Marie Lau

Comparison of twitch depression of the adductor pollicis and the respiratory muscles : pharmacodynamic modeling without plasma concentrations

BackgroundAlthough the respiratory muscles (the diaphragm and the laryngeal adductors) recover from paralysis more rapidly than does the adductor pollicis, patients can develop complete paralysis of the respiratory muscles, but not of the adductor pollicis, after bolus administration of vecuronium. The authors used a pharmacodynamic model not requiring muscle relaxant plasma concentrations to reconcile these findings. MethodsThe pharmacodynamic model is based on the traditional model, in which: (1) vecuronium concentration at the neuromuscular junction (Ceffect) is a function of the plasma concentration versus time curve and a rate constant for equilibration between plasma and the neuromuscular junction (kco); and (2) effect is a function of Ceffect, the steady-state plasma concentration that produces 50% effect (C50), and a factor to explain the sigmoid relationship between concentration and effect. In the absence of vecuronium plasma concentrations, an empiric model (rather than the usual effect compartment model) can be used to mimic the time delay (proportional, but not identical, to 1/kco) between dose and effect. The model can be used to estimate the steady-state infusion rate that produces 50% effect (IR50), equal to the product of C50 and vecuronium plasma clearance; IR50 for different muscle groups then can be compared to assess relative sensitivity. The authors applied this model to published effect data for subjects given 40–70 μg/kg vecuronium in whom paralysis of three muscle groups was measured during opioid/propofol anesthesia. ResultsFor IR50, the ratio of values for the larynx:diaphragm:adductor pollicis was 1.4:1.2:1; for the equilibration constant (inversely proportional to the time delay), the ratio for the respiratory muscles to the adductor pollicis was 2.5:1. ConclusionsVecuronium concentrations peak earlier at the respiratory muscles than at the adductor pollicis, possibly the result 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 pollicis, despite greater resistance of the respiratory muscles, can be explained by differential rates of equilibration between plasma and various muscles.

Pharmacodynamic modeling of vecuronium-induced twitch depression : Rapid plasma-effect site equilibration explains faster onset at resistant laryngeal muscles than at the adductor pollicis

Background After bolus doses of nondepolarizing muscle relaxants, the adductor pollicis recovers from paralysis more slowly than the diaphragm and the laryngeal adductors, suggesting that the adductor pollicis is more sensitive than the respiratory muscles to effects of those drugs. In contrast, during onset, the respiratory muscles are paralyzed more rapidly than the adductor pollicis, suggesting that the respiratory muscles are more sensitive than the adductor pollicis. To reconcile these apparently conflicting findings, we determined vecuroniums pharmacokinetics and its pharmacodynamics at both the adductor pollicis and the laryngeal adductors. Methods Six volunteers were studied on two occasions during anesthesia with propofol. Mechanical responses to train‐of‐four stimulation were measured at the adductor pollicis and at the laryngeal adductors. Vecuronium (15–60 micro gram/kg) was given and arterial plasma samples were obtained from 0.5–60 min. Vecuronium doses differed by twofold on the two occasions. A pharmacokinetic model accounting for the presence and potency of vecuroniums 3‐desacetyl metabolite and a sigmoid e‐max pharmacodynamic model were fit to the resulting plasma concentration and effect (adductor pollicis and laryngeal adductors) data to determine relative sensitivities and rates of equilibration between plasma and effect site concentrations. Results The steady‐state plasma concentration depressing laryngeal adductor twitch tension by 50% was approximately 1.5 times larger than that for the adductor pollicis. The equilibration rate constant between plasma and laryngeal adductor concentrations was about 1.5 faster than that between plasma and adductor pollicis concentrations. The Hill factor (gamma) that describes the steepness of the laryngeal adductor concentration‐effect relation was approximately 0.6 times that of the adductor pollicis. Conclusions More rapid equilibration between plasma and laryngeal adductor vecuronium concentrations explains why onset is more rapid at the laryngeal adductors than at the adductor pollicis. During recovery, both rapid equilibration and lesser sensitivity of the laryngeal adductors contribute to earlier recovery.

A pharmacodynamic explanation for the rapid onset/offset of rapacuronium bromide.

