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

Introduction

Malignant Hyperthermia (MH) is a pharmacogenetic disorder triggered during surgery by exposure to volatile anesthetics such as sevoflurane and desflurane as well as depolarizing neuromuscular junction (NMJ) blockers, such as succinylcholine (3, 2). Exposure to the trigger leads to excessive calcium release from the muscle's sarcoplasmic reticulum resulting in sustained muscle contractions which result in hypercatabolic state (3). The cardinal signs of MH are sustained muscle contraction (“lead pipe” muscle rigidity), tachycardia, hyperthermia (≥38.5 °C), and elevated end tidal carbon dioxide. Rhabdomyolysis, demonstrated by an elevated creatine kinase (3–5), altered mental status, hypertension and diaphoresis can occur (3). Immediate treatment with dantrolene (Dantrium, Revonto Ryanodex) is critical to prevent fatal complications (5).

Hypermetabolic crises in perioperative settings may pose diagnostic challenges for anesthesia or critical care providers as they can present with overlapping symptoms such as hyperthermia, tachycardia, muscle rigidity, and autonomic dysfunction. Among the conditions responsible for these clinical manifestations are MH, Neuroleptic Malignant Syndrome (NMS), Thyroid Storm, Paroxysmal Sympathetic Hyperactivity (PSH), and Drug Intoxication. Although these conditions may present with some similarities, they have distinct pathophysiological mechanisms, triggers, and management strategies. Early recognition and accurate differentiation between these conditions are critical for effective management.

Case description patient presentation

An 18-year-old Caucasian male with a remote history of childhood asthma was brought in by ambulance to the ED following a roll over motor vehicle accident. On evaluation, he was found to have a right midshaft femur fracture, right distal tibia/fibula fracture, and right talar fracture, necessitating surgical intervention. He had no prior surgical history and denied any family history of adverse reactions to anesthesia.

The patient was evaluated and cleared for surgery after initial imaging and laboratory studies were obtained. He had a remote history of childhood asthma previously treated with Albuterol. He had no recent asthma exacerbations or asthma-related hospitalizations. He had no known drug allergies. He denied the use of tobacco, vaping, or recreational drugs. He had no prior anesthesia or surgery history or family history of anesthesia complications.

Pre-induction physical examination documented a Mallampati class III airway, thyromental distance greater than three fingerbreadths, full neck range of motion and normal dentition. Cardiovascular examination showed a regular rhythm with tachycardia. Pulmonary examination was normal and the patient denied chest pain or shortness of breath. Abdominal examination was notable for obesity. Neurologic examination was normal. Functional capacity was estimated at less than 4 metabolic equivalents, limited by his acute traumatic injuries.

Intraoperative course: One day after his injury, the patient underwent an open reduction and internal fixation (ORIF) with a trochanteric femoral nail (TFN) and intramedullary rod placement for the tibia under general anesthesia. He was induced with Midazolam 2 mg, Fentanyl 125 mcg, Etomidate 40 mg, Esmolol 10 mg, and Succinylcholine 180 mg. Succinylcholine was administered as part of a rapid sequence induction strategy in the setting of recent polytrauma and presumed full-stomach status, with concern for aspiration risk. Although nondepolarizing neuromuscular blockade was also administered, succinylcholine was selected to facilitate rapid intubating conditions during trauma induction. The procedure began uneventfully; however, approximately 3 h into the operation the patient exhibited hyperthermia (skin temperature 39.4 °C (103°F)), hypercarbia (ETCO₂ of 58.5 mm Hg) and tachycardia (heart rate 120–130 beats/min). The anesthesiology team promptly recognized an impending MH crisis. Immediate measures as part of the MH protocol included discontinuation of sevoflurane, TIVA anesthesia with propofol infusion, 100% O2, administration of IV dantrolene 260 mg, corresponding to approximately 2.3 mg/kg based on the patient's perioperative weight of 113 kg, and application of external cooling measures, including ice packs and IV acetaminophen. Within 15 min of the initial dantrolene bolus, the patient's temperature decreased and his ETCO₂ levels normalized. Surgery was completed, and the patient was transported to the intensive care unit (ICU) intubated and sedated. The intraoperative course is shown in Table 1.

