Trigger Of Malignant Hyperthermia Research Articles

Kasuistik: Fulminante Maligne Hyperthermie - Untypischer Verlauf während der 9. Allgemeinanästhesie

Malignant hyperthermia (MH) is a rare, often life-threatening complication of general anaesthesia. The timely diagnosis of an MH crisis in onset, as a prerequisite for successful therapy, can be difficult for the anaesthetist because of the few and non-specific early symptoms. This is even more so in patients in whom anaesthesia with MH trigger substances has already been performed in the past without any particular complications so leading to a false sense of security with regard to MH sensitivity. The case presented is a healthy young man with a congenital cleft lip, jaw and palette who developed a fulminant MH crisis during his ninth general anaesthesia. Post-operative research into the course of the previous anaesthesias revealed signs of MH crises which however proceeded abortively and were therefore unnoticed. In the case presented, the diagnosis was additionally complicated by the untypical course of the early symptoms. Tachycardia which in 80 % of cases is described as the first symptom of an MH crisis in onset, was at first completely absent and was only moderately pronounced in the full clinical picture of MH. On the other hand, a steady increase in body temperature, a cardinal symptom which usually appears later, was registered early. The suspected diagnosis of MH was then finally confirmed in the fourth hour after start of anaesthesia on the basis of the repeatedly increased end expiratory CO(2) levels. These could not otherwise be explained although several respiratory corrections were performed. Despite immediate MH specific therapy, the crisis developed in the following hour into the full clinical picture: maximum temperature of 41.4 degrees C, end expiratory CO(2) 100mm Hg, consumptive coagulopathy, acute renal failure and shock (systolic blood pressure < 50mm Hg, heart rate 115/minute). After 2 hours of specific intensive therapy, the patient was finally stabilized and transfer to the intensive care unit was possible. 24 hours after the event, the patient was could be extubated without any complications and 2 days later, he was transferred to the normal ward. The intra-operative diagnosis of MH was confirmed 3 days later by means of genetic analysis. Two mutations of the RYR1 gene were identified.

The Dose-Response Relationship and Regional Distribution of Lactate After Intramuscular Injection of Halothane and Caffeine in Malignant Hyperthermia-Susceptible Pigs

We hypothesized that IM halothane and caffeine injection increases local lactate concentration dose-dependently in malignant hyperthermia-susceptible (MHS) and nonsusceptible (MHN) pigs and that the hypermetabolic reaction measured by regional distribution of lactate and carbon dioxide is limited to a small muscle volume. Microdialysis probes were placed in the hindlimbs of 7 MHS and 7 MHN pigs and perfused with Ringer's solution. After equilibration, boluses of increasing halothane and caffeine concentrations were injected. For the second hypothesis regarding regional distribution, microdialysis probes were positioned in 7 MHS and 6 MHN pigs at the injection site for halothane and caffeine and at a distance of 10 mm and 25 mm. Lactate was measured in the dialysate by spectrophotometry. In addition, PCO2 was measured in the halothane experiments. Halothane and caffeine increased IM lactate dose-dependently in MHS pigs significantly more than in MHN pigs. Lactate and PCO2 were increased only at the injection site but not at 10 mm and 25 mm distance. MH susceptibility leads to a leftward shift of the dose-response curve for IM lactate after local injection of halothane and caffeine. The increase of lactate and carbon dioxide levels after local MH trigger injection is limited to a small area around the probe.

Dantrolene Use in 3,4-Methylenedioxymethamphetamine (“Ecstasy”)–Mediated Hyperthermia

