Ketone supplementation abolished isoflurane anesthesia-induced elevation in blood glucose level and increased recovery time from anesthesia in Wistar Albino Glaxo Rijswijk rats

Abstract

Background It has been suggested that administration of exogenous ketone supplements (EKSs) not only increases blood ketone body levels but also decreases blood glucose level and modulates isoflurane-induced anesthesia in different rodents, such as Wistar Albino Glaxo Rijswijk (WAG/Rij) rats. Thus, we investigated whether administration of EKSs can modulate the isoflurane anesthesia-generated increase in blood glucose level and the time required to recover from isoflurane-induced anesthesia. Methods To investigate the effect of EKSs on isoflurane anesthesia-induced changes in blood glucose and R-β-hydroxybutyrate (R-βHB) level as well as recovery time from anesthesia, we used KEMCT (mix of ketone ester/KE and medium chain triglyceride/MCT oil in a 1:1 ratio) in WAG/Rij rats. First, to accustom the animals to the method, water gavage was carried out for 5 days (adaptation period). After adaptation period, rats of first group (group 1) were gavaged by water (3 g/kg), whereas, in the case of second group (group 2), the diet of animals was supplemented by KEMCT (3 g/kg, gavage) once per day for 7 days. One hour after the last gavage, isoflurane (3%) anesthesia was induced for 20 min (group 1 and group 2) and the time required for recovery from anesthesia was measured by using righting reflex. Subsequently, blood levels of both R-βHB and glucose were also evaluated. Changes in blood glucose and R-βHB levels were compared to control, which control glucose and R-βHB levels were measured on the last day of the adaptation period (group 1 and group 2). Time required for recovery from isoflurane anesthesia, which was detected after 7th KEMCT gavage (group 2), was compared to recovery time measured after 7th water gavage (group 1). Results The KEMCT maintained the normal glucose level under isoflurane anesthesia-evoked circumstances preventing the glucose level elevating effect of isoflurane. Thus, we demonstrated that administration of KEMCT not only increased blood level of R-βHB but also abolished the isoflurane anesthesia-generated increase in blood glucose level. Moreover, the time required for recovery from isoflurane-evoked anesthesia increased significantly in KEMCT treated animals. Conclusions Putative influence of elevated blood ketone body level on isoflurane-evoked effects, such as modulation of blood glucose level and recovery time from anesthesia, should be considered by anesthesiologists.

Exogenous Ketone Supplement Administration Abrogated Isoflurane-Anesthesia-Induced Increase in Blood Glucose Level in Female WAG/Rij Rats

“…These results suggest that blood glucose level changes may be significantly different between female and male rats in response to KEMCT treatment during isoflurane anesthesia. Thus, in this study, we extended our previous experiments on ten-month-old males [23] to similar-age female WAG/Rij rats.…”

“…Consequently, it was hypothesized that EKSs would reduce isoflurane-anesthesia-evoked changes in blood glucose level and recovery time. Indeed, the administration of KEMCT by intragastric gavage enhanced the blood R-βHB level and reduced the blood glucose level, as well as decreased the isofluraneanesthesia-evoked increase in blood glucose level and prolonged the time required for recovery from isoflurane-generated anesthesia in an animal model of human absence epilepsy, Wistar Albino Glaxo Rijswijk (WAG/Rij) rats [23]. Moreover, KEMCT treatment delayed the onset of isoflurane-generated anesthesia in WAG/Rij rats [24].…”

“…It has also been demonstrated that an EKS-generated increase in ketone body levels can enhance the level of adenosine in the brain [25,26], leading to enhanced activity of adenosine A1 receptors (A1Rs) and neuronal hyperpolarization [27,28]. These last effects may modulate the influences evoked by EKSs, such as KEMCT, on the isoflurane-generated onset of anesthesia and, theoretically, on the isoflurane-evoked increase in both glucose level and recovery time from isoflurane anesthesia [23,24,29]. Although the KEMCT-induced reduction in blood glucose level and increase in R-βHB level is sex-dependent in WAG/Rij rats [30], the influence of KEMCT administration on isoflurane-anesthesia-induced changes in blood R-βHB and glucose levels and recovery time were investigated only in males so far, but not in female WAG/Rij rats [23].…”

Dose-Dependent Beneficial Effect of Ketone Supplement-Evoked Ketosis on Anxiety Level in Female WAG/Rij Rats: Sometimes Less Is More

“…We demonstrated previously that intragastric administration (gavage) of KEMCT for 7 days was well tolerated, did not evoke side effects (e.g., diarrhea) and was able not only to increase but also to maintain blood R-βHB level (ketosis) in WAG/Rij rats [29][30][31]. In this study, the KEMCT was a mix of 1,3-butanediol-acetoacetate diester (ketone ester/KE) (developed at University of South Florida, Tampa, FL, USA, and Savind Inc., Urbana, IL, USA) [32], as well as medium-chain triglyceride (MCT) oil in 1:1 ratio (containing ~60% caprylic triglyceride, ~40% capric triglyceride, Bloomingdale, IL, USA).…”

“…To determine the effect of KEMCT on blood glucose and R-βHB levels, measurements were taken on the last (fifth) adaptation day (baseline level), as well as first and last (seventh) treatment days about 70 min after treatment (on the last/seventh day: about 5 min after LDB test; group 1-group 3). To measure blood glucose, as well as R-βHB levels, a commercially available blood glucose and ketone monitoring system (Precision Xtra, Abbott Laboratories, Abbott Park, IL, USA) was used [9,31]. For the test, blood was taken from the rats' tail veins.…”