Malignant hyperthermia (MH) is a well-known condition to anesthesiologists but rarely encountered. The basic pathophysiology of MH is dysregulated intracellular calcium handling leading to a hypermetabolic state and profound rhabdomyolysis.1 Despite the relatively unique constellation of signs and laboratory findings associated with MH (rigidity, tachypnea, tachycardia, hyperthermia, hyperkalemia, and mixed acidosis),1 anesthesiologists must consider a wider differential diagnosis including carcinoid crisis. Correct diagnosis is critical as the treatment varies by condition with prompt and effective management paramount for patient survival. Management of an MH crisis is well defined but complex and labor intensive and requires the administration of dantrolene.2 Dantrolene dosing is based on studies involving slim healthy volunteers with no existing studies to address appropriate dosing for the overweight or obese patient.
We describe the challenges of diagnosing an acute hypermetabolic crisis in a patient undergoing resection of a carcinoid tumor and the basis for current dantrolene dosing and lack of evidence for dosing in the context of a morbidly obese patient.
The patient gave written permission for the authors to publish this report.
A 28-year-old (height, 169 cm; weight, 153 kg; body mass index, 53 kg/m2) woman was scheduled for laparotomy to remove a duodenal carcinoid tumor. The asymptomatic carcinoid tumor was discovered 10 months earlier during a workup for abdominal pain. Preoperatively the patient denied symptoms of carcinoid syndrome (flushing, wheezing, diarrhea, and palpitations), and biochemical testing was negative for elevated urine 5-hydroxyindoleacetic acid. The patient’s other medical history included successfully treated lymphoma, obstructive sleep apnea, type 2 diabetes mellitus, hypertension, gout, and major depressive disorder. The patient’s home medications included perindopril, allopurinol, metformin, mirtazapine, zopiclone, and insulin. She had no allergies to medications. The patient had previously undergone uneventful MH-triggering general anesthesia for an appendectomy, placement and removal of a dynamic hip screw, and third molar extraction. In addition, there was no family history of problems with anesthesia. Preoperative vital signs and bloodwork including complete blood count, electrolytes, and coagulation studies were unremarkable.
After the placement of standard monitors, 2 large bore IV catheters, a thoracic epidural, and radial arterial line were placed. General anesthesia was induced at 9:00 am with sufentanil, propofol, and rocuronium. Videolaryngoscopy was used to place the endotracheal tube, and an esophageal temperature probe was inserted. Anesthesia was maintained with desflurane starting at approximately 9:05 am (expiratory concentrations ranging from 3.3% to 3.8%) and infusions of sufentanil (0.5 μg/kg/h), dexmedetomidine (0.2 μg/kg/h), cisatracurium (titrated to 1-to-2 twitches), and epidural lidocaine (1.5 mg/kg/h). A prophylactic octreotide infusion was started at 50 μg/h. A permissive hypercapnia ventilation strategy was employed with a minute ventilation of 7.0 to 7.6 L to target end-tidal carbon dioxide (Etco2) of 45 to 50 mm Hg. The patient’s baseline esophageal temperature was 36.4°C, and an external warmer (3M Bair HuggerTM System, Maplewood, MN) was set to 43°C to maintain normothermia.