We thank Dr. Rusyniak et al. for their critical comments on our study about the induction of malignant hyperthermia (MH) in susceptible swine by 3,4-methylenedioxymethamphetamine (MDMA) (“ecstasy”).1However, some of the criticisms of our study must be relativized.First, to our knowledge, this is the first controlled study investigating the association between MDMA-induced hypermetabolic syndrome and MH. MH crisis is an acute clinical complication; therefore, the experimental setting for this study was following the clinical situation, and diagnosis of MH in our experiment could only be based on clinical parameters. The definition of the clinical cutoff parameters for MH crisis in our study was following the recommendations for clinical diagnosis of human MH crisis and previous animal studies. Increasing doses of MDMA induced a hypermetabolic state in MH-susceptible (MHS) as well as MH-normal (MHN) swine. However, the changes in the MHN swine after receiving a higher dose of MDMA (12 mg/kg) were moderate compared with the changes in MHS swine after 8 mg/kg MDMA, and all MHS swine fulfilled the defined criteria for MH.The only known differentiation between MHS and MHN swine is the presence of the Arg615-Cys point mutation on chromosome 6 leading to a functional impairment of the skeletal muscle ryanodine receptor (RyR1). We share the opinion of Dr. Rusyniak et al. that MDMA-induced hypermetabolism is not solely mediated through RyR1 complexes. However, the different reactions of MHS and MHN swine in our study are an indirect hint for activation of RyR1 after in vivo MDMA administration. The current study was aimed to prove whether MDMA is capable of inducing an MH syndrome, not to clarify the exact pathomechanism, i.e. , a possible mediation via the RyR1. Whether the RyR1 activation could be attributed to a direct effect of MDMA at the skeletal muscle or to a secondary effect of central stimulation, hyperthermia, or an MDMA-metabolite must therefore be clarified in future studies.The definition of an MH “trigger” is not as clear as mentioned in the letter of Dr. Rusyniak et al. From a clinical point of view, an MH trigger is a substance that is able to induce an MH crisis in a genetically determined individual in a clinically relevant dosage without any relevant cofactors. Following this definition, MDMA triggered MH in MHS swine in our study. We agree that cumulative intravenous administration of MDMA is not the common method of MDMA abuse. However, this course of action and measurement of corresponding MDMA plasma concentrations allowed us to determine a dose response and to underline the clinical relevance.The therapeutic regimen of MDMA-induced MH in our study was based on the standard clinical therapy of MH. Standardized therapy of MH in the MHS swine performed with dantrolene, sodium bicarbonate, and hyperventilation partly removed the clinical signs of MH immediately. The body temperature of the swine remained unchanged 15 min after therapy induction. We agree that the short observation time without the possibility to detect changes in body temperature was a weakness in our study design.Whether administration of dantrolene is useful in all patients with MDMA-induced hyperthermia could not be answered by our study. However, in a life-threatening clinical situation, “simple hyperthermia” could not be distinguished from “true malignant hyperthermia.” Therefore, in our opinion, dantrolene might be a lifesaving therapy option, and consequently, administration of dantrolene should be considered with respect to patient safety in cases of MDMA-mediated hyperthermic syndrome.* University Hospital Hamburg-Eppendorf, Hamburg, Germany. fiege@uke.uni-hamburg.de

Malignant hyperthermia: pathophysiology, clinical presentation, and treatment.

Malignant hyperthermia (MH) was first described as an inherited highly lethal disorder in 1960. There has since been significant progress in the clinical management, identification of MH susceptible (MHS) persons, and understanding of the underlying pathophysiology. When patients are known to be MHS prior to surgery, an MH episode can easily be avoided by the use of safe nontriggering anesthetic agents. Current MH mortality is <10%, but many experts believe this can be significantly reduced by improved MH preparedness. MH is triggered in humans by an MH triggering anesthetic agent, which causes the release of calcium from the sarcoplastic reticulum of the skeletal muscle cell at an uncontrolled rate resulting in a hypermetabolic state. Recent molecular genetic studies have shown that MH is related to an abnormal ryanodine receptor that controls the release of calcium from the sarcoplastic reticulum. This article reviews the current understanding of the pathophysiology, diagnosis, clinical presentation, and treatment of MH.

Induction of Malignant Hyperthermia in Susceptible Swine by 3,4-Methylenedioxymethamphetamine (“Ecstasy”)

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") can mediate acute toxic effects such as muscle rigidity, metabolic acidosis, and hyperthermia. Because of close clinical similarities, an association between MDMA intoxication and malignant hyperthermia (MH) was suggested. The aim of this study was to investigate whether MDMA is a trigger of MH in susceptible swine. MH-nontriggering general anesthesia was performed in six MH-susceptible (MHS) and six MH-normal swine. The animals were exposed to MDMA in cumulative doses of 0.5, 1, 2, 4, 8, and 12 mg/kg. The clinical occurrence of MH was defined by achievement of two of three conditions: central venous Pco2 >/=75 mmHg, central venous pH </= 7.20, and increase of body core temperature >/= 2.0 degrees C. Once MH occurred, a standardized therapy with dantrolene, sodium bicarbonate, and hyperventilation with 100% oxygen was initialized. Administration of 8 mg/kg MDMA triggered MH in all MHS swine. The MH-normal swine also developed clinical signs of hypermetabolism, but even after administration of 12 mg/kg MDMA, changes were moderate compared with the MHS swine. Dantrolene therapy of MDMA-induced MH crisis in the MHS swine partially counteracted the clinical signs of MH immediately. MDMA induces MH in genetically susceptible swine in relevant doses. Therefore, MHS patients should avoid use of MDMA or related drugs. Patients with a personal or family history of MDMA-induced hyperthermia should be tested for a diagnosis of MH susceptibility. Dantrolene is effective in therapy of MDMA-induced porcine MH.

In-vitro-effects of cocaine in skeletal muscle specimens of patients susceptible to malignant hyperthermia

The abuse of cocaine can cause serious medical complications like tachycardia, rhabdomyolysis, and hyperthermia. Because of the clinical similarities, it has been suggested that cocaine might be a trigger of malignant hyperthermia (MH). Therefore, aim of this study was to investigate the in-vitro effects of cocaine in skeletal muscle specimens of MH susceptible (MHS) and normal (MHN) patients. 62 patients undergoing the in-vitro contracture test (IVCT) according to the protocol of the European MH Group (EMHG) for diagnosis of MH susceptibility were included in this study. In muscle specimens surplus to diagnostic requirements cocaine was added in order to achieve tissue bath concentrations of 0.01, 0.1 and 1.0 mM. The contracture development and twitch response have been registered. 21 patients were diagnosed as MHS and 36 patients as MHN. 5 patients tested as MH-equivocal (MHE) were excluded from the study. Following bolus administration of cocaine, no contracture development was observed in MHS, as well as MHN specimens. The muscle twitch decreased after cocaine administration significantly in both diagnostic groups. In contrast to the established MH trigger substances like volatile anaesthetics, cocaine produced no contracture development in MHS muscle specimens. Furthermore, cocaine produced a negative inotropic effect in all skeletal muscle preparations, which might be explained by local anaesthetic effects. Regarding these results, cocaine seems not to be a MH trigger agent.

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

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. For the measurements, single saponin-skinned muscle fiber preparations of BALB/c mice were used. For Ca2+ release experiments, liquid desflurane at 0.6 and 3.5 mm was applied to weakly calcium-buffered solutions with no added Ca2+. Desflurane was diluted in strongly Ca2+-buffered solutions, with [Ca2+] between 3.0 and 24.9 micrometer for [Ca2+]-force relations. Force transients were transformed into Ca2+ transients based on the individual [Ca2+]-force relations. As controls, 30 mm caffeine and equimolar sevoflurane were investigated in the same muscle fibers. At 3.5 mm, desflurane induced peak force transients of 8 +/- 4% (mean +/- SD) of maximal Ca2+-activated force (Tmax). These peak values were significantly smaller than those in the presence of 3.5 mm sevoflurane (24 +/- 10% of Tmax, P < 0.05), and 4 or 5 times smaller than previously reported Ca2+-release-induced force transients by equimolar halothane. Calculated peak Ca2+ 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 [Ca2+]-force relation was shifted by desflurane, resulting in a Ca2+-sensitizing effect. The maximal Ca2+-activated force was significantly increased by 0.6 mm desflurane in comparison with the control, with no added substance (P </= 0.05). Desflurane induces only slight Ca2+ release in skinned skeletal muscle fibers.

4-chloro-m-cresol triggers malignant hyperthermia in susceptible swine at doses greatly exceeding those found in drug preparations.

Chlorocresols are used as preservatives in numerous commercial drugs that have been shown to induce myoplasmic Ca2+ release; the most potent isoform is 4-chloro-m-cresol. The aims of this study were to (1) examine the in vivo effects of 4-chloro-m-cresol on swine susceptible to malignant hyperthermia and (2) contrast in vivo versus in vitro dose-response curves. Susceptible swine (weight: 38.5 kg+/-3.55 kg) were anesthetized and monitored for variations in physiological responses, including end-tidal CO2, heart rate, blood pressure, blood chemistry, and temperatures. In the first animals studied, 4-chloro-m-cresol, at equivalent cumulative doses of 0.14, 0.28, 0.57, 1.14, 2.27, 4.54, and 9.08 mg/kg (n = 3; 12.5, 25, 50, 100, 200, 400, and 800 micromol) were administered, and in a second group, larger doses were used: 1.14, 3.41, 7.95, 17.04 (n = 4), and/or 35.22 (n = 1) mg/kg (100, 300, 700, 1,500, and/or 3,100 micromol). For comparison, in vitro rectus abdominis muscle preparations obtained from normal and susceptible swine were exposed to 4-chloro-m-cresol, at cumulative concentrations of 6.25, 12.5, 25, 50, 100, 200, 400, 800, and 1,600 micromol; standard caffeine and halothane contracture testing was also performed. Episodes of malignant hyperthermia were not triggered in response to administration of low doses of 4-chloro-m-cresol, but transient cardiovascular reactions (e.g., tachycardia, arrhythmias, and hypotension) were observed. Subsequently, episodes in these animals were triggered when halothane (0.87; 1 MAC) and succinylcholine (2 mg/kg) were given. Animals administered the higher doses of 4-chloro-m-cresol all had fulminant episodes of malignant hyperthermia that were fatal, when equivalent cumulative concentrations were greater than 1,500 micromol. The levels of 4-chloro-m-cresol in the plasma rapidly decreased: e.g., 5 min postadministration of the 1,500-micromol dose, the mean plasma level was only 52+/-18 micromol (n = 4). Hemolysis was detected following 4-chloro-m-cresol administration at concentrations > 200 micromol. In vitro, muscle from susceptible animals elicited contractures > 200 mg at 50-micromol bath concentrations of 4-chloro-m-cresol (n = 29), whereas normal muscle did not elicit such contractures until bath concentrations were > 800 micromol (n = 10). 4-chloro-m-cresol is a trigger of malignant hyperthermia in susceptible swine, but only when serum concentrations are far above those likely to be encountered in humans. A relatively low concentration of 4-chloro-m-cresol, 50 micromol, is sufficient to activate sarcoplasmic [Ca+2] release in vitro (e.g., contractures); this same bolus dose administered in vivo (0.57 mg/kg) has minimal effects due to the rapid decrease in its plasma levels.

4-chloro-m-cresol is a trigger of malignant hyperthermia in susceptible swine.

4-Chloro-m-cresol (4-CmC) induces marked contractures in skeletal muscle specimens from individuals susceptible to malignant hyperthermia (MHS). In contrast, 4-CmC induces only small contractures in specimens from normal (MHN) patients. 4-CmC is a preservative within a large number of commercially available drug-preparations (e.g., insulin, heparin, succinylcholine), and it has been suggested that 4-CmC might trigger malignant hyperthermia. This study was designed to investigate the effects of 4-CmC in vivo and in vitro in the same animals. After approval of the animal care committee, six Pietrain MHS and six control (MHN) swine were anesthetized with azaperone 4 mg/kg intramuscularly and metomidate 10 mg/kg intraperitoneally. After endotracheal intubation, lungs were mechanically ventilated (inspired oxygen fraction 0.3) and anesthesia was maintained with etomidate 2.5 mg x kg(-1) x h(-1) and fentanyl 50 microg x kg(-1) x h(-1). Animals were surgically prepared with arterial and central venous catheters for measurement of hemodynamic parameters and to obtain blood samples. Before exposure to 4-CmC in vivo, muscle specimens were excised for in vitro contracture tests with 4-CmC in concentrations of 75 and 200 microM. Subsequently, pigs were exposed to cumulative administration of 3, 6, 12, 24, and 48 mg/kg 4-CmC intravenously. If an unequivocal episode of malignant hyperthermia occurred, as indicated by venous carbon dioxide concentration > or = 70 mmHg, pH < or = 7.25, and an increase of temperature > or = 2 degrees C, the animals were treated with dantrolene, 3.5 mg/kg. All MHS swine developed malignant hyperthermia after administration of 4-CmC in doses of 12 or 24 mg/kg. Venous carbon dioxide concentration significantly increased and pH significantly decreased. Temperature increased in all MHS animals more than 2 degrees C. Blood lactate concentrations and creatine kinase levels were significantly elevated. All MHS swine were treated successfully with dantrolene. In contrast, no MHN swine developed signs of malignant hyperthermia. After receiving 4-CmC in a concentration of 48 mg/kg, however, all MHN animals died by ventricular fibrillation. The in vitro experiments showed that both concentrations of 4-CmC produced significantly greater contractures in MHS than in MHN specimens. 4-CmC is in vivo a trigger of malignant hyperthermia in swine. However, the 4-CmC doses required for induction of malignant hyperthermia were between 12 and 24 mg/kg, which is about 150-fold higher than the 4-CmC concentrations within clinically used preparations.

This Month in ANESTHESIOLOGY

This Month in ANESTHESIOLOGY

ELTANOLONE (5-β-PREGNANOLONE) DOES NOT TRIGGER, AND ATTENUATES HALOTHANE TRIGGERING OF, MALIGNANT HYPERTHERMIA IN MALIGNANT HYPERTHERMIA SUSCEPTIBLE SWINE

Eltanolone is the lipid emulsion formulation, for intravenous use, of the steroid anaesthetic 5-β-pregnanolone. We have screened this agent in malignant hyperthermia susceptible (MHS) Landrace swine to assess its potential to trigger the Malignant Hyperthermia (MH) syndrome in MHS subjects or to influence halothane triggering of MH in such patients. Administered in anaesthetic concentration, eltanolone did not trigger the MH syndrome in MHS swine. When co-administered in low dosage with halothane, the drug prevented initiation of the MH syndrome in four of eight pigs and attenuated its progress in the remainder.

Human Malignant Hyperthermia Associated with Desflurane Anesthesia

Human Malignant Hyperthermia Associated with Desflurane Anesthesia

Prior hypothermia attenuates malignant hyperthermia in susceptible swine.

This study was designed to determine the extent by which mild or moderate hyperthermia attenuates the triggering of malignant hypothermia (MH) induced by the combined administration of halothane and succinylcholine. Sixteen susceptible swine were initially anesthetized with nontriggering drugs and then either kept normothermic (approximately equal to 38 degrees C, n = 6) or cooled to induce mild (approximately equal to 35 degrees C, n = 6), or moderate (approximately equal to 33 degrees C, n = 4) hypothermia. Next, after a 30-min control period, the normothermic and mildly hypothermic animals were administered 1 minimum alveolar anesthetic concentration (MAC) halothane followed by a bolus dose of succinylcholine (2 mg/kg). Within 10 min all normothermic animals developed fulminant MH, whereas the onset of MH was slowed or was absent in the mildly hypothermic group. To test whether moderate hypothermia could more effectively minimize the signs of a MH episode, this group of animals was exposed to 1.5 MAC halothane followed 10 min later by a 3-mg/kg bolus of succinylcholine. MH was not induced and anesthesia was then changed to nontriggering drugs (ketamine and pancuronium). The animals were then aggressively rewarmed to 38 degrees C: a slight increase in the ETCO2 was detected, but MH episodes did not spontaneously occur. Subsequently, the readministration of halothane and succinylcholine rapidly provoked fulminant MH. We concluded that the induction of mild hypothermia impairs triggering and reduces the progression of MH induced by the combined administration of halothane and succinylcholine, whereas moderate hypothermia was completely protective and thus could be considered for prophylaxis.

Norepinephrine does not potentiate porcine malignant hyperthermia.

Malignant hyperthermia (MH) is a rare genetic trait characterized by potential life-threatening episodes of hypermetabolism, hyperthermia, and muscle rigidity when susceptible humans or animals are exposed to triggering drugs. The role of norepinephrine (NE) in triggering MH is controversial. The purpose of this study was to show that NE does not initiate nor speed the onset of MH in susceptible swine exposed to known triggering drugs. Three groups of MH susceptible (MHS) pigs were exposed to two times the minimum alveolar anesthetic concentrations (MAC) halothane (2%) for 60 min and monitored continuously until a PaCO2 of 70 mm Hg was obtained as an end point for fulminant MH. This dose of halothane is associated with significant hypotension which was addressed by three modalities: no treatment; NE infusion at 8 micrograms.kg-1.min-1; and intraaortic balloon pump (IABP) with 1:1 augmentation (7.0-mL balloon catheter). NE and epinephrine (Epi) plasma levels were determined at 15-min intervals and at trigger time. All animals developed signs of MH during the study. There was no difference in pHa, lactate, PaCO2, or temperature at control or trigger times between groups. Time to trigger was longer in the untreated group compared to both the NE and the IABP groups which were equal. The NE group had greater NE and Epi plasma levels at all times than either the untreated or IABP group and the levels increased at each sample time. The IABP group had increased NE levels at time of trigger compared to control time period, however, Epi levels did not increase. In the untreated group, individual animals had marked increases in NE levels, but extreme variability in response prevented achievement of a single mean change. This group showed no increase in plasma Epi levels throughout the study. There was no difference in NE levels between the untreated and IABP groups. Three animals in the untreated group died prior to trigger due to complications of hypotension. In conclusion, addition of exogenous NE in high doses did not enhance triggering of MH. The large dose NE infusion resulted in increased total catecholamines throughout the study in the NE group with no effect on time to MH trigger compared to animals where mean arterial pressure (MAP) was maintained by IABP. Animals in all three groups with times to trigger of less than 30 min had significantly higher MAPs at control, 15 min, and trigger time than those with times to trigger of greater than 30 min. We conclude that NE does not trigger MH and that severe reduction of MAP delays the the onset of MH in susceptible swine.

Norepinephrine Does Not Potentiate Porcine Malignant Hyperthermia

Malignant hyperthermia (MH) is a rare genetic trait characterized by potential life-threatening episodes of hypermetabolism, hyperthermia, and muscle rigidity when susceptible humans or animals are exposed to triggering drugs. The role of norepinephrine (NE) in triggering MH is controversial. The purpose of this study was to show that NE does not initiate nor speed the onset of MH in susceptible swine exposed to known triggering drugs. Three groups of MH susceptible (MHS) pigs were exposed to two times the minimum alveolar anesthetic concentration (MAC) halothane (2%) for 60 min and monitored continuously until a PaCO2 of 70 mm Hg was obtained as an end point for fulminant MH. This dose of halothane is associated with significant hypotension which was addressed by three modalities: no treatment; NE infusion at 8 micro gram centered dot kg-1 centered dot min-1; and intraaortic balloon pump (IABP) with 1:1 augmentation (7.0-mL balloon catheter). NE and epinephrine (Epi) plasma levels were determined at 15-min intervals and at trigger time. All animals developed signs of MH during the study. There was no difference in pHa, lactate, PaCO (2), or temperature at control or trigger times between groups. Time to trigger was longer in the untreated group compared to both the NE and the IABP groups which were equal. The NE group had greater NE and Epi plasma levels at all times than either the untreated or IABP group and the levels increased at each sample time. The IABP group had increased NE levels at time of trigger compared to control time period, however, Epi levels did not increase. In the untreated group, individual animals had marked increases in NE levels, but extreme variability in response prevented achievement of a significant mean change. This group showed no increase in plasma Epi levels throughout the study. There was no difference in NE levels between the untreated and IABP groups. Three animals in the untreated group died prior to trigger due to complications of hypotension. In conclusion, addition of exogenous NE in high doses did not enhance triggering of MH. The large dose NE infusion resulted in increased total catecholamines throughout the study in the NE group with no effect on time to MH trigger compared to animals where mean arterial pressure (MAP) was maintained by IABP. Animals in all three groups with times to trigger of less than 30 min had significantly higher MAPs at control, 15 min, and trigger time than those with times to trigger of greater than 30 min. We conclude that NE does not trigger MH and that severe reduction of MAP delays the onset of MH in susceptible swine. (Anesth Analg 1996;82:790-5)

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.

Thyroid Storm Is Not a Trigger of Malignant Hyperthermia in Anesthetized Susceptible Swine

Thyroid Storm Is Not a Trigger of Malignant Hyperthermia in Anesthetized Susceptible Swine

Delayed Onset of Malignant Hyperthermia Induced by Isoflurane and Desflurane Compared with Halothane in Susceptible Swine

Desflurane (difluoromethyl 1-fluoro 2,2,2-trifluoroethyl ether) is a new inhalational anesthetic currently under investigation for use in humans. Recently, the authors showed that desflurane is a trigger of malignant hyperthermia (MH) in susceptible swine. To date, there has been no in vivo comparison of the relative ability of inhalational anesthetics to trigger MH. The effects of desflurane, isoflurane, and halothane on six MH-susceptible purebred and six MH-susceptible mixed-bred Pietrain swine were examined. The animals were exposed to 1 MAC and 2 MAC (if MH was not triggered after 1 MAC hour) doses of each of the three volatile anesthetics in random sequence at 7-10-day intervals and changes in end-tidal CO2, arterial blood gases, serum lactate, core and muscle temperature, blood pressure, and heart rate were measured. There was a statistical difference between anesthetics in the time required to trigger MH; halothane exposure resulted in the fastest onset of an MH episode (20 +/- 5 min), compared with isoflurane (48 +/- 24 min) and desflurane (65 +/- 28 min), both of which required significantly longer exposures. There was no statistical difference between the MH purebred and mixed-bred swine in the time required to trigger MH (defined as a PaCO2 of 70 mmHg) with a given agent, and time to triggering was also independent of the order of exposure to the three anesthetics. Malignant hyperthermia susceptibility was confirmed in ten surviving animals, by both in vivo succinylcholine challenge and in vitro contracture testing. Although all three volatile anesthetics triggered MH, exposure to halothane resulted in significantly shorter times to MH triggering when compared with desflurane and isoflurane.

Effects of droperidol, haloperidol and ketamine on halothane, succinylcholine and caffeine contractures: implications for malignant hyperthermia.

The effects of two structurally similar butyrophenones (droperidol and haloperidol) and ketamine were evaluated in an in vitro system to determine their potential for eliciting or exacerbating an episode of malignant hyperthermia. Muscle strips from patients referred for diagnostic testing for malignant hyperthermia and muscle strips from the rat diaphragm were exposed to droperidol, haloperidol, or ketamine prior to challenge with halothane, succinylcholine or caffeine. If any agent augmented the contracture response to the malignant hyperthermia triggering or diagnostic agents, then the agent was considered unsafe for use in malignant hyperthermia susceptible patients. Droperidol 10 mumol/l and ketamine 100 mumol/l did not induce contractures in human or rat skeletal muscle when added alone, nor did they augment halothane, succinylcholine or caffeine contractures. These agents appear to be safe for use in patients susceptible to malignant hyperthermia. In contrast, haloperidol 10 mumol/l augmented the response to succinylcholine about 1.5-fold and may be contraindicated in MH susceptibles.

Malignant Hyperthermia

<h3>To the Editor.</h3> —We have read with interest the excellentArchivesarticle by Dodd et al. After reading this review, one is tempted to believe that the triggering of malignant hyperthermia can be prevented by use of a "safe" anesthetic agent. We, however, have had the disconcerting experience of seeing a phenomenon, to our knowledge not previously reported—development of an episode of malignant hyperthermia after oral pretreatment with dantrolene sodium and administration of an anesthetic agent suggested by most to be nontriggering. Details of this ophthalmic case can be found in<i>Anesthesiology</i>(1981;54:1-2, 73-75). This first reported case of such an occurrence stresses the continued vigilance one must maintain despite following the usual and accepted protocol for patients suspected of having malignant hyperthermia. Other details associated with malignant hyperthermia that we would emphasize are as follows: There may not be any temperature rise in a specific person in whom