RARE DISEASE
Malignant hyperthermia of anesthesia
Malignant hyperthermia of anesthesia
Malignant hyperthermia of anesthesia
Synonyms: Hyperthermia of anesthesia
Synonyms: Hyperthermia of anesthesia
Synonyms: Hyperthermia of anesthesia
Drug discovery
3
drugs
With orphan designations
Overview
Malignant hyperthermia (MH) is a life-threatening pharmacogenetic disorder triggered by volatile anesthetics and succinylcholine, causing uncontrolled skeletal muscle hypermetabolism. It stems from RYR1/CACNA1S gene mutations, leading to excessive calcium release in muscle cells. Acute presentations include hypercapnia, tachycardia, rigidity, hyperthermia (>39°C), and acidosis. Immediate trigger cessation, IV dantrolene (2.5–10 mg/kg), and active cooling are critical to reduce mortality from 70% to <5% [1][7][11][12].
Therapies
Emergency: Stop triggers; administer dantrolene (2.5 mg/kg IV bolus, repeated until resolved); hyperventilate with 100% O₂; active cooling (iced fluids, surface cooling) [3][8][17].
Prophylaxis: Use charcoal filters to prep anesthesia machines (<5 ppm volatile agents); avoid triggers in confirmed/suspected cases [1][7].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
877 drug discovery papers about Malignant hyperthermia of anesthesia, with 2 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
877 drug discovery papers about Malignant hyperthermia of anesthesia, with 2 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-05-31 | Anesthesia Management in a Patient With a History of Fulminant Malignant Hyperthermia and a Homozygous RYR1 p.Arg530His Variant Undergoing Laparoscopic Surgery: A Case Report.
BACKGROUND Malignant hyperthermia (MH) is a rare but potentially fatal pharmacogenetic disorder triggered by volatile anesthetics or suxamethonium, most commonly associated with variants in the ryanodine receptor type 1 (RYR1) gene. Patients with confirmed or suspected MH susceptibility are advised to avoid triggering agents and undergo regional anesthesia or total intravenous anesthesia (TIVA). Remimazolam, an ultra-short-acting benzodiazepine approved in Japan for general anesthesia, has been shown in vitro not to increase intracellular calcium concentrations in cells expressing MH-associated RYR1 variants. However, clinical evidence regarding its safety in genetically confirmed MH remains limited. CASE REPORT An 80-year-old man with a history of fulminant MH at age 39, successfully treated with dantrolene, was scheduled for laparoscopic inguinal hernia repair. Previous calcium-induced calcium release testing confirmed MH susceptibility. Genetic analysis revealed homozygosity for the RYR1 c.1589G>A (p.Arg530His) variant, classified as likely pathogenic. Given his history and cardiovascular comorbidities, remimazolam-based TIVA was selected. Anesthesia was induced and maintained with remimazolam, remifentanil, and rocuronium under strict MH precautions, including immediate availability of dantrolene. Intraoperative end-tidal carbon dioxide, core temperature, and hemodynamics remained stable, with no signs of MH. Neuromuscular blockade was reversed with sugammadex, and recovery was uneventful without postoperative complications. CONCLUSIONS Remimazolam-based TIVA was successfully administered in a patient with genetically confirmed MH susceptibility carrying a homozygous likely pathogenic RYR1 variant. The perioperative course was uneventful, suggesting that remimazolam-based TIVA may be a feasible anesthetic approach in selected high-risk MH-susceptible patients, including those with severe prior episodes and significant cardiovascular comorbidities.
2026-05-26 | Beyond the first bout: Adaptations to repeated injuries across physiological and pathological conditions.
Skeletal muscle exhibits remarkable plasticity following injury, yet most research has focused on responses to a single bout of eccentric contractions. This review addresses adaptations to repeated eccentric contraction-induced injuries across physiological and pathological conditions, with emphasis on insights from preclinical rodent models. In healthy muscle, the repeated bout effect (RBE) reduces strength loss and accelerates recovery after subsequent bouts. However, these adaptations are highly condition dependent. Aging can attenuate the RBE, while dystrophic muscle remains vulnerable to repeated injury despite compensatory remodeling. Other factors, including but not limited to, chronic alcohol intake and malignant hyperthermia can influence these responses, though their effects vary and do not universally abolish adaptation. Collectively, these findings highlight that the trajectory of muscle adaptation depends on its physiological state and underlying pathology. Understanding these condition-specific mechanisms is essential for developing targeted strategies to optimize recovery, maximize adaptations, and preserve muscle health across diverse populations.