BACKGROUND Nondepolarizing muscle relaxants differ in their time course at the laryngeal adductors and the adductor pollicis, a result of differences in equilibration delays between plasma and effect sites, the sensitivity of each muscle to the relaxant, and the steepness of the concentration-effect relation at each muscle (the Hill factor). To determine whether similar differences exist for rapacuronium, a muscle relaxant with rapid onset and offset, the authors determined its pharmacodynamic characteristics. METHODS The twitch tensions of the adductor pollicis and the laryngeal adductors (via a tracheal tube cuff positioned at the vocal cords) were measured in 10 volunteers who were anesthetized with propofoL Rapacuronium, 1.5 mg/kg, was given and blood samples were collected. A semiparametric effect compartment pharmacodynamic model was fit to values for rapacuronium plasma concentrations and twitch tension of the adductor pollicis and laryngeal adductors. RESULTS Equilibration between the rapacuronium plasma concentration and both effect sites was rapid (typical values for the rate constant for equilibration between plasma and the effect site are 0.405 per min for the adductor pollicis and 0.630 per min for the laryngeal adductors) and was more rapid at the laryngeal adductors than at the adductor pollicis (ratio, 1.59+/-0.16; mean +/- SD). The steady state rapacuronium plasma concentration that depressed twitch tension by 50% and the Hill factor were similar for the two muscles. CONCLUSIONS The rapid onset and offset of rapacuronium can be explained by the rapid equilibration between concentrations in plasma and at the effect site. Unlike the finding for other nondepolarizing muscle relaxants, the laryngeal muscles are not resistant to rapacuronium.

Improving the Design of Muscle Relaxant Studies: Stabilization Period and Tetanic Recruitment

Background The results from studies of muscle relaxants show wide variations among institutions. The authors hypothesized that some of this variability could be explained by differences in duration of nerve stimulation before drug administration (stabilization period). Methods Train‐of‐four stimulation was applied every 12 s to both ulnar nerves and adductor pollicis twitch tension was measured in anesthetized participants given 30 micro gram/kg vecuronium. In phase 1, the stabilization period was > 30 min for both extremities. In phases 2–4, stabilization period was 20 min for one extremity and 2 min for the other. In addition, in phase 3, a 2‐s 50‐Hz tetanus initiated the 2‐min stimulation period; in phase 4, duration of tetanus was 5 s. Twitch recovery was recorded until stable for more than 15 min. Time to 25% recovery (clinical duration) was calculated based on two indices: predrug and final (recovery) twitch tension. Values for onset and clinical duration were compared by paired parametric and nonparametric tests. Results In phase 1, predrug and recovery twitch tension were similar in each extremity, and onset and clinical duration did not differ between extremities, permitting paired comparisons in remaining studies. In phase 2, onset was more rapid with 20‐min of prestimulation. With 20‐min prestimulation, predrug and recovery twitch tension were similar; with 2‐min prestimulation, recovery twitch tension exceeded predrug values. When referenced to predrug twitch tension, clinical duration was shorter with 2‐min, than with 20‐min prestimulation. Initiating stimulation with 2‐s or 5‐s 50‐Hz tetani (phases 3, 4) abolished differences between extremities in onset and recovery. Conclusions With only train‐of‐four stimulation (no tetani), onset and clinical duration vary with duration of prestimulation, suggesting that a brief period of predrug stimulation is inadequate. However, lengthy prestimulation may be impractical in clinical studies. Tetanic stimulation for 2 or 5 s obviates the need for prolonged stabilization during studies of muscle relaxants.

The Magnitude and Time Course of Vecuronium Potentiation by Desflurane Versus Isoflurane