The tumor was resected by 11:00 am, but its location necessitated a pancreaticoduodenectomy. Arterial blood gas (ABG) results at 11:02 am (Table) showed hyperkalemia and a mixed acidosis. At approximately 12:40 pm, the patient’s temperature surged initially from 36.8°C to 37.6°C and then to 38.2°C, and simultaneously Etco2 increased from 51 to 58 within a few minutes. Given these clinical signs in conjunction with the ABG (drawn at 12:28 pm) demonstrating hyperkalemia and a mixed acidosis, a clinical diagnosis of MH crisis was made. Muscular rigidity was not appreciated at the time. Standard MH management was initiated including summoning extra human resources, discontinuing volatile anesthesia, placement of activated charcoal filters in both limbs of the ventilator circuit, and hyperventilation with 100% fraction of inspired oxygen flows at 15 L/min. The external warmer was set to ambient room temperature to help cool the patient. Dantrolene sodium (20 mg/vial) was administered in 2.5 mg/kg boluses. The first bolus occurred at approximately 13:00 pm (4 hours after anesthetic induction and approximately 15 minutes after the diagnosis of MH). Simultaneously supportive measures for hyperkalemia were instituted including repeated administration of furosemide, sodium bicarbonate, calcium gluconate, salbutamol, as well as insulin and epinephrine infusions. ABG results at 13:10 pm showed worsening hypercarbia, despite hyperventilation, and persistent hyperkalemia. Serum myoglobin was elevated at 368 μg/L (normal value, 11.4–46.7 μg/L). In consultation with the surgical team, the patient’s abdomen was left open, the case concluded at 16:10 pm, and the patient was transferred to the intensive care unit (ICU).
After ICU admission, further dantrolene was required to control hyperthermia and hypercarbia. The total dantrolene dose was 33 mg/kg or 252 vials over 72 hours (including intraoperative administration). The patient’s creatine kinase and myoglobin levels peaked at 11,345 U/L and 4332 μg/L, respectively, on postoperative day 2. The patient underwent an uneventful trigger-free anesthetic for closure of her abdomen 3 days later, but her course in the ICU was complicated by prolonged need for hemodialysis and invasive respiratory support. Complete MH genetic testing did not reveal known MH-susceptible genetics. Caffeine–halothane contracture testing was not performed due to lack of a local testing facility. The patient was discharged home approximately 75 days after the first surgical procedure.
The intraoperative diagnosis of MH crisis can be challenging as some signs are nonspecific and others appear late. A mixed acidosis and mild hyperkalemia were already present on ABG analysis in our patient at 11:02 am (2 hours after induction of anesthesia). In retrospect, this likely early biochemical evidence of evolving MH was overlooked for numerous reasons, including our chosen lung protective ventilation strategy and stable hemodynamics and temperature. A diagnosis of MH crisis was not made until the patient developed rapidly increasing Etco2, tachycardia, peaked T-waves, and hyperthermia. This diagnosis was supported by an ABG revealing both worsening mixed acidosis and hyperkalemia. At that stage, well-described therapy for MH was initiated, including IV dantrolene, which required redosing because of nonsustained improvement of hyperthermia and hypercarbia.2
The most plausible alternative diagnoses given the symptom complex include neuroleptic malignant syndrome and carcinoid crisis with the former very unlikely without exposure to a neuroleptic medication. Several features of our case argue against a carcinoid crisis. First, the tumor was isolated to a prehepatic location; tumor-secreted hormones in this location are most often rapidly metabolized by the liver before reaching the systemic circulation.3 In addition, the presence of normal preoperative 5-hydroxyindoleacetic acid levels and prophylactic octreotide infusion suggest that this was not a carcinoid crisis.3,4 Finally, the lack of other intraoperative features consistent with carcinoid crisis (flushing, bronchoconstriction, hemodynamic instability) make this diagnosis less likely. Other possible, but less likely, diagnoses of intraoperative hyperthermia include sepsis and endocrinopathies such as thyroid storm and pheochromocytoma.
