MH Non-susceptible Research Articles

A Stressful Question ‐ How Does 3′ 5′ cyclic adenosine monophosphate Signaling Affect Oxygen Metabolism Within Malignant Hyperthermia Susceptible (MHS) B‐lymphocytes?

BackgroundEven though the MHS trait is inherited by an autosomal dominant pattern, the variable penetrance and symptom presentation suggest involvement of oligogenic or post‐translational modifications. Since malignant hyperthermia (MH) includes hypermetabolic pathologies as its defining characteristics, the metabolic pathways offer biomarker targets which may segregate with the MHS phenotype.ProblemIdentifying the malignant hyperthermia susceptible (MHS) trait using pathogenic mutations has limitations. Causative mutations within the ryanodine receptor type I (RYR1),the SH3 and cysteine rich domain 3 (STAC3),or the (CACNA1S), voltage dependent calcium channel, alpha‐1s subunit genes account for only 50‐86% of subjects diagnosed with MH.HypothesisThe adrenergic agonist norepinephrine (NOR) and the membrane permeable 3′,5′ cyclic adenosine monophosphate (cAMP) analog, adenosine 3ʹ,5ʹ‐cyclic monophosphate, 8‐bromo‐, sodium salt, (8Br‐cAMP‐Na) will significantly alter oxygen metabolism between human MHS and MH non‐susceptible (MHN) b‐lymphocyte groups.MethodsMHN and MHS cells (8.5x104 and 3.7 x104 cells/well, respectively), were treated with NOR 1μM, or 10μM 8Br‐cAMP‐Na, for 1 hr. Electron transport chain inhibitors were sequentially added to form a bioenergetic profile. The Seahorse Xfe96 AnalyzerTM analyzed the oxygen consumption rate (OCR, pmol/min/cells) to calculate the basal and maximal OCR and the spare respiratory capacity (SRC). This value quantifies the metabolic ability of the cell to respond to an energetic demand.ResultsWhen compared to the naive MHN group, 8Br‐cAMP‐Na decreased the MHN SRC by 48%, p <.001. In contrast, the SRC increased 67%, p< .01, within the 8Br‐cAMP‐Na MHS group vs the MHS naive group. 1μM NOR produced similar SRC changes within each group. The SRC decreased by 22% ,p <.05, and increased by 35%, p >.05, within the NOR MHN and MHS groups, respectively (n = 4‐12 wells/group).ConclusionThe intracellular cAMP signaling affect the oxygen metabolism differently within MHN and MHS groups during adrenergic stress. The cAMP pathways contributing to a subclinical hypermetabolic response need further research. The adrenergic signaling may “prime” the conditions for an MH crisis until a specific metabolic threshold is obtained. The MHN group compensates for the increased metabolism and does not reach a thresh hold.DisclaimersThe opinions and assertions expressed herein are those of the author(s) and do not necessarily reflect official policy or position of the Uniformed Services University or the Department of Defense.This work was prepared by a military or civilian employee of the US Government as part of the individual’s official duties and therefore is in the public domain and does not possess copyright protection (public domain information may be freely distributed and copied; however, as a courtesy it is requested that the Uniformed Services University and the authors be given an appropriate acknowledgement).The protocol DBS.2019.008, was reviewed and approved by the USU Institutional Review Board, in accordance with all applicable Federal regulations governing the protection of humans in research.

In vitro effects of levosimendan on muscle of malignant hyperthermia susceptible and non-susceptible swine

