Escape From Oblivion: Neural Mechanisms of Emergence From General Anesthesia

Kelz, Max B.; García, Paul S.; Mashour, George A.; Solt, Ken

doi:10.1213/ane.0000000000004006

Cited by 56 publications

(34 citation statements)

References 152 publications

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“…By contrast, our paradigm reflects spontaneous emergence with residual isoflurane levels predicted to be 1 to 4 orders of magnitude below those required for hypnosis, which likely accounts for evidence of the robust return of cortical dynamics. However, it is worth noting that—in addition to the subcortical sites identified in human and animal studies ( Kelz et al, 2019 ) —the prefrontal cortex might play a critical role in the control of arousal states of relevance to general anesthesia. One animal study demonstrated that cholinergic stimulation of medial prefrontal cortex, but not two sites in posterior parietal cortex, was sufficient to reverse the anesthetized state despite continuous administration of clinically relevant concentrations of sevoflurane ( Pal et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Recovery of consciousness and cognition after general anesthesia in humans

Mashour

Palanca

Basner

et al. 2021

eLife

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Understanding how the brain recovers from unconsciousness can inform neurobiological theories of consciousness and guide clinical investigation. To address this question, we conducted a multicenter study of 60 healthy humans, half of whom received general anesthesia for three hours and half of whom served as awake controls. We administered a battery of neurocognitive tests and recorded electroencephalography to assess cortical dynamics. We hypothesized that recovery of consciousness and cognition is an extended process, with differential recovery of cognitive functions that would commence with return of responsiveness and end with return of executive function, mediated by prefrontal cortex. We found that, just prior to the recovery of consciousness, frontal-parietal dynamics returned to baseline. Consistent with our hypothesis, cognitive reconstitution after anesthesia evolved over time. Contrary to our hypothesis, executive function returned first. Early engagement of prefrontal cortex in recovery of consciousness and cognition is consistent with global neuronal workspace theory.

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Section: Discussionmentioning

confidence: 99%

Recovery of consciousness and cognition after general anesthesia in humans

Mashour

Palanca

Basner

et al. 2021

eLife

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“…Therefore, identification of a drug that reverses general anesthetics would be of considerable utility in clinical practice and in a laboratory setting. The neural mechanisms of emergence from general anesthesia are complicated and not completely known [ 31 ]. There have been ongoing efforts to reverse the effects of anesthesia in animals, with intracerebral injection of various agents including a cAMP analog [ 3 ], an antibody directed against potassium channels [ 4 ], a cholinesterase inhibitor and muscarinic agonist [ 5 , 12 ], nicotine [ 6 ] and adenosine receptor antagonists, including caffeine [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

“…Power spectra (dB) were computed over 2-minute long epoch of EEG, partitioned into 512-point epochs, and averaged, yielding a temporal resolution of 2 Hz. Normalized power was calculated as the fraction of a specific frequency power, including delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), spindle (12)(13)(14)(15), beta (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) and gamma (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40), in the total power over all frequency bands from 0.5-40 Hz. The mean powers in percent for pre (1), post saline or caffeine injection (2), during 1.2% isoflurane (3) and before RORR (4) were computed by the MATLAB program.…”

Section: Power Spectramentioning

confidence: 99%

Caffeine reverses the unconsciousness produced by light anesthesia in the continued presence of isoflurane in rats

