COMPARISON OF TWITCH DEPRESSION OF THE ADDUCTOR POLLICIS AND THE RESPIRATORY MUSCLES - PHARMACODYNAMIC MODELING WITHOUT PLASMA-CONCENTRATIONS

Background: Although the respiratory muscles (the diaphragm and the la ryngeal adductors) recover from paralysis more rapidly than does the a dductor pollicis, patients can develop complete paralysis of the respi ratory muscles, but not of the adductor pollicis, after bolus administ ration of vecuronium. The authors used a pharmacodynamic model not req uiring muscle relaxant plasma concentrations to reconcile these findin gs. Methods: The pharmacodynamic model is based on the traditional mod el, in which: (1) vecuronium concentration at the neuromuscular juncti on (C-effect) is a function of the plasma concentration versus time cu rve and a rate constant for equilibration between plasma and the neuro muscular junction (k(eo)); and (2) effect is a function of C-effect, t he steady-state plasma concentration that produces 50% effect (C-50), and a factor to explain the sigmoid relationship between concentration and effect. In the absence of vecuronium plasma concentrations, an em piric model (rather than the usual effect compartment model) can be us ed to mimic the time delay (proportional, but not identical, to 1/k(eo ) between dose and effect. The model can be used to estimate the stead y-state infusion rate that produces 50% effect (IR(50)), equal to the product of C-50 and vecuronium plasma clearance; IR(50) for different muscle groups then can be compared to assess relative sensitivity. The authors applied this model to published effect data for subjects give n 40-70 mu g/kg vecuronium in whom paralysis of three muscle groups wa s measured during opioid/propofol anesthesia. Results: For IR(50), the ratio of values for the larynx:diaphragm:adductor pollicis was 1.4:1. 2:1; for the equilibration constant (inversely proportional to the tim e delay), the ratio far the respiratory muscles to the adductor pollic is was 2.5:1. Conclusions: Vecuronium concentrations peak earlier at t he respiratory muscles than at the adductor pollicis, possibly the res ult of greater perfusion to these organs, leading to earlier onset of paralysis. The observation that bolus injection of vecuronium produces greater paralysis of the respiratory muscles than of the adductor pol licis, despite greater resistance of the respiratory muscles, can be e xplained by differential rates of equilibration between plasma and var ious muscles.