Abstract
Introduction: Mitochondrial injury occurs following cardiac arrest (CA) and contributes to myocardial stunning and anoxic brain injury. Hypoxia has been proposed as a therapeutic strategy for neurodegenerative diseases associated with mitochondrial respiration defects, but its benefits in the post-CA setting remain unexplored. Here, we hypothesized mild hypoxia as therapy for post-CA mitochondrial injury. Methods and Results: Mice underwent brief asystolic CA (12 min) followed by cardiopulmonary resuscitation (CPR). One hour following successful CPR, mice were randomized to receive a brief episode (6 hours) of hyperoxia (33% O 2 ), normoxia (21% O 2 ), or hypoxia (10% O 2 ) in an environmental chamber. Post exposure, the mice were returned to room air (21% O 2 ). Hypoxia improved myocardial fractional shortening compared to normoxia and hyperoxia (Hypoxia: 45.6±2.3 %, Normoxia: 40.0±0.8 %, Hyperoxia: 29.0±4.0 %, n=5, P<0.05, respectively). Hypoxia also elevated neurological scores (Hypoxia: 8.4±1.3, Hyperoxia: 5.6±1.2, n=5, P<0.05) 48 hours post CA compared to hyperoxia. Ten-day survival was prolonged by hypoxia (Hypoxia: 87.5 %, Normoxia: 62.5 %, Hyperoxia: 12.5 %, n=10, P<0.05, respectively). Hypoxia also improved mitochondrial function (28% increase in basic oxygen consumption and 49% increase in ATP-related oxygen consumption, n=3, P<0.05, respectively) and a 20% decrease in ROS production (n=6, P<0.05) compared to normoxia. Conclusion: This study has two important findings: First , we demonstrate that oxygen availability in the early post-CA period is a critical determinant of long-term post-CA outcomes. Second , we show that mild hypoxic therapy in the early post-CA period improves early mitochondrial function and long-term post-CA outcomes. These findings reveal an important oxygen-dependent therapeutic window following resuscitation from CA that has implications for post-CA critical care.
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