Malignant hyperthermia 5 hours into a second general anesthetic for maxillofacial trauma surgery: a case report

Introduction

Background

Malignant hyperthermia (MH) is an autosomal-dominant pharmacogenetic disorder with studies showing a prevalence of 1.23–1.91 per 100,000 in various US states (1,2). According to the Malignant Hyperthermia Association of the United States (MHAUS), MH complicates 1:100,000 surgeries in adults (3) and 1:30,000 in children (4). It manifests as a hypermetabolic response to anesthetic agents such as isoflurane, sevoflurane, and desflurane, and the depolarizing neuromuscular blocker succinylcholine (5).

Features of MH include an inappropriate increase in end-tidal carbon dioxide (EtCO₂), inappropriate tachycardia, unexplained increase in temperature, and masseter or diffuse muscular rigidity. This can subsequently lead to acidosis, hyperkalemia, arrhythmias, myoglobinuria, disseminated intravascular coagulation, and compartment syndrome (6).

Rationale and knowledge gap

While MH typically occurs soon after anesthesia induction, it can occur hours into an anesthetic or even after a previous uneventful anesthetic. As it is a life-threatening disorder, it is imperative that the signs are recognized and treatment is initiated quickly. Previous studies have shown that the presentation of MH can have significant variability (7-10). This case report contributes to the literature by depicting an episode of MH occurring over 5 hours into a general anesthetic after a previous uneventful anesthetic.

Objective

The purpose of this article is to discuss a case of MH where signs presented 5 hours into a second general anesthetic after an uneventful first general anesthetic. We present this article in accordance with the CARE reporting checklist (available at https://joma.amegroups.com/article/view/10.21037/joma-25-15/rc).

Case presentation

A male in his 30s with no medical conditions, no known drug allergies, no personal history or family history of MH, presented to the Duke University Medical Center by Emergency Medical Services after experiencing a ballistic injury from a low-energy weapon to the face. Originally from South America, he has no previous history of surgery or anesthesia. Entry wound was the left nasal ala, and exit wound was the right preauricular region. After intubation and stabilization by Emergency Medicine, he was found to have a dens type 2 fracture of his C2 vertebra in addition to a comminuted hemi-LeFort I fracture of his right maxilla, right zygomaticomaxillary fracture, comminuted fracture of his right coronoid process, and a right condylar neck fracture (Figure 1).

Figure 1 3D rendering of CT face depicting injuries as a result of low-velocity ballistic weapon. Red arrow shows the right mandibular condylar neck fracture. Blue arrow shows the right zygomaticomaxillary complex fracture. Green arrow shows the right hemi-LeFort I fracture with fracture of the maxillary alveolus. 3D, three-dimensional; CT, computed tomography.

On day 4 of his hospital admission, he was taken to the operating room (OR) for the placement of a tracheostomy and a percutaneous gastrostomy tube under general anesthesia. His preoperative labs included a hemoglobin of 12.6 g/dL (normal: 13.5–17.5 g/dL), partial pressure of carbon dioxide (pCO₂) of 48 mmHg (normal: 35–45 mmHg), a pH of 7.37 (normal: 7.35–7.45), a temperature of 38.0 ℃, and a heart rate (HR) was 95 bpm. A combination of inhalation anesthesia with sevoflurane and intravenous medications, which included propofol, fentanyl, midazolam, dexmedetomidine, and rocuronium, among others, was used. Succinylcholine was not administered. The anesthesia time was 2 hours and 35 minutes and was uneventful. His HR (range, 75–100 bpm) and temperature (37.6 ℃) were within a normal range throughout this surgery. His EtCO₂ was above normal (normal: 35–45 mmHg) for under 5 minutes (range, 45–50 mmHg); however, it spontaneously returned to the normal range, where it was stable for the remainder of the surgery. An arterial blood gas was obtained in the surgical intensive care unit (SICU) with a temperature of 37.6 ℃, an elevated pCO₂ of 50 mmHg, a normal pH of 7.38, and an elevated bicarbonate (HCO₃⁻) of 30 mmol/L (normal: 20–28 mmol/L).

