Neurological Outcome at 30 Months of Age after Mild Hypothermia via Selective Head Cooling in Term Neonates with Perinatal Asphyxia Using Low-Cost CoolCap: A Single-Center Randomized Control Pilot Trial in India

Abstract

The objective of this study was to determine the effectiveness and safety of mild systemic hypothermia by selective head cooling in hospital born neonates with hypoxic-ischemic encephalopathy using low-cost CoolCap. The primary outcome was to determine whether selective head cooling reduces neonatal mortality and neurodevelopmental delay (NDD) at > 30 months of age. The secondary outcome was to determine the serious adverse effects during selective head cooling such as thrombocytopenia requiring platelets transfusion, renal and hepatic dysfunction, bradycardia, hypoglycemia, and dyselectrolytemia (hyperkalemia, hyponatremia, and hypocalcemia). This is a single-center randomized control trial. The risk ratios, risk differences, and numbers needed to treat plus 95% confidence interval (CI) were measured. This study was done at the tertiary care perinatal center. Inborn neonates with ≥ 37 completed weeks of gestation with indicators of perinatal asphyxia and moderate to severe clinical encephalopathy were randomly allocated to hypothermia (n = 30) or standard care (n = 30) groups. The neonates were subjected to mild systemic hypothermia via selective head cooling using ice caps, the target rectal temperature being 34 to 35°C for 72 hours. Therapeutic hypothermia reduced the risk of death and NDD at ≥ 30 months of age: 6 of 30 infants (20%) in the hypothermia group and 18 of 30 infants (60%) in the control group died or had a NDD at ≥ 30 months (risk ratio: 0.33 [95% CI: 0.15–0.72]; p = 0 0.0015). The mortality rate decreased, and the survival rate free of any sensorineural disability increased. The benefits were statistically significant in moderately asphyxiated infants. Adverse effects of hypothermia were minimal. Selective head cooling with mild systemic hypothermia in term asphyxiated neonates is safe and inexpensive in low-resource setting. Hypothermia showed statistically significant reduction in mortality and NDD at ≥ 30 months of age when commenced within 6 hours of birth and was not associated with serious adverse effects. The Institutional Clinical Trial Registry number is CNMC/ETHI/317/P.

2021 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations: Summary From the Basic Life Support; Advanced Life Support; Neonatal Life Support; Education, Implementation, and Teams; First Aid Task Forces; and the COVID-19 Working Group

“…189,191,195,198,199,[201][202][203][204][205]208,209 This subgroup comparison found significant improvements in the critical outcome of survival to discharge from later (delayed) clamping (≥30 seconds) compared with early cord clamping (<30 seconds) in high-income countries 190,191,195,[201][202][203][204][205][206] but not low-and middle-income countries. 189,192,198,199,209 Inotropic support for hypotension within 24 h after birth Dong et al, 194 195 Both this and the 5 included trials involving 331 infants with cord cut before respiratory support 195,199,203,204,208,209 and the 10 trials involving 2174 infants from studies that were unclear about whether re-spiratory support was given with intact or cut cord could not exclude benefit or harm from later clamping at ≥30 compared with <30 seconds. [189][190][191][192]198,201,202,205,206,…”

“…189,192,198,199,209 Inotropic support for hypotension within 24 h after birth Dong et al, 194 195 Both this and the 5 included trials involving 331 infants with cord cut before respiratory support 195,199,203,204,208,209 and the 10 trials involving 2174 infants from studies that were unclear about whether re-spiratory support was given with intact or cut cord could not exclude benefit or harm from later clamping at ≥30 compared with <30 seconds. [189][190][191][192]198,201,202,205,206,210 Subgroup…”

“…the critical outcome of survival to discharge, moderatecertainty evidence from 12 trials involving 1075 infants could not exclude benefit or harm from clamping at 30 to <60 compared with <30 seconds (RR, 1.00 [95% CI, 0.97-1.04]; I 2 =0%). 189,190,192,199,[201][202][203][204][205][206]208,209 Low-certainty evidence from 3 trials involving 1643 infants showed improved survival or no difference from clamping at 60 to 120 compared with <30 seconds (RR, 1.03 [95% CI, 1.00-1.10]; number needed to treat to benefit, 45 [95% CI, 21->1000]; I 2 =40%). 191,198,210 Low-certainty evidence from 1 trial involving 270 infants could not exclude benefit or harm from clamping at ≥2 minutes compared with <30 seconds (RR, 1.07 [95% CI, 0.99-1.15]).…”

2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations

“…-Survival (critical) -Neurodevelopmental impairment (any) (important) The EvUp (see Supplement Appendix C-11) identified 142 studies; 13 of these were thought worthy of inclusion. [126][127][128][129][130][131][132][133][134][135][136][137][138] The NLS Task Force agreed that these 13 studies did not identify sufficient new evidence to consider a new SysRev and, even if added to previous studies, would not likely add to the level of certainty of the evidence summarized in 2015. 1,9,10 It is becoming increasingly difficult (as a result of clinician and parent preferences) to perform large, multicenter randomized trials with a "no-therapeutic hypothermia" control group.…”

Whole-Body Hypothermia, Cerebral Magnetic Resonance Biomarkers, and Outcomes in Neonates With Moderate or Severe Hypoxic-Ischemic Encephalopathy Born at Tertiary Care Centers vs Other Facilities

“… 26 Moreover, many pilot RCTs are difficult to interpret. For example, 6 trials 27 , 28 , 29 , 30 , 31 , 32 with different event rates but overlapping recruitment periods were reported from the same hospital, 1 trial 33 reported outcomes at 8 years within a year of completing neonatal recruitment, and another trial 34 reported a 68% reduction in adverse outcomes using ice cubes on the neonate’s head.…”