Evaluating The Efficacy Of Endotracheal Epinephrine Administration At Standard Versus High Dose During Resuscitation Of Severely Asphyxiated Newborn Lambs: A Randomized Preclinical Study

Background Epinephrine treatment is recommended during neonatal resuscitation, if ventilation and chest compressions are ineffective. Endotracheal administration is an option, if the preferred intravenous route is unavailable. We aimed to determine the efficacy of endotracheal epinephrine for achieving return of spontaneous circulation (ROSC), and maintaining physiological stability after ROSC, at standard and higher dose, in severely asphyxiated newborn lambs. Methods Near-term fetal lambs were instrumented for physiological monitoring, and asphyxiated until asystole. Resuscitation was commenced with ventilation and chest compressions as per ILCOR recommendations. Lambs were randomly allocated to: IV Saline placebo (5 ml/kg, n=6), IV Epinephrine (20 micrograms/kg, n=9), Standard-dose ET Epinephrine (100 micrograms/kg, n=9), and High-dose ET Epinephrine (1 mg/kg, n=9). After three allocated treatment doses, rescue IV Epinephrine was administered if ROSC had not occurred. Lambs achieving ROSC were ventilated and monitored for 60 minutes before euthanasia. Brain histology was assessed for micro-hemorrhage. Results ROSC in response to allocated treatment (without rescue IV Epinephrine) occurred in 1/6 Saline, 9/9 IV Epinephrine, 0/9 Standard-dose ET Epinephrine, and 7/9 High-dose ET Epinephrine lambs respectively. Three Saline, six Standard-dose ET Epinephrine, and one High-dose ET Epinephrine lambs achieved ROSC after rescue IV Epinephrine. Blood pressure during CPR increased after treatment with IV Epinephrine and High-dose ET Epinephrine, but not Saline or Standard-dose ET Epinephrine. After ROSC, both ET Epinephrine groups had lower pH, higher lactate, and higher blood pressure than the IV Epinephrine group. Cortex micro-hemorrhage was more frequent in the High-dose ET Epinephrine lambs (8/8 lambs examined, versus 3/8 in IV Epinephrine lambs). Conclusions The currently recommended dose of ET Epinephrine was ineffective in achieving ROSC. In the absence of convincing clinical or preclinical evidence of efficacy, use of ET Epinephrine at this dose may not be appropriate. High-dose ET Epinephrine requires further evaluation before clinical translation. ### Competing Interest Statement The authors have declared no competing interest.