Administration Of Dantrolene Research Articles

Dantrolene is neuroprotective in vitro, but does not affect survival in SOD1G93A mice

Amyotrophic Lateral Sclerosis (ALS) is a devastating progressive neurodegenerative disease. One of the proposed disease mechanisms is excitotoxicity, in which excessive cytosolic calcium causes neuronal death. Although most calcium may originate from the extracellular space through activation of calcium-permeable AMPA receptors, we investigated in this study the contribution of endoplasmic reticulum calcium release by blocking the ryanodine receptor (RyR) using dantrolene. In vitro, dantrolene provides a significant protection to motor neurons exposed to a brief excitotoxic insult. However, daily administration of dantrolene to mice overexpressing superoxide dismutase 1 glycine to alanine at position 93 (SOD1G93A) does affect neither survival nor the number of motor neurons and ubiquitin aggregates indicating that calcium release through RyRs does not contribute to the selective motor neuron death in this animal model for ALS.

Multi-minicore disease in pregnancy: avoiding malignant hyperpyrexia

Multi-minicore disease (minicore myopathy) is a rare form of myopathy, which usually presents in childhood, but can occasionally present later in life or early infancy. It is characterised by slowly...

Neuroleptic malignant syndrome: A diagnostic challenge

We report the case of a 7-year-old girl operated for craniopharyngioma who developed hyperkalemic cardiac arrest in the post-operative period. She was diagnosed as Neuroleptic malignant syndrome (NMS) and the causative drug was carbamazepine. It was essentially a diagnosis of exclusion, and treatment was mainly supportive in form of withdrawal of the neuroleptic medication (carbamazepine) and administration of dantrolene and bromocriptine. Although, relatively uncommon, NMS can be fatal. NMS presents a clinical challenge as the patient outcome depends on its prompt recognition and treatment.

A suspected case of malignant hyperthermia that was successfully treated with dantrolene administration via nasogastric tube

A suspected case of malignant hyperthermia that was successfully treated with dantrolene administration via nasogastric tube

P-579 - Neuroleptic malignant syndrome

Neuroleptic malignant syndrome is a rare but potentially life threatening idiosyncratic complication of neuroleptic drugs. Levenson criteria do help guide in diagnosis of NMS and the major manifestations of the syndrome are muscular rigidity, fever, autonomic dysfunction and altered consciousness. NMS mortality is approximately between 10 to 20%. The authors present and discuss the case of a patient with mental retardation who developed neuroleptic malignant syndrome after receiving haloperidol and zuclopenthixol for agitation. Supportive therapy including rehydratation, electrolyte restoration, paracetamol, dantrolene and biperideno were given to the patient. supportive therapy, dantrolene and biperideno yielded clinical benefits for neuroleptic malignant syndrome. However the patient developed acute hepatic failure probably secondary to dantrolene with need of admission to an intensive gastroenterological care unit, where he stayed for approximately one month. Although neuroleptic malignant syndrome and acute liver failure due to dantrolene are rare emergencies, the patient presented in this case developed theses two idiosyncratic, rare and potentially fatal reactions due to haloperidol, zuclopenthixol and dantrolene administration. This report clearly represents a successful clinical outcome only possible due to an early diagnosis and prompt treatment interventions.

