James E. Caldwell, M.D.

TIt is unlikely that any new muscle relaxants (MRs) will be introduced in the foreseeable future. Consequently, this discussion will focus on the increasing awareness of the problems of residual neuromuscular block and a radically new pharmacology for reversal of neuromuscular block.

Problem of Inadequate Reversal of Neuromuscular Block
The most important problem in current clinical use of MRs is failure to achieve adequate recovery from their effect. Omitting pharmacologic reversal (e.g., neostigmine) is a common practice, and the clear consequence is inadequate recovery of neuromuscular function.¹ Even at two or more hours after a single endotracheal intubating dose of vecuronium, rocuronium or atracurium, the incidence of inadequate neuromuscular function, defined as a train-of-four (TOF) ratio < 0.7, was 10 percent in patients who did not receive pharmacologic reversal.¹ This probably underestimates the true incidence of inadequate recovery of neuromuscular function.

Reassessing Standards for Adequate Neuromuscular Function
The gold standard for adequate recovery of neuromuscular function has been a TOF ratio of ≥ 0.7.² A better standard is a TOF ratio ≥ 0.9. The complex coordination of swallowing is disrupted by even minor degrees of neuromuscular block, with consequent risk of aspiration.³ Subtle changes such as unsteadiness sitting up in bed, a decrease in grip strength and diplopia are associated with small degrees of residual block, and these effects decrease “street readiness” for discharge from the recovery room.⁴ In the study by Debaene et al.¹ of patients not receiving pharmacologic reversal, the prevalence of a TOF ratio < 0.9 was 37 percent when measured more than two hours after a single dose of MR.

New Monitoring Techniques
Currently most clinicians cannot determine whether the TOF ratio is greater or less than 0.9. A novel technique, the tongue depressor test, may be useful. If the patient can grasp a tongue depressor between his or her incisor teeth and cannot be pulled out, the TOF ratio is likely to be at least 0.85.⁴ More objective monitoring techniques are becoming available, but they have not been validated.

Acceleromyography calculates the force generated by the adductor pollicis muscle from the acceleration of the thumb. Unfortunately TOF ratios measured with acceleromyography and the gold standard mechanomyography may not correspond exactly.⁵ Phonomyography uses the low-frequency sounds generated by muscle contraction.⁶ There are insufficient data to validate this technique as a reliable measure of neuromuscular recovery.

Minimizing Doses of Muscle Relaxants
What can be done to decrease the risk of residual block? In the short term, the best strategy is to minimize the use of large and frequent doses of MRs. Tracheal intubation can be achieved without MR using large-dose opioid and propofol combinations. However, this may come at the cost of hypotension and bradycardia. The addition of a small dose of MR allows the doses of propofol and opioid to be decreased and quality of tracheal intubation maintained or improved.⁷ Rocuronium, 0.30 – 0.45 mg/kg, is the most appropriate drug for this because of its acceptable rate of onset (two to three minutes) even in such small doses.⁷ The smaller the dose of relaxant used, the greater the degree of recovery at the end of the case and the higher the probability of achieving adequate reversal.

Whenever a nondepolarizing MR has been used, pharmacological reversal should be administered.¹ A small dose of neostigmine in the range of 20 µg/kg, or edrophonium 0.3-0.5 mg/kg, should almost always be used if an MR has been administered in the preceding four hours.⁸

Cyclodextrins: A Revolution in Reversal
Cyclodextrin-mediated reversal of neuromuscular block is potentially the greatest advance in neuromuscular pharmacology in the last 20 years.⁹ Anticholinesterase-mediated reversal of neuromuscular block has limited efficacy and activates muscarinic receptors producing cardiovascular, gastrointestinal and pulmonary effects that must be blocked by atropine or glycopyrrolate.

The cyclodextrins take a radically new approach: they encapsulate (chelate) the MR and decrease its effective plasma concentration to zero. In theory, even profound degrees of block can be reversed.⁹ Neuromuscular recovery will occur rapidly and completely as the relaxant diffuses from the neuromuscular junction back into the plasma. Because cyclodextrins do not work through cholinesterase inhibition, they are free of muscarinic effects.⁹

A cyclodextrin is a doughnut-shaped molecule with a cavity that has high stereo-selectivity for the target drug. Cyclodextrins are known to have good biological tolerance.⁹ The compound ORG25969 is being prepared for Phase 3 clinical trials.¹⁰ This drug is optimized to encapsulate rocuronium. Barring unforeseen problems in the clinical trials, cyclodextrin-mediated reversal has the potential to revolutionize our practice.

James E. Caldwell, M.D., is Professor of Anesthesia and Perioperative Care, Department of Anesthesia and Perioperative Care, University of California-San Francisco, San Francisco, California.