Malignant hyperthermia (MH) is a potentially life-threatening disorder of skeletal muscle characterized by a hypermetabolic response to volatile inhalant anesthetics and the depolarizing muscle relaxant succinylcholine in susceptible individuals [1]. These inducing agents trigger uncontrolled calcium release from the sarcoplasmic reticulum in these individuals. This release leads to abnormally sustained skeletal muscle contraction and clinical signs of MH, which include hyperthermia, rhabdomyolysis, and lactic acidosis [2,3]. The incidence of MH is reported to range from 1:100,000 to 1:250,000 administered anesthetics [1]. Previous studies have shown that 52.1% of all MH episodes occur in children under 15 years old [4].

Dantrolene is the only drug known to specifically treat MH by inhibiting the release of calcium from the sarcoplasmic reticulum [5]. Following the introduction of dantrolene, the mortality rate of MH dramatically decreased from 70%–80% to 5% [1]. For MH patients unresponsive to medical treatments, extracorporeal membrane oxygenation (ECMO) may be considered. However, there have only been two reported cases of successful ECMO use in adults, with no reported cases in pediatric patients [6,7].

Here, we present the case of an 8-year-old boy diagnosed with MH who was supported with venoarterial (VA) ECMO but did not survive. The Institutional Review Board of Samsung Medical Center approved this study and waived the need for informed consent (IRB No. 2024-11-128).

An 8-year-old boy was transferred to Samsung Medical Center, a tertiary hospital, from an ophthalmology hospital with a suspected diagnosis of MH. His height was 125 cm (10th–25th percentile), and his weight was 24.0 kg (10th–25th percentile). His medical history was unremarkable, except for bilateral ptosis that had been monitored since he was 13 months old. He had never been under general anesthesia before, and there was no family history of MH.

In the operating room, he was given 0.1 mg of glycopyrrolate, followed by 25 μg of fentanyl, 50 mg of propofol and 15 mg of rocuronium. After successful intubation, anesthesia was maintained with sevoflurane, and end-tidal carbon dioxide (EtCO₂) levels were monitored. Shortly after administering sevoflurane, the patient's EtCO₂ levels increased, although there was no evidence of impaired ventilation. Following the administration of 50 mg of sugammadex, the patient was extubated once spontaneous respiration resumed. However, immediately after extubation, his body temperature rose to 39 °C, and his heart rate increased to 200–210 beats per minute. His respiration became unstable, and reintubation was unsuccessful due to his inability to open his mouth. Instead, a subglottic airway device (I-gel, Intersurgical) was inserted and he was transferred while being ambu-bagged for further management, including dantrolene administration, which was not available before transfer. During the transfer, ventricular fibrillation occurred, lasting less than 10 seconds, and sinus conversion was achieved without defibrillation.

