Matthias Paul

Are estimates of MAC reliable

Background Potency of inhaled anesthetics (minimum alveolar concentration [MAC]) is typically studied in humans using an “up–down” approach in which the (quantal) response to skin incision is assessed only once for each individual, so that each individual’s MAC is never determined. The authors examined the influence of interindividual variability and study design issues (e.g., the number of patients enrolled in a study) on the accuracy of MAC estimates. Methods The typical sequence of a MAC study was simulated. The authors varied and tested the impact of several factors: anesthetic concentration used to start a study; number of “crossovers” (successive patients having different responses to skin incision) to terminate a study; concentration increment between consecutive patients; interindividual variability; and “measurement error.” For each factor, simulations were replicated 500 times, and the resulting estimates were summarized. Results Starting an experiment below or above the “true” value led to slightly biased MAC estimates; in contrast, variability was underestimated with starting concentrations close to the true value. More than six crossovers improved MAC estimates minimally but increased variability estimates toward true values. A larger increment size affected MAC minimally and increased variability estimates toward true values. A larger interindividual variability led to more “outlier” estimates for MAC. Under many conditions, several of 500 replicates yielded MAC estimates that deviated more than 10% or even more than 25% from the “true” value. Conclusion Individual experiments may yield inaccurate MAC estimates. This inaccuracy is minimized as the number of crossovers increases; however, improvement diminishes as the number of crossovers exceeds six.

Propofol impairs the central but not the peripheral part of the motor system.

Propofol provides some degree of muscle relaxation. Previous studies have investigated the effects of propofol on either the central or peripheral parts of the motor system. In this study, we simultaneously assessed both central (spinal) and peripheral effects. In 15 patients, general anesthesia was induced and maintained with fentanyl and midazolam. Neuromuscular blocking drugs were not administered. To investigate the central portion of the motor system, we monitored spinal F waves, an electrophysiologic variable of alpha-motoneuron excitability. Direct electrophysiologic muscle responses (M waves) and mechanomyography were studied to detect the peripheral effects of propofol on neuromuscular transmission or muscle contraction strength. After baseline recordings, 3 IV boluses of propofol (2 times 1 mg/kg followed by 2 mg/kg) were administered at 5-min intervals. Mean F-wave amplitudes were significantly reduced compared with baseline measurements (mean +/- SD, 0.22 +/- 0.13 mV) after the first (0.13 +/- 0.08 mV; P < 0.05), second (0.08 +/- 0.09 mV; P < 0.05), and third (0.03 +/- 0.04 mV; P < 0.01) propofol injections. M-wave amplitudes and mechanomyography signals remained unchanged. Our data suggest that the central part, but not the peripheral part, of the motor system is impaired after bolus administration of propofol.

Characterization of the interactions between volatile anesthetics and neuromuscular blockers at the muscle nicotinic acetylcholine receptor.

Volatile anesthetics enhance the neuromuscular blockade produced by nondepolarizing muscle relaxants (NDMRs). The neuromuscular junction is a postulated site of this interaction. We tested the hypothesis that volatile anesthetic enhancement of muscle relaxation is the result of combined drug effects on the nicotinic acetylcholine receptor. The adult mouse muscle nicotinic acetylcholine receptor (&agr;2, &bgr;, &dgr;, &egr;) was heterologously expressed in Xenopus laevis oocytes. Concentration-effect curves for the inhibition of acetylcholine-induced currents were established for vecuronium, d-tubocurarine, isoflurane, and sevoflurane. Subsequently, inhibitory effects of NDMRs were studied in the presence of the volatile anesthetics at a concentration equivalent to half the concentration producing a 50% inhibition alone. All individually tested compounds produced rapid and readily reversible concentration-dependent inhibition. The calculated 50% inhibitory concentration values were 9.9 nM (95% confidence interval [CI], 8.4–11.4 nM), 43.4 nM (95% CI, 33.6–53.3 nM), 897 &mgr;M (95% CI, 699–1150 &mgr;M), and 818 &mgr;M (95% CI, 685–1001 &mgr;M) for vecuronium, d-tubocurarine, isoflurane, and sevoflurane, respectively. Coapplication of either isoflurane or sevoflurane significantly enhanced the inhibitory effects of vecuronium and d-tubocurarine, especially so at small concentrations of NDMRs. Volatile anesthetics increase the potency of NDMRs, possibly by enhancing antagonist affinity at the receptor site. This effect may contribute to the clinically observable enhancement of neuromuscular blockade by volatile anesthetics.