Malignant hyperthermia: Dantrolene sodium - A must have

Sir, Malignant hyperthermia is a disorder that manifests as a life-threatening hypermetabolic crisis in susceptible individuals after exposure to inhalational anaesthetics, mainly halogenated compounds (the most common being halothane), and depolarizing neuromuscular blocking agents (the most common being succinylcholine). A 1-year-old child presented with a swelling over the back since birth without any neurological symptoms. Systemic examination was normal. Magnetic resonance imaging scan of the spine showed kyphoscoliosis and spina bifida from C7-D7 with diplomyelia with an intraspinal dermoid neuroenteric cyst. There was no past or family history of anaesthetic complication, malignant hyperthermia or neuromuscular disorders. The child was premedicated with syrup Triclofos 300 mg orally and injection glycopyrrolate 0.024 mg IV. Pre-operatively, the heart rate (HR) was 170/min and the skin temperature was 36.5°C. The heating mattress was adjusted to 38°C. After pre-oxygenation with 100% O2 for 3 min, general anaesthesia was given with 1.5% halothane and 50% nitrous oxide in oxygen. Injection thiopentone 30 mg and injection atracurium 4.5 mg were given intravenously. The trachea was intubated. Anaesthesia was maintained using 0.5% halothane intermittently and 50% nitrous oxide in oxygen. Muscle relaxation was maintained with atracurium boluses. Analgesia was provided with injection tramodol 6 mg intravenously and diclofenac 12.5 mg suppository. The HR after induction increased to 180/min and the core temperature increased to 38.4°C. Injection paracetamol 30 mg IV was given and the warming mattress was switched off. The ambient temperature was reduced. After 40 min, the temperature reduced to 37°C with a HR of 160/per min; thus, a prone position was given and surgery was started. In the next half an hour, the nasopharyngeal temperature increased to 38.6°C. Halothane was switched off and surface cooling was started with cold sponges. Additional 50 mL cold 0.9% NaCl intravenously was given. During the major part of the surgery, the core temperature was 38°C and the skin temperature was 34°C. SpO 2was maintained above 98%. Tachycardia of 160–180/min persisted throughout surgery. After about 5 h of anaesthesia, another rapid rise in temperature and HR was noted. Urine output was reduced. Injection paracetamol was repeated. Surgery was quickly completed. Surface cooling and gastric lavage was done using ice cold saline. A differential diagnosis of thyroid storm, pheochromocytoma, malignant hyperthermia and neuroleptic malignant syndrome was considered. The absence of history of headache and weight loss made the possibility of pheochromocytoma less likely. The patient was not on dopamine receptor antagonists, which ruled out neuroleptic malignant syndrome. The absence of history of thyrotoxic symptoms/thyromegaly on pre-operative anaesthetic evaluation and high carbon dioxide level and arterial hypoxemia on intraoperative arterial blood gas analysis made the diagnosis of malignant hyperthermia more likely. Suspecting malignant hyperthermia, attempts to procure dantrolene sodium were started. Anaesthesia was maintained with thiopentone and the patient was hyperventilated with 100% O2. However, the SpO2 fell below 90% with hypotension and ventricular tachyarrhythmia. Injection lidocaine 20 mg IV, adrenaline, atropine and sodium bicarbonate were given with external cardiac massage. After a brief recovery, she went into ventricular tachycardia again with HR 215/min. Defibrillation with 30 J was done and injection lidocaine was repeated. The rhythm reverted back to sinus tachycardia. Arterial blood gas arterial blood gases, revealed respiratory and metabolic acidosis (pH 7.2) with a PCO2 of 58.2 mmHg, bicarbonate 20 mEq/L and a PO2 of 96.4 mmHg. Serum potassium was 5.8 meq/L. The temperature remained over 39°C despite surface cooling and cold saline gastric lavage. Hyperventilation with 100% O2 was continued. Another episode of ventricular tachycardia was reverted with defibrillation and sodium bicarbonate. Acidosis and hypercarbia continued to worsen (pH 6.9, PCO2 70 mmHg). Creatine Phosphokinase (CPK) was elevated (44 units) and diagnosis of malignant hyperthermia was made. Dantrolene sodium was still not available. Finally, about 12 h after the onset of symptoms, the patient developed intractable ventricular fibrillation and died. Halothane-induced MH is associated with increased levels of 5 HT with concomitant increase in muscle tone, body temperature, venous CO2 and plasma lactate.[1] Patients with muscular dystrophies, myotonic dystrophy, central cord disease, kyphoscoliosis and meningomyelocoele may be at risk for developing malignant hyperthermia.[23] As soon as a MH crisis is suspected, all trigger agents should be stopped. Besides symptomatic treatment, high-flow O2, termination/postponement of surgery, dantrolene sodium should be given at 2 mg/kg i.v. and repeated until the cardiac and respiratory systems stabilize.[4] Early dantrolene administration may decrease the 35% MH morbidity rate.[5] But, in a country like ours, this drug is too expensive and, hence, is rarely available. As was done in our case, only symptomatic treatment is usually possible. This, however, usually does not help. Hence, this life-saving drug should be kept available in larger tertiary care hospitals to prevent fatalities from this potentially lethal condition.

