326 - Ethanol doses in excipients cause alterations of the hypoxic and hypercapnic response in rat pups which are prevented by choline.

Publication Number: 4320.326

Mrinaj Janampalli, Case Western Reserve University School of Medicine, Cleveland, OH, United States; Catherine Mayer, UH Rainbow Babies & Children's Hospital, Cleveland, OH, United States; Peter MacFarlane, UH Rainbow Babies & Children's Hospital, Cleveland, OH, United States; Cynthia Bearer, UH Rainbow Babies & Children's Hospital, Cleveland, OH, United States

Background: Apnea of prematurity (AOP) is a common respiratory morbidity in preterm infants, which can be exacerbated upon exposure to ethanol (EtOH). Preterm infants in the NICU can be routinely exposed to EtOH via several medications, as EtOH is used in some as an excipient. We have previously shown that two doses of 2.5 g/kg/day 2 hours apart on postnatal day (P)5 decreases ventilatory responses to hypoxia and hypercapnia on P6 as measured by whole-body plethysmography. Choline has been shown in humans to improve neurodevelopmental outcome of children with FASD and improve behavior in rat pup models of FASD. Here we show that doses of EtOH equivalent to those that preterm infants receive as excipients, impairs both the hypoxic and hypercapnic ventilatory response and prior choline supplementation mitigates this effect.

Objective: To investigate the dose-response relationship between EtOH exposure and respiratory function in a neonatal rat model.

Design/Methods: From postnatal day (P) 3 to P5, Sprague Dawley rat pups were gavaged with intralipid mixed with EtOH to provide 0.25, 0.5, 1, and 2 g/kg/day of EtOH or an isocaloric mixture of intralipid and sucrose. Choline at 100 mg/kg/d was given subcutaneously on P1 - P6 to some animals that received 2 g/kg/d of EtOH. On P6, each animal underwent whole-body plethysmography to measure the hypoxic ventilatory response (HVR) (10% O2) and the hypercapnic ventilatory response (HCVR) (5% CO2) at 5 minutes. The difference between minute ventilation between the 0 minute (baseline) and 5-minute recording were calculated.

Results: The ventilatory response to HVR and HCVR were reduced at 5 minutes in both males and females. Animals treated with EtOH showed limited compensation in minute ventilation from baseline breathing after 5 minutes of hypoxia or hypercapnia in comparison to control animals. Importantly, choline supplementation in animals given the highest dose of EtOH (2g/kg/d), restored response to HVR and HCVR.

Conclusion(s): The results suggest that lower, more chronic exposure to EtOH may impair respiratory drive. This effect may be ameliorated by choline supplementation. Our findings may have widespread implications for preterm infants in the NICU being administered EtOH containing medications.

Change in minute ventilation in response to hypoxia and hypercapnia in ethanol exposed rat pups.
Bar graphs of mean change in ventilation between baseline and 5th minute of hypoxia or hypercapnia in males and females +/- SEM. One-way ANOVA Tukey post hoc. *p < 0.05