Malignant hyperthermia (MH) is a rare pharmacogenetic syndrome, which is characterized as a severe hypermetabolic reaction followed by halogenated inhalational anesthetic administration and/or depolarizing muscle relaxants, such as succinylcholine. Therefore, patients at risk of MH need trigger-free anesthesia in order to avoid life-threatening metabolic crises. This report discusses a case of MH in a six-year-old patient, during an Orchidopexy and Urethrocutaneous Fistul's Correction under general anesthesia. Inhalational induction was carried out using Sevoflurane, whereas propofol and fentanyl were afterward administered. During the procedure, the patient developed hypercapnia, significant temperature rise, masseter rigidity, and hyperkalemia. With a diagnostic hypothesis of MH, a protocol guided by the Hotline for MH was applied, leading to a great patient response that made it possible to transfer the child to the Pediatric Intensive Care Unit where dantrolene was administered, allowing good control of the patient's general condition. 

Keywords: Malignant hyperthermia, Pediatric anesthesia, Patient Safety, Trigger-free anesthesia, Case report. 

MH, malignant hyperthermia; creatine phosphokinase (CK); RYR1, ryanodine receptor; CACNA1S, dihydropyridine receptor.

Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic disease triggered by the use of muscle relaxants, such as succinylcholine and halogenated anesthetics (halothane, isoflurane, and sevoflurane).¹ This disease is usually characterized by tachycardia, tachypnea, hypercarbia, and muscular rigidity, with a strong potential to progress to hyperthermia, metabolic acidosis, rhabdomyolysis, and death. Its prevalence is more common in children (1:10 000 anesthesia procedures) with half of cases recorded in patients under 15 years.² The disease's physiopathology is caused by mutations in dihydropyridine and ryanodine receptor genes that, when  exposed to stimulant agents, induce calcium release that leads to local or generalized muscular rigidity. Additionally, when the sarcoplasmic reticulum releases calcium ions beyond physiological levels, the excessive contractures encourage increased oxygen use, excessive CO2 production, hyperthermia (an increase in body temperature of 1 to 2°C per five minutes), and rhabdomyolysis.²

Treatment options include prompt cessation of the trigger agents, 100% oxygen delivery, prompt intravenous administration of dantrolene (via rapid intravenous bolus), temperature management, and control and infusing sodium bicarbonate, to minimize death chances.¹ We report the case of a six-year-old patient with a clinical presentation of MH who responded adequately to discontinuation of the inhalational anesthetic infusion, hyperoxygenation, dantrolene (2.5 mg/kg) administered twice, and cold packs application. After being extubated and transferred to the Pediatric Intensive Care Unit and having dantrolene administered every 6 hours followed by hydration, the patient’s clinical condition was controlled.

A six-year-old male was admitted to an Orchidopexy and Urethrocutaneous Fistul's Correction under general anesthesia. An inhalational induction was performed using sevoflurane, and later, propofol and fentanyl were managed. Thus, during the surgical procedure, the patient developed hypercapnia with PCO₂ up to 170. Besides, a significant rise in his temperature was noticed (40.39ºC), along with masseter rigidity and hyperkalemia of 5.7mmol/L. Therefore, a protocol guided by the Hotline for Malignant Hyperthermia was applied, achieving the following outcomes: discontinuation of inhalational anesthetic infusion, hyperoxygenation, following intravenous administration of dantrolene at a dose of 2.5 mg/kg administered twice, and an application of cold packs. The child tolerated the procedure well, exhibiting reduced CO₂ levels, improvement of muscle rigidity, and lowered body temperature. Subsequently, the patient was extubated and transferred to the Pediatric ICU, where he stayed for 24 hours, in ambient air with a central venous catheter that was inserted in the right subclavian vein. In addition, a 20mm gauge peripheral venous catheter was inserted in the right cubital region, and through an indwelling bladder probe, a clear yellow urine could be observed. Maintenance doses of dantrolene were administered every 6 hours, and hydration was maintained with BIC over 24 hours. Among the laboratory findings, the changes related to MH found in the patient were an elevation of muscle enzymes (creatine kinase – CK 7.900U/L in 08/08/2023; Potassium 3,3 mg), highlighting rhabdomyolysis. On the next day (09/08/2023), the patient was transferred to the hospital ward, where the use of dantrolene every 6 hours was continued until the next morning. Thus, on August 10th at 6:00 am, it was given to the patient his last dose of dantrolene, and also new tests were collected to monitoring the patient's overall conditions since it is expected development of acute renal failure. 

