Difficult diagnosis of malignant hyperthermia during laparoscopic surgery

Field: Medicine (Health Sciences)

Editor, Malignant hyperthermia is a hypermetabolic state of skeletal muscle, triggered by volatile anaesthetics and succinylcholine. It is a rare condition, and its clinical manifestations vary widely. A high level of vigilance on the part of the anaesthesiologist is needed to recognise a potential episode of malignant hyperthermia, followed by a timely response and a specific management plan if a lethal outcome is to be avoided. However, some physicians consider malignant hyperthermia to be a thing of the past, in part because modern volatile agents such as desflurane have a low potential for triggering malignant hyperthermia. For this reason, with consent of the patient, we describe this case of a confirmed episode of malignant hyperthermia triggered by desflurane. A 66-year-old male patient (85 kg, 175 cm, BMI 28 kg m−2) with known asymptomatic posterior mitral valve prolapse underwent elective robot-assisted laparoscopic prostatectomy under general anaesthesia. He had no known allergies and took no medication prior to surgery and had had uncomplicated spinal anaesthesia years before. Three milligrams of midazolam were administered intravenously 15 min prior to induction of anaesthesia. General anaesthesia was induced with thiopental, fentanyl and atracurium and was maintained with desflurane, remifentanil and fentanyl. Initial end-tidal CO2 was 4.3 kPa and oesophageal temperature was 36.5°C. Thirty minutes after induction, SBP and heart rate dropped to 80 mmHg and 40 beats min−1, respectively. Ephedrine 10 mg and atropine 0.75 mg were administered intravenously. The patient was positioned in a steep Trendelenburg position for surgery. After insufflation of CO2 into the peritoneal cavity, SBP increased to 180 mmHg. A total of 150 μg clonidine was administered intravenously, divided into four doses. Subsequently, haemodynamic variables remained stable. A forced warm air device (Bair Hugger, 3M, Rueschlikon, Switzerland) was installed to maintain the core temperature, which measured 36.5°C at that time. Over the next 210 min, vital signs remained stable. Minute ventilation was increased shortly after capnoperitoneum from 4.5 to 9.5 l min−1, whereas a constant end-tidal pCO2 was measured to be 4.1 to 4.5 kPa. About 240 min after induction, there was a continuous increase of end-tidal CO2 from 4.5 to 5.3 kPa, as well as a rise in core temperature from 37.1 to 37.7°C. The forced warm air was stopped and minute ventilation was increased from 9.5 to more than 11.5 l min−1. During the next 90 min, the patient's core temperature rapidly increased from 37.7 to 39.4°C, and end-tidal CO2 rose to 8.8 kPa; heart rate increased from 80 to 130 beats min−1, whereas blood pressure remained stable at 110/50 mmHg. A blood gas analysis 390 min after induction showed respiratory acidosis (pH 7.25, paO2 28.9 kPa, paCO2 9.6 kPa, lactate 2.6 mmol l−1, base excess +2.9 mmol l−1, glucose 6.0 mmol l−1, potassium 4.9 mmol l−1). Oxygen saturation remained stable at 99% with an inspiratory oxygen concentration of 50%. At this moment, malignant hyperthermia was suspected. Desflurane was stopped; anaesthesia was maintained by propofol; the ventilator was changed, and dantrolene 200 mg (2.3 mg kg−1) was given as an intravenous bolus. The patient was uncovered and cool wet blankets were applied. Within 30 min, core temperature and end-tidal CO2 returned to 37.2°C and 5.0 kPa, respectively. At that time, surgery had terminated. The patient was transferred to the ICU under controlled ventilation. Serum levels of creatine kinase rose from 284 U l−1 before surgery to 1480 U l−1 4 h thereafter and peaked at 7133 IU l−1 on the next day. The patient's trachea was extubated on the day of surgery and he made a full recovery. Three months after discharge, the patient was tested for malignant hyperthermia susceptibility according to the European Malignant Hyperthermia Group (EMHG) protocol with an open muscle biopsy and an in-vitro contracture test. The two halothane and both caffeine tests were positive with a contracture of 7.5 and 18 mN at 0.44 mmol l−1 halothane and 2 mmol l−1 caffeine, respectively. Following the positive contracture testing, molecular genetic analysis of the ryanodine receptor gene (RYR1) revealed mutation c.7007G>A (p.Arg2336His). The patient was given an emergency warning card and several of his first-degree relatives were subsequently tested by molecular genetic analyses and labelled malignant hyperthermia susceptible (Fig. 1, Table 1).Fig. 1: No captions available.Table 1: Results of arterial blood gas analysisWe consider this case to be of particular interest for the following reasons. First, desflurane might be (incorrectly) considered as having a low potential to trigger malignant hyperthermia. Second, clinical symptoms of hypermetabolism could be attributed to the capnoperitoneum. Third, the clinical suspicion of malignant hyperthermia was confirmed by both in-vitro contracture testing and molecular genetic analysis. During