Effect of prolonged sedation with dexmedetomidine, midazolam, propofol, and sevoflurane on sleep homeostasis in rats

Brian H Silverstein; Anjum Parkar; Trent Groenhout; Zuzanna Fracz; Anna M Fryzel; Christopher W Fields; Amanda Nelson; Tiecheng Liu; Giancarlo Vanini; George A Mashour; Dinesh Pal

doi:10.1016/j.bja.2023.11.014

Effect of prolonged sedation with dexmedetomidine, midazolam, propofol, and sevoflurane on sleep homeostasis in rats

Br J Anaesth. 2024 Jun;132(6):1248-1259. doi: 10.1016/j.bja.2023.11.014. Epub 2023 Dec 8.

Affiliations

¹ Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA; Center for Consciousness Science, University of Michigan, Ann Arbor, MI, USA.
² Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA.
³ Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA; Center for Consciousness Science, University of Michigan, Ann Arbor, MI, USA; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA; Center for Consciousness Science, University of Michigan, Ann Arbor, MI, USA; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. Electronic address: dineshp@med.umich.edu.

PMID: 38071152
DOI: 10.1016/j.bja.2023.11.014

Abstract

Background: Sleep disruption is a common occurrence during medical care and is detrimental to patient recovery. Long-term sedation in the critical care setting is a modifiable factor that affects sleep, but the impact of different sedative-hypnotics on sleep homeostasis is not clear.

Methods: We conducted a systematic comparison of the effects of prolonged sedation (8 h) with i.v. and inhalational agents on sleep homeostasis. Adult Sprague-Dawley rats (n=10) received dexmedetomidine or midazolam on separate days. Another group (n=9) received propofol or sevoflurane on separate days. A third group (n=12) received coadministration of dexmedetomidine and sevoflurane. Wakefulness (wake), slow-wave sleep (SWS), and rapid eye movement (REM) sleep were quantified during the 48-h post-sedation period, during which we also assessed wake-associated neural dynamics using two electroencephalographic measures: theta-high gamma phase-amplitude coupling and high gamma weighted phase-lag index.

Results: Dexmedetomidine-, midazolam-, or propofol-induced sedation increased wake and decreased SWS and REM sleep (P<0.0001) during the 48-h post-sedation period. Sevoflurane produced no change in SWS, decreased wake for 3 h, and increased REM sleep for 6 h (P<0.02) post-sedation. Coadministration of dexmedetomidine and sevoflurane induced no change in wake (P>0.05), increased SWS for 3 h, and decreased REM sleep for 9 h (P<0.02) post-sedation. Dexmedetomidine, midazolam, and coadministration of dexmedetomidine with sevoflurane reduced wake-associated phase-amplitude coupling (P≤0.01). All sedatives except sevoflurane decreased wake-associated high gamma weighted phase-lag index (P<0.01).

Conclusions: In contrast to i.v. drugs, prolonged sevoflurane sedation produced minimal changes in sleep homeostasis and neural dynamics. Further studies are warranted to assess inhalational agents for long-term sedation and sleep homeostasis.

Keywords: dexmedetomidine; functional connectivity; phase-amplitude coupling; propofol; rat; sedation; sevoflurane; sleep homeostasis.

MeSH terms

Anesthetics, Inhalation / administration & dosage
Anesthetics, Inhalation / pharmacology
Animals
Dexmedetomidine* / administration & dosage
Dexmedetomidine* / pharmacology
Electroencephalography* / drug effects
Homeostasis* / drug effects
Hypnotics and Sedatives* / administration & dosage
Hypnotics and Sedatives* / pharmacology
Male
Midazolam* / administration & dosage
Midazolam* / pharmacology
Propofol* / administration & dosage
Propofol* / pharmacology
Rats
Rats, Sprague-Dawley*
Sevoflurane* / administration & dosage
Sevoflurane* / pharmacology
Sleep* / drug effects
Wakefulness / drug effects

Substances

Sevoflurane
Propofol
Dexmedetomidine
Hypnotics and Sedatives
Midazolam
Anesthetics, Inhalation