BackgroundThe calcium sensitizer levosimendan is increasingly used to improve hemodynamics in patients with acutely decompensated heart failure. By binding to cardiac troponin C the conformation of the calcium-troponin C complex is stabilized, which leads to acceleration of actin-myosin crossbrigde formation and increased force generating capacity of muscle fibers. Besides indications in cardiac failure, beneficial effects of levosimendan in skeletal muscle disorders are currently evaluated. The aim of this study was to investigate differential effects of levosimendan on skeletal muscle of pigs with and without susceptibility to malignant hyperthermia (MH) in order to identify possible risks of this emerging drug for patients with predisposition to MH.MethodsMuscle bundles of 17 pigs (9 MH susceptible (MHS); 8 MH non-susceptible (MHN)) were excised under general anesthesia and examined in the tissue bath with increasing concentrations of levosimendan (0.065; 0.125; 0.5; 1.0; 10 and 50 μg/ml). Baseline tension and twitch force were monitored continuously. Data are presented as median and interquartile range. Statistical evaluation was performed using D’Agostino & Pearson test for normal distribution and student’s t test and 2-way ANOVA for differences between the groups. P < 0.05 was considered significant.ResultsThere were no differences between the groups concerning length, weight, initial twitch force and pre-drug resting tension of the investigated muscle strips. After an initial decrease in both groups, twitch amplitude was significantly higher in MHN (− 3.0 [− 5.2–0.2] mN) compared to MHS (− 7.5 [− 10.8- -4.5] mN) (p = 0.0034) muscle at an applied levosimendan concentration of 50 μg/ml. A marked increase in resting tension was detected following levosimendan incubation with 50 μg/ml in MHS muscle bundles (3.3 [0.9–6.1] mN) compared to MHN (− 0.7 [− 1.3–0.0] mN) (p < 0.0001).ConclusionsThis in vitro investigation revealed the development of significant contractures in muscle bundles of MHS pigs after incubation with levosimendan. However, the effect appeared only at supra-therapeutic concentrations and further research is needed to determine the impact of levosimendan on MHS individuals in vivo.

Effect of caffeine on intrinsic mechanical properties of normal and malignant hyperthermia-susceptible muscle.

Malignant hyperthermia (MH) is a potentially lethal anesthesic complication. Pathological symptoms develop after exposure to triggering substances. It remains uncertain whether cellular alterations pre-exist. Mechanical properties of isolated muscle bundles were examined before and after exposure to a triggering substance. With prior written consent, muscle bundles of 12 MH-susceptible (MHS) and 56 MH-nonsusceptible (MHN) individuals were examined before and after exposure to incremental doses of caffeine. Mechanical properties (baseline tension, peak tension, time to peak tension, and relaxation time) were measured. Contraction and relaxation derivatives and contraction-relaxation coupling were calculated and analyzed. Mechanical properties were not different between the groups before caffeine application. Caffeine increased peak tension in both groups and baseline tension only in MHS muscle bundles; relaxation time/derivative and contraction-relaxation coupling were prolonged. Cellular changes seen in MH are not pre-existing. Exposure to triggering substance impairs relaxation in MHS muscle.

Ondansetron-Induced Muscular Contractures in Malignant Hyperthermia-Susceptible Individuals

The 5-HT(3)-receptor antagonist ondansetron, commonly used to treat nausea and vomiting, was suspected of triggering malignant hyperthermia (MH) when a 5-year-old boy died after receiving a therapeutic dose of ondansetron. To evaluate a possible influence of ondansetron on the onset of MH, we investigated its effect on muscle specimens of MH-susceptible (MHS) and MH-nonsusceptible (MHN) individuals in vitro. Muscle bundles of 6 MHS and 10 MHN patients were incubated in a tissue bath with ondansetron at increasing concentrations (0.1 to 300 μg/mL). Changes in resting tension and twitch height were monitored continuously. Data are reported as median and interquartile range; Mann-Whitney U test for differences between the groups (P < 0.05). Weight, length, initial resting tension, and twitch height of the muscle bundles did not significantly differ between the investigated groups. An increasing twitch amplitude after ondansetron application was observed in both groups. However, contractures developed only in MHS but not in MHN muscle at ondansetron concentrations of 50 μg/mL (MHS 2.5 [2.1 to 4.0] vs. MHN 0 [0 to 0] mN) and 100 μg/mL (18.0 [11.8 to 22.8] vs 0 [0 to 0] mN). At 300 μg/mL ondansetron, a muscular response was also observed in MHN (23.3 [20.1 to 40.1] vs 1.8 [0.3 to 4.9] mN). Ondansetron induced contractures in skeletal muscle bundles in vitro. The effect was significantly higher in MHS than in MHN muscle. Because the necessary concentration of ondansetron exceeded the therapeutic plasma levels by a minimum of 500 times, a trigger potency in vivo seems unlikely.

