The increase in acetylcholine caused by cholinester-ase inhibitors affects more than the nicotinic recep-tors of skeletal muscle (Table 12–2). Cholinesterase
inhibitors can act at cholinergic receptors of several other organ systems, including the cardiovascular and gastrointestinal systems.
Cardiovascular receptors—The predominantmuscarinic effect on the heart is bradycardia that can progress to sinus arrest.
Pulmonary receptors—Muscarinic stimulationcan result in bronchospasm (smooth muscle contraction) and increased respiratory tract secretions.
Cerebral receptors—Physostigmine is acholinesterase inhibitor that crosses the blood– brain barrier and can cause diffuse activation of the electroencephalogram by stimulating muscarinic and nicotinic receptors within the central nervous system. Inactivation of nicotinic acetylcholine receptors in the central nervous system may play a role in the action of general anesthetics. Unlike physostigmine, cholinesterase inhibitors used to reverse neuromuscular blockers do not cross the blood–brain barrier.
Gastrointestinal receptors—Muscarinicstimulation increases peristaltic activity (esophageal, gastric, and intestinal) and glandular secretions (eg, salivary). Postoperative nausea, vomiting, and fecal incontinence have been attributed to the use of cholinesterase inhibitors.
Unwanted muscarinic side effects are mini-mized by prior or concomitant administration of anticholinergic medications, such as atropine sulfate or glycopyrrolate. The duration of action is similar among the cholinesterase inhibitors. Clearance is due to both hepatic metabolism (25% to 50%) and renal excretion (50% to 75%). Thus, any pro-longation of action of a nondepolarizing muscle relaxant from renal or hepatic insufficiency will probably be accompanied by a corresponding increase in the duration of action of a cholinesterase inhibitor.
As a rule, no amount of cholinesterase inhibitor can immediately reverse a block that is so intense that there is no response to tetanic peripheral nerve stimulation. Moreover, the absence of any palpable single twitches following 5 sec of tetanic stimulation at 50 Hz implies a very intensive blockade that can-not be reversed. Excessive doses of cholinesterase inhibitors may actually prolong recovery. Some evi-dence of spontaneous recovery (ie, the first twitch of the train-of-four [TOF]) should be present before reversal is attempted. The posttetanic count (the number of palpable twitches after tetanus) generally correlates with the time of return of the first twitch of the TOF and therefore the ability to reverse intense paralysis. For intermediate-acting agents, such as atracurium and vecuronium, a palpable posttetanic twitch appears about 10 min before spontaneous recovery of the first twitch of the TOF. In contrast, for longer-acting agents, such as pan-curonium, the first twitch of the TOF appears about 40 min after a palpable posttetanic twitch.The time required to fully reverse a nondepo-larizing block depends on several factors, including the choice and dose of cholinesterase inhibitor administered, the muscle relaxant being antagonized, and the extent of the blockade before reversal. For example, reversal with edrophonium is usually faster than with neostigmine; large doses of neostigmine lead to faster reversal than small doses; intermediate-acting relaxants reverse sooner than long-acting relaxants; and a shallow block is easier to reverse than a deep block (ie, twitch height >10%). Intermediate-acting muscle relaxantstherefore require a lower dose of reversal agent (for the same degree of blockade) than long-acting agents, and concurrent excretion or metabolism provides a proportionally faster reversal of the short- and intermediate-acting agents. These advantages can be lost in conditions associated with severe end-organ disease (eg, the use of vecuronium in a patient with liver failure) or enzyme deficien-cies (eg, mivacurium in a patient with homozygous atypical pseudocholinesterase). Depending on the dose of muscle relaxant that has been given, sponta-neous recovery to a level adequate for pharmaco-logical reversal may take more than 1 hr with long-acting muscle relaxants because of their insig-nificant metabolism and slow excretion. Factors associated with faster reversal are also associated with a lower incidence of residual paralysis in the recovery room and a lower risk of postoperative respiratory complications.
A reversal agent should be routinely given to patients who have received nondepolarizingmuscle relaxants unless full reversal can be demon-strated or the postoperative plan includes continued intubation and ventilation. In the latter situation, adequate sedation must also be provided.
A peripheral nerve stimulator should also be used to monitor the progress and confirm the ade-quacy of reversal. In general, the higher the fre-quency of stimulation, the greater the sensitivity ofthe test (100-Hz tetany > 50-Hz tetany or TOF > single-twitch height). Clinical signs of adequate reversal also vary in sensitivity (sustained head lift > inspiratory force > vital capacity > tidal volume). Therefore, the suggested end points of recov-ery are sustained tetanus for 5 sec in responseto a 100-Hz stimulus in anesthetized patients or sus-tained head or leg lift in awake patients. Newer quantitative methods for assessing recovery from neuromuscular blockade, such as acceleromyogra-phy, may further reduce the incidence of residual postoperative neuromuscular paralysis.