G. Haudecoeur

The association between the neuroleptic malignant syndrome and malignant hyperthermia

The neuroleptic malignant syndrome (NMS) is an uncommon but dangerous complication of treatment with neuroleptic drugs. A primary defect in skeletal muscle has been suggested in view of similarities in the clinical presentations of NMS and anaesthetic‐induced malignant hyperthermia (MH). The in vitro halothanecaffeine contracture tests are the most reliable method of identifying individuals susceptible to MH. The aim of this study was to define if a relationship exists between NMS and MH susceptibility. Hence, the in vitro halothane and caffeine contracture tests were performed on muscle tissue obtained from eight NMS, ten MH‐susceptible and ten control patients. The results, which are expressed in accordance with the criteria of the European MH Group, defined the eight NMS subjects as MH non‐susceptible. The response to halothane and caffeine exposure of skeletal muscle from NMS and control subjects was the same and significantly different from that of muscle from patients susceptible to MH. Furthermore, muscle from subjects in NMS and control group responded similarly to increasing concentrations of chlorpromazine. These results do not point towards an association between NMS and MH.

Halothane and isoflurane decrease calcium sensitivity and maximal force in human skinned cardiac fibers.

BackgroundReports of the direct effects of volatile anesthetics on cardiac myofibrils, studied in various mammalian species but not in humans, have conflicted. To determine whether volatile anesthetics directly affect cardiac contractile proteins in humans, we examined the effects of various equianesthetic doses of halothane (0.46, 0.83, and 1.23 mM, equivalent to 0.75, 1.50, and 2.25%, respectively) and isoflurane (0.63, 1.22, and 1.93 mM, equivalent to 1.15, 2.30, and 3.50%, respectively) on the Ca2+ sensitivity and maximal force in human skinned cardiac fibers. MethodsLeft ventricular muscle strips were obtained from seven patients undergoing cardiac surgery. Sarcolemma was disrupted with EGTA (ethylene glycol bis (β-aminoethyl ether)-N,N,N‘,N’-tetraacetic acid), and sarcoplasmic reticulum was destroyed with EGTA plus BRIJ 58 detergent. Ca2+ sensitivity was studied by observing the isometric tension developed by skinned fiber bundles challenged with solutions of increasing Ca2+ concentrations expressed in pCa (where pCa = -log10[Ca2+]). Maximal force was measured with a pCa 4.8 solution. ResultsBoth anesthetics shifted the pCa-tension curves toward higher Ca2+ concentrations and decreased pCa for half-maximal activation in a dose-dependent and reversible fashion (from 5.71 for control to 5.56 and 5.55 for 1 MAC halothane and isoflurane, respectively) without changing the slope of this relationship (Hill coefficient). No differences between agents were observed at equianesthetic concentrations. The two agents also decreased the maximal activated tension in a dose-dependent fashion (-27 and −28% vs. control for 2 MAC halothane and isoflurane, respectively). ConclusionsThe current study indicates that halothane and isoflurane decrease Ca2+ sensitivity and maximal force in human skinned cardiac fibers at 20°C. If these effects extend to higher temperatures, they may contribute to the negative inotropic effect of these agents.

Fiber-type caffeine sensitivities in skinned muscle fibers from humans susceptible to malignant hyperthermia.

BackgroundThe response to contracture tests may depend upon the relative proportion of muscle fiber types within the muscle specimen. To determine whether a difference in fiber-type caffeine sensitivities exists between malignant hyperthermia susceptible (MHS) and malignant hyperthermia-non-susceptible (MHN) skeletal muscle, we compared the fiber-type caffeine sensitivities in chemically skinned muscle fibers dissected from vastus lateralis muscle from 15 MHS and 16 MHN patients. MethodsMuscle fiber type was determined in each fiber by the difference in strontium-induced tension measurements and in 36 fibers, after contracture testing, by ATPase enzyme his-tochemistry. Caffeine sensitivity was defined as the threshold concentration inducing more than 10% of the maximal tension obtained with a calcium 1.6 × 10 2 HIM solution. ResultsSignificant difference in the mean (±SD) caffeine sensitivity was found between type I MHS fibers (2.63 ± 0.85 HIM) versus type II MHS fibers (3.47 ± 1.2 HIM) and between type I MHN fibers (5.89 ± 1.8 HIM) versus type II MHN fibers (10.46 ± 2.6 miu). The mean (±SD) caffeine sensitivities for a given muscle fiber type (I or II) were different between groups of MHS and MHN patients. Both type I and II MHS fibers had significantly lower caffeine sensitivities, and this increase in caffeine sensitivity was significantly smaller in type I than in type II fiber. ConclusionsThe current study indicates that a truly MHS patient cannot have a false-negative result solely related to abnormal type II fibers contained In a given muscle strip. Although the occurrence of a very high proportion of type I fibers in MHN human muscle could result in a false-positive contracture outcome, such an occurrence is expected to be rare.