Complications Associated With the Administration of Dantrolene 1987 to 2006

Complications Associated With the Administration of Dantrolene 1987 to 2006

Creation of a Guide for the Transfer of Care of the Malignant Hyperthermia Patient from Ambulatory Surgery Centers to Receiving Hospital Facilities

Volatile anesthetics and/or succinylcholine may trigger a potentially lethal malignant hyperthermia (MH) event requiring critical care crisis management. If the MH triggering anesthetic is given in an ambulatory surgical center (ASC), then the patient will need to be transferred to a receiving hospital. Before May 2010, there was no clinical guide regarding the development of a specific transfer plan for MH patients in an ASC. MECHANISM BY WHICH THE STATEMENT WAS GENERATED: A consensual process lasting 18 months among 13 representatives of the Malignant Hyperthermia Association of the United States, the Ambulatory Surgery Foundation, the Society for Ambulatory Anesthesia, the Society for Academic Emergency Medicine, and the National Association of Emergency Medical Technicians led to the creation of this guide. EVIDENCE FOR THE STATEMENT: Most of the guide is based on the clinical experience and scientific expertise of the 13 representatives. The list of representatives appears in Appendix 1. The recommendation that IV dantrolene should be initiated pending transfer is also supported by clinical research demonstrating that the likelihood of significant MH complications doubles for every 30-minute delay in dantrolene administration (Anesth Analg 2010;110:498-507). This guide includes a list of potential clinical problems and therapeutic interventions to assist each ASC in the development of its own unique MH transfer plan. Points to consider include receiving health care facility capabilities, indicators of patient stability and necessary report data, transport team considerations and capabilities, implementation of transfer decisions, and coordination of communication among the ASC, the receiving hospital, and the transport team. See Appendix 2 for the guide.

Safety of Low-Dose Oral Dantrolene Sodium on Hepatic Function

Kim JY, Chun S, Bang MS, Shin H-I, Lee S-U. Safety of low-dose oral dantrolene sodium on hepatic function. Objective To investigate the incidence of hepatobiliary dysfunction after administration of low-dose dantrolene sodium. Design A retrospective survey of medical records. Setting One secondary and 2 tertiary hospitals. Participants Patients (N=243; 144 men, 27 children; mean age ± SD, 47.8±19.7y) who were administered dantrolene at a daily dose of 12.5 to 400mg for more than 4 weeks. Interventions Not applicable. Main Outcome Measures Liver function test (LFT) results, including serum total bilirubin, aspartate transaminase, alanine transaminase, and alkaline phosphatase, were recorded before and at least 1 month after the initial dose of dantrolene. In cases of treatment cessation, the reason was investigated. Significantly elevated LFT levels were defined as ≥ to 2 times the upper limit of the normal range. Results Treatment duration was 268.0±428.5 days with a daily dose of 65.2±44.7mg. At the end of the investigation, 95 patients (39.1%) had been lost to follow-up, and 105 (43.2%) had stopped treatment. The reasons for cessation were improved spasticity (42.9%), no effect of the medication (27.6%), weakness (6.7%), and other medical problems (5.7%). Patients with weaknesses did not have elevated LFT values. A 32-year-old man with head injuries and multiple trauma developed hepatic dysfunction 82 days after the initial dose and 43 days after a dose increment to 400mg/d. Other patients did not experience significant LFT abnormalities. Conclusions One case of hepatic dysfunction was recorded in 243 cases after at least 4 weeks of low-dose oral dantrolene administration. Low-dose dantrolene can be used safely with meticulous clinical and laboratory monitoring.

Comparison of the therapeutic effectiveness of a dantrolene sodium solution and a novel nanocrystalline suspension of dantrolene sodium in malignant hyperthermia normal and susceptible pigs

