Expect the unexpected: A case of malignant hyperthermia in a 14-year-old boy undergoing gastroscopy

Annie Xin


Annie Xin
Fourth Year Medicine
University of Melbourne

Annie is a final-year medical student at the University of Melbourne. She has a keen interest in paediatric anaesthesia.


Malignant hyperthermia (MH) is a rare pharmacogenetic disorder, in which volatile anaesthetic agents trigger deregulated calcium release causing hypermetabolic crisis in susceptible individuals. MH is an anaesthetic emergency that requires prompt recognition due to the high mortality related to delayed treatment. This report documents an unexpected case of MH during an elective gastroscopy at the Royal Children’s Hospital in a 14 year old boy who had previously undergone uneventful general anaesthesia. The patient developed early signs suggestive of MH after exposure to sevoflurane and was treated with dantrolene. He made a full recovery and a later muscle biopsy confirmed MH susceptibility. This case highlights the importance of clinical vigilance for this rare condition, especially in “low risk” patients without any past or family history for MH. This case also illustrates how early recognition of non-specific clinical signs and efficient implementation of a local MH action plan can lead to successful outcomes despite the potential life-threatening nature of an acute MH crisis.

Introduction

Malignant hyperthermia (MH) is a life-threatening anaesthetic emergency most commonly triggered by inhalational anaesthetic agents. The disease was first described in 1962, after ten members in a Melbourne family died after general anaesthesia with ether. [1] It was later found to be an inherited pharmacogenetic disorder where anaesthetic agents cause abnormal calcium release in skeletal muscle leading to a hypermetabolic crisis. MH is a rare disease with an estimated incidence of <0.02%. [2] It may only be encountered once in an anaesthetist’s career, but prompt recognition and treatment may make the difference between life and death for the patient. This case report describes an unexpected occurrence of MH in a low-risk paediatric patient undergoing routine gastroscopy. This case highlights the importance of clinical vigilance and a well-implemented action plan in achieving good clinical outcomes in an acute MH event. The key points in the clinical diagnosis and management of MH as well as the values of genetic testing are discussed.

Case report

A 14 year old boy with a five week history of intermittent epigastric pain associated with food was referred to the Royal Children’s Hospital (RCH) Day Surgery for an elective gastroscopy under general anaesthesia (GA) for investigation of peptic ulcer disease. He had previously undergone wisdom tooth extraction under GA at another Victorian hospital without any adverse reaction to volatile anaesthetics. There was no known family history of unexpected intraoperative deaths. Except for an enlarged body habitus (body weight of 110 kg), his peri-operative assessment was unremarkable, and he was an otherwise healthy boy.

On the day of the gastroscopy, anaesthesia was induced with IV fentanyl (100 μg) and propofol (200 mg). A size 4 laryngeal mask airway (LMA) was inserted and the patient maintained spontaneous ventilation on 2.8% sevoflurane. The first 20 minutes after the induction of anaesthesia were uneventful. However, over the following ten minutes, the patient became increasingly diaphoretic with signs of abdominal distension. His heart rate increased from 80 to 120 bpm, mean arterial blood pressure from 80 to 140 mmHg and end-tidal pCO2 (ETCO2) from 45 to 60 mmHg. Gastroscopy was suspended. The LMA was exchanged for a size 7.5 cuffed endotracheal tube for airway protection. A senior staff anaesthetist was consulted. Although possible diagnoses including pain, light anaesthesia, and obstructed ventilation were considered, there were no obvious painful stimuli or signs of emergence, and the minute ventilation volumes as well as normal chest movement and breath sounds were inconsistent with obstructed ventilation. MH was strongly suspected. An oral temperature probe was inserted and measured a temperature of 40°C, and arterial blood gas (ABG) revealed mixed respiratory and metabolic acidosis (pH 7.02, pCO2 102 mmHg, lactate 8.8 mmol/L, base excess -8 mmol/L). The RCH Malignant Hyperthermia Crisis Plan was activated. The patient was given 250 mg of dantrolene in a large, single IV bolus. Sevoflurane was ceased immediately and he was hyperventilated on 100% oxygen using a Laerdal bag and a separate oxygen source. GA was maintained using a target-controlled infusion of propofol. Cooling was achieved with topical application of ice packs to the neck, axillae and groin. Within ten minutes, the patient’s body temperature returned to 37 °C, heart rate to 80 bpm, ETCO2 to 45 mmHg and his ABG improved dramatically (pH 7.46, pCO2 28 mmHg, lactate 3.7 mmol/L, base excess -3 mmol/L).