The patient arrived at the hospital 30 minutes after induction. Upon arrival, his non-invasively measured blood pressure was 43/17 mm Hg, his heart rate was 180/min, his oxygen saturation was 99%, and his body temperature measured through an esophageal monitor was 42 °C. Physical and neurological examinations revealed a comatose mental status, normal pupil reflexes, and whole-body rigidity. He suffered a cardiac arrest due to asystole, and return of spontaneous circulation was achieved after 6 minutes of cardiopulmonary resuscitation. An induction dose of 2.5 mg/kg of dantrolene was administered 20 minutes after arrival and was repeated for two more doses at 10-minute intervals because there were no signs of improvement. His arterial blood pressure was 33/26 mm Hg, heart rate was 130/min, oxygen saturation was 98%, and body temperature was 40.7 °C when the first dose of dantrolene was given. After the third dose of dantrolene, rigidity improved, and we were able to intubate the patient and started mechanical ventilation. EtCO₂ was measured at 33 mm Hg. The patient’s body temperature also dropped to 36.5 °C. Dantrolene was maintained with a dose of 1 mg/kg four times per day after reintubation. Initial arterial blood gas analysis after the return of spontaneous circulation showed the following values: pH, 6.97; pCO₂, 69 mm Hg; pO₂, 55 mm Hg; bicarbonate, 15.9 mmol/L; base excess, –15.9 mmol/L; and lactic acid, 19.6 mmol/L (Table 1). The initial potassium level was 8.6 mmol/L and continuous renal replacement therapy was started. The MH clinical grading scale was 88 points, indicating that MH was almost certain [8]. Despite the use of dopamine, dobutamine, norepinephrine, vasopressin, and epinephrine at the highest doses, his arterial blood pressure did not rise above a mean arterial pressure of 45 mm Hg, and bedside echocardiography showed an ejection fraction of 35%–45% in the left ventricle. Due to medically refractory shock with left ventricular dysfunction and the risk of additional episodes of arrhythmia, it was decided to initiate VA-ECMO. Peripheral VA-ECMO was inserted using a 17-Fr cannula in the right femoral vein for drainage, a 5-mm Gore-Tex graft with a 14-Fr cannula to the right femoral artery for perfusion, and a Permanent Life Support (MAQUET GmbH) oxygenator. The initial blood flow rate was 1.2 L/min, and the sweep gas-flow rate was 1.0 L/min. Disseminated intravascular coagulation developed during the insertion of VA-ECMO, and active bleeding was noted from the central line insertion site, endotracheal tube, Levin tube, and arterial line. Due to the bleeding tendency, no anticoagulation was used to maintain VA-ECMO. However, despite ongoing care, shock was not reversed. The mean arterial blood pressure failed to recover, and diffuse intravascular coagulation along with multi-organ failure progressed. Bleeding continued despite transfusions of 53 packs of fresh frozen plasma, 3 packs of cryoprecipitate, 14 packs of platelets, and 22 packs of RBC over 5 days. Muscle enzymes and the liver profile increased continuously, and the coagulation profile did not improve. On the fourth day of admission, the pupils became fully dilated and fixed. Brain computed tomography showed diffuse cerebral edema with a suspected watershed injury, and an electroencephalogram confirmed electrocerebral silence (Fig. 1). He was deemed brain-dead the next day.

Next-generation sequencing for skeletal muscle channelopathies and related disorders was performed on the 3rd day of admission and demonstrated heterozygous pathogenic variants of Ryanodine receptor 1 (RyR1) gene (c. 529C>T [p. Arg177Cys] and c. 9310G>A [p. Glu3104Lys]). Parents were counseled on the result, and genetic testing for parents and the patient’s brother was recommended.

We present the first case of pediatric MH supported with VA-ECMO. The patient did not recover from refractory shock and multi-organ failure associated with MH despite VA-ECMO support. Compared to previous cases of MH supported with ECMO, our case suggests that the application of VA-ECMO may prolong survival but not improve overall outcomes without the improvement of underlying MH.

MH is a pharmacogenetic disorder characterized by a hypermetabolic response to certain triggering agents in susceptible individuals [1]. The most well-known triggers are volatile anesthetic gases and muscle relaxants; however, vigorous exercise and heat can also occasionally provoke MH [9]. In susceptible individuals, exposure to these triggers causes the sarcoplasmic reticulum in skeletal muscle cells to release calcium uncontrollably, resulting in sustained muscle contraction and increased consumption of oxygen and adenosine triphosphate [10]. If this hypermetabolic state and muscle contraction continue, clinical signs such as hyperthermia, tachycardia, rigidity, and hypercarbia may develop, often indicated by an unexplained rise in EtCO₂ in operating rooms [1]. MH can be fatal when complications develop, including rhabdomyolysis, disseminated intravascular coagulation, and multi-organ dysfunction [11]. Recrudescence, or the return of signs and symptoms of MH hours after the initial event, is also reported in as many as 25% of cases [1]. A previous report suggested that the clinical presentation of pediatric MH may differ from that seen in adults. In pediatric cases, sinus tachycardia is the most commonly observed symptom, followed by hypercarbia and a rapid increase in temperature [12]. Masseter rigidity has been more frequently observed in children aged 2 to 12 years, as in our case. In cases where MH is suspected but not confirmed, the MH clinical grading scale can be used to assess the likelihood of MH. A higher score on this scale is also associated with a higher rate of recrudescence. Scores above 50 are categorized as almost certainly indicative of MH, as in our case [8].