The Potency of New Muscle Relaxants on Recombinant Muscle-Type Acetylcholine Receptors

We studied the inhibition of fetal (&ggr;-nAChR) and adult (&egr;-nAChR) muscle-type nicotinic acetylcholine receptors by the two new nondepolarizing muscle relaxants (NDMRs) rocuronium and rapacuronium, the metabolite 3-desacetyl rapacuronium (Org 9488), and five other, longer-used NDMRs (pancuronium, vecuronium, mivacurium, d-tubocurarine, and gallamine). Receptors were expressed in Xenopus laevis oocytes by cytoplasmic injection of subunit complementary RNAs. Functional channels were activated with 10 &mgr;M acetylcholine, alone or in combination with various concentrations of the NDMRs. Currents were recorded with a whole-cell two-electrode voltage clamp technique. All NDMRs reversibly inhibited acetylcholine-activated currents in a dose-dependent fashion. Potencies of rapacuronium and Org 9488 were not statistically different at either &ggr;-nAChR (half-maximal response = 58.2 and 36.5 nM, respectively) or &egr;-nAChR (half-maximal response = 80.3 and 97.7 nM, respectively). The rank order of potencies at the &egr;-nAChR (pancuronium > vecuronium ∼ mivacurium > rocuronium ∼ d-tubocurarine > rapacuronium ∼ Org 9488 > gallamine) correlated highly with the clinical doses needed to produce 50% twitch depression at the adductor pollicis muscle in adults. Neuromuscular blockade by rapacuronium may be enhanced by its metabolite Org 9488. Different drug-receptor affinities of the tested NDMRs contribute to the differences in clinical dose requirements of these drugs needed to achieve appropriate muscle relaxation.

Antiemetics of the 5-hydroxytryptamine 3A antagonist class inhibit muscle nicotinic acetylcholine receptors.

Antagonists of the serotonergic 5-hydroxytryptamine 3A receptor (5-HT3AR) and muscle nicotinic acetylcholine receptors (nAChR) are widely used in anesthesia practice. Both 5-HT3AR and nAChR are ligand-gated ion channels with known pharmacological overlap between some of their agonists and antagonists. We studied the actions of clinically used 5-HT3AR antagonist antiemetics and nondepolarizing muscle blockers on ionic currents elicited by the activation of mammalian 5-HT3AR and muscle nAChR, expressed in Xenopus laevis oocytes. Currents were recorded using a whole-cell two-electrode voltage clamp technique. Dolasetron, ondansetron, and granisetron reversibly inhibited 5-HT3AR function at nanomolar concentrations with 50% inhibitory concentrations (IC50) of 11.8, 6.4, and 0.2 nM; the rank order of inhibition correlated well with their clinical antiemetic potencies. The principal metabolite of dolasetron, hydrodolasetron, was 40 times more potent than the parent compound on 5-HT3AR (IC50 = 0.29 nM). The potency of the nondepolarizing muscle blocker d-tubocurarine in blocking 5-HT3AR was similar to that of the antiemetics and significantly more than vecuronium and rapacuronium (IC50 = 11.4 nM, 18.9 &mgr;M, 60.5 &mgr;M). Conversely, ondansetron, dolasetron, and granisetron also reversibly inhibited nAChR currents in a dose-dependent manner with IC50s of 14.2, 7.8, and 4.4 &mgr;M for the adult nAChR and 16.0, 18.6, and 13.9 &mgr;M for the embryonic nAChR. Again, hydrodolasetron showed significantly (10 times) more inhibitory potency on the adult nAChR than the parent compound dolasetron. These results indicate that drugs that target specific ligand-gated ion channels may also affect other ion channel types.

