Although malignant hyperthermia after application of sevoflurane has been reported, little is known about its action on intracellular calcium homeostasis of skeletal muscle. The authors compared the effect of sevoflurane with that of isoflurane and halothane on Ca2+ release of mammalian sarcoplasmic reticulum and applied a novel method to quantify Ca2+ turnover in permeabilized skeletal muscle fibers.
Liquid sevoflurane, isoflurane, and halothane at 0.6 mM, 3.5 mM, and 7.6 mM were diluted either in weakly calcium buffered solutions with no added Ca2+ (to monitor Ca2+ release) or in strongly Ca2+ buffered solutions with [Ca2+] values between 3 nM and 24.9 [micro sign]M for [Ca2+]-force relations. Measurements were taken on single saponin skinned muscle fiber preparations of BALB/c mice. Individual [Ca2+]-force relations were characterized by the Ca2+ concentration at half-maximal force that indicates the sensitivity of the contractile proteins and by the steepness. Each force transient was transformed directly into a Ca (2+) transient with respect to the individual [Ca2+]-force relation of the fiber.
At 0.6 mM, single force transients induced by sevoflurane were lower compared with equimolar concentrations of isoflurane and halothane (P < 0.05). Similarly, calculated peak Ca2+ transients of sevoflurane were lower than those induced by equimolar halothane (P < 0.05). The Ca2+ concentrations at half maximal force were decreased after the addition of sevoflurane, isoflurane, and halothane in a concentration-dependent manner (P < 0.05).
Whereas sevoflurane, isoflurane, and halothane similarly increase the Ca2+ sensitivity of the contractile apparatus in skeletal muscle fibers, 0.6 mM sevoflurane induces smaller Ca2+ releases from the sarcoplasmic reticulum than does equimolar halothane.

Differential effects of sevoflurane, isoflurane, and halothane on Ca2+ release from the sarcoplasmic reticulum of skeletal muscle.

Background Our aim was to quantify human involuntary isometric skeletal muscle strength during anaesthesia with propofol, sevoflurane, or spinal anaesthesia using bupivacaine. Methods Thirty-three healthy patients undergoing anaesthesia for elective lower limb surgery were investigated. Twenty-two patients received a general anaesthetic with either propofol ( n =12) or sevoflurane ( n =10); for the remaining 11 patients spinal anaesthesia with bupivacaine was used. We used a non-invasive muscle force assessment system before and during anaesthesia to determine the contractile properties of the ankle dorsiflexor muscles after peroneal nerve stimulation (single, double, triple, and quadruple stimulation). We measured peak torques; contraction times; peak rates of torque development and decay; times to peak torque development and decay; half-relaxation times; torque latencies. Results Males elicited greater peak torques than females, medians 6.3 vs 4.4 Nm, respectively ( P =0.0002, Mann-Whitney rank-sum test). During sevoflurane and propofol anaesthesia, muscle strength did not differ from pre-anaesthetic values. During spinal anaesthesia, torques were diminished for single-pulse stimulation from 3.5 to 2.0 Nm ( P =0.002, Wilcoxon signed rank test), and for double-pulse from 7.6 to 5.6 Nm ( P =0.02). Peak rates of torque development decreased for single-pulse stimulation from 113 to 53 Nm s −1 and for double pulse from 195 to 105 Nm s −1 . Torque latencies were increased during spinal anaesthesia. Conclusions At clinically relevant concentrations, propofol and sevoflurane did not influence involuntary isometric skeletal muscle strength in adults, whereas spinal anaesthesia reduced strength by about 20%. Muscle strength assessment using a device such as described here provided reliable results and should be considered for use in other scientific investigations to identify potential effects of anaesthetic agents.

