In most circumstances, all efforts should be made to ensure that the patient leaves the operating room with unimpaired muscle strength (respiratory and upper airway muscles functioning normally to permit breathing, coughing, swallowing, and maintaining a patent airway). Strategies to achieve this goal include titrating the NMBDs so that no residual effect is manifest at the end of surgery, accelerating recovery by administering an anticholinesterase agent, and selective binding of NMBDs with a cyclodextrin molecule to restore neuromuscular function. Regardless of the strategy selected, careful monitoring of blockade is necessary.

1. Assessment of Neuromuscular Blockade. Spontaneous breathing (adequate to prevent hypercapnia if a patent airway is maintained) can resume even if relatively deep degrees of paralysis are present because of the relative diaphragm-sparing effect of NMBDs. The weakest point in the respiratory system is the upper airway. (Swallowing is impaired, and laryngeal aspiration may occur in the presence of vecuronium when the TOF ratio is ≤0.9.)
   1. Residual paralysis (neuromuscular blockade) is frequent in patients in the recovery room after surgery. Patients emerging from anesthesia with a TOF ratio <0.9 are more likely to experience episodes of oxygen desaturation, airway obstruction, and muscle weakness. The most important reason for the high incidence of residual paralysis seems to be omission of reversal.
   2. Clinical Importance. Residual paralysis in the recovery room is associated with significant morbidity.
2. Anticholinesterase Agents. The pharmacologic principle involved is inhibition of ACh breakdown to increase its concentration of ACh at the NMJ, thus tilting the competition for receptors in favor of the neurotransmitter. The traditional use of neostigmine for reversal is now being challenged by the introduction of a selective binding agent, sugammadex.
   1. Neostigmine: Mechanism of Action
      1. Inhibition of acetylcholinesterase by neostigmine (similar for pyridostigmine and edrophonium) results in an increase in the amount of ACh that reaches the receptor and a longer time for Ach to remain in the synaptic cleft.
      2. Anticholinesterases may also have presynaptic effects.
   2. Neostigmine Block. Large doses of anticholinesterases, especially if given in the absence of neuromuscular block (TOF ratio, 1.0), may produce evidence of neuromuscular dysfunction. Although there are no clinical reports of postoperative weakness attributed to reversal agents, it seems prudent to reduce the dose of anticholinesterase agent if recovery from neuromuscular block is almost complete.
   3. Potency. Anticholinesterase-assisted recovery is the sum of (1) spontaneous recovery from the NMBD itself (reflection of the pharmacokinetics of the drug) and (2) assisted recovery that depends on the specific anticholinesterase agent given.
   4. Pharmacokinetics of anticholinesterase drugs reflect the dependence of these drugs on renal clearance (Table 20-12: Pharmacokinetics of Anticholinesterase Drugs).
   5. Pharmacodynamics. The time to peak action of neostigmine is 5 minutes, and its duration of action is 1 to 2 hours. Cases of alleged recurization most likely reflect incomplete reversal that was initially thought to be complete.
3. Factors Affecting Neostigmine Reversal (Table 20-13: Factors Affecting Neostigmine Reversal and Table 20-14: Recommended Doses of Anticholinesterase Drugs and Anticholinergic Drugs Based On Train-Of-Four Stimulation)
4. Neostigmine: Other Effects
   1. Cardiovascular. Anticholinesterase agents provoke profound vagal stimulation that can be prevented by with anticholinergic agents. Atropine has a rapid onset of action (1 minute), has a duration of 30 to 60 minutes, and crosses the blood–brain barrier (glycopyrrolate does not cross the blood–brain barrier). Given in combination with neostigmine (atropine dose is half that of neostigmine), it gives rise to an initial tachycardia. With glycopyrrolate (dose is one-fourth to one-fifth that of neostigmine), the onset is slower but still faster than that of neostigmine.
   2. Other Cholinergic Effects. Anticholinesterase drugs produce increased salivation and bowel motility (causing a concern about an increase in bowel anastomotic leakage). There seems to be no relationship between postoperative nausea and vomiting and administration of neostigmine.
   3. Respiratory Effects. Neostigmine may cause an increase in airway resistance, but anticholinergics reduce this effect.
5. Clinical Use. Several strategies have been proposed to restore neuromuscular function at the end of surgery. Pharmacologically assisted recovery is expected in most cases because it is illusory to aim for complete recovery only by careful titration of NMBDs.
   1. Administration of anticholinesterase agents accelerates recovery, no matter when they are given in the course of recovery. However, there are advantages in giving reversal agents when spontaneous recovery is underway.
   2. If four twitches are not visible after TOF stimulation, it is recommended to keep the patient anesthetized and mechanically ventilated until four twitches reappear and then administer anticholinesterases.
   3. Edrophonium is not recommended for intense block.
   4. Pyridostigmine has a slow onset of action and does not appear to accelerate reversal of short- and intermediate-duration drugs to a great extent.
6. Sugammadex
   1. This cyclodextrin leads to restoration of normal neuromuscular function by selectively binding to rocuronium (and to a lesser extent to vecuronium and pancuronium). Because it does not bind to any known receptors, it is devoid of cardiovascular and other side effects. Block-produced by SCh or any of the benzylisoquinolines (atracurium, cisatracurium, mivacurium) is unaffected by sugammadex.
   2. Pharmacology. If sugammadex is given upon return of the second twitch in the TOF, a dose of 2 mg/kg results in return of the TOF ratio to 0.9 in 2 to 4 minutes (Fig. 20-5: Median time to recovery to a train-of-four ratio of 0.9 with neostigmine and sugammadex). The availability of sugammadex may make SCh obsolete for intubation (sugammadex 8 mg/kg effective as early as 3 minutes after administration of rocuronium 0.6 mg/kg).
   3. Pharmacokinetics. Sugammadex and sugammadex–rocuronium complexes are excreted unchanged via the kidneys. (Clearance of sugammadex decreased markedly in patients with renal failure.)
   4. Special Populations
      1. In infants and children, the dose of sugammadex appears to be similar to that recommended for adults against rocuronium blockade (Fig. 20-6: Median time to recovery of a train-of-four (TOF) ratio greater than 0.9 in adult patients when sugammadex 2 mg/kg was given at recovery of the second twitch in the TOF).
      2. In morbidly obese individuals, sugammadex produces slower recovery if the dose is based on ideal body weight versus the dose calculated by adding 40% to the ideal body weight.
   5. Clinical Use (Table 20-15: Sugammadex and Clinical Use)

Neuromuscular Blocking Agents

1. Physiology and Pharmacology
2. Neuromuscular Blocking Agents
3. Depolarizing Blocking Drugs: Succinylcholine
4. Nondepolarizing Drugs
5. Drug Interactions
6. Altered Responses to Neuromuscular Blocking Agents
7. Monitoring Neuromuscular Blockade
8. Reversal of Neuromuscular Blockade