The work up for delayed emergence began in our case with the most common reasons: too much narcotic, inhalational anesthetic or anxiolytic. After considering residual anesthetic effects in a patient who experiences delayed emergence, a rapid check of the other common causes is undertaken. These include acute intoxication from recreational agents (drugs, EToH), residual neuromuscular blockade, ventilatory failure resulting in somnolence from hypercarbia, and metabolic derangements such as hypo/hyperglycemia, hyponatremia. Other causes are hypothermia, hypoxic brain injury, hypoxemia, or neurological insult such as ischemia, or hemorrhagic stroke, or acute increase in ICP. In most cases, the above causes of delayed emergence are either iminently obvious, or can be quickly ruled out by history and context.
In our case an extensive effort was undertaken to rule out all of the above including EEG and CT. EEG was ordered by the consulting neurologist to rule out complex partial status epilepticus or absence status epilepticus, which are non convulsive constant seizure activity. Unfortunately, no obvious cause for our patients comatose state was apparent and it was decided to admit her to the ICU for further observation.
In 1988, a 5 year old boy presented for surgery. He received oral midazolam for anxiolysis, and a short volatile anesthetic. Postoperatively the boy experienced an unusual emergence, was given a small dose of physostigmine and improved dramatically. The diagnosis of central anticholinergic syndrome was offered in the published case report. Indeed, there are many case reports in the literature describing patients with unusual emergence characteristics that have been attributed to CAS. (5,6,7)
CAS presentation is variable with symptoms including: ataxia, dry mouth and throat, cessation of perspiration (leads to hyperthermia), mydriasis (results in photophobia), cycloplegia (leading to blurry vision), tachycardia, urinary retention, increased IOP, shaking, confusion, agitation, hallucinations, respiratory depression, myoclonic jerking, and coma. The central anticholingergic syndrome (CAS) typically results from drugs that act to inihibit or compete with acetylcholine in the CNS where it plays a critical role in arousal states and REM sleep. Physostigmine is a tertiary amine that penetrates the blood brain barrier and inhibits the breakdown of acetylcholinesterase, leading to increased acetylcholine in the synpatic cleft. In fact, while CAS is a difficult diagnosis and typically requires excluding other causes first, a clinical response to physostigmine is indicative that CAS is the cause.
While in some cases it is clear that a patient may have developed CAS a reaction to anticholinergic drugs such as atropine or scopolamine, it is often less commonly realized that our typical intravenous and volatile anesthetics can induce CAS as well.
Indeed, physostigmine has been utilized as a reversal agent for general anesthetics and there are case reports of physostigmine reversing benzodiazepines, opioid narcotics, volatile anesthetics, ketamine, and propofol. However, prospective double blind studies have failed to find a benefit when given to reverse benzodiazepines or opioid narcotics. On the other hand, in a series of nine patients sedated with propofol and monitored with a BIS monitor, phyosostigmine was effective in reversing sedation in 7 of the patients. (3) In this study, it was shown that an iv dose (~0.4mg) of scopolamine prior to physostigmine prevented reversal of propofol anesthesia. This indicates that muscarinic acetylcholine receptors are at least in part responsible for the sedative effects of propfol. Whether propofol causes sedation and a sleep like state by interfering with the central cholinergic neurotransmission directly or indirectly is unknown. It is thoughtthat propofol binds to the GABAa receptor to induce anesthesia. Furthermore, it has been shown that GABAergic stimulation in the medial pontine reticular formation inhibits acetylcholine release resulting in arousal and inhibition of the REM sleep like state. Other brain regions also play a role GABAergic modulation of acetlycholine release to effect arousal and sedation in animals. Further evidence for propfol's action on the central cholinergic system is provided by another study showing that the dose of propfol required to induce anesthesia is slightly higher in patients given physostigmine. (8) It is also proposed that volatile anesthetics bind to GABAa receptors. Central cholinergic transmission is also effected by volatile anesthetics. In animal models, increased cholinergic transmission antagonizes halothane, isoflurance and sevoflurane anesthesia respectively. (3,11) In humans, Hill and collegues (9)reported that physostigmine was able to decrease the time to return to consciouness after halothane anesthesia indicating the cholinergic transmission is important in arousal after anesthesia. Physostigmine was also shown to partially reverse sevoflurane anesthesia, although physostigmine was not as effective as it was in reversing propofol. (10) However, Paraskeva A and collegues was unable to show BIS reversal or improved recovery using physostigmine in patients receiving sevoflurane. (12)
The central anticholinergic syndrome may be an underrecognized syndrome in patients who receive anesthesia. One report(4) found an incidence of 1.8% in patients who underwent general anesthesia for a myriad of conditions. In the same report, they found that women who underwent a hysterectomy had a higher incidence of CAS (10%). Because of the variable presentation of CAS and the relative frequency of its appearance in controlled trials, it is likely that thousands of patients a year suffer medical work ups or delays in discharge as clinicians attempt to deal with delayed or unusual emergence phenomena.