Effect of three anaesthetic techniques on isometric skeletal muscle strength

Malignant hyperthermia (MH) is an anesthetic-drug–induced, life-threatening hypermetabolic syndrome caused by abnormal calcium regulation in skeletal muscle. Often inherited as an autosomal dominant trait, MH has linkage to 30 different mutations in the RYR1 gene, which encodes a calcium-release–channel protein found in the sarcoplasmic reticulum membrane in skeletal muscle. All published RYR1 mutations exclusively represent single-nucleotide changes. The present report documents, in exon 44 of RYR1 in two unrelated, MH-susceptible families, a 3-bp deletion that results in deletion of a conserved glutamic acid at position 2347. This is the first deletion, in RYR1, found to be associated with MH susceptibility. MH susceptibility was confirmed among some family members by in vitro diagnostic pharmacological contracture testing of biopsied skeletal muscle. Although a single-amino-acid deletion appears to be a subtle change in the protein, the deletion of Glu2347 from RYR1 produces an unusually large electrically evoked contraction tension in MH-positive individuals, suggesting that this deletion produces an alteration in skeletal-muscle calcium regulation, even in the absence of pharmacological agents.

https://www.cell.com/ajhg/pdf/S0002-9297(07)61459-1.pdf

Single-amino-acid deletion in the RYR1 gene, associated with malignant hyperthermia susceptibility and unusual contraction phenotype.

When neuromuscular blocking agents (NMBA) were introduced into clinical practice in 1942, the event was called the "second revolution in anesthesia." Despite some significant side effects, NMBAs have remained in the anesthetists' repertoire, not at least because muscle relaxation has been claimed to allow or facilitate many surgical procedures. Aim of this literature review was to investigate the evidence for the use of NMBA as well as the optimum depth of neuromuscular blockade during laparoscopic surgery. Muscle relaxation may optimize laparoscopic operating conditions by preventing patient movement and achieving more intra-abdominal space for a given intra-abdominal insufflation pressure. In this context, deeper than normally maintained levels of neuromuscular blockade appear to be superior. However, the decision to utilize deeper than standard muscle relaxation should currently be based on a risk-benefit analysis for each individual patient. Thus good communication between surgeon and anesthetist remains crucial to achieve best outcomes.

Muscle Relaxation in Laparoscopic Surgery: What is the Evidence for Improved Operating Conditions and Patient Outcome? A Brief Review of the Literature.

Background: Desflurane is a weaker trigger of malignant hyperthermia than is halothane. There are very few data of the pathophysiologic background of this observation. Therefore, the authors' aim was to investigate the direct effect of desflurane on calcium release in skinned skeletal muscle fibers. Metbods: For the measurements, single saponin-skinned muscle fiber preparations of BALB/c mice were used. For Ca 2+ release experiments, liquid desflurane at 0.6 and 3.5 mM was applied to weakly calcium-buffered solutions with no added Ca 2+ . Desflurane was diluted in strongly Ca 2+ -buffered solutions, with [Ca 2+ ] between 3.0 and 24.9 μM for [Ca 2+ ]-force relations. Force transients were transformed into Ca 2+ transients based on the individual [Ca 2+ ]-force relations. As controls, 30 mM caffeine and equimolar sevoflurane were investigated in the same muscle fibers. Results: At 3.5 mM, desflurane induced peak force transients of 8 ± 4% (mean ± SD) of maximal Ca 2+ -activated force (T max ). These peak values were significantly smaller than those in the presence of 3.5 mM sevoflurane (24 ± 10% of T max , P < 0.05), and 4 or 5 times smaller than previously reported Ca 2+ -release-induced force transients by equimolar halothane. Calculated peak Ca 2+ transients derived from force transients and induced by 3.5 and 0.6 mM desflurane were significantly smaller than those induced by 30 mM caffeine. The [Ca 2+ ]-force relation was shifted by desflurane, resulting in a Ca 2+ -sensitizing effect. The maximal Ca 2+ -activated force was significantly increased by 0.6 mM desflurane in comparison with the control, with no added substance (P ≤ 0.05). Conclusion: Desflurane induces only slight Ca 2+ release in skinned skeletal muscle fibers.