Isobolographic analysis of non-depolarising muscle relaxant interactions at their receptor site

Administration of certain combinations of non-depolarising muscle relaxants produces greater than expected neuromuscular blockade. Synergistic effects may be explained by drug interactions with the postsynaptic muscle nicotinic acetylcholine receptor. To investigate this hypothesis, the adult mouse muscle nicotinic acetylcholine receptor (alpha(2)beta delta epsilon) was heterologously expressed in Xenopus laevis oocytes and activated by the application of acetylcholine (10 microM). The effects of five individually applied muscle relaxants and six combinations of structurally similar and dissimilar compounds were studied. Drug combinations containing equipotent concentrations of two agents were tested and dose-response curves were determined. All compounds tested alone and in combination produced rapid and readily reversible, concentration-dependent inhibition. Isobolographic and fractional analyses indicated additive interactions for all six tested combinations. These findings suggest that synergistic neuromuscular blocking effects, observed for the administration of certain combinations of muscle relaxants, do not result from purely postsynaptic binding events at the muscle nicotinic acetylcholine receptor, but rather from differential actions on pre- and postsynaptic sites.

Pharmacodynamic modeling of muscle relaxants: effect of design issues on results.

Background Pharmacodynamic studies of muscle relaxants use different dosing regimens (such as administration by bolus vs. infusion and doses that produce complete vs. incomplete paralysis). The authors used published data to evaluate the effect of modeling assumptions on pharmacodynamic estimates. Methods The authors used a pharmacokinetic–pharmacodynamic dataset in which patients received cisatracurium, 75 or 300 &mgr;g/kg (1.5 or 6 × ED95), to generate plasma concentration (Cp) and twitch depression (effect) curves. They then evaluated the impact of the following: assuming that Cp decreased monotonically versus increasing initially before decreasing monotonically; misrecording effect data by 6 s or less; and doses targeting incomplete versus complete paralysis. Parameters evaluated were the steady state Cp depressing twitch tension 50% (C50) and the rate constant for equilibration between plasma and effect site concentrations (ke0). Results With the large dose, increasing the time at which Cp peaked from 0.0 to 1.5 min decreased C50 and increased ke0 markedly; with the small dose, changes in both were small. Misrecording the timing of effect had a larger impact with the large dose compared with the small dose. Doses smaller than ED50 or those producing prolonged, complete twitch depression yielded biased and variable estimates. Conclusion The erroneous assumption that Cp decreases monotonically after bolus administration affects accuracy of pharmacodynamic estimates with doses producing rapid, complete twitch depression. Other errors (e.g., misrecording the time of drug administration) impact on pharmacodynamic estimates, particularly with large doses. The authors’ findings suggest that investigators performing neuromuscular (and other) pharmacodynamic studies should carefully consider the impact of study design on their parameter estimates.

Different F-wave recovery after neuromuscular blockade with pancuronium and mivacurium.

We performed this study to assess the recovery period after neuromuscular blockade by electromyographic F-wave analysis, a method that supplies more information about more proximal parts of the motor system than conventionally used methods, e.g., mechanomyography (MMG). In 20 neurosurgical ASA physical status I or II patients anesthesia was induced and maintained with IV fentanyl and midazolam. Patients were randomly assigned to receive either 0.25 mg/kg mivacurium (MV group, n = 10) or 0.1 mg/kg pancuronium (PC group, n = 10) intraoperatively. MMG monitoring of the adductor pollicis muscle was performed continuously. F waves were recorded at the abductor pollicis muscle of the contralateral hand at train-of-four (TOF) ratios of 0.1, 0.25, 0.5, 0.7, 0.75, 0.8, 0.85, 0.9, and 0.95. Recovery of F-wave amplitudes after neuromuscular blockade with pancuronium was significantly slower compared with mivacurium (P = 0.004) during the clinically important recovery period defined by MMG TOF ratios from 0.7 to 0.95. This electrophysiologic finding suggests a differential recovery of the motor system after administration of pancuronium and mivacurium not detected by MMG.