Table 1. Intraoperative course.

In the ICU, the patient remained persistently tachycardic (heart rate 130–140 beats/min) and hypertensive despite an intravenous fluid bolus and 1 unit of packed red blood cells. He received two additional doses of dantrolene (1 mg/kg every 6 h) per MHAUS Hotline recommendations (1). Laboratory results showed an elevated creatine kinase (CK), peaking at 6,397 U/L, likely secondary to MH and up-trending since his recent trauma, with normal kidney function. The patient was extubated the following day and transitioned to trauma surgery service for continued management. Three days later, the patient underwent ORIF of the right talar neck under TIVA and regional anesthesia without recurrence of MH symptoms.

Prior to discharge, the patient and family were counseled regarding suspected malignant hyperthermia susceptibility and the need to avoid future exposure to triggering agents, including volatile anesthetics and succinylcholine, unless evaluated by a MH specialist. The event was communicated to the patient's primary care provider, and referral to MHAUS/MH specialist evaluation was recommended for confirmatory testing, including consideration of RYR1/CACNA1S genetic testing and/or caffeine-halothane contracture testing. The available documentation did not confirm whether MedicAlert counseling had been completed before discharge, but was advised to inform future anesthesia teams of suspected MH susceptibility. Family counseling and screening were recommended given the inherited nature of MH susceptibility.

Discussion

Differential diagnosis

Neuroleptic malignant syndrome

NMS occurs due to dopamine receptor blockade from neuroleptic or antipsychotic drugs (6). Like MH, NMS is marked by hyperthermia, muscle rigidity, and autonomic instability, with laboratory findings demonstrating elevated CPK and white blood cell (WBC) counts (6). While many of the manifestations of NMS overlap with those of MH, MH tends to occur acutely, often within minutes or hours of induction of anesthesia while NMS is usually more gradual, occurring over the course of several days (24–72 h) following initiation or dosage adjustments of neuroleptic or antipsychotic drugs (6). Unlike MH, NMS is treated with dopamine agonists like bromocriptine, although dantrolene has been shown to be effective as well (6).

Thyroid storm

Thyroid storm is a life-threatening exacerbation of thyrotoxicosis, characterized by abnormally elevated levels of circulating thyroid hormones (T3/T4), in the case of underlying hyperthyroidism or thyrotoxicosis (7). It manifests tachycardia, hypertension, hyperthermia, and widened pulse pressure (7). These nonspecific symptoms can mimic other hypermetabolic emergencies, such as MH and NMS. However, intraoperative thyroid function tests will reveal low TSH and elevated T3/T4, helping differentiate thyroid storms from other conditions (7). Treatment includes intravenous thionamides to control thyroid hormone production and beta-blockers to maintain hemodynamic stability (7).

Paroxysmal sympathetic hyperactivity

PSH is a feared complication following traumatic brain injury (TBI), especially in trauma patients, and is characterized by episodic hypertension, tachycardia, fever, diaphoresis, and dystonia (8). Unlike MH, PSH is associated with abnormal autonomic regulation due to excessive sympathetic nervous system activity, rather than calcium release in skeletal muscle (8).

Diagnostic tools like the Paroxysmal Sympathetic Hyperactivity- Assessment Measure (PSH-AM) help differentiate PSH from other conditions based on the core features of heart rate, respiratory rate, systolic pressure, temperature, diaphoresis, and posturing (9). When compared to MH, PSH is often accompanied by posturing and lack of CPK or WBC count, as seen in MH. Since PSH does not result from excess extracellular calcium release like in MH, treatment for PSH is targeted towards controlling hyperexcitation of the SNS with agents such as opioids, intravenous anesthetics, Beta-Adrenergic blockers, Alpha-2 agonists and benzodiazepines (9).