Effects of Calcium-free Solution, Calcium Antagonists, and the Calcium Agonist BAY K 8644 on Mechanical Responses of Skeletal Muscle from Patients Susceptible to Malignant Hyperthermia

The purpose of this investigation was to determine if alteration in the function of the dihydropyridine receptor may in turn modify halothane-induced contractures in muscle bundles from patients susceptible to malignant hyperthermia (MH). The effects of Ca(2+)-free Krebs Ringer (KR) solution, 5 microM verapamil, 5 microM nifedipine, and 10 microM of the Ca2+ agonist BAY K 8644 on halothane-induced contracture were therefore investigated. The halothane-induced contracture was prevented in the absence of extracellular Ca2+ and significantly reduced in the presence of verapamil or nifedipine. BAY K 8644 significantly enhanced the 0.5-, 1.0-, and 1.5-vol % halothane-induced contracture in MH-susceptible muscle bundles. When BAY K 8644 was dissolved in Ca(2+)-free KR solution, no contracture was observed in MH-susceptible muscle bundles. These results on cut MH-susceptible human muscle bundles support the hypothesis that halothane-induced contracture in MH can be modified by the binding of Ca2+ agonists or antagonists to the dihydropyridine receptor. The role of Ca2+ entry phenomena remains unclear, but the results suggest that extracellular Ca2+ is required to reprime or to bind to some sites of the dihydropyridine receptors.

Is resting membrane potential a possible indicator of viability of muscle bundles used in the in vitro caffeine contracture test

In 22 patients susceptible to and 34 patients not susceptible to malignant hyperthermia, we examined which muscle conditions may influence the degree of sensitivity of skeletal muscle to the in vitro caffeine contracture test: predrug resting membrane potential, predrug twitch tension, and maximum contracture induced by 32 mM caffeine in two caffeine tests performed respectively at 30 and 75 min after biopsy. No differences in the measured variables were observed between the first and the second caffeine tests in the 34 patients susceptible to malignant hyperthermia. The first caffeine test was found to be positive in all of the 22 patients susceptible to malignant hyperthermia. However, in eight patients, the second caffeine test was negative and the muscle fibers were found to be significantly depolarized. Resting membrane potential was-73.4 ± 7.9 mV before the first caffeine test and-65.8 ± 8.8 mV before the second test. We suggest that when time-induced partial depolarization of malignant hyperthermia-susceptible fibers occurs, fibers may become less sensitive to caffeine.

Halothane induces calcium release from human skinned Masseter muscle fibers

BACKGROUND An increase in masseter muscle tone in response to halothane or succinylcholine anesthesia (or both) can be observed in healthy persons. Thus the authors compared the fiber-type halothane and succinylcholine sensitivities in human masseter and vastus lateralis muscles. METHODS Masseter and vastus lateralis muscle segments were obtained from 13 and 9 healthy persons, respectively. After chemical skinning of a single fiber and loading the sarcoplasmic reticulum with Ca++ 0.16 microM solution, halothane (0.5-4 vol% bubbled in the incubating solution), succinylcholine (0.1 microM to 10 mM), or both sensitivities were defined as the concentration inducing more than 10% of the maximum tension obtained by application of 16 microM Ca++ solution. The myofilament response to Ca++ was studied with and without halothane by observing the isometric tension of skinned masseter fibers challenged with increasing concentrations of Ca++. Muscle fiber type was determined by the difference in strontium-induced tension measurements. RESULTS A significant difference in halothane sensitivity was found between type 1 masseter fibers (0.6+/-0.2 vol%; mean +/- SD) versus type 1 (2.7+/-0.6 vol%) and type 2 vastus lateralis muscle (2.5+/-0.4 vol%). Succinylcholine did not induce Ca++ release by the sarcoplasmic reticulum. In the masseter muscle, 0.75 vol% halothane decreased the maximal activated tension by 40% but did not change the Ca++ concentration that yields 50% of the maximal tension. CONCLUSIONS The very low halothane threshold for Ca++ release from the masseter muscle usually could be counteracted by a direct negative inotropic effect on contractile proteins. However, halothane may increase the sensitivity of the sarcoplasmic reticulum Ca++ release to succinylcholine-induced depolarization, leading to an increase in masseter muscle tone.