Stopping trigger agents and prompt administration of dantrolene are the cornerstones of treatment of malignant hyperthermia. However, significant time is lost in treatment of the condition because of the cumbersome preparation and administration of the commercially available dantrolene sodium for injection. A potential improvement has become available in the form of a novel nanocrystalline dantrolene sodium suspension (DSS), which is 150 times more concentrated (50 mg ml(-1)) than the standard dantrolene sodium solution (0.33 mg ml(-1)). The aims of this study were to measure the effects of DSS on clinical and laboratory variables in malignant hyperthermia normal pigs and to compare the therapeutic management and clinical effectiveness of DSS with standard dantrolene sodium in a fulminant malignant hyperthermia crisis in susceptible pigs. The pig model is a well accepted method of studying the malignant hyperthermia crisis and is an ideal way to evaluate the variables of interest in this study. Seven malignant hyperthermia normal and 10 malignant hyperthermia susceptible pigs were studied. Malignant hyperthermia susceptible pigs (body weight approximately 24 kg) were allocated to a dantrolene sodium group or a DSS group. After induction of anaesthesia, a 22-gauge catheter was placed in an ear vein and trigger-free anaesthesia was performed. After achieving stable conditions, administration of halothane was started with 0.1% and then 0.15%. Halothane was discontinued after the administration of 0.2% (malignant hyperthermia normal pigs) or when a fulminant malignant hyperthermia crisis was achieved (malignant hyperthermia susceptible pigs). After halothane was discontinued, FIO2 was set to 1.0, respiratory minute volume was doubled and sodium bicarbonate 2 mmol kg(-1) was administered. The time required to prepare and administer each formulation was measured. To simulate the administration of the substances under typical clinical conditions for a child weighing approximately 24 kg, dantrolene sodium (5 mg kg(-1)) or DSS (5 mg kg(-1)) was prepared and injected via the intravenous 22-gauge cannula. Bolus administrations of dantrolene sodium or DSS were repeated after 24 min. Arterial pH, arterial pCO2, mean arterial pressure and arterial lactate concentration remained stable during the experiment with DSS in malignant hyperthermia normal pigs. A significant decrease in cardiac index and increases in systemic vascular resistance and serum potassium concentration occurred after administration of DSS. In all malignant hyperthermia susceptible animals, the inhaled administration of halothane 0.15% led to a fulminant malignant hyperthermia crisis. The therapeutic regimens with administration of dantrolene sodium or DSS were successful in treating the malignant hyperthermia crisis in all animals. The course of the malignant hyperthermia crisis and the therapeutic effects of dantrolene sodium or DSS were comparable in the two groups. The time needed to prepare DSS for administration was significantly shorter (51 ± 9 s) compared to dantrolene sodium (860 ± 202 s). The time taken to inject DSS (4 ± 2 s) was significantly shorter than for dantrolene sodium (472 ± 51 s). The therapeutic action of DSS in a malignant hyperthermia crisis in pigs was effective and comparable to that of standard dantrolene sodium. However, preparation and administration of DSS were significantly faster, which may offer a clinically significant advantage in the treatment of a fulminant malignant hyperthermia crisis and may result in a reduction in stress for the anaesthesia team.

Complications Associated with the Administration of Dantrolene 1987 to 2006

Dantrolene is the only specific treatment for malignant hyperthermia (MH), a genetic disorder in which life-threatening temperature increase has been induced by inhalation anesthetics and succinylcholine. Because MH presents with nonspecific signs and delay of treatment can be fatal, dantrolene may be given as soon as MH is suspected. We report the complications associated with dantrolene administration as documented in AMRA (adverse metabolic/musculoskeletal reaction to anesthesia) reports submitted to the North American Malignant Hyperthermia Registry. AMRA reports were analyzed for differences between subjects with and without complications attributed to dantrolene. Documentation of dantrolene dose and subject weight were inclusion criteria. Because some reported complications were likely due to factors other than dantrolene, a reduced set of cases was also defined. We used χ(2) and Mann-Whitney tests. Logistic regression was applied to describe factors associated with increased risk of complications. In the full dataset of 368 subjects, the most frequent complications associated with dantrolene were muscle weakness (21.7%), phlebitis (9%), gastrointestinal upset (4.1%), and respiratory failure (3.8%). Logistic regression described a 29% increase in risk of any complication when the total dantrolene dose was doubled, a 144% increase in risk when fluid administration was part of treatment, an 83% decrease in risk in the presence of neurosurgery, and a 74% decrease in risk in the presence of oral surgery. In the dataset reduced by removal of some serious complications that were judged likely to have been due to preexisting disease or the MH event, there were 349 subjects. The most frequent complications associated with dantrolene were muscle weakness (14.6%), phlebitis (9.2%), and gastrointestinal upset (4.3%). In this reduced dataset, logistic regression described a 25% increase in risk of any complication when the total dantrolene dose was doubled, a 572% increase in risk in the presence of obstetric or gynecologic surgery, a 56% decrease in risk if furosemide was given, and no relationship with fluid administration or other types of surgery. Complications after dantrolene are common, but rarely life threatening. Unidentified factors in the surgical environment are associated with changes in the risk of complications. Fluid management, as part of the treatment of MH, has an important association with the risk of complications after dantrolene administration and should be monitored closely.

