In 1847, just 1 year after the first public demonstration of ether anesthesia, von Bibra and Harless proposed the first theory of general anesthetic mechanism.1 Since that time, understanding how general anesthetics suppress consciousness and other neural functions has been the foundational scientific question in the field of anesthesiology. There has, however, been a recent shift from understanding the “entry” to the anesthetized state to understanding the “exit” from the anesthetized state.2 This shifting focus might not, prima facie, seem justified: if we know how anesthetics cause unconsciousness, then we should simply be able to deduce how consciousness returns by a reversal of the neural events that caused general anesthesia in the first place. This assertion rests on the assumption that emerging from general anesthesia is simply the reverse process of inducing general anesthesia.
In the past decade, this assumption has been brought into question for 2 reasons. First, particular neuronal subpopulations responsible for sleep or wake states appear to be differentially involved in the entry to and exit from the anesthetized state.3,4 For example, as discussed in a subsequent section, orexinergic neurons of the hypothalamus do not appear to be involved in induction but are critically involved in emergence.5 Second, there is a clear hysteresis between the process of induction and emergence, that is, the forward and reverse pathways of anesthetic state transitions are not the same.6 In practical terms, this means that the anesthetic concentration at which one loses consciousness is higher than the anesthetic concentration at which one regains consciousness. Although this has traditionally been attributed to pharmacokinetics, emerging evidence suggests that hysteresis is a general property of neural systems during state transitions.7,8
In this narrative review, we focus on the exit from the anesthetized state. This focus is organized around specific neurotransmitter systems and the neuronal subpopulations that synthesize and transmit them. Furthermore, we will describe how these various arousal- and sleep-promoting transmitter systems can be manipulated to control the exit from anesthetic-induced unconsciousness. While many of the studies are drawn from the animal literature, the choice of signaling systems in this review has been restricted to those for which translational data affecting emergence exist in humans.
Acetylcholine in the cerebral cortex has long been argued to create the conditions for conscious experience, during both waking states and dream states associated with rapid eye movement sleep.9 Indeed, cholinergic tone in the cortex is high during the waking state, low during slow-wave sleep, and highest during rapid eye movement sleep.10,11 There are parallels in anesthetic state transitions. Anesthetics working through γ-aminobutyric acid receptors, such as propofol or halogenated ethers reversibly depress cortical acetylcholine, in association with slow-wave electroencephalographic activity and unconsciousness.12–15 Ketamine and nitrous oxide, by contrast, enhance cortical cholinergic tone14,16 and can be associated with higher-frequency electroencephalographic activity and a higher probability of subjective experience (eg, dream states or hallucinations). As such, a consideration of acetylcholine is of critical importance to the neurobiology of emergence from the anesthetized state.
Acetylcholine is generated in the neurons of the laterodorsal tegmentum and pedunculopontine tegmentum, which project to other subcortical structures such as the thalamus and which, when activated, can trigger rapid eye movement sleep states.17 Cortical acetylcholine is derived from the cholinergic neurons of the basal forebrain, which have a tripartite circuitry with frontal and more posterior cortices18 (Figure 1). Increasing acetylcholine levels in the prefrontal cortex will result in increased cholinergic tone in the parietal cortex, but the reverse is not true.19 Because of the role of acetylcholine in consciousness, the thalamic and cortical cholinergic systems have been investigated in spontaneous and induced recovery from general anesthesia.
