Identifying Predictive Markers of CNS Oxygen Toxicity and Ketone Ester Effects on Latency to Seizure and Antioxidant Capacity

Abstract

Hyperbaric oxygen (HBO2) is used in hyperbaric oxygen therapy and in undersea and aerospace medicine. What limits the use of HBO2 is the risk of seizures, i.e. central nervous system oxygen toxicity (CNS‐OT). In undersea medicine, the threat of CNS‐OT is what limits the time that the warfighter remains at depth while breathing HBO2. In addition, when breathing HBO2, various non‐convulsive signs and symptoms often precede onset of seizures, including bradycardia followed by tachycardia, hypothermia, and hyperventilation. We hypothesized that the early cardiorespiratory responses to HBO2 during the safe latent period could be used as predictive physiological markers (or physio‐markers) prior to the onset of CNS‐OT. Furthermore, using a ketone ester (KE) supplement, R,S‐1,3‐butanediol diacetoacetate ester, we posited that the KE would increase the antioxidant capacity and the latency time to seizure (LSz) when exposed to HBO2. Accordingly, 18 male, Sprague Dawley (SD) rats were implanted with DSI 4‐ET radio telemetry to record EEG, ECG, and respiratory EMG for offline analyses of physio‐markers. At least 1 week following surgery, each rat was placed in a hyperbaric chamber and “dived” to 5 ATA O2 (1 ATG/min) after oral gavage of either water (control group) or KE (treatment group). An additional 9 SD rats were also dived to 5 ATA O2, but not implanted with telemetry, to collect blood samples to measure antioxidant capacity with the RedoxSys® device before and after HBO2 exposure. HBO2 caused a 3‐phase hyperoxic ventilatory response: decreased respiration, transient hyperventilation, and a secondary later hyperventilation prior to seizures. Results showed that LSz increased in the KE group by 307% (controls: 6.42 ± 0.44 (n=15); KE: 22.16 ± 5.10 (n=18)). Additionally, minute ventilation and RR‐Interval (1/heart rate) were significantly different beginning ~15 minutes prior to onset of seizures. Receiver operating characteristic (ROC) analyses indicated that both hyperoxic hyperpnea and bradycardia were reliable physio‐markers for seizure prediction; that is, ROC for minute ventilation in both control and KE group, and for RR‐Interval in controls, was 1 (excellent predictor), and in the KE group was 0.84 (good predictor). However, core body temperature did not decrease significantly during HBO2 exposure and thus was not a physio‐marker for CNS‐OT. In addition, KE increased antioxidant capacity of blood from animals that were exposed to HBO2 with (p=0.0399) or without (p=0.0018) the development of CNS‐OT. In conclusion, hyperoxic hyperpnea and bradycardia can be used as predictive physio‐markers in conjunction with ketone therapy to reliably predict and delay CNS‐OT in rodents, and KE delays seizures in part by increasing overall antioxidant capacity during exposure to HBO2. Together this may enable safer and longer exposures for applications in undersea/aerospace medicine as well as hyperbaric oxygen therapies.