et al. 2020

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Currently no drugs are employed clinically to reverse the unconsciousness induced by general anesthetics. Our previous studies showed that caffeine, when given near the end of an anesthesia session, accelerated emergence from isoflurane anesthesia, likely caused by caffeine’s ability to elevate intracellular cAMP levels and to block adenosine receptors. These earlier studies showed that caffeine did not rouse either rats or humans from deep anesthesia (≥ 1 minimum alveolar concentration, MAC). In this current crossover study, we examined whether caffeine reversed the unconsciousness produced by light anesthesia (< 1 MAC) in the continued presence of isoflurane. The primary endpoint of this study was to measure isoflurane levels at the time of recovery of righting reflex, which was a proxy for consciousness. Rats were deeply anesthetized with 2% isoflurane (~1.5 MAC) for 20 minutes. Subsequently, isoflurane was reduced to 1.2% for 10 minutes, then by 0.2% every 10 min; animals were monitored until the recovery of righting reflex occurred, in the continued presence of isoflurane. Respiration rate, heart rate and electroencephalogram (EEG) were monitored. Our results show that caffeine-treated rats recovered their righting reflex at a significantly higher inspired isoflurane concentration, corresponding to light anesthesia, than the same rats treated with saline (control). Respiration rate and heart rate increased initially after caffeine injection but were then unchanged for the rest of the anesthesia session. Deep anesthesia is correlated with burst suppression in EEG recordings. Our data showed that caffeine transiently reduced the burst suppression time produced by deep anesthesia, suggesting that caffeine altered neuronal circuit function but not to a point where it caused arousal. In contrast, under light anesthesia, caffeine shifted the EEG power to high frequency beta and gamma bands. These data suggest that caffeine may represent a clinically viable drug to reverse the unconsciousness produced by light anesthesia.

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“…Recent studies have revealed that arousal-promoting neural circuits and neurotransmitters can accelerate recovery from anesthetic-induced unconsciousness ( Kelz et al, 2019 ). In rats, administration of a cholinergic agonist in the PFC induces emergence from sevoflurane anesthesia ( Pal et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

D-Amphetamine Rapidly Reverses Dexmedetomidine-Induced Unconsciousness in Rats

et al. 2021

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D-amphetamine induces emergence from sevoflurane and propofol anesthesia in rats. Dexmedetomidine is an α2-adrenoreceptor agonist that is commonly used for procedural sedation, whereas ketamine is an anesthetic that acts primarily by inhibiting NMDA-type glutamate receptors. These drugs have different molecular mechanisms of action from propofol and volatile anesthetics that enhance inhibitory neurotransmission mediated by GABAA receptors. In this study, we tested the hypothesis that d-amphetamine accelerates recovery of consciousness after dexmedetomidine and ketamine. Sixteen rats (Eight males, eight females) were used in a randomized, blinded, crossover experimental design and all drugs were administered intravenously. Six additional rats with pre-implanted electrodes in the prefrontal cortex (PFC) were used to analyze changes in neurophysiology. After dexmedetomidine, d-amphetamine dramatically decreased mean time to emergence compared to saline (saline:112.8 ± 37.2 min; d-amphetamine:1.8 ± 0.6 min, p < 0.0001). This arousal effect was abolished by pre-administration of the D1/D5 dopamine receptor antagonist, SCH-23390. After ketamine, d-amphetamine did not significantly accelerate time to emergence compared to saline (saline:19.7 ± 18.0 min; d-amphetamine:20.3 ± 16.5 min, p = 1.00). Prefrontal cortex local field potential recordings revealed that d-amphetamine broadly decreased spectral power at frequencies <25 Hz and restored an awake-like pattern after dexmedetomidine. However, d-amphetamine did not produce significant spectral changes after ketamine. The duration of unconsciousness was significantly longer in females for both dexmedetomidine and ketamine. In conclusion, d-amphetamine rapidly restores consciousness following dexmedetomidine, but not ketamine. Dexmedetomidine reversal by d-amphetamine is inhibited by SCH-23390, suggesting that the arousal effect is mediated by D1 and/or D5 receptors. These findings suggest that d-amphetamine may be clinically useful as a reversal agent for dexmedetomidine.

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Escape From Oblivion: Neural Mechanisms of Emergence From General Anesthesia

Cited by 56 publications

References 152 publications

Recovery of consciousness and cognition after general anesthesia in humans

Recovery of consciousness and cognition after general anesthesia in humans

Caffeine reverses the unconsciousness produced by light anesthesia in the continued presence of isoflurane in rats

D-Amphetamine Rapidly Reverses Dexmedetomidine-Induced Unconsciousness in Rats

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