Simultaneous malignant hyperthermia reactions in two siblings during living donor liver transplantation

Summary

We report a case of simultaneous malignant hyperthermia reactions occurring in two siblings during living donor liver transplantation. This report highlights the conflicting goals in the clinical management of liver transplantation and malignant hyperthermia, including the use of total intravenous anaesthesia and dantrolene in the face of the potential for drug‐induced hepatotoxicity in the remnant liver or transplanted liver graft, as well as cautious fluid management needed for liver transplantation balanced against the liberal fluid therapy required to prevent acute kidney injury associated with malignant hyperthermia. The logistical challenges of managing this emergency in two closely related patients are discussed, including rapid preparation of two vapour‐free anaesthesia machines, the need for availability of additional dantrolene and the requirement for additional personnel. Prompt recognition, immediate removal of the triggering agents and conversion to total intravenous anaesthesia helped to curtail the malignant hyperthermic reactions in our patients, both of whom made a full recovery.

Introduction

Malignant hyperthermia (MH) is a pharmaco‐genetic disorder, presenting as an acute life‐threatening hypermetabolic response, commonly following exposure to potent inhalational anaesthetic agents and the depolarising muscle relaxant succinylcholine and rarely to vigorous exercise or heat. The genetic mutations rendering an individual MH susceptible often run in families. A family history of a positive reaction or unexplained anaesthetic complications in the past may alert an anaesthetist to a potential issue.

Living donor liver transplantation (LDLT) is a procedure that involves concurrent surgery in a donor and a recipient who are often related. We report a case where two siblings undergoing LDLT developed MH simultaneously. We discuss the clinical management, diagnostic challenges, and the logistical constraints faced.

Case report

A 13‐year‐old boy with decompensated liver disease secondary to hepatic haemangio‐endothelioma was scheduled to undergo LDLT. He had undergone general anaesthesia (GA) three times in the past, without incident. The liver donor was his 28‐year‐old sister, who had never had a general anaesthetic. They had no family history of anaesthetic complications.

The donor was given propofol, fentanyl and rocuronium for the induction of GA; maintenance was with sevoflurane, and intravenous fentanyl and atracurium were given. In addition to the standard ASA monitoring, oesophageal temperature, intra‐arterial blood pressure and central venous pressure were monitored. Approximately 1 h and 15 min after induction her temperature increased, to a maximum of 37.3°C, and her end‐tidal carbon dioxide level increased to 7.1 kPa which was unresponsive to hyperventilation. A presumptive diagnosis of MH was established, the sevoflurane was stopped and total intravenous anaesthesia (TIVA) was commenced. She was transferred onto the designated vapour‐free anaesthesia machine. At this point in the surgery, the liver splitting was almost complete, hence liberal fluid therapy was commenced. Within 2 h and 15 min from the onset, these interventions had allowed for clinical stabilisation of the patient without the need for administration of dantrolene.

About an hour after the start of the donor surgery the recipient was sent for, and by about 2 h and 30 min GA was performed with a similar technique (induction with fentanyl, propofol, atracurium, and maintenance with sevoflurane and intravenous infusions of fentanyl and atracurium). Soon after induction, an oesophageal temperature probe was inserted, recording a temperature of 38.9°C, in the context of an end‐tidal CO₂ level of 5.1 kPa. While this was being addressed, an alert was received from the donor’s anaesthesia team regarding possible MH susceptibility; an MH reaction was assumed and was managed by stopping the sevoflurane and commencing a propofol infusion. As there were no charcoal filters available and the vapour‐free machine was in use with the donor, the recipient’s lungs were ventilated manually with wall oxygen supply and a self‐inflating bag‐valve (Ambu, Copenhagen, Denmark). The anaesthesia circuit and CO₂ absorber were changed, and the machine was purged with pure oxygen for 30 min to make it ‘vapour‐free’. Within the next hour, the end‐tidal CO₂ level and the temperature settled, while the other vital signs remained stable. As with the donor patient, the suspected MH reaction was managed without the need for dantrolene administration. After stabilisation of the recipient, the decision was made to continue with the surgery which was completed uneventfully. Serum creatine kinase was transiently mildly elevated in both patients, but they made good recovery. The recipient subsequently received three more uneventful general anaesthetics for surgical complications, with MH precautions observed.

The anaesthesia charts related to the index event for both siblings (Fig. 1) were reviewed by the National MH Referral Centre in Leeds, United Kingdom, who advised to treat them as ‘MH susceptible’ until definitive diagnosis was established using genetic testing and in vitro contracture testing on a fresh muscle biopsy. The siblings were referred for next‐generation sequencing, which showed heterozygous mutation in RYR1 c.7123G>C; p. Glyc2375Arg in both. The National MH Referral Centre confirmed that the finding was supportive of our clinical diagnosis and the geneticist at our institution advised that the mutation was likely pathogenic. In vitro contracture testing is not available anywhere in the Gulf region, and unfortunately the patients do not have access to state, insurance, or private funding for testing in foreign centres so this element remains unresolved.

Figure 1.

Anaesthesia charts of the donor (a) and the recipient (b). The red boxes highlight the suspected MH reaction.

Discussion

Malignant hyperthermia requires prompt recognition, and intervention helps to curtail the profound metabolic response and improves survival of the patient. The commonest signs are an unexplained tachycardia, muscle rigidity, and rise in end‐tidal CO₂ levels despite increasing minute ventilation; an increasing body temperature may be one of the earliest signs in 63.5% of MH reactions and disseminated intravascular coagulation is the usual cause of death if hyperthermia (above 41°C) is not controlled [1].