BACKGROUND Preliminary studies suggest that desflurane and isoflurane potentiate the action of muscle relaxants equally. However, variability between subjects may confound these comparisons. A crossover study was performed in volunteers on the ability of desflurane and isoflurane to potentiate the neuromuscular effect of vecuronium, to influence its duration of action, and on the magnitude and time course of reversal of potentiation when anesthesia was withdrawn. METHODS Adductor pollicis twitch tension was monitored in 16 volunteers given 1.25 MAC desflurane on one occasion, and 1.25 MAC isoflurane on another. In eight subjects, vecuronium bolus dose potency was determined using a two-dose dose-response technique; the vecuronium infusion dose requirement to achieve 85% twitch depression also was determined. Also in these subjects, the magnitude and time course of spontaneous neuromuscular recovery were determined when the anesthetic was withdrawn while maintaining a constant vecuronium infusion. In the other eight subjects, the time course of action of 100 micrograms/kg vecuronium was determined. RESULTS Vecuroniums ED50 and infusion requirement to maintain 85% twitch depression were 20% less during desflurane, compared to isoflurane, anesthesia; vecuronium plasma clearance was similar during the two anesthetics. After 100 micrograms/kg vecuronium, onset was faster and recovery was longer during desflurane anesthesia. When the end-tidal anesthetic concentration was abruptly reduced from 1.25 to 0.75 MAC, twitch tension increased similarly (approximately 15% of control), and time for the twitch tension to reach 90% of the final change was similar (approximately 30 min) with both anesthetics. Decreasing anesthetic concentration from 0.75 to 0.25 MAC increased twitch tension by 46 +/- 10% and 25 +/- 7% of control (mean +/- SD, P < 0.001) with desflurane and isoflurane, respectively; 90% response times for these changes were 31 +/- 10 min and 18 +/- 7 min (P < 0.05), respectively. CONCLUSIONS Desflurane potentiates the effect of vecuronium approximately 20% more than does an equipotent dose of isoflurane.

The effect of plasma cholinesterase activity on mivacurium infusion rates.

Although mivacurium is eliminated by plasma cholinesterase, previous investigations have revealed either no relationship or limited correlation between mivacurium infusion rates (IRs) and plasma cholinesterase activity.Assuming that such a relationship should exist, we used a novel approach to better demonstrate the relationship in humans. Fourteen isoflurane-anesthetized adults underwent standard neuromuscular monitoring. Mivacurium was then infused at 1.0 micro gram centered dot kg-1 centered dot min-1 until twitch tension stabilized. The IR was then adjusted, using the Hill equation, to produce approximately steady state 50% (n = 14) or 90% (n = 13) twitch depression. Using these values for IR and steady-state twitch depression, the IRs expected to produce 50% and 90% twitch depression (IR50 and IR90, respectively) were estimated by nonlinear regression. Both IR50 (r2 = 0.51, P < 0.005) and IR90 (r2 = 0.48, P < 0.01) were related to plasma cholinesterase activity; the coefficient of the Hill Equation didnot vary with plasma cholinesterase activity. We conclude that mivacurium IRs are, as expected, influenced by the activity of the enzyme responsible for its elimination. (Anesth Analg 1995;80:760-3)

Cumulative characteristics of atracurium and vecuronium. A simultaneous clinical and pharmacokinetic study.

BackgroundCumulative effects (Increased 25–75% recovery time with increasing dose) are evident with vecuronium but not with atracurium. Pharmacokinetic simulations suggest that vecuroniums cumulation occurs as recovery shifts from distribution to elimination whereas atracuriums recovery always occurs during elimination. The purpose of this study was to examine this pharmacokinetic explanation. MethodsWe assigned 12 volunteers to receive atracurium or vecuronium on three occasions during nitrous oxide-isoflurane anesthesia. Evoked adductor pollicis twitch tension was monitored. On occasion 1, the dose expected to produce 95% block (ED95) was estimated for each subject. On occasions 2 and 3, 1.2 or 3.0 multiples of ED95 were given as a bolus. Plasma was sampled for 128 min to determine muscle relaxant concentrations; pharmacodynamic modeling was used to determine effect-compartment drug concentrations (Ce). For each drug, recovery time, recovery phase half-life (rate of decrease in Ce during recovery), and Ce at 25% and 75% recovery were compared between doses. ResultsAtracuriums recovery time increased 2.4 ± 2.2 min (mean ± SD) with the larger dose, less than the Increase with vecuronium (8.2 ± 3.8 min). Atracuriums recovery phase half-life was 14.6 ± 1.7 and 20.1 ± 2.3 min with the small and large doses (P < 0.05); vecuroniums recovery phase half-life increased similarly from 13.5 ± 2.3 to 18.5 ± 5.0 min (P < 0.05). At 75% recovery, vecuroniums Ce decreased from 65 ± 18 ng/ml with the small dose to 55 ± 15 ng/ml with the large dose (P < 0.05). Assuming that neuromuscular junction sensitivity was constant, this difference could be explained by considering neuromuscular effects of vecuroniums metabolite, 3-desacetylvecuronium. ConclusionsAlthough vecuronium was cumulative (as predicted), atracurium was also slightly cumulative. Inconsistent with our hypothesis, recovery phase half-lives for both drugs Increased similarly between doses; therefore, differences In cumulation were not solely explained by pharmacokinetics of the muscle relaxant. It appears that 3-desacetyIvecuronium contributes to vecuroniums cumulative effect, even after usual clinical doses.