Dantrolene is the only known antidote to MH. It works by binding to the RYR1 receptor, which regulates the flow of calcium from the sarcoplasmic reticulum to the intracellular space. This action helps reverse MH by reducing intracellular calcium levels [13]. Since the introduction of dantrolene, the mortality rate of MH has dramatically decreased from 70% to less than 10% [1]. Early administration of dantrolene is also crucial in reducing complications. It was reported that the complication rate increased 1.6 times for every 30-minute delay between the first sign of MH and the first dose of dantrolene [11]. A Canadian study also reported that every 10-minute delay in dantrolene administration after the first sign increased the complication rate, and a 50-minute delay was associated with a 100% complication rate [14]. Therefore, a loading dose of 2.5 mg/kg of dantrolene is recommended as soon as MH is suspected, with additional doses considered if the patient does not respond [1]. However, the diagnosis should be reconsidered if the patient does not respond to doses beyond 10 mg/kg [11]. Similarly, in our case, the patient showed clinical signs of improvement in body temperature and rigidity after receiving the third loading dose of dantrolene.

ECMO is generally not considered in the management of MH, with only two reported cases of successful adult ECMO use [6,7]. One case involved a 29-year-old male with refractory MH during elective surgery for a traumatic lumbar vertebral fracture. He was maintained on venovenous ECMO for less than 24 hours and subsequently recovered [7]. The other case involved a 56-year-old male who developed refractory MH during emergency surgery for a transurethral resection of a bladder tumor [6]. This patient experienced a 15-second cardiac arrest, and VA-ECMO was initiated due to refractory shock. Over the next 60 hours, the patient improved and was successfully weaned off VA-ECMO. The reasons for the different clinical outcomes in our case compared to the previously described adult ECMO cases may vary. First, the 50-minute delay between induction and the administration of the first dose of dantrolene could have heightened the risk of complications such as diffuse intravascular coagulation and multi-organ failure, as noted in a Canadian study [14]. Second, VA-ECMO could have contributed to active bleeding in our case, as hematologic derangements are common while maintaining VA-ECMO [15]. Third, persistent or recurrent MH may have influenced the clinical course, as suggested by the lack of improvement in disseminated intravascular coagulation, creatine kinase, and myoglobin levels. Additionally, the flow temperature of VA-ECMO could have obscured the actual high body temperature. Regarding our case, it is crucial to highlight the importance of early dantrolene administration, along with vigilant monitoring and supportive care for disseminated intravascular coagulation and multi-organ failure in pediatric MH. Regardless of the underlying reasons, we believe that the patient could not have survived the first day without VA-ECMO. However, without recovery of underlying MH, VA-ECMO may only prolong the hospital stay without improvement. Further studies are necessary to evaluate the efficacy of ECMO in pediatric MH.

Genetic tests can provide additional information regarding MH patients and their family members. Most MH cases follow an autosomal dominant pattern of inheritance with incomplete penetrance [16]. The most commonly associated gene is RYR1, which encodes a calcium channel in the sarcoplasmic reticulum whose activation releases calcium from the sarcoplasmic reticulum, leading to muscle contraction [17]. It is the main target of dantrolene, and as many as 75% of susceptible MH cases are associated with RYR1 gene variants [18]. Detecting pathogenic mutations in relatives of a known MH patient can help prevent future episodes of MH. Therefore, genetic testing is recommended for individuals with a family history of a causative MH mutation [19]. Compared to the caffeine halothane contracture test, which is the current gold standard but invasive and expensive, genetic tests only require a blood sample and are more feasible for critically ill patients [20]. In our case, genetic tests were conducted, and known pathogenic variants were detected. Although the genetic test results for other family members were not available in our case, reporting pathogenic mutations and recommending genetic testing for family members remain crucial for preventing future MH episodes.

In conclusion, the use of VA-ECMO in pediatric MH could be considered when refractory shock and multi-organ failure progress. However, recovery from underlying MH is crucial for survival. Genetic tests should be considered in MH for further management of the patient and family members.