As noted, cortical acetylcholine levels decrease during propofol- and sevoflurane-induced unconsciousness in animals, then return after recovery.15 Agonizing nicotinic acetylcholine receptors in the central thalamus can induce reversal of sevoflurane and desflurane anesthesia, despite ongoing administration.20 However, antagonizing nicotinic receptors does not modify the process of anesthetic induction, suggesting an asymmetric role. In addition to modulation of acetylcholine receptors, acetylcholinesterase inhibitors—which block the degradation of acetylcholine—have been explored as a tool to reverse anesthesia. For example, intracerebroventricular infusion of neostigmine in animals reversed the effects of isoflurane on the electroencephalogram.21 Physostigmine, which crosses the blood–brain barrier, has been shown in humans to reverse both sevoflurane and propofol anesthesia,22,23 although restoration of consciousness is not a consistent phenomenon. When physostigmine is effective in reversing anesthesia in humans, there is an associated activation of the thalamus and precuneus.24 A recent study of isoflurane in animals did not show any behavioral effect of physostigmine, but electroencephalographic activation was observed.25
The role of the cholinergic system in recovery from, or reversal of, general anesthesia has been more recently explored in what has been termed paradoxical emergence.26 In 1 animal study, subanesthetic ketamine was administered during general anesthesia with isoflurane. Compared with saline injection, administration of ketamine was associated with the induction of burst suppression. However, despite the ostensible deepening of general anesthesia, animals exposed to ketamine emerged from isoflurane anesthesia almost 45% faster. This was considered “paradoxical” because the anesthetic itself appeared more profound yet recovery was accelerated. Ketamine-induced acceleration of recovery was associated with a significant elevation of acetylcholine in the prefrontal cortex26 as well as enhanced functional connectivity between frontal and parietal cortices.27
Increased cortical acetylcholine during paradoxical emergence was only an association, raising the question of the causal effect of enhancing cholinergic tone in the prefrontal cortex on arousal. More recently, carbachol—a mixed cholinergic agonist—was reverse dialyzed into medial prefrontal cortex in rodents anesthetized with approximately 1 minimum alveolar concentration sevoflurane. Carbachol activated the electroencephalogram, enhanced acetylcholine levels by >500%, and led to consistent behavioral recovery—despite continuous administration of sevoflurane.28 By contrast, reverse dialysis of carbachol in 2 areas of parietal cortex had no behavioral effect but did increase electroencephalographic frequency. The differential role of cholinergic tone in the prefrontal versus parietal cortices has been explained by a mesocircuit model involving basal forebrain, basal ganglia, and thalamus.18 These studies suggest that achieving critical acetylcholine concentrations in particular neuroanatomic loci might be required for the reversal of anesthetic effects. Of note, administration of norepinephrine—both in prefrontal and posterior cortex—activated the electroencephalogram but did not result in behavioral recovery.28 However, infusion of norepinephrine in the basal forebrain, the source of cortical acetylcholine, leads to microarousals and electroencephalographic activation during desflurane anesthesia.29 The role of norepinephrine and other monoaminergic transmitters in arousal will be addressed in the next section.
Norepinephrine is also a wake-promoting neurotransmitter that plays a role in the regulation of attention and endogenous states of arousal. Noradrenergic neurons are restricted to the pons and medulla with the largest source arising from the locus coeruleus. The other brainstem noradrenergic neurons are clustered into distinct groups including the A1, A2, A5, and A7 nuclei.30,31 These lesser-studied regions primarily innervate subcortical structures regulating cardiorespiratory, thermoregulatory, hormonal, and nutritional functions.32 Noradrenergic neurons project widely across brain and to all known wake-active areas (Figure 2). Locus coeruleus noradrenergic neurons display state-dependent firing patterns with the highest discharge rates occurring