On day 10, he returned to the OR for the open reduction and internal fixation of his facial fractures. General anesthesia was administered with sevoflurane, ranging from 2.1% to 2.2%, and intravenous medications, which included propofol (40 mg administered upon induction), remifentanil (0.2–0.3 mcg/kg/minute), fentanyl (100 mcg), midazolam (2 mg), and ketamine (4 mcg/kg/minute), among others. Neither depolarizing nor nondepolarizing neuromuscular blocking agents were used to facilitate nerve monitoring during the surgery. Five hours and 42 minutes into the surgery, the nurse anesthetist requested the assistance of the anesthesiologist as the EtCO₂ was increasing despite adjustments to ventilation, with an EtCO₂ greater than 50 mmHg. Although MH was considered as part of the differential diagnosis, due to the delayed presentation, concerns regarding inadequate ventilation were addressed first. The minute ventilation was increased, and surgery was paused to obtain arterial line for blood gases, airway suctioning, administration of albuterol, and ultimately direct visualization via flexible bronchoscope for mucous plugging. These efforts were unsuccessful in normalizing the EtCO₂, and when ventilation resumed following bronchoscopy, he had an EtCO₂ greater than 90 mmHg. He was tachycardic with a HR ranging from 100 to 125 bpm. His temperature increased, peaking at 41.0 ℃ from 36.6 ℃ preoperatively. Masseter rigidity or muscle rigidity was never experienced. At this point in time, it was determined that he was experiencing an episode of MH. Treatment included stopping the administration of sevoflurane, hyperventilation was performed with >95% O₂ saturation, aborting the surgery, and administering IV Ryanodex dantrolene 250 mg (2.5 mg/kg). Intraoperative cooling with intravenous fluids and ice compress was performed. Chemistry revealed potassium of 7.2 mmol/L (normal: 3.5–5.0 mmol/L), which eventually increased to 8.5 mmol/L, and a profound respiratory acidosis, with a pH of 7.17 and a pCO₂ of 65 mmHg. Hyperkalemia was treated with three doses of 1 g calcium gluconate, 24 puffs of albuterol inhaler, 16 U of regular insulin with administration of 25 g of dextrose 50% in water (D50W) solution, and 50 mEq of sodium bicarbonate. He was admitted to the SICU for the continuation of care. Laboratory studies found an elevated creatine kinase of 288 U/L (normal: 60–270 U/L) which peaked at 1,231 U/L that evening, an elevated fibrinogen of 671 mg/dL (normal: 213–435 mg/dL), a slightly elevated international normalized ratio (INR) of 1.2 (normal: 0.9–1.1), decreased activated partial thromboplastin time (aPTT) of 24.1 seconds (normal: 26.8–37.1 seconds). His creatinine was within normal limits (normal: 0.6–1.3 mg/dL) throughout. The MHAUS was contacted and recommended to continue dantrolene 1 mg/kg every 6 hours for the first 24 hours. By the following morning, his pH (7.45), pCO₂ (40 mmHg), potassium (4.5 mmol/L), and temperature (37.4 ℃). HR (68 bpm) had all normalized.

On day 14, 4 days after his episode of MH, he returned to the OR to complete the open reduction internal fixation of his facial fractures. Prior to the procedure, the anesthesia machine was prepared, removing any previous inhalation anesthetic from the machine, changing of the carbon dioxide scrubber, in addition to a new breathing circuit. A total intravenous anesthetic (TIVA) was utilized, which included propofol (100–150 mcg/kg/minute), ketamine (4–7 mcg/kg/minute), fentanyl (100 mcg), midazolam (2 mg), rocuronium (50 mg) remifentanil (0.3 mcg/kg/minute), phenylephrine (0–0.4 mcg/kg/minute in addition to boluses), hydromorphone (2 mg), and dexamethasone (8 mg). The anesthesia and surgery were uneventful, and his facial fractures were successfully repaired. During his hospital admission, he was counseled on the genetic nature of MH. He denied any previous family history of MH, and it was recommended that family members pursue genetic testing in addition to making anesthesia teams aware for future anesthetics. On day 21, he returned to the OR for incision and drainage of an infection of his right preauricular infection. The event was uneventful, and he was subsequently discharged later that day. He presented for follow-up 5 and 19 days after discharge and on clinical examination, was healing appropriately. He then had his semi-rigid composite dental splint removed at 7 weeks post-discharge.