Although MH‐susceptible individuals may develop a clinical response on their first exposure, on average they require three anaesthetic episodes before triggering. The true relationship between genetic predisposition and phenotypical expression of MH is poorly understood. The most recent estimates of prevalence of MH are quoted as 1:400 for the genotype, and between 1:250,000 and 1:10,000 for the phenotype [1]. The gold standard for diagnosing MH susceptibility is in vitro contracture testing, whereby a biopsied fresh muscle specimen exposed to increasing concentrations of halothane or caffeine produces a sustained muscle contraction. However, up to 50% of index patients testing positive on in vitro contracture testing do not have a known associated genetic mutation identified. With the advent of cost effective DNA sequencing techniques such as next‐generation sequencing, the pool of relevant genetic mutations in the previously unknown loci is expanding, improving prediction and diagnosis of MH susceptibility [2], yet a diagnostic void persists.

The MH reaction tends not to occur beyond 40 min after the removal of trigger [3], as was observed in our patients as well when the reaction subsided with the removal of the trigger alone. According to the Association of Anaesthetists Malignant Hyperthermia guidelines 2020, administration of prophylactic dantrolene is not required in the majority of cases, hence not recommended after control of the initial reaction; continuation of surgery is also not contraindicated in this situation [4].

As there was control of the situation in both patients and ongoing management of the sequelae was not required, in line with these guidelines there were no contraindications to the continuation and completion of the surgical procedure [4]. There were, however, some potential clinical management conflicts. For example, conservative fluid management is practiced in LDLT particularly during dissection phase, whereas liberal fluid therapy is needed to prevent renal injury with MH‐associated rhabdomyolysis. Fortunately, in case of the donor, the surgery had already progressed to the point when we would ordinarily be administering liberal fluid therapy, hence it did not impact the clinical management. Likewise, in the recipient, the reaction terminated before the surgery started, so it remained inconsequential.

Dantrolene should be used with caution in patients with liver transplant as it is metabolised by the liver and carries a black box warning from the Food and Drugs Authority, United States of America, for the potential for hepatotoxicity. In a newly transplanted liver, graft dysfunction with dantrolene has been reported [5]; however, low‐dose dantrolene has been used in this setting without hepatotoxic effects [6]. If needed, it should be administered in low dose and for shorter period to avoid the consequences [7].

The use of TIVA with propofol carries a theoretical risk of over‐sedation and lipid overload in patients with liver pathology. Pharmacokinetic models have been shown to underestimate the plasma propofol concentrations in patients undergoing liver transplantation [8], hence doses should be carefully titrated according to depth of anaesthesia monitoring. In some patients with significant mitochondrial dysfunction (e.g. domino liver transplant), lipid loads may not be metabolised and may accumulate, compounding liver injury [7].

The logistics of dealing with concurrent cases of MH can present a challenge to the operating theatre team. Management of a suspected MH reaction includes immediately removing the inhalational trigger by switching to a vapour‐free anaesthesia machine in addition to deploying the pre‐prepared MH box and other medical measures. Effective and precise time management is of great essence for damage control and may even help abort the MH reaction. Typically, most theatre suites have only one MH‐ready anaesthesia machine kept available and preparing a second anaesthesia machine by purging with pure oxygen to make it vapour free may take a minimum of 30 min. The European Malignant Hyperthermia Group guidelines recommend using activated charcoal filters in the anaesthesia machines to adsorb the volatile anaesthetic agent vapour and clear the system quickly making it ready for use with a patient with MH within 3 min. Additional dantrolene supplies may be necessary and may have to be retrieved from geographically distant sites within a hospital. A newer dantrolene 250 mg preparation (Ryanodex; Eagle Pharmaceuticals, Inc., Woodcliff Lake, NJ, USA) contains more than one adult dose, hence is easier to store and use. Supplementary human resources may be required for such scenarios, which may be needed for helping with manual ventilation, fluid therapy, and reconstituting dantrolene, particularly if the older preparation is used.

Following the acute event, diagnostic diligence is crucial before issuing an MH‐susceptibility label as it may have lifelong implications for the patient, namely consideration of elevated risk, the need for anaesthetic adaptations for the individual and their close relatives, higher cost of medical insurance and unsuitability for some professions such as military service, among others [9]. In our context, the true incidence of MH and MH susceptibility in Saudi Arabia is unknown. Several families have been identified with potentially relevant mutations, but only a few have received a confirmed diagnosis by travelling abroad as unfortunately in vitro contracture testing is not available in the region, meaning the diagnosis of MH and identification of MH‐susceptible patients in Saudi Arabia is at present limited to verification of genetic predisposition.

In terms of global health, genetic testing requires a stored specimen be sent to a laboratory whereas in vitro contracture testing can only be done in a suitable laboratory on a fresh muscle biopsy taken minutes before performing the test. Both facilities are available in only a handful of centres around the globe and access to them can be expensive and time‐consuming, yet this investigation does not always provide a conclusive answer. Like our patients, most individuals in our region who experience such a reaction are constrained due to eligibility, affordability, and border control issues, so will live with a presumed MH susceptibility label. Universally available MH diagnostic facilities are a need of our times.