Effect of feed restriction on plasma dantrolene concentrations in horses

Dantrolene sodium is used to prevent exertional rhabdomyolysis in predisposed horses. Food intake might negatively impact dantrolene bioavailability in horses; however, prolonged feed restriction might be detrimental to performance. To determine a minimum duration of feed restriction that would optimise plasma dantrolene concentrations in horses after nasogastric administration. It was hypothesised that feed restriction for 4, 8 or 12 h before dantrolene administration would result in higher plasma dantrolene concentrations than achieved with no feed restriction before treatment. Five healthy horses were randomly rotated through 4 feed restriction periods of 0, 4, 8 and 12 h duration prior to nasogastric administration of dantrolene sodium (6 mg/kg bwt). Plasma dantrolene concentration was measured by spectrofluorometry at 60, 90, 120, 150, 180 and 210 min after administration. Data were analysed via repeated measures ANOVA. Peak plasma dantrolene concentration was highest when horses had 0 and 4 h of feed restriction (0.65 ± 0.10 µg/ml at 120 min; 0.66 ± 0.17 at 180 min, respectively) and was lower when horses were restricted from feed for 8 h (0.45 ± 0.15 at 150 min) and 12 h (0.21 ± 0.09 at 180 min). Mean plasma dantrolene concentration did not differ between 0 and 4 h feed restriction at any sample time, but feed restriction for 8 h resulted in significantly lower plasma dantrolene concentration at 60 and 180 min after treatment than when horses were restricted 0 and 4 h, respectively. Plasma dantrolene concentration was significantly lower at all sample times when horses were restricted from feed 12 h compared to 0 or 4 h. Absorption of nasogastrically administered dantrolene is inhibited by feed restriction before administration. To achieve optimal plasma dantrolene concentrations, feed restriction before oral administration should not exceed 4 h.

Dantrolene for the treatment of MDMA toxicity

MDMA (3,4-methylenedioxymethamphetamine), popularly known as “Ecstasy,” was first introduced and patented by Merck & Co., Inc., in 1914 as an appetite suppressant. Currently, its primary role is as an illegal stimulant used to produce a euphoric effect during parties. This case report de scribes a 31-year-old man who, after taking 3 tablets of Ecstasy, presented to an emergency department with a decreased level of consciousness and became progressively hyperthermic and rigid. During the course of his acute illness, his temperature reached 42.2°C rectally. He was given mechanical ventilation. He was aggressively cooled and dantrolene was initiated. Soon after the administration of dantrolene his temperature decreased and his rigidity began to resolve. The only complication was rhabdomyolysis with a creatine kinase level increasing to over 150 μkat/L. This did not progress to acute renal failure. The patient made a full recovery and was discharged to psychiatry for assessment.

Clinical Presentation, Treatment, and Complications of Malignant Hyperthermia in North America from 1987 to 2006

We analyzed cases of malignant hyperthermia (MH) reported to the North American MH Registry for clinical characteristics, treatment, and complications. Our inclusion criteria were as follows: AMRA (adverse metabolic/musculoskeletal reaction to anesthesia) reports between January 1, 1987 and December 31, 2006; "very likely" or "almost certain" MH as ranked by the clinical grading scale; United States or Canadian location; and more than one anesthetic drug given. An exclusion criterion was pathology other than MH; for complication analysis, patients with unknown status or minor complications attributable to dantrolene were excluded. Wilcoxon rank sum and Pearson exact chi(2) tests were applied. A multivariable model of the risk of complications from MH was created through stepwise selection with fit judged by the Hosmer-Lemeshow statistic. Young males (74.8%) dominated in 286 episodes. A total of 6.5% had an MH family history; 77 of 152 patients with MH reported >or=2 prior unremarkable general anesthetics. In 10 cases, skin liquid crystal temperature did not trend. Frequent initial MH signs were hypercarbia, sinus tachycardia, or masseter spasm. In 63.5%, temperature abnormality (median maximum, 39.1 degrees C) was the first to third sign. Whereas 78.6% presented with both muscular abnormalities and respiratory acidosis, only 26.0% had metabolic acidosis. The median total dantrolene dose was 5.9 mg/kg (first quartile, 3.0 mg/kg; third quartile, 10.0 mg/kg), although 22 patients received no dantrolene and survived. A total of 53.9% received bicarbonate therapy. Complications not including recrudescence, cardiac arrest, or death occurred in 63 of 181 patients (34.8%) with MH. Twenty-one experienced hematologic and/or neurologic complications with a temperature <41.6 degrees C (human critical thermal maximum). The likelihood of any complication increased 2.9 times per 2 degrees C increase in maximum temperature and 1.6 times per 30-minute delay in dantrolene use. Elevated temperature may be an early MH sign. Although increased temperature occurs frequently, metabolic acidosis occurs one-third as often. Accurate temperature monitoring during general anesthetics and early dantrolene administration may decrease the 35% MH morbidity rate.

