Sudden death in response to severe acute hypoxemia under urethane anesthesia is caused by catastrophic failure of respiratory control

Abstract

Respiratory autoresuscitation is normally a robust process that restores eupneic breathing rhythm following severe hypoxemia‐induced respiratory arrest. We previously found that urethane anesthesia prevents autoresustitation and causes predictable cardiorespiratory collapse and sudden death as a result of even a single episode of severe hypoxemia [Krause et al (2016); Respir Physiol Neurobiol. 232:43–53]. It is unknown whether this failure to autoresuscitate is due to a respiratory or cardiovascular deficit. We hypothesized that sudden death in this condition is primarily related to a respiratory deficit, and that intervention with mechanical ventilation (MV) would promote restoration of eupnea. To test this hypothesis we studied 40 urethane‐anesthetized adult male rats that were surgically instrumented to measure tracheal airflow and femoral artery blood pressure during severe hypoxic challenge. Animals were randomly assigned to one of 4 experimental groups (n=10 for each group). Following baseline measurements, animals were subjected to an episode of acute severe hypoxia via breathing 100% N2, and received MV at one of the following time points following respiratory arrest: (1) 70 sec, (2) 90 sec, (3) 110 sec. The ventilator was set to provide room air breaths at 10/min with a 10% inspiratory duty cycle and a volume of 6.6 mL/kg body weight. A fourth group received no intervention but was given access to room air following respiratory arrest. One‐way ANOVA testing and relative risk analyses were performed to compare cardiorespiratory variables and probability of sudden death between groups (a set a prior at 0.05). All animal groups were similar with respect to animal weight, and baseline cardiorespiratory parameters while breathing room air. The ten animals in the control group that did not receive intervention with MV all experienced sudden death in response to acute severe hypoxemia. Only 1/10 of these animals even attempted to gasp. In contrast, MV following respiratory arrest was effective in restoring rhythmic spontaneous breathing and preventing sudden death (p<0.001 for all groups combined vs. control). MV at 70, 90, and 110 sec post‐respiratory arrest rescued 9/10 (p<0.001), 5/10 (p<0.033), and 6/10 (p<0.011) animals respectively, allowing these animals to restore eupneic breathing and recover cardiorespiratory parameters. These results demonstrate that under urethane anesthesia the cardiovascular system is fully capable of distributing oxygen to the brainstem, and that eupneic breathing can be restored provided that sufficient lung ventilations occur post‐respiratory arrest. We interpret these findings to suggest that urethane anesthesia impairs the normal process of triggering gasping rhythm in vivo, supporting our study hypothesis that sudden death in this model is due to a profound respiratory deficit. Urethane anesthesia therefore provides a reliable and reproducible in vivo model of sudden death in response to acute severe hypoxemia, caused by catastrophic failure of respiratory control.Support or Funding InformationAAS was the recipient of a CMU College of Medicine Summer Research Scholars Award. These experiments were funded through an Early Career Award received by HB from the Office of Research and Sponsored Programs at Central Michigan University.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.