Neostigmine: how much is necessary for patients who receive a nondepolarizing neuromuscular blocking agent?

FORTY-FIVE years after Beecher and Todd 1 first described an increase in mortality associated with the use of D-tubocurarine, anesthesiologists are still learning how best to use neuromuscular blocking agents (NMBAs) and their antagonists. Practices regarding antagonism of residual neuromuscular block vary based on the country of practice, type of anesthetic practice, and individual clinician preference. These disparate practices developed in part because of concern of adverse effects, such as arrhythmias, nausea, and vomiting, resulting from anticholinesterase administration as well as an inability to reliably detect the presence of residual neuromuscular block. Although a patient with four equal responses to train-of-four (TOF) stimulation, on either visual or tactile assessment, might be completely recovered from neuromuscular blockade, the TOF ratio (TOFR) could be as low as 0.4. Subjective detection of fade is improved by monitoring the response to double-burst stimulation that allows detection of 40% fade in the response. However, satisfactory recovery of neuromuscular function is defined as a TOFR 0.9. In the absence of subjective fade on double burst or TOF stimulation, the clinician cannot distinguish a TOFR 0.9 from 0.6 and, hence, cannot be certain whether neostigmine is indicated. Although not administering an anticholinesterase increases the risk of residual neuromuscular blockade, unwarranted administration of neostigmine (at a TOFR 0.9) can exacerbate weakness. Herein lies the quandary for the practicing clinician—whether to administer an anticholinesterase and if so, how much? The article by Fuchs-Buder et al. in this month’s ANESTHESIOLOGY provides new insight into this increasingly complex topic by addressing the appropriate dosing of anticholinesterase when subjective fade to double burst or TOF stimulation cannot be detected. Fuchs-Buder et al. administered neostigmine when patients had spontaneously recovered to a TOFR 0.4 or 0.6 after administration of atracurium. Patients received 10, 20, or 30 g/kg of neostigmine, and recovery to TOFR 0.9 and 1.0 was monitored with an acceleromyograph. Doses of 40 g/kg or less of neostigmine have been found effective for reversing 90% neuromuscular block when monitoring for recovery to a TOFR 0.7. –12 No study, however, has looked at the effect of administration of these small doses of neostigmine on the time required for complete recovery of neuromuscular function. Depth of neuromuscular block depends on the balance of the NMBA and acetylcholine at the neuromuscular junction, and recovery depends on increasing acetylcholine concentration relative to the NMBA. This can occur in one of the two ways: ongoing elimination of the NMBA from the plasma and inhibition of acetylcholinesterase with administration of an anticholinesterase, such as neostigmine. The potential for neostigmine to rapidly restore neuromuscular function is limited. It will not effectively antagonize 100% neuromuscular block, and requiring 10 min to peak effect, it cannot instantaneously restore neuromuscular function. Fortunately, there is a remarkable amount of redundancy built into the anatomic and physiologic processes of neuromuscular transmission. Even when the TOFR has recovered to unity, the majority of acetylcholine receptors may still be occupied by NMBA—potentially rendering a patient susceptible to failure of muscle strength with a physiologic change, such as decrease in temperature or respiratory acidosis. Fade in the twitch response occurs after tetanic stimulation of a neuromuscular unit that has recovered after vecuroniuminduced neuromuscular blockade. This observation supports the notion that even recovery to a TOFR 1.0 is not a true baseline, and all patients who receive an NMBA should receive an anticholinesterase. However, administering an anticholinesterase does not facilitate elimination of the NMBA from the body, and administration of neostigmine is not without adverse effects. Neostigmine directly blocks acetylcholine receptors, and excessive acetylcholine can cause both a depolarizing block and an open-channel block. Potentiation of, rather than recovery from, neuromuscular block has been demonstrated when 40 g/kg of neostigmine is administered after recovery to a TOFR 0.9 after administration of 0.1 mg/kg of vecu-