during waking, decreased rates accompanying nonrapid eye movement sleep, and—in contrast to cholinergic neurons described previously—virtual quiescence during rapid eye movement sleep.33 Mapping onto this framework of locus coeruleus activity modulating endogenous arousal, administration of hypnotic doses of many general anesthetics, including propofol, isoflurane, dexmedetomidine, and barbiturates, decreases the firing of locus coeruleus neurons both in vitro and in vivo.34–39 Microinjection of the α2 adrenergic agonist dexmedetomidine targeting locus coeruleus neurons in the rostral pons is sufficient to produce hypnosis, while injections 2 mm more lateral fail to do so.40 Nevertheless, inhibition of locus coeruleus neurons is not a requirement for hypnosis—a finding supported both neurophysiologically and genetically.39,41
A rich history of research supports the notion that modulation of noradrenergic output affects the anesthetic state. Drugs that reduce norepinephrine release including reserpine and α-methyldopa create anesthetic hypersensitivity, reducing the dose of volatile anesthetics required to immobilize rodents. Conversely, drugs that acutely increase noradrenergic tone either by preventing reuptake or by stimulating release, such as cocaine, amphetamine, and the monoamine oxidase inhibitor iproniazid, elicit partial resistance to anesthetic-induced immobility.42–44 Although the lack of drug specificity tempers definitive conclusions in these aforementioned studies, when interpreted together with the lesion and genetic studies, a clearer picture for adrenergic contributions to anesthetic action emerges. Chemical lesions that deplete norepinephrine and ultimately destroy adrenergic neurons produce hypersensitivity to both volatile and barbiturate anesthesia.45–48 Similarly, electrolytic lesions that ablate the locus coeruleus bilaterally to cause a loss of noradrenergic output together with its copackaged neurotransmitters and simultaneous damage to adjacent tissue also increase sensitivity to halothane and cyclopropane.49 Lesions also suggest a role for locus coeruleus signaling in modulating ketamine anesthesia. However, as is true for cholinergic signaling, compared to other anesthetics, ketamine’s actions both differentially impact adrenergic signaling and are differentially affected by adrenergic manipulations.48,50
Although earlier studies focused on the end point of anesthetic-induced immobility, more recent ones have confirmed that modulating adrenergic signaling similarly affects anesthetic-induced unconsciousness. Studies conducted in dopamine β-hydroxylase–deficient mice that lack adrenergic ligands reveal that animals that do not generate norepinephrine (and epinephrine) exhibit an approximate 10%–20% left shift in their induction sensitivity dose–response curve (hypersensitivity) for all tested volatile anesthetics: sevoflurane, isoflurane, and halothane.6,51 However, the most profound change in dopamine β-hydroxylase–deficient mice is their marked deficit in exiting states of anesthetic hypnosis. The dose–response curve for emergence exhibits an extreme left shift when compared to sibling controls. At isoflurane levels 50% below those in which sibling controls emerge, dopamine β-hydroxylase–deficient mice still remain in a state of anesthetic hypnosis. Moreover, even after correcting for the volatile anesthetic induction hypersensitivity, dopamine β-hydroxylase–deficient mice take twice as long to emerge as sibling controls when both groups are given equipotent (strain-specific corrected) anesthetic exposures. Last, hypersensitivity in dopamine β-hydroxylase–deficient mice is not limited to volatile anesthetics. These adrenergic-deficient animals are also hypersensitive to dexmedetomidine, displaying shorter latency to lose their righting reflex and a 2- to 3-fold longer duration of hypnosis after IV administration than sibling controls. Using a processed electroencephalographic measure of sensitivity, studies suggest that, as with volatile anesthetics, the major deficit associated with dopamine β-hydroxylase–deficient mice is exiting the unconscious state.51 Together with the pharmacological and lesions studies, experiments in these mice prove that it is the specific loss of adrenergic ligands, norepinephrine (and possibly epinephrine but not of copackaged neurotransmitters), that delay anesthetic emergence.
