Delaying latency to hyperbaric oxygen-induced CNS oxygen toxicity seizures by combinations of exogenous ketone supplements.

Csilla Ari,Ilya Bederman,Andrew P Koutnik,Dominic P D′Agostino,Carol Landon,Jay B Dean,Michelle Puchowicz,Sahil Bharwani,John Vallas,Janine Deblasi,Mark S Kindy,David M Diamond,Christopher Q Rogers

doi:10.14814/phy2.13961

Abstract

Central nervous system oxygen toxicity (CNS‐OT) manifests as tonic‐clonic seizures and is a limitation of hyperbaric oxygen therapy (HBOT), as well as of recreational and technical diving associated with elevated partial pressure of oxygen. A previous study showed that ketone ester (1,3‐butanediol acetoacetate diester, KE) administration delayed latency to seizures (LS) in 3‐month‐old Sprague‐Dawley (SD) rats. This study explores the effect of exogenous ketone supplements in additional dosages and formulations on CNS‐OT seizures in 18 months old SD rats, an age group correlating to human middle age. Ketogenic agents were given orally 60 min prior to exposure to hyperbaric oxygen and included control (water), KE (10 g/kg), KE/2 (KE 5 g/kg + water 5 g/kg), KE + medium‐chain triglycerides (KE 5 g/kg + MCT 5 g/kg), and ketone salt (Na+/K+ β HB, KS) + MCT (KS 5 g/kg + MCT 5 g/kg). Rats were exposed to 100% oxygen at 5 atmospheres absolute (ATA). Upon seizure presentation (tonic‐clonic movements) experiments were immediately terminated and blood was tested for glucose and D‐beta‐hydroxybutyrate (D‐β HB) levels. While blood D‐β HB levels were significantly elevated post‐dive in all treatment groups, LS was significantly delayed only in KE (P = 0.0003), KE/2 (P = 0.023), and KE + MCT (P = 0.028) groups. In these groups, the severity of seizures appeared to be reduced, although these changes were significant only in KE‐treated animals (P = 0.015). Acetoacetate (AcAc) levels were also significantly elevated in KE‐treated animals. The LS in 18‐month‐old rats was delayed by 179% in KE, 219% in KE + MCT, and 55% in KE/2 groups, while only by 29% in KS + MCT. In conclusion, KE supplementation given alone and in combination with MCT elevated both β HB and AcAc, and delayed CNS‐OT seizures.

Highlights

Hyperbaric oxygen (HBO2) is an FDA-approved medical therapy for at least 14 conditions including air/gas embolism, decompression sickness, carbon monoxide poisoning, and diabetic wounds, among others
Delayed latency to seizures (LS) from central nervous system oxygen toxicity (CNS-OT) was documented in KE+Medium-chain triglyceride (MCT) group (P = 0.049; Fig. 1A), when all animals included in the experiment were considered
The KE group experienced a delay to seizure of 179%, as compared to the control group, while the KE+MCT group showed a trend of greater anti-seizure effect with LS = 219%, these groups were not statistically different (Fig. 1C)

Summary

Introduction

Hyperbaric oxygen (HBO2) is an FDA-approved medical therapy for at least 14 conditions including air/gas embolism, decompression sickness, carbon monoxide poisoning, and diabetic wounds, among others. HBO2 involves breathing pressurized oxygen which results in increased dissolved oxygen in the blood plasma (Neuman and Thom 2008). Prolonged HBO2-induced hyperoxia has been shown to increase the risk, severity, and frequency of seizures (Clark and Thom 1997). This condition, which is a result of elevated tissue partial pressures of O2, is known as central nervous system oxygen toxicity (CNS-OT), and occurs when breathing 100% O2 at barometric pressures (Pb) >2.4 atmospheres absolute (ATA), and poses a limitation on the use of HBO2 as a therapy (HBOT), and other applications of hyperbaric oxygen, such as recreational and technical divers using elevated O2 partial pressures

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