Let’s say you’re in the middle of a case and the surgeon yells that the patient is not adequately paralyzed. Let’s also say that you have a neuromuscular transmission monitor and can see the minute-by-minute effect on the train-of-four ratio after you’ve injected either rocuronium or cisatracurium. You’ll nicely see that the onset time for rocuronium is shorter than it is for cisatracurium, and yet you also know that the duration of action of both drugs is similar. You’ll likely scratch your head and wonder why this is the case. Dr. James P. Dilger, Department of Anesthesiology, Stony Brook University, Stony Brook, New York, used a computer simulation of cell signaling to help answer this very question. The results of his work appear in this month’s issue of Anesthesia & Analgesia in the article titled “Simulation of the Kinetics of Neuromuscular Block: Implications for Speed of Onset.”
Variables that relate to the geometry of the rat diaphragm muscle’s neuromuscular junction as well as association and dissociation constants for acetylcholine and the different neuromuscular blocking agents were included in the computer model used for the simulation. Initially Dr. Dilger showed that onset time of twitch suppression was proportional to drug potency. After the model was adjusted to increase the width of the synaptic cleft 2-3 times wider than what is seen in a standard rat model and with the rate constant for equilibration of drug between plasma and muscle as 0.6 min−1, onset times matched what is seen clinically. Therefore, this model bolsters the explanation that buffered diffusion, i.e., time needed for drug diffusion into the neuromuscular junction, is the rate-limiting step for the onset of nondepolarizing muscle relaxant drug action.
Other experiments have been performed in isolated animal neuromuscular junctions, but onset times are much shorter than what is seen clinically. In this study, factors were adjusted until the model matched clinical observations.
Is this merely a computer exercise then? Probably not. Dr. François Donati, Department of Anesthesiology, Université de Montréal, Québec, Canada, writes, “In this particular case, perhaps the next step would not be so much repeating the study with a better model of neuromuscular junction geometry but rather refining the simulations by incorporating not 1 but several neuromuscular junctions, each with slightly different characteristics and access to neuromuscular blocking agents. When we inject our drugs, we do not target the neuromuscular junction, but rather many of them, each with a different geometry. Twitch depression is not the result of partial transmission failure at every neuromuscular junction, but rather the summation of failures and successes at many junctions, each of which responds in an all-or-none fashion. It is likely that the differences in onset times predicted for the drugs in Dilger’s study3 would be accentuated by a more refined model, incorporating many neuromuscular junctions.” Dr. Donati’s comments appear in the editorial “Onset of Neuromuscular Blockade: More than Just the Time to Get There,” which was also published in this month’s edition of Anesthesia & Analgesia.
OpenAnesthesia discusses neuromuscular transmission and ions.