Although deficits in adrenergic signaling can enhance anesthetic potency and impair anesthetic emergence, multiple studies demonstrate that enhancing adrenergic signaling destabilizes anesthetic states. Studies in humans using processed electroencephalographic demonstrate that systemic administration of ephedrine or isoproterenol activates the cortical electroencephalographic and rouses the cortex.52,53 Studies in rodents demonstrate that more localized delivery of norepinephrine into the brain of anesthetized animals also leads to signs of arousal. Compared to saline controls, infusions of norepinephrine into the basal forebrain targeting the nucleus basalis of Meynert cause transient behavioral and electroencephalographic activation despite continuous, steady-state desflurane anesthesia.29 These microarousals are hypothesized to mimic adrenergic recruitment of cholinergic neurons within the basal forebrain. Mimicking adrenergic stimulation of α2 adrenergic receptors expressed on neurons in the sleep-promoting ventrolateral preoptic nucleus, microinjections of dexmedetomidine also transiently destabilize otherwise invariant states of isoflurane anesthesia.54 Adrenergic inputs into the central medial thalamus are also hypothesized to regulate endogenous arousal. Congruent with the aforementioned genetic studies, infusions of norepinephrine into the central medial thalamus accelerate emergence from propofol anesthesia but does not alter induction.55 Although these infusions fail to overtly antagonize the state of propofol anesthesia, they do produce electroencephalographic signs of cortical arousal relative to control.55 As a compelling confirmation, chemogenetic activation of locus coeruleus adrenergic neurons, which do project into centromedial thalamus, during steady-state isoflurane anesthesia fully replicate the results of norepinephrine infusions into centromedial thalamus both in activating the cortical electroencephalographic during isoflurane and in hastening emergence from isoflurane relative to controls.56 Hence, adrenergic signaling appears to prime the brain for transitions to wakefulness, though on its own it lacks to the overt power to enforce and stabilize such transitions.
Independently discovered by 2 research teams in 1998,57,58 as evidenced by its dual names, the orexin/hypocretin system has become neurobiology’s most famous arousal-promoting and stabilizing system. Loss of function of orexin/hypocretin signaling causes the only known single gene deficit leading to a primary disorder in the organization of sleep and wakefulness: narcolepsy with cataplexy.59 This occurs in dogs that inherit mutations in 1 of its 2 neurotransmitter receptors, in mice that harbor knockouts of the orexin/hypocretin gene (or both of its receptors), and in humans with an autoimmune-mediated destruction of the 70,000 neurons that make these neuropeptides.60 Perhaps the most remarkable feature of the orexin/hypocretin system is its spatial confinement.61 The brain’s orexin/hypocretin neurons are exclusively found in the perifornical, lateral, and posterior hypothalamus in a location that von Economo62 first hypothesized should serve as a wake-promoting region 7 decades before their discovery. Despite their exquisitely restricted origin, orexin/hypocretin neurons project across the entire neuroaxis, stretching monosynaptic fibers caudally into the spinal cord and rostrally into the anterior most reaches of the frontal cortex (Figure 3). Orexin/hypocretin neurons depolarize arousal-regulating neurons in the noradrenergic locus coeruleus, serotonergic dorsal raphe nucleus, the dopaminergic ventral tegmental area, the cholinergic pedunculopontine and lateral dorsal tegmental areas, the histaminergic neurons of the tuberomammillary nucleus, as well as neurons in the thalamus.64 They are thus well positioned to orchestrate the regulation of endogenous states of arousal. In turn, orexin/hypocretin neurons receive inputs from the amygdala, cholinergic neurons of the basal forebrain, GABAergic neurons in the preoptic area, and serotonergic neurons of the median raphe plus allocortex, claustrum, lateral septum, and lateral parabrachial nuclei.65,66 Electrophysiological studies confirm that orexin/hypocretin neurons are depolarized by glutamate, by acetylcholine (although cholinergic actions are not uniform and a subset is inhibited), by orexin/hypocretin itself, by hypoglycemia or ghrelin.67,68 Orexin/hypocretin neurons serve as primary chemoreceptors and are also depolarized by low pH and elevated carbon dioxide levels.69 Orexin/hypocretin neurons are inhibited by norepinephrine, serotonin, and γ-aminobutyric acid (GABA) as well as by insulin and under hyperglycemic conditions. Hence, these neurons help to coordinate changes in arousal in conjunction with feeding, energy homeostasis, and autonomic cues.67–70
In addition to its role in regulating arousal, the orexin/hypocretin system also regulates metabolism, cardiovascular, thermoregulatory, respiratory, motor, and sensory functions71,72—all systems affected by anesthetics. Hence, early hypotheses of potential hypersensitivity of narcoleptic humans to anesthetic drugs that might pharmacologically impair and consequently mimic narcoleptic physiology seemed both plausible and possible. Many anesthetics drugs reduce c-Fos protein induction (a convenient histological marker of antecedent neuronal activity) in these neurons and further reduce the efficacy of residual orexin/hypocretin signaling through its receptors.41,73 However, despite the initial reports confirming that injections of orexin/hypocretins into the cerebrospinal fluid of rodents could reduce the duration of barbiturate anesthesia38 or separately rouse the cortex from states of isoflurane or propofol-induced burst suppression into less deeply anesthetized patterns,74 the fundamental role of orexin/hypocretin signaling proved far more intriguing for anesthetic mechanisms.