2026-04-11 | Use of total intravenous anesthesia with propofol and a vaporizer-free ventilator to prevent recurrence of malignant hyperthermia in a dog.
Malignant hyperthermia (MH) is a rare, life-threatening perioperative complication most commonly triggered by inhalant anesthetics or depolarizing neuromuscular blocking agents. Genetic variants affecting skeletal muscle are believed to underlie the susceptibility to MH. Although total intravenous anesthesia (TIVA) has been employed in human patients with MH susceptibility as a nontriggering alternative, comparable data and standardized protocols are limited in veterinary medicine. A 13-year-old spayed female Toy Poodle dog with a history of suspected MH during isoflurane anesthesia 4 years earlier, characterized by a rapid increase in body temperature (42.0 °C) and end-tidal carbon dioxide tension (PE´CO2), and successfully treated with active cooling and dantrolene administration, presented for treatment of an asymptomatic tongue mass. General anesthesia was planned to facilitate a thorough oral examination and biopsy. TIVA with propofol was performed to prevent MH recurrence, using a vaporizer-free ventilator. Following anesthetic premedication with buprenorphine (20 μg kg-1, intravenously) and atropine sulfate (25 μg kg-1, subcutaneously), anesthesia was induced with propofol to allow endotracheal intubation and maintained with a propofol variable rate intravenous infusion (0.4-0.5 mg kg-1 minute-1) under mechanical ventilation with 100% oxygen. Dantrolene was available but was not required. During the 37-minute anesthetic period, rectal temperature gradually decreased, and PE´CO2 remained stable. Inspired isoflurane fraction was undetectable during the perioperative period. Recovery was smooth, and postoperative blood tests revealed only mild creatine kinase elevation. Whole-genome sequencing of peripheral blood DNA revealed a missense variant in the ryanodine receptor gene (RYR1), identical to a known human MH-causing mutation (p.Arg2435His). This case suggests that propofol-based TIVA combined with a vaporizer-free ventilator can safely prevent MH recurrence in genetically susceptible dogs, highlighting the importance of eliminating all potential MH triggers in susceptible individuals.
2026-05-31 | Anesthesia Management in a Patient With a History of Fulminant Malignant Hyperthermia and a Homozygous RYR1 p.Arg530His Variant Undergoing Laparoscopic Surgery: A Case Report.
BACKGROUND Malignant hyperthermia (MH) is a rare but potentially fatal pharmacogenetic disorder triggered by volatile anesthetics or suxamethonium, most commonly associated with variants in the ryanodine receptor type 1 (RYR1) gene. Patients with confirmed or suspected MH susceptibility are advised to avoid triggering agents and undergo regional anesthesia or total intravenous anesthesia (TIVA). Remimazolam, an ultra-short-acting benzodiazepine approved in Japan for general anesthesia, has been shown in vitro not to increase intracellular calcium concentrations in cells expressing MH-associated RYR1 variants. However, clinical evidence regarding its safety in genetically confirmed MH remains limited. CASE REPORT An 80-year-old man with a history of fulminant MH at age 39, successfully treated with dantrolene, was scheduled for laparoscopic inguinal hernia repair. Previous calcium-induced calcium release testing confirmed MH susceptibility. Genetic analysis revealed homozygosity for the RYR1 c.1589G>A (p.Arg530His) variant, classified as likely pathogenic. Given his history and cardiovascular comorbidities, remimazolam-based TIVA was selected. Anesthesia was induced and maintained with remimazolam, remifentanil, and rocuronium under strict MH precautions, including immediate availability of dantrolene. Intraoperative end-tidal carbon dioxide, core temperature, and hemodynamics remained stable, with no signs of MH. Neuromuscular blockade was reversed with sugammadex, and recovery was uneventful without postoperative complications. CONCLUSIONS Remimazolam-based TIVA was successfully administered in a patient with genetically confirmed MH susceptibility carrying a homozygous likely pathogenic RYR1 variant. The perioperative course was uneventful, suggesting that remimazolam-based TIVA may be a feasible anesthetic approach in selected high-risk MH-susceptible patients, including those with severe prior episodes and significant cardiovascular comorbidities.
