Malignant hyperthermia is a life-threatening reaction triggered by exposure to certain anesthetic agents, most commonly the volatile anesthetics sevoflurane and desflurane as well as the depolarizing muscle relaxant succinylcholine. In susceptible individuals, these drugs provoke an uncontrolled release of calcium ions from the sarcoplasmic reticulum, the intracellular storage compartment that normally regulates muscle contraction. The result is sustained, rigid contraction of skeletal muscle fibers, a massively accelerated metabolic rate, and a cascade of physiological derangements that can quickly become fatal. The cardinal signs include so-called lead pipe muscle rigidity, tachycardia, hyperthermia at or above 38.5 degrees Celsius, and a striking elevation of end-tidal carbon dioxide, the concentration of carbon dioxide measured in exhaled breath during mechanical ventilation. As the crisis progresses, muscle breakdown releases creatine kinase into the bloodstream, and patients may develop altered mental status, hypertension, and profuse sweating.

The patient in this case had been brought to the emergency department by ambulance after a rollover crash that left him with a right midshaft femur fracture, a right distal tibia and fibula fracture, and a right talar fracture. He had a remote history of childhood asthma treated with albuterol, no prior surgical history, and, crucially, no family history of adverse reactions to anesthesia. His preoperative examination documented a Mallampati class III airway, normal cardiovascular and pulmonary findings, and obesity, with functional capacity limited to less than four metabolic equivalents by his acute injuries. Nothing in his history flagged him as being at risk for malignant hyperthermia, which is precisely the point the authors emphasize: many susceptible individuals carry no warning signs until their first exposure to a triggering agent.

One day after his injury, the patient underwent open reduction and internal fixation of his fractures using a trochanteric femoral nail and an intramedullary rod for the tibia. Because he was a recent polytrauma patient with a presumed full stomach and elevated aspiration risk, the team used a rapid sequence induction strategy. He received midazolam, fentanyl, etomidate, esmolol, and succinylcholine, the latter chosen specifically to achieve rapid intubating conditions. Rocuronium was also administered for ongoing neuromuscular blockade, and sevoflurane maintained general anesthesia throughout the procedure. The operation began uneventfully, but approximately three hours after induction the surgical team noticed something alarming: the patient’s skin temperature had climbed to 39.4 degrees Celsius, or 103 degrees Fahrenheit, his end-tidal carbon dioxide had risen to 58.5 millimeters of mercury, and his heart rate was running between 120 and 130 beats per minute.

The anesthesiology team recognized an impending malignant hyperthermia crisis and immediately activated the standard protocol. Sevoflurane was discontinued, and the anesthetic was switched to total intravenous anesthesia using a propofol infusion. The patient received 100 percent oxygen, external cooling measures including ice packs, and intravenous acetaminophen. Most critically, he was given 260 milligrams of intravenous dantrolene, corresponding to approximately 2.3 milligrams per kilogram based on his perioperative weight of 113 kilograms. Within 15 minutes of the initial dantrolene bolus, the patient’s temperature began to fall and his end-tidal carbon dioxide levels normalized. The surgical team completed the operation, and the patient was transported to the intensive care unit intubated and sedated. Intraoperative records show that by 17:15, roughly 45 minutes after the crisis began, his end-tidal carbon dioxide had dropped to 37.3 millimeters of mercury and his temperature had returned to 36.7 degrees Celsius.

In the intensive care unit, the patient remained persistently tachycardic at 130 to 140 beats per minute and hypertensive despite an intravenous fluid bolus and a unit of packed red blood cells. Following recommendations from the Malignant Hyperthermia Association of the United States hotline, he received two additional doses of dantrolene at 1 milligram per kilogram every six hours. Laboratory results showed an elevated creatine kinase peaking at 6,397 units per liter, a level likely attributable to both the malignant hyperthermia episode and the up-trending muscle damage from his recent trauma, with kidney function remaining normal. He was extubated the following day and transitioned to the trauma surgery service for continued management. Three days later, he underwent a second operation to fix his talar neck fracture using total intravenous anesthesia and regional techniques, and he experienced no recurrence of malignant hyperthermia symptoms.

