclusions: This study illuminates some mechanisms of the action of therapeutic hypothermia. It also suggests clinical measurables that may be used as surrogates to diagnose underlying diseases such as atrial fibrillation.

QTc Intervals Are Prolonged in Late Preterm and Term Neonates during Therapeutic Hypothermia but Normalize Afterwards

Background: There are anecdotal reports on reversible QTc prolongation during therapeutic hypothermia (TH) for moderate to severe neonatal encephalopathy after asphyxia. As the QTc interval is a relevant biomarker for pharmacovigilance during medication development, a structured search and review on published neonatal QTc values to generate reference values is warranted to facilate medication development in this specific population. Methods: A structured search and literature assessment (PubMed, Embase, and Google Scholar) with ‘Newborn/Infant, QT and hypothermia’ was conducted (October 2021). Retrieved individual values were converted to QTc (Bazett) over postnatal age (day 1–7). Results: We retrieved 94 QTc intervals (during TH (n = 50, until day 3) or subsequent normothermia (n = 44, day 4–7)) in 33 neonates from 6 publications. The median (range) of QTc intervals during TH was 508 (430–678), and 410 (317–540) ms afterwards (difference 98 ms, or +28 ms/°C decrease). Four additional cohorts (without individual QTc intervals) confirmed the pattern and magnitude of the effect of body temperature on the QTc interval. Conclusions: We highlighted a relevant non-maturational covariate (°C dependent TH) and generated reference values for the QTc interval in this specific neonatal subpopulation. This knowledge on QTc during TH should be considered and integrated in neonatal medication development.

Lipid Profiles from Dried Blood Spots Reveal Lipidomic Signatures of Newborns Undergoing Mild Therapeutic Hypothermia after Hypoxic-Ischemic Encephalopathy

Hypoxic-ischemic encephalopathy (HIE) is associated with perinatal brain injury, which may lead to disability or death. As the brain is a lipid-rich organ, various lipid species can be significantly impacted by HIE and these correlate with specific changes to the lipidomic profile in the circulation. Objective: To investigate the peripheral blood lipidomic signature in dried blood spots (DBS) from newborns with HIE. Using univariate analysis, multivariate analysis and sPLS-DA modelling, we show that newborns with moderate–severe HIE (n = 46) who underwent therapeutic hypothermia (TH) displayed a robust peripheral blood lipidomic signature comprising 29 lipid species in four lipid classes; namely phosphatidylcholine (PC), lysophosphatidylcholine (LPC), triglyceride (TG) and sphingomyelin (SM) when compared with newborns with mild HIE (n = 18). In sPLS-DA modelling, the three most discriminant lipid species were TG 50:3, TG 54:5, and PC 36:5. We report a reduction in plasma TG and SM and an increase in plasma PC and LPC species during the course of TH in newborns with moderate–severe HIE, compared to a single specimen from newborns with mild HIE. These findings may guide the research in nutrition-based intervention strategies after HIE in synergy with TH to enhance neuroprotection.

New possibilities for neuroprotection in neonatal hypoxic-ischemic encephalopathy

Around 0.75 million babies worldwide suffer from moderate or severe hypoxic-ischemic encephalopathy (HIE) each year resulting in around 400,000 babies with neurodevelopmental impairment. In 2010, neonatal HIE was associated with 2.4% of the total Global Burden of Disease. Therapeutic hypothermia (TH), a treatment that is now standard of care in high-income countries, provides proof of concept that strategies that aim to improve neurodevelopment are not only possible but can also be implemented to clinical practice. While TH is beneficial, neonates with moderate or severe HIE treated with TH still experience devastating complications: 48% (range: 44–53) combined death or moderate/severe disability. There is a concern that TH may not be effective in low- and middle-income countries. Therapies that further improve outcomes are desperately needed, and in high-income countries, they must be tested in conjunction with TH. We have in this review focussed on pharmacological treatment options (e.g. erythropoietin, allopurinol, melatonin, cannabidiol, exendin-4/exenatide). Erythropoietin and allopurinol show promise and are progressing towards the clinic with ongoing definitive phase 3 randomised placebo-controlled trials. However, there remain global challenges for the next decade. Conclusion: There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials to avoid exposure to harmful medications or abandoning putative treatments. What is Known:• Therapeutic hypothermia is beneficial in neonatal hypoxic-ischemic encephalopathy.• Neonates with moderate or severe hypoxic-ischemic encephalopathy treated with therapeutic hypothermia still experience severe sequelae. What is New:• Erythropoietin, allopurinol, melatonin, cannabidiol, and exendin-4/exenatide show promise in conjunction with therapeutic hypothermia.• There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials.