General anesthesia is a reversible coma, actively induced and maintained by administering intravenous and inhalational drugs.1 In contrast, emergence from general anesthesia is a slow passive process achieved simply by allowing the effects of the drug to wear off. Emergence of anesthesia is therefore a passive process whereby anesthetic drugs are merely discontinued at the end of surgery, and no drugs are administered to actively reverse their effects on the brain and central nervous system. That is, the general anesthetic agents are merely discontinued at the end of surgery, leaving the anesthesiologist and surgeon to wait for the patient to recover consciousness. The timing of emergence can be unpredictable because many factors including the nature and duration of the surgery, and the age, physical condition and body habitus of the patient, can greatly affect the pharmacokinetics and pharmacodynamics of general anesthetics. Although the actions of many drugs used in anesthesiology are pharmacologically reversed when no longer desired (e.g. muscle relaxants, opioids, benzodiazepines, and anticoagulants), this is not the case for general anesthetic induced loss of consciousness.
This current clinical paradigm of passive emergence is dangerous because patients are highly susceptible to potentially severe complications such as laryngospasm, respiratory depression, hemodynamic instability, and delirium. In addition, operating room (OR) time, estimated to cost between $12.37 to $17.11 per minute at MGH, is an expensive resource that is squandered during the time spent waiting for patients to emerge from general anesthesia.
At present, there is no agent available to actively induce emergence from general anesthesia. This is largely due to our limited knowledge of the molecular mechanisms of general anesthetic actions, hampering the development of drugs that antagonize the actions of general anesthetics. However, accumulating evidence suggests that ascending arousal pathways in the brain can play important roles in emergence from general anesthesia.2 While cholinergic,3,4 orexinergic,5 and histaminergic6 arousal pathways have been implicated in emergence, the roles of other arousal pathways are yet unknown. Methylphenidate is widely prescribed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children and adults, and acts primarily by inhibiting the dopamine and norepinephrine reuptake transporters,7 thereby increasing dopaminergic and adrenergic neurotransmission. Recently, methylphenidate has also been reported to increase prefrontal cortex histamine levels in rats.8 Dopamine, norepinephrine, and histamine are monoamine neurotransmitters that promote arousal through pathways emanating from nuclei in the pons, midbrain and hypothalamus.2,9 