Effect of Bay K 8644 on the Magnitude of Isoflurane and Halothane Contracture of Skeletal Muscle from Patients Susceptible to Malignant Hyperthermia

Isoflurane has a lesser ability than halothane to induce contracture in malignant hyperthermia (MH) muscle in vitro. This does not necessarily imply that isoflurane is not as potent an MH trigger as halothane in vivo. A hypothesis was tested that in vitro treatment with Bay K 8644, an activator of both the dihydropyridine receptors as well as the sodium channels of the T-tubules, potentiates isoflurane-induced MH-susceptible skeletal muscle contracture. In addition to the usual halothane-caffeine test, other muscle bundles were exposed to 10 microM Bay K 8644-halothane and equipotent anesthetic concentrations (expressed in multiple minimum alveolar concentration [MAC]) of isoflurane either alone or combined with Bay K 8644. In 14 MH-susceptible muscle bundles, the mean maximum contracture induced by 2 MAC isoflurane was 0.20 +/- 0.22 g (mean +/- SD), and this value was significantly less than that obtained with 2 MAC halothane (0.68 +/- 0.40 g). Bay K 8644 did not induce muscle contracture on its own but consistently enhanced both the 0.5 MAC isoflurane and halothane to the same maximal isometric tension (1.09 +/- 0.35 g and 1.11 +/- 0.37 g, respectively). Such an effect was not observed in the MH-nonsusceptible group. Under the conditions of this in vitro study, 0.5 MAC isoflurane appears to be as potent as halothane in inducing muscle contracture in skeletal muscle bundles from individuals susceptible to MH.

Effects of veratridine on mechanical responses of human malignant hyperthermic muscle fibers

Background: To determine if alteration in the function of the sodium channel may in turn modify halothane‐induced changes in mechanical responses of muscle bundles from patients susceptible to malignant hyperthermia (MH).

Diltiazem and nifedipine reduce thein vitro contracture response to halothane in malignant hyperthermia-susceptible muscle

The effects of diltiazem (1 μM) and nifedipine (I μM) were examined separately on the in vitrohalothane tests for malignant hyperthermia (MH) susceptibility. Eighteen patients with MH susceptibility were diagnosed as MH-susceptible (MHS) according to the protocol of the European MH Group. In addition, halothane tests were carried out in the presence of either diltiazem (ten patients) or nifedipine (eight patients). These two calcium channel blockers significantly reduced the halothane contracture. Furthermore, in five of the ten MHS patients tested in the presence of diltiazem as well as in five of the eight MHS patients tested in the presence of nifedipine the halothane contracture test could be classified as negative. It is concluded that the presence of clinical concentrations of either diltiazem or nifedipine in the muscle bath affects the in vitrodiscrimination for MH susceptibility to halothane.RésuméLes effets du diltiazem (1 μM) et de la nifedipine (1 μM) ont été étudiés separement sur le test halothane in vitrode depistage de l’hyperthermie maligne (HM). Des lambeaux musculaires provenant de dix huit patients sensibles à l’HM ont été testes suivant le protocole del’« European MH Group ». Le test à l’halothane à été realise seul, puis en présence de diltiazem (dix patients) ou de nifédipine (huit patients). Le pretraitement des lambeaux musculaires au diltiazem classe cinq des dix sujets susceptibles comme negatif à l’halothane. De meme cinq des huit lambeaux musculaires pretraités à la nifedipine classe ces sujets suceptibles comme negatif au test à i halothane. Il semble done que la présence de concentrations cliniques de diltiazem ou de nifedipine dans le liquide de perfusion affecte les resultats du test à l’halothane.

In Vitro Human Masseter Muscle Hypersensitivity: A Possible Explanation for Increase in Masseter Tone

To determine whether a difference in fiber-type caffeine and Ca2+ sensitivities exists between human masseter and vastus lateralis skeletal muscle, we compared the fiber-type caffeine sensitivities in chemically skinned muscle fibers from 13 masseter and 18 vastus lateralis muscles. Caffeine sensitivity was defined as the threshold concentration inducing > 10% of the maximal tension obtained after the fiber was loaded with a 1.6 x 10(-2) mM Ca2+ solution for 30 s. Significant difference in the mean caffeine sensitivity was found between type I masseter fibers [2.57 +/- 1.32 (SD) mM] vs. type I (6.02 +/- 1.74 mM) and type II vastus lateralis fibers (11.25 +/- 3.13 mM). Maximal Ca(2+)-activated force per cross-sectional area was significantly different between masseter and vastus lateralis fibers. However, the Ca2+ concentration corresponding to half-maximal tension (pCa50) was not significantly different between type I masseter (pCa50 5.9 +/- 0.02) and type I vastus lateralis muscle (pCa50 6.01 +/- 0.08). These results suggest that the increase in caffeine sensitivity of masseter muscle reflects the presence of a low reactivity threshold of the sarcoplasmic reticulum.