Succinylcholine in malignant hyperthermia: Evaluation of a novel in vivo model

Malignant hyperthermia (MH) is a potentially lethal anesthetic complication characterized by muscle hypermetabolism and generalized rigor. The exact mechanism of succinylcholine as an MH trigger cannot be examined in existing in vitro models. Therefore, a novel in vivo model was used to examine the metabolic response to succinylcholine. With institutional review board approval, 6 MH susceptible (MHS) and 6 MH non-susceptible (MHN) pigs were anesthetized with hemodynamic and systemic metabolic monitoring. Microdialysis catheters were placed intramuscularly. After equilibration, succinylcholine, halothane, and Ringer solution were injected. Lactate was measured in the dialysate and statistically analyzed by Mann-Whitney U-test (significance level P < 0.05). Hemodynamic and systemic metabolic parameters were not different between the groups throughout the experiment. In the MHS pigs, halothane induced a significant increase of lactate. In MHN pigs, no substance induced a reaction. Halothane, but not succinylcholine, induced a hypermetabolic reaction in this model. Therefore, the role of succinylcholine as an MH trigger remains questionable.

Novel missense mutations and unexpected multiple changes of RYR1 gene in 75 malignant hyperthermia families

Malignant hyperthermia (MH) is an autosomal dominant pharmacogenetic disorder of skeletal muscle characterized by disturbance of intracellular calcium homeostasis in the sarcoplasmic reticulum. Mutations of the ryanodine receptor 1 (RYR1) gene account for most cases, with some studies claiming up to 86% of mutations in this locus. However, RYR1 gene is large and variants are common even in the normal population. We examined 54 families with MH susceptibility and 21 diagnosed with equivocal MH. Thirty-five were selected for an anesthetic reaction, whereas the remainder for hyperCKemia. In these, we studied all 106 exons of the RYR1 gene. When no mutation was found, we also screened: sodium channel voltage-gated, type IV alpha subunit (SCN4A), calcium channel voltage-dependent, L type, alpha 1S subunit (CACNA1S), and L-type voltage-gated calcium channel alpha 2/delta-subunit (CACNL2A). Twenty-nine different RYR1 mutations were discovered in 40 families. Three other MH genes were tested in negative cases. Fourteen RYR1 amino acid changes were novel, of which 12 were located outside the mutational 'hot spots'. In two families, the known mutation p.R3903Q was also observed in malignant hyperthermia-nonsusceptible (MHN) individuals. Unexpectedly, four changes were also found in the same family and two in another. Our study confirms that MH is genetically heterogeneous and that a consistent number of cases are not due to RYR1 mutations. The discordance between in vitro contracture test status and the presence of a proven causative RYR1 mutation suggests that the penetrance may vary due to as yet unknown factors.

Intramuscular injection of malignant hyperthermia trigger agents induces hypermetabolism in susceptible and nonsusceptible individuals

A new minimally invasive metabolic test for the diagnosis of susceptibility for malignant hyperthermia measuring intramuscular p(CO(2)) and lactate following local application of caffeine and halothane in humans was recently proposed. The present study tested the hypothesis that a more simplified test protocol allows a differentiation between malignant hyperthermia susceptible (MHS) and malignant hyperthermia nonsusceptible (MHN) and control individuals. With approval of the local ethics committee and informed consent, microdialysis and p(CO(2)) probes with attached microtubing were placed into the lateral vastus muscle of six MHS, seven MHN and seven control individuals. Following equilibration, boluses of 500 microl caffeine 80 mmol l(-1) and halothane 10 vol% dissolved in soybean oil were injected locally. p(CO(2)) and lactate were measured spectrophotometrically. The maximal rate of p(CO(2)) increase was significantly higher in MHS than in MHN and control individuals following application of halothane and caffeine, respectively. Intramuscular caffeine injection leads to a significantly higher increase of local lactate levels in MHS than in MHN and control individuals, whereas halothane increased local lactate levels in all investigated groups. Haemodynamic and systemic metabolic parameters did not differ between the investigated groups. Local caffeine and halothane injection increased intramuscular metabolism in MHS individuals significantly more than in the two other groups. In contrast to previous investigations, direct injection of the concentrations of halothane described here increased lactate and p(CO(2)) even in MHN skeletal muscle.

An In-Vivo Metabolic Test for Detecting Malignant Hyperthermia Susceptibility in Humans: A Pilot Study

In vitro contracture testing to diagnose malignant hyperthermia (MH) susceptibility requires a muscle biopsy, which may be associated with severe side effects for the patient. After investigation of several different protocols, we present a less invasive metabolic test that involves IM injection of caffeine and halothane, and subsequent measurement of interstitial lactate to differentiate between MH susceptible (MHS) and MH non-susceptible (MHN) individuals. Two microdialysis probes with attached microtubing for trigger injection were inserted into the lateral vastus muscle of eight previously diagnosed MHS patients (representing three genetic variants Gly2434Arg, Thr2206Met, and Arg614Cys), seven MHN patients, and seven control individuals. After equilibration and lactate baseline recording, a single bolus of 200 muL caffeine 80 mM and a suspension of 200 muL halothane 4%V/V in soy bean oil (triggers) were injected locally. Lactate was measured spectrophotometrically. Data are presented as medians and interquartile ranges. Although baseline lactate values were similar in the investigated groups before trigger injection, caffeine increased local lactate in MHS patients significantly more (2.0 [1.8-2.6] mM) than in MHN (0.8 [0.6-1.1] mM) or in control individuals (0.8 [0.6-0.8 mM]). Similarly, halothane lead to a significant lactate increase in MHS compared to MHN and control individuals (8.6 [3.7-8.9] mM vs 0.9 [0.5-1.1] mM and 1.7 [0.9-2.3] mM, respectively). However, a relevant increase of lactate was observed in one MHN and in two control individuals. Systemic hemodynamic and metabolic variables did not differ between the investigated groups. Metabolic monitoring of IM lactate after local caffeine and halothane injection may allow less invasive testing to detect MH susceptibility, without systemic side effects.

Enhanced response to caffeine and 4-chloro-m-cresol in malignant hyperthermia-susceptible muscle is related in part to chronically elevated resting [Ca2+]i

Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic syndrome caused by exposure to halogenated volatile anesthetics and/or depolarizing muscle relaxants. We have measured intracellular Ca(2+) concentration ([Ca(2+)](i)) using double-barreled, Ca(2+)-selective microelectrodes in myoballs prepared from skeletal muscle of MH-susceptible (MHS) and MH-nonsusceptible (MHN) swine. Resting [Ca(2+)](i) was approximately twofold in MHS compared with MHN quiescent myoballs (232 +/- 35 vs. 112 +/- 11 nM). Treatment of myoballs with caffeine or 4-chloro-m-cresol (4-CmC) produced an elevation in [Ca(2+)](i) in both groups; however, the concentration required to cause a rise in [Ca(2+)](i) elevation was four times lower in MHS than in MHN skeletal muscle cells. Incubation of MHS cells with the fast-complexing Ca(2+) buffer BAPTA reduced [Ca(2+)](i), raised the concentration of caffeine and 4-CmC required to cause an elevation of [Ca(2+)](i), and reduced the amount of Ca(2+) release associated with exposure to any given concentration of caffeine or 4-CmC to MHN levels. These results suggest that the differences in the response of MHS skeletal myoballs to caffeine and 4-CmC may be mediated at least in part by the chronic high resting [Ca(2+)](i) levels in these cells.

Contractures in skeletal muscle of malignant hyperthermia susceptible patients after in vitro exposure to sevoflurane.

Sevoflurane, a potent inhalational anaesthetic agent that is structurally similar to halothane, has some favourable characteristics, but may also be able to trigger malignant hyperthermia (MH) in susceptible patients. The diagnosis of malignant hyperthermia susceptibility relies on the in vitro contracture test on skeletal muscle. The present study was undertaken to investigate whether exposure to sevoflurane of muscles of malignant hyperthermia susceptible (MHS) patients would also cause an abnormal contracture. Muscle fascicles obtained from three MHS patients, one malignant hyperthermia non-susceptible (MHN) patient, two control patients and one malignant hyperthermia equivocal (MHE) patient were exposed to sevoflurane instead of halothane in the in vitro contracture test, carried out according to the protocol of the European Malignant Hyperthermia Group. The muscle fascicles were surplus to diagnostic requirements. Sevoflurane concentrations in the testbath were measured using a headspace gas chromatographic technique. The kinetics of sevoflurane concentration in the testbath were similar to those of halothane. An in vitro contracture response of 2 mN or more was seen in all four MHS/MHE patients with sevoflurane but not in the three control/MHN patients. The magnitude of muscle contracture in the sevoflurane test was less than in the conventional halothane test at comparable testbath concentrations. Sevoflurane can trigger an abnormal contracture in human muscle in vitro. This is indicative of malignant hyperthermia susceptibility. Exposure to sevoflurane should be avoided in patients thought to be susceptible to malignant hyperthermia.

Attenuation of serotonin-induced contractures in skeletal muscle from malignant hyperthermia-susceptible patients with dantrolene.

Porcine malignant hyperthermia (MH) can be triggered by administration of certain serotonin2 receptor agonists. Pretreatment with dantrolene completely abolished serotonin-induced MH. The purpose of this study was to investigate the effects of the serotonin2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in skeletal muscle specimens from MH-susceptible (MHS) and MH-nonsusceptible (MHN) patients following pretreatment with dantrolene. We used muscle specimens surplus to diagnostic requirements from 12 MHS and 13 MHN patients in this study. In the first experiment, DOI 0.02 mM was added to the organ bath. In the second experiment, muscle specimens were preincubated with dantrolene 0.5 microM or 1.0 microM, respectively, for 10 min before DOI 0.02 mM was administered. Administration of DOI 0.02 mM induced contractures in muscle specimens from MHS and MHN patients. Contracture development started significantly earlier in MHS than in MHN specimens. In MHS muscle the maximum contracture was significantly greater than in MHN. Pretreatment with dantrolene significantly delayed the start of contracture development in MHS muscles, whereas in MHN muscles no contractures were observed after dantrolene. The contracture maximum was significantly reduced in MHS. The acceleration of DOI-induced contracture development in skeletal muscle specimens from MHS patients indicates that an altered serotonin system might be involved in human MH. Dantrolene effectively delayed serotonin-induced contractures. Further investigations are needed to determine whether serotonin2 receptors of skeletal muscle from MHS subjects are altered in function or structure, or whether this response is a secondary phenomenon.

Effects of the 5-HT2 receptor antagonist ritanserin on halothane-induced increase of inositol phosphates in porcine malignant hyperthermia.

Recent studies have shown a significant increase of inositol phosphates (IPs) in skeletal muscle during episodes of halothane-induced malignant hyperthermia (MH) in pigs. After treatment with dantrolene and disappearance of MH crisis the IP concentrations returned to basal levels. In order to examine if the increase of IPs during halothane-induced MH may be related to an enhanced IP synthesis in response to activation of 5-HT2 (5-hydroxytryptamine) receptors, the effects of ritanserin, a selective 5-HT2 receptor antagonist, on IP levels were investigated. Biopsies of skeletal muscle of the hindlimbs were obtained in random order and IPs were determined in homozygous MH-susceptible (MHS) and MH-non-susceptible (MHN) swine in the following order: (1) basal, (2) after treatment with ritanserin (2.0 mg/kg), (3) after halothane challenge (3 vol% for 20 min). Basal concentrations of all IPs were higher in MHS than in MHN swine. Ritanserin did not cause any significant changes of IP levels compared to the basal concentrations in MHS and MHN pigs. In MHS pigs, ritanserin did not prevent a halothane-induced MH-crisis. After halothane challenge, 1,3,4-IP3, 1,3,4,6-IP4 and 1,3,4,5-IP4 levels were increased in MHS (during MH crisis) vs. basal concentrations, whereas no changes were found in MHN pigs. Since the increases of IP levels in MHS pigs during MH crisis found in the present study were comparable to those without pretreatment with ritanserin, shown by recent studies, it may be concluded that ritanserin does not prevent the increase of IPs during a halothane-induced MH. Thus, the present data indicate that increases of IP levels during halothane-induced MH in swine are due to other mechanisms than 5-HT mediated enhancement of IP synthesis.

Exclusion of defects in the skeletal muscle specific regions of the DHPR alpha 1 subunit as frequent causes of malignant hyperthermia.

The molecular defect predisposing to the majority of malignant hyperthermia (MH) cases is unknown, although various point mutations in the ryanodine receptor gene (RYR1) have been associated with susceptibility in...

Alterations of inositol polyphosphates in skeletal muscle during porcine malignant hyperthermia

Malignant hyperthermia (MH) may result from increased intracellular calcium concentrations. Increased 1,4,5-IP3 concentrations could mediate this increase in Ca2+. In this study we measured inositol polyphosphates in selectively bred MH susceptible (MHS) and MH non-susceptible (MHN) swine. MH crisis was induced by halothane challenge, and dantrolene was administered in order to measure inositol polyphosphates after MH reversal. Muscle biopsies of skeletal muscles of the hind limbs were obtained in random order and inositol polyphosphates determined by high pressure liquid chromatography using a metal dye detection method. Inositol polyphosphates were determined in three groups: (1) MHS vs MHN basal, (2) during MH crisis induced by halothane and (3) following treatment with dantrolene after halothane challenge. Clinical variables (P(_)VO2, P(-)VCO2, PE'CO2 and pH) indicated that MH was readily induced in MHS swine. Basal concentrations of all inositol polyphosphates were higher in MHS swine compared with MHN swine. After halothane challenge, 1,3,4-IP3, 1,3,4,6-IP4 and 1,3,4,5-IP4 concentrations increased in MHS animals compared with the respective baseline values, whereas no changes in MHN animals could be detected. Dantrolene administration decreased inositol polyphosphate concentrations in MHS swine. MHN swine showed no changes in inositol polyphosphates after dantrolene. These findings indicate that inositol polyphosphates may be involved in metabolic changes after triggering and treatment of MH.

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

The 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-nonsusceptible (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. Muscle 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 histochemistry. Caffeine sensitivity was defined as the threshold concentration inducing more than 10% of the maximal tension obtained with a calcium 1.6 x 10(-2) mM solution. Significant difference in the mean (+/- SD) caffeine sensitivity was found between type I MHS fibers (2.63 +/- 0.85 mM) versus type II MHS fibers (3.47 +/- 1.2 mM) and between type I MHN fibers (5.89 +/- 1.8 mM) versus type II MHN fibers (10.46 +/- 2.6 mM). 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. The 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.

USE OF THE CALCIUM AGONIST BAY K 8644 FOR IN VITRO DIAGNOSIS OF SUSCEPTIBILITY TO MALIGNANT HYPERTHERMIA

We have studied the effects of the calcium agonist BAY K 8644 on the in vitro halothane test in 10 malignant hyperthermia-susceptible (MHS), 12 MH "equivocal" to halothane (MHEh), 30 MH non-susceptible (MHN) and 10 control patients. BAY K 8644 potentiated the halothane-induced contracture in muscle strips from both MHS and MHEh patients. The drug produced a more obvious difference in contracture responses between the MHEh group compared with the MHN and control groups.

Influence of salbutamol on the in vitro muscle response to caffeine and halothane in malignant hyperthermia

In vitro contracture tests for susceptibility to malignant hyperthermia (MH) were performed with halothane and caffeine in 34 patients, according to the protocol of the European MH Group. Additional halothane and caffeine tests were performed in the presence of salbutamol 50 micrograms/l. Contractures after exposure to halothane were seen only in MH-susceptible (MHS) patients (n = 16), and were not changed by salbutamol. Salbutamol did not influence the caffeine dose-response curves in any of the groups (n = 14 in the MH-non-susceptible (MHN) group). The caffeine threshold concentration was significantly increased by salbutamol in the MHS group.

USE OF VECURONIUM AND DOXAPRAM IN PATIENTS SUSCEPTIBLE TO MALIGNANT HYPERTHERMIA

Neuromuscular blockade was obtained with vecuronium 108 micrograms kg-1 in 44 patients undergoing diagnostic muscle biopsy as part of an investigation of malignant hyperthermia (MH) susceptibility. At the termination of anaesthesia doxapram 1.43 mg kg-1 was given in an attempt to antagonize postoperative respiratory depression. Rectal, muscle and skin temperatures, blood lactate concentration and venous PCO2 were measured before, during and after anaesthesia. Susceptibility to MH was established by in vitro contracture tests according to the protocol of the European MH Group. Twenty patients were susceptible to MH (MHS), 19 were MH non-susceptible (MHN) and five MH equivocal (MHE). No adverse effects of the drugs were observed. There were no differences between the three groups in rectal or muscle temperature, blood lactate concentration or venous PCO2 at any time. Doxapram did not prevent an increase in postoperative PCO2. It is concluded that vecuronium and doxapram may be safely administered to patients susceptible to MH.