Rhabdomyolysis and cocaine toxicity

Many sympathomimetic drugs, such as cocaine and amphetamines, can cause toxicity and lead to rhabdomyolysis, demonstrating many of the cardinal symptoms seen in MH, such as hyperthermia, muscle rigidity, and elevated CPK levels (10). Patients with a history of cocaine abuse can present with a positive enzyme multiplied immunoassay technique (EMIT) screen for cocaine metabolite, raising the possibility of drug- induced rhabdomyolysis (10). Cocaine blocks the presynaptic reuptake of norepinephrine and dopamine, causing prolonged vasoconstriction and ischemia in muscle beds, subsequently leading to rhabdomyolysis (10). However, cocaine-induced rhabdomyolysis is distinguished from MH due to its association with stimulant use and negative history of anesthetic exposure. Muscle biopsies from affected areas can confirm necrosis consistent with rhabdomyolysis, supporting the diagnosis of drug induced rhabdomyolysis (10).

Differential diagnosis analysis

In this clinical presentation, hyperthermia, tachycardia, and muscle rigidity raised suspicion for MH, thyroid storm, NMS, and PSH. Key diagnostic steps included assessing patient history, thyroid function testing, neuroleptic medication history, and toxicology screening. Malignant hyperthermia (MH) was identified as the top differential in this case due to the patient's specific intraoperative clinical presentation, timeline, and response to treatment, which aligned strongly with the known pathophysiology and diagnostic criteria for MH.

Although a formal Malignant Hyperthermia Clinical Grading Scale score (Larach score) was not calculated during clinical care, the patient's exposure to known triggering agents, acute hypercarbia, hyperthermia, tachycardia, CK elevation, and rapid response after dantrolene administration would support a high clinical probability of malignant hyperthermia. We therefore interpreted the event as clinically consistent with a suspected malignant hyperthermia crisis, while recognizing that confirmatory IVCT/CHCT or genetic testing was not performed.

The patient presented with hyperthermia (skin temperature 39.4 °C (103°F)), hypercarbia (ETCO2 = 58.5 mmHg), and tachycardia (HR 120–130 beats/min) in the setting of triggering agents, succinylcholine and sevoflurane. Notably, the combination of succinylcholine used during induction and sevoflurane as an anesthetic throughout the case likely acted synergistically to precipitate the MH crisis. In review Additionally, MH treatment with dantrolene, discontinuation of sevoflurane, clearing the anesthesia machine, and supportive measures with cooling and oxygenation led to a rapid improvement in the patient's hyperthermia and hypercarbia within 15 min, strongly supporting the MH diagnosis. Although this patient had a history of polytrauma secondary to MVA rollover, the rapid increase of CK, peaking at 6,397 U/L, in the setting of MH symptoms strongly implicates a hypermetabolic crisis. The hypermetabolic presentation raised suspicion for MH, thyroid storm, NMS, and PSH.

Diagnostic steps, including thyroid function tests, medication history, and toxicology screening, ruled out alternative diagnoses. Thyroid Storm was excluded based on no medical history of thyroid disease and normal thyroid function tests. NMS was unlikely due to the absence of neuroleptic medication use, and PSH was ruled out given the lack of neurological injury. Additionally, the acute intraoperative setting was inconsistent with the typical presentation of thyroid storm, NMS, and other diagnoses such as drug-induced rhabdomyolysis.

In this patient, the absence of a family history of MH demonstrates the importance of vigilance in all patients, as de novo mutations in the RYR1 or CACNA1S genes can lead to MH susceptibility. The timely recognition of MH considering the presenting symptoms and findings and initiation of the MH protocol with dantrolene were crucial in preventing further complications such as rhabdomyolysis, hyperkalemia, and multi-organ failure.