Before discharge, the patient and his family were counseled about suspected malignant hyperthermia susceptibility and the need to avoid future exposure to volatile anesthetics and succinylcholine unless evaluated by a malignant hyperthermia specialist. The event was communicated to his primary care provider, and referral for confirmatory testing was recommended, including consideration of genetic testing for the RYR1 and CACNA1S genes and possibly caffeine-halothane contracture testing. Family counseling and screening were also advised given the inherited nature of the condition. Notably, the authors point out that the absence of any family history in this case underscores the importance of vigilance in all patients, because de novo mutations in RYR1 or CACNA1S can produce malignant hyperthermia susceptibility in individuals with no prior warning.

One of the most instructive aspects of the case is the differential diagnosis it forced the team to work through. Hypermetabolic crises in the perioperative setting can mimic one another, and several conditions share the overlapping features of hyperthermia, tachycardia, muscle rigidity, and autonomic dysfunction. Neuroleptic malignant syndrome, caused by dopamine receptor blockade from antipsychotic drugs, produces similar findings but typically evolves over 24 to 72 hours rather than minutes, and it responds to dopamine agonists such as bromocriptine in addition to dantrolene. Thyroid storm, a life-threatening exacerbation of thyrotoxicosis, presents with tachycardia, hypertension, hyperthermia, and widened pulse pressure, but it can be distinguished by low thyroid-stimulating hormone and elevated T3 and T4 levels. Paroxysmal sympathetic hyperactivity, a feared complication after traumatic brain injury, produces episodic hypertension, fever, and dystonia through abnormal autonomic regulation rather than calcium release in skeletal muscle. Sympathomimetic toxicity from drugs such as cocaine can also cause rhabdomyolysis with hyperthermia and rigidity, but it is associated with stimulant use rather than anesthetic exposure.

In this patient, the acute intraoperative timeline, the exposure to known triggering agents, and the rapid response to dantrolene aligned strongly with malignant hyperthermia. Thyroid storm was excluded based on the absence of thyroid disease and normal thyroid function tests. Neuroleptic malignant syndrome was unlikely given no neuroleptic medication use, and paroxysmal sympathetic hyperactivity was ruled out by the lack of neurological injury. Although a formal Malignant Hyperthermia Clinical Grading Scale score was not calculated during clinical care, the combination of triggering agent exposure, acute hypercarbia, hyperthermia, tachycardia, creatine kinase elevation, and dramatic improvement after dantrolene would support a high clinical probability of the diagnosis. The authors acknowledge that confirmatory in vitro contracture testing or genetic analysis was not performed, so the event is best characterized as clinically suspected rather than definitively confirmed malignant hyperthermia.

The case also highlights the pharmacology of dantrolene, the only specific antidote for malignant hyperthermia. Dantrolene works by antagonizing ryanodine receptors within the sarcoplasmic reticulum, inhibiting the release of calcium ions and thereby dampening the overactive muscle contraction that drives the crisis. A Japanese study of 128 patients with very likely or almost certain malignant hyperthermia found that mortality dropped from 30.8 percent in those who did not receive dantrolene to 9.6 percent in those who did, a statistically significant difference. The same study found that timing mattered enormously: patients given dantrolene at an average interval of 100 minutes from the first sign of crisis had a significantly higher mortality rate than those treated within an average of 45 minutes, and higher body temperature at the time of administration was also associated with greater mortality. Since dantrolene entered clinical use, the overall mortality rate for malignant hyperthermia has fallen from roughly 70 percent in the 1960s to about 15 percent today. The most common first sign of the crisis in that study was end-tidal carbon dioxide elevation, seen in 55.8 percent of patients, followed by temperature abnormality at 19.5 percent, a finding that reinforces the value of continuous capnography in every anesthetized patient.