Edrophonium Increases Mivacurium Concentrations during Constant Mivacurium Infusion, and Large Doses Minimally Antagonize Paralysis

Background Mivacurium, a nondepolarizing muscle relaxant, is metabolized by plasma cholinesterase. Although edrophonium does not alter plasma cholinesterase activity, we have observed that doses of edrophonium that antagonize paralysis from other nondepolarizing muscle relaxants are less effective with mivacurium. We speculated that edrophonium might alter metabolism of mivacurium, thereby hindering antagonism of paralysis. Accordingly, we determined the effect of edrophonium on neuromuscular function and plasma mivacurium concentrations during constant mivacurium infusion. Methods We infused mivacurium to maintain 90% depression of adductor pollicis twitch tension and then gave edrophonium in doses ranging from 125-2,000 micro gram/kg without altering the mivacurium infusion. Peak twitch tension after edrophonium was determined to estimate the dose of edrophonium antagonizing 50% of twitch depression for antagonism of mivacurium; plasma cholinesterase activity and mivacurium concentrations before and after edrophonium were measured. Additional subjects were given 500 micro gram/kg edrophonium to antagonize continuous infusions of d-tubocurarine and vecuronium. Results With mivacurium, edrophonium increased twitch tension in a dose-dependent manner: the dose of edrophonium antagonizing 50% of twitch depression was 2,810 micro gram/kg. The largest dose of edrophonium (2,000 micro gram/kg) produced only 45 plus/minus 7% antagonism. Edrophonium, 500 micro gram/kg, antagonized mivacurium markedly less than it antagonized d-tubocurarine and vecuronium. Edrophonium increased plasma concentrations of the two potent stereoisomers of mivacurium 48% and 79%, these peaking at 1-2 min; plasma cholinesterase activity was unchanged. Conclusions Edrophonium doses that antagonize d-tubocurarine and vecuronium are less effective in antagonizing the neuromuscular effects of mivacurium during constant infusion. Edrophonium increases plasma mivacurium concentrations, partly or completely explaining its limited efficacy; the mechanism by which edrophonium increases mivacurium concentrations remains unexplained. Our results demonstrate that antagonism of mivacurium by edrophonium is impaired, and therefore we question whether edrophonium should be used to antagonize mivacurium.

The effect of neostigmine on twitch tension and muscle relaxant concentration during infusion of mivacurium or vecuronium.

Background An investigation suggested that neostigmine may not effectively antagonize mivacurium, presumably because neostigmine impairs mivacuriums metabolism. However, the effect of neostigmine on mivacuriums metabolism in vivo has not been reported. Therefore, the effect of neostigmine on neuromuscular function and plasma mivacurium concentrations during constant mivacurium infusion was determined.

Bioavailability of Intramuscular Rocuronium in Infants and Children

Background: Intramuscular rocuronium, in doses of 1,000 micro gram/kg in infants and 1,800 micro gram/kg in children, produces complete twitch depression in 5–6 min. To determine the rate and extent of absorption of rocuronium after intramuscular administration, blood was sampled at various intervals after rocuronium administration by both intramuscular and intravenous routes to determine plasma concentrations (Cp) of rocuronium. Methods: Twenty‐nine pediatric patients ages 3 months to 5 yr were anesthetized with N2 O and halothane. The trachea was intubated, ventilation was controlled, and adductor pollicis twitch tension was measured. When anesthetic conditions were stable, rocuronium (1,000 micro gram/kg for infants and 1,800 micro gram/kg for children) was injected either intramuscularly (in the deltoid muscle) or intravenously. Four venous plasma samples were obtained from each child 2–240 min after rocuronium administration. A mixed‐effects population pharmacokinetic analysis was applied to these values to determine bioavailability, absorption rate constant, and time to peak Cp with intramuscular administration. Results: With intramuscular administration, rocuroniums bioavailability averaged 82.6% and its absorption rate constant was 0.105 min sup ‐1. Simulation indicated that Cp peaked 13 min after rocuronium was given intramuscularly, and that 30 min after intramuscular administration, less than 4% of the administered dose remained to be absorbed from the intramuscular depot. Conclusions: After rocuronium is administered into the deltoid muscle, plasma concentrations peak at 13 min, and approximately 80% of the administered drug is absorbed systemically.