Pharmacological antagonism or targeted genetic destruction that impairs orexin/hypocretin signaling does not alter the process of anesthetic induction.74,75 However, under such conditions, emergence from isoflurane and sevoflurane (but not of halothane) is delayed as evidenced in rodents both by behavioral and processed electroencephalographic markers.5,39,76–78 Impaired anesthetic emergence in narcoleptic mice validates the findings in a subset of human narcoleptic patients who may also exhibit delayed emergence from general anesthesia.79 However, anesthetic drug choice and presumed disease heterogeneity make delayed emergence incompletely penetrant in narcoleptic humans.80
Exogenous administration of orexin/hypocretins to rodents will foreshorten the duration of anesthesia that follows a bolus delivery of propofol as well as ketamine.75,81 This may occur through enhanced cortical acetylcholine signaling,82 in keeping with cholinergic arousal mechanisms,28 through increased acetylcholine and GABA release in the pontine reticular formation,83,84 as well as through enhanced noradrenergic and dopaminergic activity75 (see below). Translational studies in humans also suggest that reactivation of orexin/hypocretin signaling may be an important contributor to emergence from propofol–fentanyl, sevoflurane–fentanyl, and sevoflurane–remifentanil anesthetics given in humans.85–87 Moreover, the acceleration in emergence times associated with hypercapnia in humans88 and animals89 may be partially due to direct depolarization of orexin/hypocretin neurons.
Apart from suggesting the important crossover role of orexin/hypocretin signaling for transitions back to a conscious wakeful state that is applicable both to natural sleep and anesthetic hypnosis, impaired orexin/hypocretin signaling served as the first central nervous system (CNS) clue that the process of anesthetic emergence need not be a mirror image of anesthetic induction.5,6 Rather, the findings of additional genetic mutation and pharmacological manipulations in animals have led to a revised understanding of anesthetic hysteresis—namely that forward and reverse transitions to and from states of unconsciousness follow distinct dose–response curves and may consequently have distinct neurobiological underpinnings.90–93 A necessary repercussion of anesthetic hysteresis mandates that transitions to and from states of unconsciousness are also disfavored by an inertial barrier whose presence suggests potential novel mechanisms for active reanimation from the depths of general anesthesia.94,95
Dopamine is a monoamine neurotransmitter that is synthesized and released primarily by neurons in the ventral tegmental area and substantia nigra pars compacta of the mesencephalon. Dopamine neurons in the ventral tegmental area have major projections to the prefrontal and entorhinal cortices (mesocortical pathway) and to the amygdala and nucleus accumbens (mesolimbic pathway), while substantia nigra pars compacta dopamine neurons have robust projections to the striatum (nigrostriatal pathway).96 Mesencephalic dopamine neurons have been studied extensively in the contexts of motivation, reward, executive function, and locomotor control, leading to important insights and treatments for schizophrenia, Parkinson disease, attention-deficit hyperactivity disorder, and other conditions. However, the role of dopamine in promoting wakefulness has been relatively underappreciated. This is because a series of animal studies conducted in the 1980s found that dopamine neurons in the ventral tegmental area and substantia nigra pars compacta do not change their mean firing rates across sleep-wake cycles,97–99 which defocused the study of dopamine in arousal.96 Recently, however, interest in this area has been rekindled by newer data demonstrating that dopamine plays an important role in sleep/wake modulation, and by advances in neuroscience that allow for selective activation and inhibition of neural circuits with optogenetics and chemogenetics.100