2026-05-26 | Beyond the first bout: Adaptations to repeated injuries across physiological and pathological conditions.
Skeletal muscle exhibits remarkable plasticity following injury, yet most research has focused on responses to a single bout of eccentric contractions. This review addresses adaptations to repeated eccentric contraction-induced injuries across physiological and pathological conditions, with emphasis on insights from preclinical rodent models. In healthy muscle, the repeated bout effect (RBE) reduces strength loss and accelerates recovery after subsequent bouts. However, these adaptations are highly condition dependent. Aging can attenuate the RBE, while dystrophic muscle remains vulnerable to repeated injury despite compensatory remodeling. Other factors, including but not limited to, chronic alcohol intake and malignant hyperthermia can influence these responses, though their effects vary and do not universally abolish adaptation. Collectively, these findings highlight that the trajectory of muscle adaptation depends on its physiological state and underlying pathology. Understanding these condition-specific mechanisms is essential for developing targeted strategies to optimize recovery, maximize adaptations, and preserve muscle health across diverse populations.
2026-04-11 | Use of total intravenous anesthesia with propofol and a vaporizer-free ventilator to prevent recurrence of malignant hyperthermia in a dog.
Malignant hyperthermia (MH) is a rare, life-threatening perioperative complication most commonly triggered by inhalant anesthetics or depolarizing neuromuscular blocking agents. Genetic variants affecting skeletal muscle are believed to underlie the susceptibility to MH. Although total intravenous anesthesia (TIVA) has been employed in human patients with MH susceptibility as a nontriggering alternative, comparable data and standardized protocols are limited in veterinary medicine. A 13-year-old spayed female Toy Poodle dog with a history of suspected MH during isoflurane anesthesia 4 years earlier, characterized by a rapid increase in body temperature (42.0 °C) and end-tidal carbon dioxide tension (PE´CO2), and successfully treated with active cooling and dantrolene administration, presented for treatment of an asymptomatic tongue mass. General anesthesia was planned to facilitate a thorough oral examination and biopsy. TIVA with propofol was performed to prevent MH recurrence, using a vaporizer-free ventilator. Following anesthetic premedication with buprenorphine (20 μg kg-1, intravenously) and atropine sulfate (25 μg kg-1, subcutaneously), anesthesia was induced with propofol to allow endotracheal intubation and maintained with a propofol variable rate intravenous infusion (0.4-0.5 mg kg-1 minute-1) under mechanical ventilation with 100% oxygen. Dantrolene was available but was not required. During the 37-minute anesthetic period, rectal temperature gradually decreased, and PE´CO2 remained stable. Inspired isoflurane fraction was undetectable during the perioperative period. Recovery was smooth, and postoperative blood tests revealed only mild creatine kinase elevation. Whole-genome sequencing of peripheral blood DNA revealed a missense variant in the ryanodine receptor gene (RYR1), identical to a known human MH-causing mutation (p.Arg2435His). This case suggests that propofol-based TIVA combined with a vaporizer-free ventilator can safely prevent MH recurrence in genetically susceptible dogs, highlighting the importance of eliminating all potential MH triggers in susceptible individuals.
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Drug Discovery Landscape
3 orphan drug designations for Malignant hyperthermia of anesthesia, including 1 approved therapy.
3 orphan drug designations for Malignant hyperthermia of anesthesia, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Dantrolene sodium, hemiheptahydrate [Agilus] | small molecules | EMA | 2021-05-20 | — | Norgine B.V. |
Dantrolene sodium | small molecules | EMA | 2014-11-19 | — | Maxia Strategies-Europe Limited |
dantrolene sodium suspension for injection [RYANODEX] | small molecules | FDA | 2013-08-16 | 2014-07-22 | Eagle Pharmaceuticals, Inc. |
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