Changes in Nitric oxide Levels in Basal Forebrain during Sedation with Dexmedetomidine and Sevoflurane
Authors: Nichols Mark R. , Groenhout Trent , Fryzel Anna M. , Liu Tiecheng , Pal Dinesh 
Published: May 2022

BackgroundPerioperative and critical care settings frequently require periods of prolonged sedation but the effect of sedation on sleep homeostasis is not completely understood. In the ongoing studies in our laboratory, continuous 8 h sedation with dexmedetomidine (DEX) was shown to increase wakefulness (WAKE), decrease slow‐wave sleep (SWS), and nearly eliminate rapid eye movement sleep (REMS) in the post‐sedation period [1]. In contrast, continuous 8 h sedation with sevoflurane (SEVO) did not affect the time spent in WAKE or SWS, but increased REMS in the post‐sedation period [1]. Past studies have shown nitric oxide (NO) in basal forebrain (BF) to be a key modulator of sleep homeostasis. Specifically, NO concentration in BF has been shown to increase with sleep pressure (e.g., during sleep deprivation) and decrease with the reduced sleep need (e.g., during recovery from sleep deprivation). To determine the effect of sedation produced by DEX or SEVO on sleep homeostasis, as inferred from changes in NO levels in BF, we quantified the changes in NO concentration before, during, and after sedation with DEX and SEVO.MethodsAdult male Sprague Dawley rats (N=4 male) were surgically prepared to record electroencephalogram (EEG) and electromyogram and intravenous delivery of DEX via a chronic catheter in jugular vein. In addition, an open flow microperfusion guide cannula was implanted into BF (N=2) or prefrontal cortex (N=2) for collection of perfusates for NO analysis. Prefrontal cortex (PFC) was used as an anatomical control for BF. After at least 15 days of post‐surgical recovery, rats were connected to the EEG recording system and a sampling insert was lowered into BF or PFC to route the perfusate samples directly into a high‐performance liquid chromatograph for online analysis of nitrite and nitrate levels, which are collectively termed as NOx and are considered a surrogate for endogenous NO concentration. The EEG and NOx were recorded during 2 h baseline wake condition, 8 h of sedation with either DEX (0.5‐0.7ug/kg/min) or SEVO (1.5‐3.0%), and 2 h post‐sedation period. Each rat was administered with DEX or SEVO in a counter‐balanced manner and with a washout period of at least 7 days.ResultsThe NOx levels in BF decreased during sedation with DEX (mean ± standard deviation: 0.52 μM ± 0.31 during baseline vs 0.08 μM ± 0.01 during DEX) and SEVO (mean ± standard deviation: 1.58 μM ± 0.16 during baseline vs 0.72 μM ± 0.07 during SEVO). The NOx levels in PFC during sedation with DEX stayed about at the same level as observed during baseline state (2.40 μM ± 1.39 during baseline vs. 3.01 μM ± 0.16 during DEX), but the NOx levels in PFC decreased during sedation with SEVO (1.45 μM ± 1.23 during baseline vs 0.37 μM ± 0.18 during SEVO).ConclusionAlthough these are preliminary data, the decrease in NOx levels in BF after sedation with DEX and SEVO suggest a reduced sleep pressure and is supportive of the changes in sleep homeostasis as described in our previous report.References

Parkar A, Liu T, Fryzel A, Groenhout T, Mashour GA and Pal D (2020) Effect of prolonged sedation with dexmedetomidine, midazolam, propofol, or sevoflurane on sleep homeostasis in rat. J Neurosurgical Anesthesiology, Vol 32, No 4, Page 403, Abstract no SNACC‐387.