Mesencephalic dopamine neurons have reciprocal afferent and efferent connections to many subcortical arousal-promoting pathways, including cholinergic neurons in the pedunculopontine and laterodorsal tegmental nuclei and basal forebrain, noradrenergic neurons in the locus coeruleus, serotonergic neurons in the dorsal raphe, and histaminergic neurons in the tuberomammillary nucleus.96 These interconnections between ventral tegmental area and substantia nigra pars compacta dopamine neurons and known arousal-promoting nuclei suggest that dopamine is involved in promoting wakefulness. In addition, there is a population of dopamine neurons in the ventral periaqueductal gray that increases expression of c-Fos during the awake state.101
Methylphenidate and dextroamphetamine are reuptake inhibitors for dopamine and norepinephrine that restore wake-like behaviors in animals continuously anesthetized with isoflurane, sevoflurane, and propofol.94,102,103 These drugs appear to induce emergence from general anesthesia primarily by enhancing dopaminergic neurotransmission, as the selective norepinephrine reuptake inhibitor atomoxetine does not produce signs of arousal in anesthetized rats.103 A recent rodent study also found that direct administration of norepinephrine to the prefrontal cortex or parietal cortex during sevoflurane anesthesia does not produce signs of behavioral arousal.28
There are 5 subtypes of dopamine receptors (D1–D5). D1 and D2 receptors are the most abundantly expressed in the brain and appear to be chiefly involved in the arousal-promoting actions of dopamine. Agonists for both D1 and D2 receptors have been shown to promote arousal,104,105 and a selective D1 agonist has been reported to accelerate emergence from pentobarbital anesthesia in rats.106 Another study in rats comparing anesthetic reversal with D1 and D2 agonists found that a D1 agonist was efficacious for inducing emergence from isoflurane anesthesia, while a D2 agonist was not.107 Consistent with these findings, a selective D1 antagonist was reported to inhibit emergence from sevoflurane anesthesia with dextroamphetamine.103 Taken together, the available data suggest that D1 receptors are chiefly responsible for the arousal-promoting actions of dopamine that induce emergence from general anesthesia.
Recent studies have demonstrated that the source of arousal-promoting dopamine is primarily the ventral tegmental area, rather than the substantia nigra pars compacta. Electrical deep brain stimulation of the ventral tegmental area induces emergence from isoflurane and propofol anesthesia in rats, while stimulation of the substantia nigra pars compacta is ineffective.108 A subsequent study found that selective optogenetic stimulation of ventral tegmental area dopamine neurons restores wake-like behaviors in mice anesthetized with isoflurane,109 showing that dopamine release by ventral tegmental area neurons is sufficient to induce the transition from the unconscious, anesthetized state to the awake state. Optogenetic activation of ventral tegmental area dopamine neurons was also reported to increase wakefulness and decrease sleep in mice.110 In particular, selective terminal stimulation of ventral tegmental area dopamine neurons that project to the nucleus accumbens produced the most robust increase in wakefulness, suggesting that the mesolimbic pathway is particularly important for maintaining arousal.
Lesion studies using 6-hydroxydopamine to ablate dopamine neurons in rodents have found that bilateral ventral tegmental area lesions delay emergence from propofol anesthesia.111 Interestingly, anesthetic sensitivity to isoflurane and ketamine was not affected by these lesions. Another study found that lesions to ventral periaqueductal gray dopamine neurons using 6-hydroxydopamine prolonged recovery from propofol anesthesia.112 Propofol has also been shown to reduce dopamine levels in the prefrontal cortex.113 These findings suggest that dopaminergic neurons in ventral tegmental area and ventral periaqueductal gray area contribute significantly to emergence from propofol anesthesia, and that inhibition of dopaminergic neurotransmission may play a particularly important role in the hypnotic actions of propofol.