The role of dantrolene in malignant hyperthermia

In a Japanese study of 128 patients with “very likely” or “almost certain” MH, there were 113 survivors and 16 deceased with or without the use of dantrolene (11). Dantrolene works by antagonizing ryanodine receptors within the sarcoplasmic reticulum, inhibiting the release of calcium ions and thereby dampening overactive muscle contraction (12). Since the integration and use of dantrolene in the setting of MH, the mortality rate in the case of MH has dropped from 70% to 15% since the 1960s (12). The most common first sign of MH was ETCO₂ elevation which was seen in 55.8% of patients in the study followed by a temperature abnormality at 19.5% (12). Without the use of dantrolene, the mortality rate was 30.8% with 9 survivors and 4 deceased (n = 13) (12). With the use of dantrolene, the mortality rate shrunk to 9.6% with 104 survivors and 11 deceased (n = 115) (12). Thus, not only was the mortality rate of those not administered dantrolene (30.8%) significantly greater (p = 0.047) than those who were administered dantrolene (9.6%), those who were administered dantrolene (n = 115) had significant findings depending on the time interval and body temperature at the time of administration (12). Among patients administered dantrolene at an on-average shorter time interval (45 min) from the first sign of MH compared to an on- average longer time interval (100 min), those given the medication at a longer time interval had a significantly higher mortality rate (p < 0.001) (12). A higher body temperature (41.6 °C vs. 39.1 °C) at the time of dantrolene administration was also associated with a significantly greater (p < 0.001) mortality rate (12).

Conclusion

This case underscores the diagnostic challenges of differentiating between hypermetabolic conditions such as MH, NMS, thyroid storm, PSH, and drug-induced rhabdomyolysis. While these conditions share overlapping clinical features, they differ significantly in their triggers and pathophysiology. A detailed patient history, targeted laboratory tests, and an understanding of the underlying mechanisms are essential for accurate diagnosis and appropriate management. In this case, the patient's presentation fell most in line with the manifestations of malignant hyperthermia due to the patient's specific intraoperative clinical presentation, timeline, and response to treatment, which aligned strongly with the known pathophysiology and diagnostic criteria for MH. Future genetic testing and/or muscle biopsy would be recommended to have a more confirmatory diagnosis. Overall, MH remains difficult to quantify globally due to inconsistent reporting systems. However, with improved global data collection, the understanding of not only its epidemiology but also the management can help inform guidelines for improved preparedness. This case highlights that MH diagnosis rests on early suspicion and not absolute confirmation against a differential diagnosis.Immediate intervention is required to avoid morbidity.

Patient perspective

Because the patient was under general anesthesia during the suspected malignant hyperthermia crisis, he did not have direct recollection of the intraoperative event. The patient's family reported that they were initially unaware of any malignant hyperthermia risk because he had no prior anesthetic exposure or known family history of anesthesia complications. The patient's mother was counseled that the event was clinically concerning for malignant hyperthermia and was advised to inform future healthcare teams, particularly anesthesia providers, about this event before any subsequent procedure.

The patient recovered without recurrent symptoms during the hospitalization and later underwent surgery using total intravenous and regional anesthesia without recurrence. The patient and family were advised to pursue malignant hyperthermia follow-up. However, after discharge, the patient transferred care to Kaiser and did not follow up with orthopedic surgery or primary care at ARMC. As a result, completion of confirmatory MH testing, genetic evaluation, medical-alert identification, or family screening could not be confirmed from the available records.

Limitations

This case has several limitations. First, the diagnosis of malignant hyperthermia was made clinically based on intraoperative hypercarbia, hyperthermia, tachycardia, exposure to known triggering agents, and response to dantrolene, but it was not confirmed by in vitro contracture testing or genetic analysis. Therefore, the event is best characterized as clinically suspected malignant hyperthermia rather than definitely malignant hyperthermia. Second, creatine kinase elevation was not specific to malignant hyperthermia in this case because the patient sustained significant traumatic fractures, which may have independently contributed to rhabdomyolysis and CK elevation. In addition, temperature was measured by skin temperature rather than continuous core temperature monitoring, which may underestimate or overestimate the degree of hyperthermia. Finally, post-discharge follow-up was limited because the patient transferred care to Kaiser. Although referral for malignant hyperthermia follow-up was recommended, confirmatory testing results could not be verified from the available records.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Footnotes

Edited by: Rene Buchet, Université Claude Bernard Lyon 1, France

Reviewed by: M. Bruce MacIver, Stanford University, United States

Nurgül Arpag, Bezmialem Vakıf University, Türkiye