He was transferred to the paediatric intensive care unit (PICU) for further management and monitoring. His blood test showed acute hyperkalaemia with an elevated K+ of 7.0 mmol/L but no major elevation in his creatine kinase level. After an overnight stay in PICU, the patient made a full recovery and was discharged from hospital five days later. He subsequently underwent a muscle biopsy, and the caffeine-halothane contracture test confirmed a genetic susceptibility to MH. The patient and his parents were informed of the diagnosis and educated about the condition, with an emphasis on future precautions with undergoing anaesthesia. Genetic counselling was offered to the family.

Discussion

Background

MH is an autosomal-dominant disorder of myocyte hypermetabolism most commonly triggered by volatile anaesthetic agents (e.g. halothane, isoflurane, sevoflurane, desflurane) and in rare cases by the depolarising muscle relaxant suxamethonium. [2] MH is estimated to occur once in every 5,000 to 100,000 cases of anaesthesia [2]. About 20-50% of all MH presentations occur in children, with a male-to-female ratio of 2:1. [3,4] The majority of susceptible individuals carry mutations in calcium channel genes, most commonly in the ryanodine receptor gene RYR1 (70%), and occasionally in the CACNA1S gene (1%) that encodes the α-subunit of the dihydropyridine receptor. [2] Through mechanisms still unknown, an encounter with a triggering anaesthetic agent causes deregulated calcium release from the abnormal channels in skeletal muscle, leading to a hypermetabolic crisis. If left untreated, MH carries a mortality rate of >80%. [5]

Clinical features

Timely recognition of the condition is key to patient survival. As demonstrated in this case, previous uneventful anaesthesia with triggering agents does not rule out MH. Although a detailed anaesthetic history is an important part of peri-operative assessment, 21% of MH patients report previous uneventful anaesthesia and 75% a negative family history. [4] In fact, it has been estimated that on average three anaesthesias are required before an adverse event is triggered in an MH-susceptible patient. [6] The reason for this variability in clinical penetrance is unclear; however, results from animal studies suggest that co-administration with other anaesthetic drugs could influence the onset of MH. [7] Ultimately, the diagnosis of MH falls on the vigilant mind of the anaesthetist. As in this case, the clinical signs are often non-specific (Table 1). Early signs may include increased oxygen consumption (detected by a widened FiO2 and end-tidal O2 gradient), metabolic derangement (hypercapnia, respiratory and metabolic acidosis, diaphoresis, skin mottling), cardiovascular instability (tachycardia, labile blood pressure) and masseter spasm following exposure to succinylcholine. [8]. Masseter spasm has been reported as the earliest sign of acute MH [9] but is present in less than half of paediatric presentations. [10] In children, sinus tachycardia and hypercapnia have been shown as the two most reliable early clinical signs. [10] Fever, hyperkalaemia, and elevated creatine kinase are late signs and their absence does not exclude the diagnosis. [8] The only existing set of diagnostic criteria in the literature was proposed in 1994 by Larach and colleagues [11], which is a clinical grading scale integrating some of the aforementioned early and late signs. However, its diagnostic performance has not been assessed due to the rarity of the condition, and this grading scale is not widely used in Australia. Overall, the anaesthetist needs to apply good clinical judgement and have a strong suspicion for MH if ETCO2 continues to rise despite increased minute ventilation. Other possible differential diagnoses include inadequate anaesthesia or analgesia, insufficient or obstructed ventilation, sepsis, anaphylaxis, endocrine disorders (e.g. thyroid storm, phaeochromocytoma), and neuroleptic malignant syndrome. In this patient, the combination of fever, hypertension, respiratory and metabolic acidosis, lack of exposure to neuroleptic medication, and the time course of clinical deterioration in relation to inhalational anaesthetic exposure made the diagnosis of MH most likely.

Table 1: Clinical features of MH (adapted from Hopkins TM, 2000 [12]).

Clinical Signs Changes in Monitored Variables Change in biochemistry
Early Tachypnoea Increased Fi02 and ETO2 gradient
Rising ETCO2 Increased PaCO2
Increased minute ventilation Decreased pH
Tachycardia Sinus tachycardia
Masseter spasm
Late Diaphoresis Rising core body temperature
Cyanosis Decreased SpO2 Decreased PaO2
Generalised muscle rigidity Elevated creatine kinase
Dark urine
Oliguria
Haemoglobinuria
Deranged UEC
Arrhythmia Widened QRS, VT, VF Hyperkalaemia
Prolonged bleeding Low platelets and fibrinogen
Prolonged prothrombin time
Elevated D-dimers
Death