Adenosine is a neuromodulator that is generated primarily by the metabolism of adenosine triphosphate.114 It plays an important role in sleep homeostasis (ie, the pressure to sleep that increases with prolonged wakefulness and that decreases during sleep).115 The administration of adenosine into the cerebral ventricles has been shown to increase nonrapid eye movement sleep in rats.116 Unlike neurotransmitters that are stored in synaptic vesicles and released on neuronal depolarization, adenosine levels increase during the awake state and gradually decrease during sleep.115,117
There are 4 known types of adenosine receptors (A1, A2A, A2B, and A3), all of which are G-protein–coupled receptors. These receptors are expressed both in the CNS and in the periphery. In the brain, A1 receptors are widely expressed in the cortex, hippocampus, and cerebellum, and A2A receptors are found primarily in the striatum, nucleus accumbens, and olfactory bulb.114,118 A1 and A2A receptors are important modulators of arousal, whereas A2B and A3 receptors are found at lower levels in the brain and their importance is less clear.118 Caffeine is an antagonist of both A1 and A2A receptors, and it has been shown to promote wakefulness in A1 knockout mice but not A2A knockout mice,119 suggesting that the arousal-promoting actions of caffeine are primarily mediated by A2A receptors.
Delivery of an A1 receptor agonist into the pontine reticular formation has been shown to decrease acetylcholine release and delay emergence from halothane anesthesia in cats.120 This suggests that adenosine decreases arousal by reducing cholinergic neurotransmission, and that adenosine buildup in the brain during prolonged wakefulness can increase sensitivity to anesthetic-induced hypnosis. Consistent with this notion, sleep deprivation decreases the dose requirement for loss of consciousness by propofol, sevoflurane, and isoflurane in rats,121,122 and this effect is partially reversed by A1 and A2A antagonists.123 It has also been reported that propofol and sevoflurane promote recovery from sleep deprivation,122,124 that time spent under isoflurane and sevoflurane anesthesia do not accrue nonrapid eye movement sleep debts,125 but isoflurane and sevoflurane do not satisfy the homeostatic need for rapid eye movement sleep.125,126 Taken together, these findings support the hypothesis that anesthetics partially converge onto adenosine-mediated sleep pathways to produce unconsciousness, likely in a drug-dependent fashion.
Several studies have shown that adenosine receptor antagonists facilitate emergence from general anesthesia. Microdialysis delivery of caffeine and a selective A1 antagonist into the prefrontal cortex increases local release of acetylcholine in mice, and decreases time to emergence from isoflurane anesthesia.127 Systemic administration of caffeine has been shown to accelerate emergence from isoflurane and propofol anesthesia in rats,128 and a selective A2A antagonist also accelerates emergence from isoflurane anesthesia.129 In addition, it was recently reported in a double-blind crossover study that caffeine accelerates emergence from isoflurane anesthesia in healthy human volunteers not undergoing surgery.130 Taken together, inhibition of A1 and A2A adenosine receptors appears to be an effective strategy for promoting emergence from general anesthesia.
GABA is the most abundant inhibitory neurotransmitter in the mammalian CNS. GABA-mediated inhibition of neuronal network activity underlies both sleep onset and maintenance.131–133 Common anesthetic drugs, like propofol and the halogenated ethers, produce unconsciousness in part by augmenting the effect of GABA.134
In contrast to many neurotransmitters and neuromodulators with specific anatomic constraints, GABA signaling is distributed throughout cortical and subcortical areas. Despite this global abundance, GABA type A receptors (GABAARs) do more than simply control brain excitation and prevent overactivity (eg, seizures). GABA-mediated suppression of otherwise active networks in the motor cortex results in precise selection of specific motor patterns.135 Similarly, GABA plays a critical role in thalamic coordination of cortical integration of complex information via inhibitory signals from the reticular thalamus onto specific thalamic nuclei.136,137 Enhanced GABA signaling not only impairs the function of brain networks critical for waking behaviors but also activates specific sleep networks in the preoptic hypothalamus.3,138–140