Ethical considerations

All procedures performed in this study were in accordance with the ethical standards of the research committee of Duke University Health System (IRB No. 00100269) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patients for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Key findings

The current case report depicts an unusual presentation of MH, occurring over 5 hours into a second general anesthetic after an uneventful first anesthetic. It is important to know that the presentation of MH can vary significantly and can happen at any point in time.

Strengths and limitations

This case report shows an unusual presentation of MH, which is effective in showing the variability in which MH can occur. A weakness of this case report is that, as the condition and this specific presentation are incredibly rare, the generalizability is limited.

Comparison of similar research

It is commonly thought that MH occurs soon after induction. One study showed that in 93 episodes of MH, the median time to the episode was 10 minutes (11). Over three-quarters of the MH episodes were administered succinylcholine, which is typically given on induction prior to intubation. However, published literature has also discussed unusual presentations of MH. Published case reports discuss significant variance of MH, with an 8-year-old experiencing MH after a second anesthetic while in the recovery area, a 5-year-old who experienced an MH episode 90 minutes into the second anesthetic, and another episode occurring 4 hours into the general anesthetic for the treatment of maxillofacial trauma (7-9). Of 503 cases of MH across 26 countries from 1940 to 1992, it was found that 20.6% occurred after an uneventful previous anesthetic. These cases depict the variation in presentation of MH due to its multifactorial nature, dependent on genetics and its penetrance, anesthesia including medications used (12), as well as the current physiology of the patient, influenced by infection, stress, exercise, among other things. With that being said, 5 hours into a second anesthetic is an unusual presentation of MH.

Explanation of findings

MH was first described in 1960, and in 1970 had a mortality rate of 64% (5,13,14). More recent studies show a mortality rate of 34.8% (14). Although MH susceptibility is linked to gene variants such as CACNA1S and STAC3, the most associated variant is the calcium channel ryanodine receptor 1 (RYR1) on the sarcoplasmic reticulum (SR) (15-17). RYR1 is involved in the excitation-contraction coupling in which, with depolarization, voltage-gated ion channels will open the RYR1, which releases calcium stores from the SR (18). Defect of this calcium channel results in uncontrolled release of Ca²⁺, which results in abnormal skeletal muscle metabolism, increased muscle contraction, increased oxygen consumption and CO₂ production, adenosine triphosphate (ATP) hydrolysis, and heat production. It is thought that the depleted level of ATP contributes to failure of membrane integrity, which results in the release of potassium and creatine kinase (5).

Several disorders that have an increased susceptibility to MH, including central core disease (CCD), King-Denborough syndrome, as well as myopathies such as multiminicore disease and centronuclear myopathy (5). Being aware of the relationship between these conditions and MH is important to avoid anesthesia in an office setting and as well as triggering medications.

Diagnosis of MH typically occurs through exposure of triggering anesthetics or diagnostic testing (5). Although genetic testing is now frequently used, muscle susceptibility testing, such as in-vivo contracture test (IVCT) or caffeine-halothane contracture test, was considered the gold standard (19). A clinical grading scale (CGS) has been developed and relates the overall score to the likelihood of an MH episode (20). Based on the CGS, our patient had a score of 51 [hyperkalemia 3 points, partial pressure of EtCO₂ (pEtCO₂) >55 mmHg 15 points, inappropriate increase in temperature 15 points, inappropriate sinus tachycardia 3 points, arterial pH <7.25 10 points, rapid reversal with dantrolene 5 points], giving him an MH rank of 6, making it almost certain he had a MH episode.

In our case, the first sign of MH was hypercarbia, which is the most common early symptom (14). Despite “hyperthermia” being included in the name, it is only the first sign in 8.2% of cases and is present in only 52.2% of patients (14). The four main causes of hypercarbia in association with anesthesia are reduced alveolar ventilation, inhalation of exhaled carbon dioxide, inhalation of exogenous carbon dioxide and increased metabolic rate, as in MH (21). In our case, the more likely causes were explored first. After bronchoscopy was performed, the EtCO₂ was greater than 90 mmHg. The continued rise in EtCO₂, increase in HR, along with an esophageal temperature probe reading 41.0 ℃, provoked the diagnosis of MH.