Malignant Hyperthermia-Like Syndrome and Carnitine Palmitoyltransferase II Deficiency with Heterozygous R503C Mutation

We describe a child who developed a malignant hyperthermia-like syndrome after exposure to succinylcholine and halothane. Many features of a typical malignant hyperthermia episode were present, including tachydysrhythmia, tachypnea, and fever in association with metabolic acidosis, hyperCKemia, myglobinemia, and rapid recovery without residual effects upon administration of dantrolene, sodium bicarbonate, and active cooling. Muscle rigidity, hypercarbia, and hyperkalemia were not observed. The patient was found to be heterozygous for a mutation in the carnitine palmitoyltransferase II gene (CPT2) encoding an arginine to cysteine substitution at amino acid 503 (R503C) with reduced activity of the enzyme.

Successful management of a dog that had severe rhabdomyolysis with myocardial and respiratory failure

CASE DESCRIPTION - A 6-year-old castrated male Llewelyn Setter was evaluated because of an acute onset of myalgia and respiratory distress. CLINICAL FINDINGS - Physical examination revealed a stiff stilted gait, swollen muscles that appeared to cause signs of pain, panting, and ptyalism. The dog had a decrease in palpebral reflexes bilaterally and a decrease in myotatic reflexes in all 4 limbs. The panniculus reflex was considered normal, and all other cranial nerve reflexes were intact. Serum biochemical analysis revealed markedly high cardiac troponin-I concentration and creatine kinase and aspartate aminotransferase activities. Urinalysis revealed myoglobinuria. Results for thoracic and abdominal radiography, blood pressure measurement, and an ECG were within anticipated limits. Echocardiographic findings were consistent with secondary systolic myocardial failure. Arterial blood gas analysis confirmed hypoxemia and hypoventilation. The dog had negative results when tested for infectious diseases. Examination of skeletal muscle biopsy specimens identified necrotizing myopathy. TREATMENT AND OUTCOME - Treatment included ventilatory support; IV administration of an electrolyte solution supplemented with potassium chloride; administration of dantrolene; vasopressor administration; parenteral administration of nutrients; use of multimodal analgesics; administration of clindamycin, furosemide, mannitol, and enrofloxacin; and dietary supplementation with L-carnitine and coenzyme Q(10). Other medical interventions were not required, and the dog made a rapid and complete recovery. CLINICAL RELEVANCE - Necrotizing myopathy resulting in rhabdomyolysis and myoglobinuria can lead to life-threatening physical and biochemical abnormalities. Making a correct diagnosis is essential, and patients require intensive supportive care. The prognosis can be excellent for recovery, provided there is no secondary organ dysfunction.

Anesthetic‐and heat‐induced sudden death in calsequestrin‐1‐knockout mice

Calsequestrin-1 (CASQ1) is a moderate-affinity, high-capacity Ca(2+)-binding protein in the sarcoplasmic reticulum (SR) terminal cisternae of skeletal muscle. CASQ1 functions as both a Ca(2+)-binding protein and a luminal regulator of ryanodine receptor (RYR1)-mediated Ca(2+) release. Mice lacking skeletal CASQ1 are viable but exhibit reduced levels of releasable Ca(2+) and altered contractile properties. Here we report that CASQ1-null mice exhibit increased spontaneous mortality and susceptibility to heat- and anesthetic-induced sudden death. Exposure of CASQ1-null mice to either 2% halothane or heat stress triggers lethal episodes characterized by whole-body contractures, elevated core temperature, and severe rhabdomyolysis, which are prevented by prior dantrolene administration. The characteristics of these events are remarkably similar to analogous episodes observed in humans with malignant hyperthermia (MH) and animal models of MH and environmental heat stroke (EHS). In vitro studies indicate that CASQ1-null muscle exhibits increased contractile sensitivity to temperature and caffeine, temperature-dependent increases in resting Ca(2+), and an increase in the magnitude of depolarization-induced Ca(2+) release. These results demonstrate that CASQ1 deficiency alters proper control of RYR1 function and suggest CASQ1 as a potential candidate gene for linkage analysis in families with MH/EHS where mutations in the RYR1 gene are excluded.

