Severe Renal Disease (also see Chapter 56 )

Renal failure influences the pharmacology of nondepolarizing neuromuscular blockers by producing either decreased elimination of the drug or its metabolites via the kidney or decreased activity of butyrylcholinesterase ( Table 13-14 ). Consequently, the duration of action of neuromuscular blockers may be prolonged in patients with renal failure. An early example of prolonged neuromuscular blockade as a result of renal failure was a case of postoperative respiratory failure after gallamine, reported in 1950.^[710]

Renal failure does not alter the sensitivity (dose-response relationship) of patients to the neuromuscular blocking action of gallamine,^[347] dTc,^[711] pancuronium,^[234] atracurium,^[712] vecuronium,^[713] rocuronium,^[714] or mivacurium,^[715] but it does cause resistance to metocurine.^[345]

Gallamine^[347] and metocurine, ^[345] which rely almost exclusively on the kidney for their elimination, have reduced plasma clearance and potentially a very long duration of action in patients with renal failure (see Table 13-14 ). Pancuronium and dTc are eliminated predominantly by the kidney, and renal failure is associated with reduced plasma clearance and an increased elimination half-life for these drugs as well.^{[190] [716]} As a consequence of these pharmacokinetic changes, the duration of neuromuscular blockade produced by these drugs is longer and more variable than in patients with normal renal function.^[716] In patients with renal failure, doxacurium has decreased plasma clearance, an increased elimination half-life, and a prolonged duration of action.^{[346] [717]} Pipecuronium is eliminated predominantly by the kidney.^[293] Its plasma clearance is decreased by one third, and its elimination half-life is increased twofold in patients with renal failure.^[298] Because of the potential for prolonged block and the availability of intermediate- and short-acting neuromuscular blockers, there is no longer any reason to recommend the use of long-acting neuromuscular blockers in patients with renal failure.

The pharmacokinetics and duration of action of atracurium are unaffected by renal failure.^{[705] [718] [719]} This lack of effect is due in part to the fact that Hofmann elimination and ester hydrolysis^[340] account for 50% of its total clearance.^[326] The elimination half-life of laudanosine, the principal metabolite of atracurium, increases in renal failure.^{[705] [720]} Recent evidence suggests, however, that significant concentrations of laudanosine are not achieved during the administration of atracurium in the operating room setting. ^{[705] [720]}

In patients with chronic renal failure, the duration of action of cisatracurium is not prolonged.^[257] Hofmann elimination accounts for 77% of the total clearance of cisatracurium,^[342] and renal excretion accounts for 16% of its elimination.^[342] Clearance of the drug is slightly decreased by 13% in this patient population.^[721]

Vecuronium relies principally on hepatic, not renal mechanisms for its elimination.^{[303] [707]} However, its

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The plasma clearance of rocuronium may be decreased in patients with renal failure^[725] and its distribution volume increased.^[352] The duration of action of single and repeated doses, though, is not significantly affected.^[714] When rocuronium is administered to patients with renal failure who are undergoing renal transplantation versus patients with normal renal function, plasma clearance is unchanged (2.89 mL/kg/min), the volume of distribution is increased by 28%, and the elimination half-life is lengthened by 37% (see Fig. 13-17 ).^{[352] [726]}

The effect of renal failure on the duration of action and recovery from mivacurium-induced blockade is variable. In some studies, renal failure had no effect,^[228] whereas in others, the duration of action and recovery were prolonged and the infusion dose requirements were decreased by renal failure.^[727] The effect of renal failure on mivacurium's duration of action is most probably mediated through its effect on butyrylcholinesterase. Renal failure can decrease butyrylcholinesterase activity, ^[728] and this decrease would be expected to prolong the duration of mivacurium-induced neuromuscular blockade.^{[320] [729]} Clearance of the cis-trans and trans-trans isomers of mivacurium is decreased by approximately 20% in those with renal failure.^[314] In the studies in which renal failure had no effect on mivacurium's duration of action, butyrylcholinesterase activity was similar in patients with and without renal failure.^[228] In contrast, when patients with renal failure had decreased butyrylcholinesterase activity, the duration of action of mivacurium was longer.^{[318] [727]} Because a patient's butyrylcholinesterase

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