a malignant hyperthermia episode, the skeletal muscle enters a hypermetabolic state caused by an increase in calcium influx from the sarcoplasmic reticulum via the ryanodine receptor (RYR1).1 The calcium allows subsequent actin and myosin interaction leading to myofibrillar contraction. ATP is needed to end this interaction as well as to pump the calcium back into the sarcoplasmic reticulum. This ATP turnover produces heat (body temperature increases), and muscle rigidity develops depending on intracellular calcium concentration and ATP availability.2 Further elevated ATP turnover fed by aerobic glycolysis leads to increased CO2 production. Increased demands in oxygen can be compensated by an increase in cardiac output and tachycardia. Eventually, an anaerobic state with lactate acidosis and rhabdomyolysis (elevation of creatine kinase) will develop. Both conditions may result in severe potassium leakage from the intracellular to the extracellular space. Elevated levels of serum potassium, severe hyperthermia and further acid–base imbalance may promote ventricular arrhythmia and sudden death. Since the launch of desflurane in 1992, several cases of associated malignant hyperthermia in humans have been reported.3–5 The misleading notion that desflurane is a less potent trigger of malignant hyperthermia might have evolved because in-vitro contractures of malignant hyperthermia susceptible muscle are stronger with halothane than with desflurane.6 In a retrospective analysis of the North American Malignant Hyperthermia Registry, Allen and Brubaker7 found nonsignificant differences between desflurane and halothane concerning the delay between exposure and onset of malignant hyperthermia in humans. This case report underlines the triggering potency of desflurane. Clinical symptoms of malignant hyperthermia are diverse and are mostly signs of hypermetabolism with increased production of CO2 and heat. In our patient, the modest but continuous increase in core temperature was initially attributed to the forced air warming system. An increase in end-tidal CO2 and consequently increased minute ventilation were thought to be due to the insufflation of CO2 and the long duration of surgery. At 270 min after induction and shortly before the rapid increase in body temperature, arterial blood gas analysis revealed an alveolar-arterial oxygen gradient [(A–a)DO2] of 2 kPa. The gradient might have been caused by the combination of capnoperitoneum and the Trendelenburg lithotomy position as described by Takahata et al.8 This reduces the reliability of end-tidal pCO2 measurements and an increase in paCO2 can be underestimated. A malignant hyperthermia event was first suspected after 390 min of anaesthesia. This is a remarkable delay in onset of symptoms, which might be, in part, due to both the use of nondepolarising neuromuscular blocking agents and the relatively low solubility of desflurane.9 The impact of clonidine on the symptoms of malignant hyperthermia has not yet been studied. Reducing sympathetic activity by beta blockade has been shown to diminish symptoms of malignant hyperthermia in pigs;10 therefore, a similar effect could be hypothesised for clonidine in humans. During slowly evolving episodes of malignant hyperthermia, the increase in body temperature is a key diagnostic feature that underlines the importance of measuring core body temperature whenever malignant hyperthermia triggering agents are used. Treatment was in accordance with the guidelines of the European Malignant Hyperthermia Group,11 although current recommendations do not support changing the ventilator, as it is time-consuming. More recent data recommend the use of activated charcoal filters to remove volatile anaesthetics in the inspiratory limb.12 For the time being, such filters are not available in our country. This malignant hyperthermia event is classified by the Clinical Grading Scale (CGS)13 as rank 5, which is considered ‘very likely malignant hyperthermia’. However, several clinical signs might be attributed to other causes, for example hypercapnia and acidosis due to a capnoperitoneum in combination with a steep Trendelenburg position and changes in pulmonary pathophysiology. Therefore, the clinical diagnosis of malignant hyperthermia is less than certain in this case, emphasising the importance of establishing a correct malignant hyperthermia diagnosis. According to the guidelines of the EMHG, an open muscle biopsy and in-vitro contracture testing are required for the diagnosis. The mutation p.Arg2336His, which was identified in the ryanodine receptor gene, is not on the list of diagnostic mutations (http://www.emhg.org). It has been found in different countries1,14 and has been tested for its functional properties.1 This mutation confirms the positive diagnosis and will be submitted to the European Malignant Hyperthermia Group for inclusion in the list of diagnostic mutations. Acknowledgements Assistance with the study: none declared. Financial support and sponsorship: none declared. Conflicts of interest: none declared. Presentation: none declared.