It is well described that previous uneventful triggering anesthetics do not preclude the possibility of an MH event.5,6 A recent review determined that the median onset time of MH after trigger exposure in the absence of succinylcholine was 113.5 minutes for desflurane (consistent with our case), 45 minutes for sevoflurane, and 15.5 minutes for halothane.7
Early research in swine demonstrated that IV dantrolene was effective for MH.8 Subsequently dantrolene was found to be effective in human MH.9 Malignant Hyperthermia Association of the United States (MHAUS) recommends a minimum of thirty-six 20-mg vials be available and to dose dantrolene based on actual rather than ideal or lean body weight.10 In our case, a single bolus of dantrolene entailed 380 mg or 19 vials. The current dantrolene dosing recommendations arise from studies on human volunteers.11 In adults (with a mean weight of 75.8 kg) and children, dantrolene doses 2.2 to 2.5 mg/kg (based on total body weight) resulted in blood concentrations to be at or above levels known to produce maximum effect.11,12 Currently, no data are available to guide dantrolene dosing in overweight and obese patients despite many other commonly administered anesthetic drugs accounting for this factor.13
In our case, the need for massive doses of dantrolene was recognized, and pharmacy was notified. The entire hospital supply of dantrolene, approximately sixty 20-mg vials, was depleted within the first 2 hours of management. Additional dantrolene was locally sourced from other hospitals and surgical facilities, nearby communities, as well as flown in from other cities. Given the logistical complexities of emergently procuring external sources and the high workload of managing an MH crisis, anesthesiologists are well served to involve their institution’s pharmacy early for assistance.
It may be that the patient’s obesity and prolonged exposure to desflurane led to a sustained release of desflurane from her adipose tissue and extended the duration of the MH crisis. This issue is likely to become more common with the increase in incidence of obesity in most surgical populations.14 Other care implications in our case included our health region restricting surgical procedures at some sites to “life or limb threatening” procedures until local stocks of dantrolene could be replenished over the next 1 to 2 days. This case suggests that current MHAUS recommendations for institutional dantrolene availability may be insufficient and require updating reflecting contemporary patient size.
The researchers gratefully acknowledge the assistance of our numerous colleagues who provided assistance in the management of this difficult case.
Name: Fabio Magistris, MD.
Contribution: This author helped write the initial draft and revise the manuscript.
Name: Jonathan Gamble, MD.
Contribution: This author helped revise the manuscript.
This manuscript was handled by: Raymond C. Roy, MD.
1. Hopkins PMMalignant hyperthermia: advances in clinical management and diagnosis. Br J Anaesth. 2000;85:118128.
2. Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler FDantrolene—a review of its pharmacology, therapeutic use and new developments. Anaesthesia. 2004;59:364373.
3. Bajwa SJS, Panda A, Kaur GCarcinoid tumours: challenges and considerations during anesthetic management. J Sci Soc. 2015;42:132137.
4. Powell B, Al Mukhtar A, Mills GHCarcinoid: the disease and its implications for anaesthesia. BJA Educ. 2011;11: 913.
5. Rosenberg H, Davis M, James D, Pollock N, Stowell KMalignant hyperthermia. Orphanet J Rare Dis. 2007;2:21.
6. Larach MG, Gronert GA, Allen GC, Brandom BW, Lehman EBClinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg. 2010;110:498507.
7. Visoiu M, Young MC, Wieland K, Brandom BWAnesthetic drugs and onset of malignant hyperthermia. Anesth Analg. 2014;118:388396.
8. Harrison GGControl of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium. Br J Anaesth. 1975;47:6265.
9. Kolb ME, Horne ML, Martz RDantrolene in human malignant hyperthermia. Anesthesiology. 1982;56:254262.
11. Flewellen EH, Nelson TE, Jones WP, Arens JF, Wagner DLDantrolene dose response in awake man: implications for management of malignant hyperthermia. Anesthesiology. 1983;59:275280.
12. Lerman J, McLeod ME, Strong HAPharmacokinetics of intravenous dantrolene in children. Anesthesiology. 1989;70:625629.
13. Kim TK, Obara S, Johnson KBMiller RDChapter 24 basic principles of pharmacology. In: Miller’s Anesthesia. 2015:8th ed. Philadelphia, PA: Elsevier Saunders; 590613.
14. Flegal KM, Carroll MD, Ogden CL, Curtin LRPrevalence and trends in obesity among US adults, 1999-2008. JAMA. 2010;303:235241.