Although rare, delayed onset MH is described in the literature (7,22,23). Hopkins investigated the time to onset of MH with different inhalation agents, proposing that they have different potencies to induce MH (24). He found that the median time to onset of MH for halothane was 20 minutes, 55 minutes for enflurane, 60 minutes for sevoflurane, and 30 minutes for isoflurane. He proposes that the triggering of MH is a dose-dependent process, and a threshold must be met for MH to occur. This explains why our patient underwent recent previous anesthetic with triggering agents and did not develop clinical signs of MH. There are reported cases of patients susceptible to MH who have had 30 prior anesthetics with triggering agents prior to the appearance of clinical symptoms (25). In addition, some medications may lower the threshold while others are protective against triggering MH which adds to the level of variance. Ibarra Moreno et al. investigated the penetrance of nine RYR1 diagnostic mutations and found that the penetrance of the 229 individuals was 40.6% (11). Interestingly, they found that penetrance was incomplete with a predilection towards males. They also found a correlation between the severity of the episode of MH and the time to MH and the age of the patient, with younger patients experiencing more severe episodes and faster times to onset.

In addition to the genetics and variability in penetrance, there are other components that contribute to the multifactorial aspect of MH. Physiologic stress in the form of infection, fever, or exercise, has been shown to lower the threshold for episodes of MH (5,26). In one study, succinylcholine was used in 76.0% of the MH cases and they suggest that succinylcholine could contribute to a 10- to 20-fold increase in MH (11). Succinylcholine was not used in any of the anesthetics for our patient. One author found that non-depolarizing neuromuscular blocking medications significantly increased the time to onset of MH (24). Thiopental was also shown to offer a dose-dependent protection for MH, while etomidate and propofol do not.

Dantrolene is an antagonist to the ryanodine receptor, preventing calcium influx. Since it was first used, it has greatly improved the survival of patients experiencing episodes of MH with one study showing that the mortality rate of those that did not receive dantrolene was 23% compared to a mortality rate of 10% for those that did receive dantrolene (10). Survivors of MH were 2.72 times more likely to have received dantrolene. Adverse reactions to dantrolene include muscle weakness, drowsiness/dizziness, and general malaise, with a complication rate of 24% in 349 subjects (27,28).

This case report discusses a variance in the presentation of MH, occurring after a previous uneventful anesthetic and several hours into an anesthetic episode. Having dantrolene available is not required for ambulatory center accreditation but is recommended by the MHAUS. A study by Aderibigbe showed that stocking dantrolene at ambulatory surgical centers is cost-effective relative to the values of statistical life (29).

Conclusions

Although classically thought to occur soon after the administration of a triggering medication, MH can have a delayed onset. It is also crucial to note that this can occur after an uneventful previous anesthetic, which also occurred in this case. These sequelae are due to prolonged hyperthermia, acidosis, and rhabdomyolysis. The ability to quickly recognize signs, such as a refractory elevation of EtCO₂, temperature, HR, and muscle rigidity, is paramount to early treatment and decreased mortality.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://joma.amegroups.com/article/view/10.21037/joma-25-15/rc

Peer Review File: Available at https://joma.amegroups.com/article/view/10.21037/joma-25-15/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://joma.amegroups.com/article/view/10.21037/joma-25-15/coif). D.B.P. serves as an unpaid editorial board member of Journal of Oral and Maxillofacial Anesthesia from November 2023 to October 2025. D.B.P. received payment or honoraria from AO North America, Johnson & Johnson MedTech, SORG North America, and KLS Martin, and received monetary support provided directly to Duke University for the support of the CMF Trauma Fellowship from KLS Martin and AO North America. D.B.P. served as the unpaid Board of Directors of AONA CMF Board, SORG North America, and American Board of Oral & Maxillofacial Surgeons. E.F. received consulting fees from Stryker Corporation and Payment or honoraria from SORG North America. E.F. also received support for attending meetings from American Association of Cosmetic Surgeons—February 2025 annual meeting and American Board of Oral and Maxillofacial Surgeons. E.F. is the District III Representative of American College of Oral and Maxillofacial Surgeons Board of Regents. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the research committee of Duke University Health System (IRB No. 00100269) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patients for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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