Desflurane induces only minor Ca2+ release from the sarcoplasmic reticulum of mammalian skeletal muscle.

The aim of this study was to verify whether a relationship exists between neuroleptic malignant syndrome (NMS) and anaesthetic-induced malignant hyperthermia (MH) or not. The in vitro halothane-caffeine tests were performed on muscle tissue obtained from 32 patients with documented NMS episodes. The diagnosis of NMS relied on Levenson's criteria. The results, expressed in accordance with the criteria of the European MH Group, defined 29 subjects as MH non-susceptible. Three patients were classified as MH equivocal. These findings demonstrate the lack of any link between NMS and MH. Therefore, patients with a history of NMS are not likely to be at risk of developing MH and special measures against MH are not required for anaesthesia in these patients.

Absence de sensibilité à l'hyperthermie maligne peranesthésique chez 32 patients ayant développé un syndrome malin des neuroleptiques

Background Reports of the effects of halothane on isoform contractile proteins of striated muscles are conflicting. To determine whether halothane affects cardiac and skeletal contractile proteins differently, the authors examined the effects of two doses of halothane (0.44 and 1.26 mM, equivalent to 0.75 and 2.25 vol%, respectively) on the Calcium sup ++ sensitivity and maximal force in human skinned cardiac, type I (slow twitch), and type II (fast twitch) skeletal muscle fibers. Methods Left ventricular muscle strips and skeletal muscle biopsy specimens were obtained from eight and ten patients undergoing cardiac and orthopedic surgery, respectively. Sarcolemma and sarcoplasmic reticulum were destroyed with ethylene glycol bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid plus Brij 58. Calcium sup ++ sensitivity was studied by observing the isometric tension developed by skinned fibers challenged with increasing concentrations of Calcium sup ++. Muscle fiber type was determined in each skeletal fiber by the difference in strontium-induced tension measurements. Results Halothane shifted the Calcium sup ++ tension curves toward higher Calcium sup ++ concentrations and increased the Calcium sup ++ concentration for half-maximal activation in both cardiac and type I skeletal muscle fibers (from 1.96 micro Meter and 1.06 micro Meter under control conditions to 2.92 micro Meter and 1.71 micro Meter in presence of 0.75 vol% halothane, respectively) without changing the slope of this relationship (Hill coefficient). In contrast, no significant effect was observed in type II fibers. Halothane also decreased the maximal activated tension in the three groups of fibers with a lesser effect in type II fibers. Conclusions Halothane decreases Calcium sup ++ sensitivity and maximal force in human skinned cardiac and type I fibers at 20 degrees Celsius. It is concluded that the negative inotropic effects of halothane depend on contractile proteins isoforms.

Isoform-dependent effects of halothane in human skinned striated fibers.

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.

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

The purpose of this investigation was to compare the effects of halothane on malignant hyperthermia (MH) and normal isolated muscle bundle performance during isometric contraction and relaxation phases. Mechanical parameters were measured: peak tension (PT), time to peak tension (TPT) and positive peak of isometric tension derivative (+dP/dt max) characterized the contraction phase. Half-relaxation time (RT 1/2) and negative peak of isometric tension derivative (-dP/dt max) characterized the relaxation phase. The ratio R= (+dP/dt max) /(-dP/dt max) was used to study the coupling between contraction and relaxation under isometric condition. In normal muscle, halothane increased PT by nearly 40% without altering TPT. The +dP/dt max value increased concomitantly with the -dP/dt max values, thus no changes in R was observed. In MH muscle, PT was first potentiated (0.5-1.0 vol% halothane) and then depressed (2.0–3.0 vol% halothane). TPT and +dP/dt max were not altered whereas RT 1/2 increased progressively wit...

Effects of halothane on mechanical response of skeletal muscle from malignant hyperthermia susceptible patients.

Shortening velocity of skeletal muscle from humans with malignant hyperthermia susceptibility: effects of halothane

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