Malignant Hyperthermia and Heat Stroke in Calsequestrin-1 Knockout Mice

Malignant hyperthermia (MHS) and environmental heat stroke (EHS) in humans present as similar life threatening crises triggered by volatile anesthetics and strenuous exercise and/or high temperature, respectively. Many families (70-80%) diagnosed with MH susceptibility (MHS), and a few with EHS, are linked to mutations in the gene that encodes the type 1 ryanodine receptor (RYR1) located in the sarcoplasmic reticulum (SR) of skeletal muscle. However, mutations in the RYR1 gene are not found in all MH families, suggesting that alternative genes remain to be identified. Here we investigated whether a MH/EHS-like phenotype results from deficiency in skeletal muscle calsequestrin (CASQ1), a SR Ca2+-binding protein that modulates RYR1 function. Exposure of CASQ1-null mice to halothane or heat stress triggers lethal episodes characterized by elevated core temperature, whole body contractures, and severe rhabdomyolysis. Both heat- and halothane-induced episodes are prevented by prior dantrolene administration, the standard antidote used to treat MH episodes in humans. In vitro studies indicate that CASQ1-null muscle exhibits increased contractile sensitivity to caffeine, temperature-dependent increases in resting Ca2+, and an increase in the magnitude of depolarization-induced Ca2+ release. These findings validate CASQ1 as a candidate gene for linkage analysis in MH/EHS families where mutations in RYR1 are excluded.

Malignant hyperthermia developing during esophageal resection in an 82-year-old man

Malignant hyperthermia (MH) is a rare but fatal complication that develops under general anesthesia. Reports on MH in patients over the age of 80 years are unusual. We experienced a case of MH in an 82-year-old patient during esophageal resection. Anesthesia was induced with propofol and succinylcholine, and maintained with sevoflurane. Neither masseter spasm nor rigidity of the limbs was seen during induction. Body temperature (BT) at induction was 36.0 degrees C. Three hours after incision, the level of end-tidal CO2 was elevated to 55 mmHg. We assumed that the rise in end-tidal CO2 had occurred due to secretions in the airway. However, the BT, which had risen at 3 h after incision, continued to rise, and about 60 min later, the BT exceeded 39.0 degrees C. A rise of more than 0.5 degrees C in less than 15 min was seen, and MH was suspected. With dantrolene administration, the BT decreased from 40.9 degrees C at maximum to 37.7 degrees C. With continuous infusion of dantrolene when the patient was transferred to the intensive care unit (ICU), BT remained within the normal range. The next day re-operation was performed, without further complications or recurrence of MH during the postoperative period. Because it is necessary to initiate treatment in the early stage of MH, as soon as possible, although MH prevalence is low in the elderly, it is important to suspect MH when hypercapnia and/or hyperthermia are seen.

Dantrolene may prevent organophosphate-induced oxidative stress and muscle injury

The effects of dantrolene against fenthion-induced oxidative stress and muscle injury were investigated in rats. Malondialdehyde (MDA), reduced glutathione (GSH) ascorbic acid, retinol and β-carotene levels in blood were measured. Histopathological alterations and apoptosis in diaphragm were examined. Fenthion increased the level of MDA and decreased the levels of GSH in blood. Dantrolene administration prevented the rise in MDA levels and increased the GSH levels. There was no significant difference between β-carotene levels of experimental groups. However, fenthion toxicity led to decrease in ascorbic acid and retinol levels, dantrolene administration significantly prevented this decrease. Dantrolene significantly decreased the inflammation, edema and muscle necrosis or apoptosis in diaphragm muscle. Results of present study showed that toxicity of organophosphate compound fenthion increases the lipid peroxidation and depresses endogenous antioxidative systems, and leads to muscle injury in organism. Again, dantrolene administration prevents lipid peroxidation, augments antioxidant activity, and decreases muscle injury and apoptosis.