Ultimately, this case serves as a reminder that malignant hyperthermia diagnosis rests on early suspicion rather than absolute confirmation against a differential diagnosis, and that immediate intervention is required to prevent morbidity and death. The authors note that malignant hyperthermia remains difficult to quantify globally due to inconsistent reporting systems, but that improved data collection could inform guidelines for better preparedness. For the patient in this report, the combination of perioperative vigilance, protocol-driven intervention, and prompt dantrolene administration transformed what could have been a fatal hypermetabolic crisis into a full recovery, and his subsequent uneventful surgery under total intravenous and regional anesthesia demonstrates how susceptible patients can be safely anesthetized once the risk is recognized.

Subject of Research: A case report of suspected malignant hyperthermia during orthopedic surgery, its differential diagnosis, and the role of rapid dantrolene treatment

Article Title: Unmasking malignant hyperthermia: a rapid response to a hypermetabolic crisis: case report

Article References: Chang, E., Nalchajyan, H., Fisler, D. A., Lee, C., Cintron, L. L., & Nathan, N. (2026). Unmasking malignant hyperthermia: a rapid response to a hypermetabolic crisis: case report. Frontiers in Anesthesiology, 5, Article 1829469. https://doi.org/10.3389/fanes.2026.1829469

Image Credits: AI Generated

DOI: 10.3389/fanes.2026.1829469

Keywords: malignant hyperthermia, dantrolene, anesthesia, succinylcholine, sevoflurane, hypermetabolic crisis, RYR1, case report, perioperative medicine, hypercarbia, rhabdomyolysis, differential diagnosis

Congenital myopathies are a heterogeneous family of disorders that typically announce themselves in early childhood with floppiness and generalised muscle weakness, most prominently in the muscles closest to the trunk. Severity spans an enormous range: the most affected infants are born with respiratory insufficiency and swallowing difficulties, while milder cases may only become apparent in adolescence or adulthood. Birth prevalence has been estimated at roughly 15 per 100,000 live births, and more than 40 different genes have been implicated, although about one in five patients still lack a confirmed genetic diagnosis. Despite this genetic diversity, the underlying cellular defects converge on a handful of mechanisms, including disturbed calcium handling in muscle fibres, abnormal sarcomeric proteins, and defects in membrane trafficking and cytoskeletal organisation.

It is precisely this convergence that made salbutamol an attractive candidate. As a β2-adrenergic agonist, the drug exerts anabolic effects on skeletal muscle, increasing protein synthesis, reducing protein degradation, and shifting myosin heavy chain expression from slow type I fibres towards fast type IIa fibres. Many congenital myopathies share type 1 fibre predominance and muscle fibre atrophy, so a drug that counteracts these features could plausibly help patients regardless of which faulty gene they carry. Earlier open-label studies in Duchenne muscular dystrophy and facioscapulohumeral muscular dystrophy hinted at short-term gains, but placebo-controlled trials failed to show sustained benefit, and a small pilot in core myopathies was too limited in design to be conclusive.

The new trial, known as COMPIS, was designed to settle the question with far greater rigour. Led by researchers at Queen Silvia’s Children’s Hospital in Gothenburg, with nationwide recruitment through paediatric neuromuscular centres in Stockholm, Lund/Malmö and Uppsala, the study enrolled 18 participants aged 6 to 30 with genetically verified congenital myopathies. Crucially, the cohort included both children who could walk and those who could not, and baseline functional severity ranged from severely impaired to mildly affected. Genetic causes included variants in RYR1, ACTA1, NEB, SELENON, TPM2, TPM3 and MYBPC1, reflecting the true diversity of clinical practice rather than a narrowly selected subgroup.

The crossover design meant every participant served as their own control. After a screening visit, participants were randomised to receive either 24 weeks of daily oral salbutamol added to standard of care, or standard of care alone, followed by a four-week washout and then the alternate treatment. Because participants and treating physicians inevitably knew which treatment was being given, the investigators masked the physiotherapists and occupational therapists who performed all functional assessments, ensuring that outcome measurement remained objective. The primary endpoint was the Motor Function Measure-32, a validated 32-task assessment of gross and fine motor function scored out of 96 points.