We are reporting on the case of a pediatric patient who had a clinical presentation of MH, during a surgical procedure, after being given sevoflurane anesthesia in order to perform an Orchidopexy and Urethrocutaneous Fistul's Correction.¹

Malignant Hyperthermia incident episodes during anesthesia are between 1:10,000 and 1:250,000, specifically in pediatric patients.² Even though MH may be triggered after first exposure to anesthesia with known agents, on average, these patients require three exposures to such anesthetics before it is triggered. Male patients are most affected at a 2:1 ratio. In addition to that, pediatric patients under 15 years old make up 52% of reported cases. This is an autosomal dominant genetic disease with mutation mainly in the gene for the ryanodine receptor (RYR1) and the dihydropyridine receptor (CACNA1S), that manifests as a hypermetabolism of the skeletal muscle crises associated with some anesthetics. These mutations promote the excessive and prolonged release of calcium into the cytoplasm, causing a hypermetabolism of  skeletal muscle and muscle rigidity. The muscle disease causes collapse of the muscle fiber and acute and generalized necrosis, triggering rhabdomyolysis.²

The hypermetabolism due to the increased oxygen consumption and production of CO₂ leads to metabolic acidosis and destroy the membrane of muscle fibers, and, because of that, the test results show elevated  myoglobin, as well as prothrombin time, creatine phosphokinase (CK) and potassium. Besides that, more complications can occur in other organs and systems, for instance, tachypnea, cardiac dysfunction, acute pulmonary edema, acute renal failure, hepatic dysfunction, cardiac arrest, disseminated intravascular coagulation, and coma.²

In addition, it is crucial to be attentive to the possibility of developing  risk of acute renal failure. In rhabdomyolysis, there is a release of intracellular constituents, such as myoglobin, oxidative injury associated with myoglobin, and toxic vasoactive substances, which can be transformed into hematin in the kidneys. This substance is toxic to the kidneys, increasing the risk of ischemia due to renal vasoconstriction and tubular toxicity. Additionally, hemoglobin crystals can be formed, further reducing renal flow.² There are molecular studies that can assess the occurrence and recurrence’s risk of MH episodes. However,  the genetic test isn't available for all patients because of its high cost and technical difficulty. As a result, the definitive diagnosis of MH susceptibility depends solely on caffeine-halothane contracture testing internationally. As an essential tool for MH's screening, pre-anesthetic evaluation is extremely important to consider patients with a suspected family and personal history of MH. So, beyond investigating the history of the classic clinical presentation and familial deaths related to anesthesia, it is necessary to check for previous episodes of postoperative fever, rhabdomyolysis, and myoglobinuria among others.³

The treatment consists of Dantrolene's administration, which works by increasing the RYR protein's affinity for Mg2+. In that way, the Mg2+ blocks  the RYR protein's capacity to release calcium and stops the uncontrolled cascade that causes the hypermetabolic state of MH. In addition, as prophylaxis, treatment for susceptible patients is no longer routinely recommended. This is due to the improbability of severe HM episodes without prior exposure triggering agents, besides dantrolene not being completely free of significant side effects.^1,3,4 Furthermore, it's important to highlight how the early identification of initial signs of MH allows for a swift management of the condition and, as a result, an improved prognosis. In this context, hypercarbia, sinus tachycardia, localized muscle rigidity, and hyperthermia are the initial crisis indicators, and the symptoms worsen over time and depending on the type of medication used. Once the condition is identified, it's crucial to immediately halt anesthetic medications and initiate the patient care protocol, seeking assistance, normalizing ETCO2 values, administering dantrolene, and treating the patient's temperature and hypercalcemia.³ As for the postoperative period, it is decisive to observe the patient in ICU for at least 24 hours due to the risk of recurrence. Dantrolene's administration every 4 or 6 hours can be indicated (0,25 mk.kg^-¹.h-¹), besides performing frequent arterial blood gas analysis and intermittent CK monitoring every 6 or 8 hours to observe vital, and signs and laboratory indicators.^1,4

Finally, it is part of good medical practice to guide the patients and their families about HM and future precautions, as well as refer patients above 20 kg to the nearest biopsy center for best monitoring and diagnostic confirmation.⁵

It can be concluded that Malignant Hyperthermia is a serious disease for risk patients that manifests as hypermetabolism of the skeletal muscle crises associated with some anesthetics. Considering how fast it can evolve to a worse scenario, such as hyperthermia, metabolic acidosis, circulatory collapse, and death, it is essential to know how to act in these cases and what is the best treatment for the quick handling of the patient, which demands a correct training and knowledge of the professionals in this area. In that way, a well-done pre-anesthetic evaluation is essential to recognize signs and symptoms and prevent morbidity and mortality from the disease. Also, it is crucial for the survival of these patients to the immediate use and maintenance of dantrolene for a period of minimum duration of 48 hours.

1. Butala B, Busada M, Cormican D. Malignant hyperthermia: review of diagnosis and treatment during cardiac surgery with cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 2018;32(6):2771–2779.
2. Hopkins PM, Gupta PK, Bilmen JG. Malignant hyperthermia. In: Romanovsky AA. Handbook of clinical neurology: thermoregulation: from basic neuroscience to clinical neurology. Amsterdam: Elsevier; 2018. v. 157(3rd series). p. 645–61.
3. Rosenberg H, Pollock N, Schiemann A, et al. Malignant hyperthermia: A review. Orphanet J Rare Dis. 2015;10:93.
4. Gonsalves SG, Dirksen RT, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for the use of potent volatile anesthetic agents and succinylcholine in the context of RYR1 or CACNA1S genotypes. Clin Pharmacol Ther. 2019;105(6):1338–1344.
5. SAESP. Tratado de anestesiologia. Rio de Janeiro: Atheneu; 2017. Acesso em: 15 ago. 2023.