Much of the richness in the GABAergic signaling occurs as a result of differential expression of specific subtypes of GABAARs. GABAARs are pentameric proteins made up of 5 subunits.141 Preferred subunit assemblies are specifically distributed in different brain areas.142 Subunit combinations that include α4, α5, or the α6 subunits often localize to extrasynaptic locations.143 Because each GABAAR subtype exhibits distinct biophysical and pharmacological properties, these receptors diversely influence the function of brain networks important for sleep and anesthesia. For example, experiments using brain slice recordings from rodent thalamus and hippocampus reveal that the extrasynaptic GABAARs are more sensitive to the effects of anesthetic agents.144,145 Presumably after the cessation of anesthetic delivery, low levels of anesthesia continue to impair normal network function in the thalamic and parahippocampal networks preventing the reestablishment of cognitive functions essential for normal waking behavior (attention, working memory, and integration of sensory information). Further, pharmacological research focused on antagonizing GABAARs in ex vivo brain slice preparations may identify novel strategies for hastening emergence from general anesthesia.146,147
Because the majority of anesthetics delivered in industrialized nations use GABAergic drugs, changes in electroencephalographic patterns (or increases in processed electroencephalographic measures of hypnosis) can be used to evaluate pharmacological mechanisms of emergence. Although many options exist for pharmacological antagonization of GABAARs, concern for seizure generation has understandably hindered research in this area. Thus far, only the use of flumazenil, a benzodiazepine rescue agent, has been attempted in humans as an “antidote” for the increased GABA activity occurring during anesthesia, but with mixed results. In patients anesthetized with propofol and remifentanil, flumazenil given to patients who had not received benzodiazepines both increased electroencephalographic signs of arousal and hastened emergence.148 However, in another study, flumazenil failed to speed emergence but did improve cognition in the recovery room.149 In an animal model of general anesthesia, flumazenil hastened the appearance of electroencephalographic markers of emergence from anesthesia and influenced sleep patterns in the postanesthesia period.150 Of note, enhanced GABA signaling is not exclusively associated with general anesthesia and its reduction is not exclusively associated with emergence. For example, increased GABA levels in the pontine reticular formation are associated with wakefulness and modulation of GABA levels in this brain region can enhance induction of anesthesia with no effect on emergence.90,151
Flumazenil blocks access to the benzodiazepine binding site on GABAARs and is not a true competitive antagonist of the GABAAR. Flumazenil partially offsets the isoflurane-mediated enhancement of chloride current through GABAARs, but also exhibits weak agonist properties. Because of its efficacy in modulating vigilance in patients with hypersomnic sleep disorders,152 blocking the effect of endogenously produced benzodiazepine-like substances could be involved in its efficacy in anesthetic emergence and recovery.148,150 Although flumazenil is Food and Drug Administration approved for use in humans, its role in hastening emergence and treating abnormal recovery after general anesthesia remains largely unexplored. Interestingly, flumazenil appeared to have some efficacy in a pediatric patient with an abnormal recovery from general anesthesia characterized by aphasia.153 More work will need to be done to determine which bioactive substances are preferred to enhance normal emergence and avoid abnormal recovery.
The induction and maintenance of general anesthesia have long been the focus of neuroscientific investigation in anesthesiology. Investigations over the past decade have shifted the focus to emergence from general anesthesia and highlighted the possibility that this process might be under distinct neurobiological regulation and amenable to exogenous modulation. This heralds the possibility that clinical care could shift to the active control of the emergence process. The various neurotransmitters and neuromodulators described in this review have been independently probed for their ability to affect emergence. More sophisticated studies probing multiple systems and the interactions between them hold promise for accelerating the escape from the oblivion of general anesthesia in human surgical patients.
The authors would like to acknowledge funding support from the National Institutes of General Medical Studies.
Name: Max B. Kelz, MD, PhD.
Contribution: This author helped review the literature and cowrite the manuscript.
Name: Paul S. García, MD, PhD.
Contribution: This author helped review the literature and cowrite the manuscript.
Name: George A. Mashour, MD, PhD.
Contribution: This author helped review the literature and cowrite the manuscript.
Name: Ken Solt, MD.
Contribution: This author helped review the literature and cowrite the manuscript.
This manuscript was handled by: Gregory J. Crosby, MD.
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