Management

This case illustrates the value of a well-rehearsed local management protocol in an acute MH event. At RCH, a detailed MH action plan and an emergency MH trolley are readily available in the operating suite. The immediate management includes cessation of the offending anaesthetic agent, termination of surgery, recruitment of additional personnel (especially the most senior anaesthetic staff), and prompt preparation of dantrolene. [13] Dantrolene inhibits calcium release from the sarcoplasmic reticulum by antagonising the ryanodine receptor RYR1, [14] and is the only definitive treatment for MH. Dantrolene is given at 2-3 mg/kg IV every 10-15 minutes until the patient is clinically stable. [15] In this overweight boy, there was the consideration whether to administer the dose according to his true body weight or ideal weight. The MH Association of the United States recommends that dose calculation be based on the patient’s true weight rather than ideal weight, as the major site of action of dantrolene is in the tissue space, and up to 10 mg/kg can be safely administered in boluses. [16] In this case, 250 mg of dantrolene (~2.5 mg/kg at the patient’s true weight) posed a logistical challenge. Dantrolene is manufactured in a powder form and is notoriously slow to dissolve in water. [17] Six nurses had to be recruited to mix 13 ampoules of dantrolene for the patient. Concurrent supportive therapies for MH include hyperventilation with 100% oxygen using a clean source (not the original machine that may retain traces of volatile anaesthetic), maintenance of IV anaesthesia, and in the event of rising core body temperature, employment of cooling methods such as topical application of ice packs to vascular plexuses, cold IV fluids, forced-air cooling blankets, bladder irrigation, and nasal/peritoneal lavage. [15]

Continued monitoring of the patient in an intensive care unit is crucial in the detection and early correction of complications of MH such as hyperkalaemia as seen in this case. Other serious complications include rhabdomyolysis, acidosis, arrhythmias, disseminated intravascular coagulation, and multi-organ failure. [6] Aside from regular observation of the patient’s vital signs and urine output, serial ABGs, FBEs, UECs, coagulation studies, creatine kinase, and ECGs are useful investigations in the ongoing management of MH. Continued monitoring is of particular importance as recrudescence of symptoms has been reported in 14.4% paediatric patients after the initial treatment. [10]

Confirmatory diagnosis

Confirmatory diagnosis of MH susceptibility is made with muscle biopsy that is used for in vitro caffeine-halothane contracture testing (CHCT). Currently, all of the Australian testing centres adopt the protocol recommended by the European Malignant Hyperthermia Group and the test has an estimated sensitivity of 99% and specificity of 94%. [18] In Australia, CHCT is only available to children over 12 years of age, because a relatively large piece of vastus lateralis muscle (0.5 g) is required. The muscle is immersed in a tissue bath with various concentrations of caffeine or halothane, and the test yields a positive, negative or equivocal result for MH susceptibility (Table 2). Although an equivocal CHCT result does not confirm the diagnosis, the patient should be treated clinically as having MH. With advancement in DNA sequencing technologies over the past decade, some American centres now offer genetic testing for families with MH. However, challenges remain in the interpretation of the results. Almost 400 RYR1 mutations have been identified in MH-affected families, but only a few are causal. [19] Additionally, for affected families with normal RYR1 and CACNA1S sequences, DNA testing is of limited value with the causal genes yet to be identified. For the moment, CHCT remains the gold standard of MH testing in Australia.

Table 2. Caffeine-Halothane Contracture Test result for MH susceptibility.

Contraction in caffeine Contraction in halothane
Positive (susceptible) + +
Negative (normal)
Equivocal +
+

Future anaesthetic considerations

It is essential that patients with suspected or confirmed MH avoid any triggering anaesthetic agent in future surgeries, and be anaesthetised with regional anaesthesia or total intravenous anaesthesia assisted by bispectral index monitoring to reduce the risk of intraoperative awareness. Patients should be ventilated on a clean circuit purged of any residual volatile anaesthetic and closely monitored during the procedure. Theatre staff should anticipate acute MH crisis and be ready to act with dantrolene on standby. Where appropriate, sedation and local anaesthesia are also good options for consideration.

Conclusions

Death under general anaesthesia is a medical disaster dreaded by patients and anaesthetists alike. MH is a rare but preventable cause of anaesthetic-related morbidity and mortality, and an acute MH event can be treated with an effective antidote. This case is a reminder that early recognition of MH is often based on pattern recognition of non-specific clinical signs; and excellent clinical outcomes can be achieved when the crisis is acted upon promptly by a trained team. Although a patient who reports a positive MH history invariably puts every anaesthetist on alert, as illustrated in this case report, it is often the “low risk” elective patient who is more likely to develop an acute MH crisis and put the doctor’s clinical skills to the test. For the anaesthetist, continued training on the subject will ensure a low threshold for clinical suspicion when the unexpected case arises. For the hospital, a well-rehearsed local MH action plan is paramount for an efficient response to the emergency to achieve improved patient safety.

Acknowledgements

I would like to thank Dr. Philip Ragg for his advice and discussion of this case report.

Consent

Informed consent was obtained from the patient and his family for publication of this case report.

Conflicts of Interest

None declared.

References

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