The neurobiology of sleep and arousal states is complex. However, studies are beginning to tease out the brain areas that play a role in maintaining anesthesia and causing arousal. It has become increasingly evident that altered central cholinergic transmission mediates the anesthetic state. Recent work in rats demonstrated that the nACHr may play the role of an "on" switch in anesthesia (2) (i.e. stimulation of this receptor can awake the patient). It has been shown that the sleep-wake cycle as well as the maintenance of the awake state is dependent on cholinergic neurotransmission from the medial pontine reticular formation as well as other important centers, such as the basal forebrain, thalamus, medial preoptic nucleus, and locus coeruleus.
We know that acetylcholine is critical for both arousal and cognition. For example, Carbachol (muscarinic Ach agonist) injected directly into the medial pontine reticular formation can cause a REM like sleep (EEG appearance is similar to the awake state) but also can reverse halothane anesthesia which shares a similar EEG pattern to Non REM sleep. Additionally, it is known that cortical acetylcholine release is increased during both REM sleep (EEG appearance same as awake state) and in the awake state. Conversely, Acetylcholine release is decreased during both anesthesia and during non REM sleep. This concept is important to understand as we next look at the various anesthetics and how they are known to effect either directly or indirectly acetylcholine neurotransmission.
Both opioids and ketamine have been shown in animal models to affect acetylcholine neurotransmission; i.e. they can result in decreased acetylcholine release resulting in decreased arousal. Likewise, the volatile anesthetics can result in decreased acetylcholine release when placed directly in the pontine reticular formation (important in modulating arousal and sleep). These studies are inline with the clinical work sited above wherein physostigmine (increases acetylcholine) can reverse at least partially anesthesia by propofol and inhalational agents. Acetylcholine is no the only neurotransmitter that plays a role in arousal and sleep states. When ATP is cleaved for metabolic activity in the brain, adenosine is a byproduct. This neurotransmitter has been shown to increase the drive for sleep as its levels increase in the brain. Furthermore, adenosine receptor type 1 agonists when applied to the arousal/sleep center of the brain, the pontine reticular formation will delay recovery from halothane anesthesia. A1 receptors are also thought to play a role in isoflurane anesthesia and this all combined helps explain why caffeine is utilized to avoid or delay sleep since it works as an adenosine antagonist.
GABA plays a complicated role in human sleep/wake cycles. GABAergic neurotransmission in several different key nuclei (basal forebrain, preoptic nucleus of the hypothalamus, locus coeruleus and dorsal raphe nucleus) acts modulate arousal and sleep. It is believed that it can do so by inhibiting acetylcholine release from key neurons. Many anesthetics are believed to act directly on the GABAa receptor, and in this way alone, are capable of modulating acetylcholine levels in the key sleep/arousal centers as well as in the cerebral cortex generally where muscarinic receptors are known to modulate arousal.
As mentioned above, the raphe nucleus (both midline and dorsal) and locus coeruleus play a role in sleep/wake cycles in humans. In particular, these nuclei discharge maximally during the awake state, and progressive decrease their discharge during non REM and REM sleep respectively. In addition, serotonin is known to aid in arousal (via the midline raphe nucleus), histamine aids in arousal via the posterior hypothalamus, Norepinephrine aids in arousal from the locus coeruleus, and dopamine has varying affects on the sleep wake cycle that are complicated and not fully eludcidated. Recent research has shown a role for hypocretin I and II (also known as orexin A and B) in arousal. Located in the hypothalamus with connections to important areas controlling arousal, these brain peptides are believed to play a role in narcolepsy, or rapid onset of REM sleep. Therefore, emergence from anesthesia involves a host of different neurotransmitters interacting in a complex manner in a variety of different brain nuclei. This complex interaction depends upon a careful balance of inhibition and stimulation and consequently, patients who do not emerge in an expected manner may have an increase or decrease of one or more of these systems. Fortunately, it appears that in most cases, increasing cholinergic neurtransmission (via physostigmine) can attenuate or even reverse delayed emergence when caused by unbalanced neurotransmission.
Physostigmine is often given in a dose of 30 mcg/kg and often with glycopyrrolate to offset peripheral actions of acetylcholine (bradycardia, ileus, urinary retention). Physostigmine is often associated with nausea and in some cases has been associated with ventricular arrythmias, atrial fibrillation and hypertension. Therefore, patients who receive physostigmine should have heart monitoring. The clinical duration is 35 to 45 minutes. In many cases, patients become reobtunded. Multiple dosages are often required.
Finally, delayed or unusual emergence is not uncommon and in many cases may represent continued blockade of cholinergic neurotransmission which is known to be affected by virtually all of our anesthetic medications. Diagnosis by trial of physostigmine is reasonable once other causes of delayed emergence are ruled out. Continued monitoring of these patients is required and in some cases admission to the ICU may be indicated.
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