403 - Perinatal caffeine administration does not improve motor outcomes following hypoxic ischemic encephalopathy in lambs

Poster Number: 403
Publication Number: 403.236

Yasmine N. White, University of California, San Francisco, San Francisco, CA, United States; Jana Mike, University of California, San Francisco, School of Medicine, San Francisco, CA, United States; Rachel S. Hutchings, UCSF, San Francisco, CA, United States; Courtney Losser, University of California, San Francisco, School of Medicine, Inverness, IL, United States; Christian J. Vento, University of California, San Francisco, School of Medicine, San Francisco, CA, United States; Kimberly Arellano, University of California, San Francisco, School of Medicine, San Francisco, CA, United States; Brian Goudy, University of California Davis Children's Hospital, Sacramento, CA, United States; Christine Windsor, University of California, San Francisco, School of Medicine, San Francisco, CA, United States; Janica Ha, University of California, San Francisco, San Ramon, CA, United States; Janel R. Long-Boyle, University of California, San Francisco, School of Medicine, San Francisco, CA, United States; Emin Maltepe, UCSF, San Francisco, CA, United States

Background: Over 1.15 million infants develop hypoxic ischemic encephalopathy (HIE) annually with most cases occurring in low- and middle-income countries where therapeutic hypothermia is often unavailable. Caffeine, an adenosine-receptor antagonist frequently used in neonates for the treatment of apnea, is neuroprotective in rodent models of hypoxic ischemic injury and has potential to improve neurologic outcomes.

Objective: To characterize the pharmacokinetics (PK), safety, and efficacy of perinatal caffeine administration in an ovine delivery model of neonatal HIE with resultant motor dysfunction.

Design/Methods: As previously described, near term lambs (141-143 days gestation) were partially exteriorized via C-section, intubated with an occluded endotracheal tube to prevent respiration, and instrumented via central arterial and venous catheters placed in their necks. Hypoxic ischemic injury was induced via complete umbilical cord occlusion, and lambs were resuscitated following delivery per Neonatal Resuscitation Program guidelines following the establishment of five minutes of asystole. Caffeine or vehicle was administered antenatally to each ewe (1 g) and postnatally to each lamb following resuscitation (20 mg/kg day 0, followed by 10 mg/kg day 1 and 2). PK and toxicology samples were collected throughout the study period. Lambs were monitored for hypoglycemia, seizures, and arrhythmia during the immediate post delivery period. Clinical neurologic outcomes were assessed daily for six days.

Results: Mean placental transfer of caffeine was 65.5%. PK analysis showed mean caffeine plasma half-life of 96 hours and mean peak plasma concentration of 34.7 mg/L in the lambs. Survival through resuscitation and day four was similar between the caffeine and vehicle groups (13/15 vs 13/14 and 12/15 vs 12/14, respectively). 3/12 surviving lambs in the caffeine treated group and 4/12 surviving lambs in the vehicle treated group developed a cerebral palsy-like static encephalopathy. Although caffeine treated lambs had higher mean neurologic outcome scores on days 0-6, this difference did not reach significance on any day. The incidence of seizures was higher in the caffeine group compared to the vehicle group (5/13 vs 1/13). There was no difference in toxicology markers including AST, ALT, BUN, and Cr between groups.Conclusion(s): Caffeine, when administered perinatally at doses comparable to those used to treat apnea of prematurity, does not improve motor outcomes in lambs following HIE and may increase the risk of seizure following resuscitation.