The results were unambiguous. During salbutamol treatment, the mean MFM-32 total score rose by 3.72 points, compared with an essentially flat 0.11 points during standard care alone, yielding an adjusted mean difference of 3.61 points in favour of the drug. That margin exceeds previously established thresholds for clinically meaningful change in congenital-onset neuromuscular disorders. Improvements were concentrated in the domains most affected by the disease, namely standing and transfers, and axial and proximal motor function. Dominant hand grip strength also increased significantly, and muscle strength measured by hand-held myometry trended upwards across all tested muscle groups.

Perhaps most striking were the gains in respiratory and ambulatory function. Seated forced vital capacity, a key indicator of breathing capacity, increased by 0.20 litres relative to control, a difference the authors consider particularly important because respiratory insufficiency is a common and morbid manifestation of congenital myopathies even when limb function appears stable. Among the 11 ambulatory participants, six-minute walking distance improved by an estimated 38 metres, and the time needed to rise from lying on the floor fell by 1.6 seconds, corresponding on log-scale analysis to a 9 percent increase in walking distance and a 23 percent reduction in rise time. For families, such gains translate into greater independence and delayed reliance on assistive devices and home adaptations.

Safety and tolerability were reassuring. Only two adverse events occurred during salbutamol treatment, neither clearly related to the drug, and there were no serious adverse events. Six participants experienced mild, expected pharmacological side effects, chiefly transient palpitations and one case of tremor, which resolved within one to two weeks in nearly all cases. No arrhythmias or clinically relevant electrocardiographic abnormalities emerged, blood pressure and heart rate stayed within normal ranges, and no participant discontinued treatment. Notably, every single participant chose to continue taking salbutamol after the study ended. Five participants gained a clinically significant amount of weight during treatment, reporting increased appetite, but statistical adjustment for weight change did not alter the findings.

The authors are careful to acknowledge limitations. The sample of 18 participants, while a triumph of recruitment in such a rare disease, was too small to detect differences in response by genotype, age or sex, and the open-label nature means patient-reported outcomes could be influenced by expectation. Longer-term studies will be needed to determine whether the benefits persist. Nevertheless, the trial stands as the first randomised, controlled, blinded-endpoint study of salbutamol in this population, and its implications reach beyond congenital myopathies. At a time when gene therapies for these disorders have stumbled, one trial was halted after treatment-related deaths, salbutamol offers a low-cost, globally marketed alternative that could be deployed now under multidisciplinary neuromuscular care, with baseline cardiac evaluation and monitoring. The researchers also emphasise a broader lesson: as repurposed medicines enter clinical practice, preserving the affordability and worldwide availability of generic drugs will be essential to ensuring equitable access for the patients who need them.

Subject of Research: A randomised crossover trial of oral salbutamol for motor function and muscle strength in congenital myopathies

Article Title: Effects of oral salbutamol treatment on motor function and muscle strength in congenital myopathies (COMPIS): a single-centre, randomised, open-label, blinded-endpoint, crossover trial in Sweden

Article References: Michael, E., Staaf, P., Gudmundsson, M., Klanac, B., Weichbrodt, J., Edofsson, U., Thuestad, I. J., Sejersen, T., Imberg, H., & Darin, N. (2026). Effects of oral salbutamol treatment on motor function and muscle strength in congenital myopathies (COMPIS): a single-centre, randomised, open-label, blinded-endpoint, crossover trial in Sweden. eClinicalMedicine, Article 104186. https://doi.org/10.1016/j.eclinm.2026.104186

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104186

Keywords: congenital myopathies, salbutamol, drug repurposing, neuromuscular disorders, randomised crossover trial, muscle strength, motor function, respiratory function, RYR1, pediatric neurology, eClinicalMedicine, rare disease