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Management of a Patient With a History of Nonanesthesia-Related Malignant Hyperthermia Undergoing Laparoscopic Cholecystectomy: A Case Report

Nelson, Emily P. MD*; Dorlon, Margaret E. MD; Szabo, Tamas A. MD, PhD*; Trollinger, Jonathan B. CRNA; Johnson-Mann, Crystal MD; Broderick, Gearin MD*; Warters, Robert D. MD*

doi: 10.1213/XAA.0000000000000767
Case Reports
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A 36-year-old African American with a medical history of nonanesthesia-related malignant hyperthermia (MH) who was taking chronic oral dantrolene therapy presented with right upper quadrant pain for a laparoscopic cholecystectomy. A multidisciplinary perioperative plan was implemented with the goal of avoiding triggering an MH episode or rhabdomyolysis. He developed a postoperative left brachial vein thrombus of unclear etiology, possibly related to dantrolene administration or his underlying susceptibility to MH.

From the Departments of *Anesthesia and Perioperative Medicine

Surgery, Medical University of South Carolina, Charleston, South Carolina

Department of Anesthesiology, Ralph H. Johnson VA Medical Center, Charleston, South Carolina.

Accepted for publication February 16, 2018.

Funding: None.

The authors declare no conflicts of interest.

Emily P. Nelson, MD, and Margaret E. Dorlon, MD, contributed equally to this work.

Address correspondence to Tamas A. Szabo, MD, PhD, Department of Anesthesia and Perioperative Medicine, Medical University of South Carolina, 167 Ashley Ave, Suite 301, MSC912, Charleston, SC 29425. Address e-mail to tamas.szabo@va.gov.

Anesthesiologists should be familiar with the management of malignant hyperthermia (MH), a myopathy that causes a potentially fatal hypermetabolic reaction during and after exposure to volatile anesthetics and succinylcholine. However, a subset of patients who carry the diagnosis of MH also have nonanesthesia-related MH.1 Patients with nonanesthesia-related MH have a ryanodine receptor 1 (RYR1) MH-causative mutation and recurrent rhabdomyolysis, unrelated to triggering anesthetic agents. There is a growing body of literature suggesting a relationship between exertional rhabdomyolysis and MH.1,2 Exertional rhabdomyolysis occurs in response to exercise when mechanical or metabolic stress damages skeletal muscles.3

The cases of 2 brothers with recurrent rhabdomyolysis and a RYR1 MH-causative mutation were described in A&A Case Reports.1 Although these brothers had undergone general anesthetics in the past, no one has described a plan for general anesthesia in a patient with known nonanesthesia-related MH. There are no data on the efficacy of additional dantrolene in patients chronically exposed to dantrolene, and there are no published recommendations for anesthetics in patients with a history of MH who are taking oral dantrolene.

We present the multidisciplinary management of a 36-year-old man with nonanesthesia-related MH who underwent a laparoscopic cholecystectomy. A written consent has been obtained from the patient before submitting the article.

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CASE DESCRIPTION

A 36-year-old African American (height: 188 cm, weight: 118 kg) with a medical history of nonanesthesia-related MH presented with abdominal pain and was scheduled for a laparoscopic cholecystectomy.

Of note, the patient was diagnosed with MH 6 years ago when he presented to the emergency department complaining of chest pain after working in the heat.1 He was found to have muscle cramps, increased creatinine kinase (CK), and rhabdomyolysis. He was evaluated for myopathic disorders, and his caffeine halothane contracture test was positive. He was then found to have a RYR1 positive for an Arg2454Cys mutation, a mutation that causes MH, and he was started on oral dantrolene. When he presented for laparoscopic cholecystectomy, he was taking dantrolene 100 mg 4 times daily, but he still had chronically elevated CK levels (1000–3000 U/L). He had undergone 2 uncomplicated surgical procedures under general anesthesia as a child.

The patient’s identical twin brother and mother were also found to have the same positive RYR1 mutation. The patient’s twin had a history of 2 episodes of “cardiac arrest” related to bilateral ptosis surgery. The twin had recently undergone an uneventful laparoscopic cholecystectomy under a nontriggering anesthetic at another facility. His anesthesia and perioperative records were unavailable for preoperative evaluation.

A nontriggering anesthetic was planned, but the question of whether to give additional dantrolene in the perioperative period remained. We sought data on whether dantrolene is as effective in patients who have been taking it chronically if it is needed for a MH episode. A consultant at the Malignant Hyperthermia Association of the United States (MHAUS) was contacted, but explained that there are too few cases of patients on chronic dantrolene to know if dantrolene efficacy is the same in these patients.

Vaporizers were removed from the anesthesia machine, activated charcoal filters were placed, and the machine was flushed per MHAUS protocol.

On the day of surgery, the patient explained that if his CK approached 4000 U/L that he would begin to have symptoms of diarrhea, fatigue, and muscle aches. His CK was 1487 U/L. He had taken his morning dose of 100 mg dantrolene. A 16-G right hand intravenous (IV) was placed in the holding area, 2 mg midazolam and 1 L Lactated Ringer’s were administered.

Routine American Society of Anesthesiologists monitors were placed. The patient was administered 100 μg fentanyl, and anesthesia was induced with 200 mg propofol. Neuromuscular blockade was achieved with administration of 50 mg rocuronium. After endotracheal intubation, a second 18-G IV and a radial arterial line were placed in his left hand. A Foley catheter with a temperature probe was inserted. A prophylactic dose of dantrolene 50 mg (0.4 mg/kg) was administered through the right hand 16-G cannula at the start of surgery given the patient’s chronically high CK levels, chronic dantrolene use, and history of nonanesthesia-related MH. This dose was chosen because it is equivalent to half of his home dantrolene dose and was intended as a supplementation to help prevent rhabdomyolysis, assuming that the stress of surgery could possibly trigger an event. An arterial blood gas at the start of surgery was unremarkable. He was given hydromorphone 2 mg for pain and maintained on a propofol infusion. High fresh gas flows, over 10 L/min, were used. An additional 500 mL Lactated Ringer’s was given during the case, for a total of 1500 mL (8.5 mL/kg/h). Urine output was 325 mL. He was hemodynamically stable throughout the surgery and remained normothermic. Neuromuscular blockade was reversed with 200 mg sugammadex and he was taken to the post anesthesia care unit.

His immediate postoperative course was uneventful. CK drawn in the post anesthesia care unit was 1294 U/L. He was admitted to the intensive care unit for monitoring and serial CKs. He received 1 dose of 80 mg IV dantrolene (0.7 mg/kg) in the intensive care unit, and then started on his oral home dose the evening of surgery. The 80 mg IV dantrolene dose was chosen because it is equivalent to his home dose of oral dantrolene in terms of bioavailability and he was unable to take oral medications immediately postoperatively. A Foley catheter remained in place for 24 hours to monitor volume status. Serial CK and basic metabolic panel levels were monitored to evaluate for early signs of rhabdomyolysis. Subsequent checks showed a continued downtrend in his serum CK value. He was discharged on postoperative day 2.

He was diagnosed with a left brachial vein thrombus as an outpatient on postoperative day 4. He had a documented left forearm IV during his admission without documented evidence of thrombophlebitis on its removal. This was not the site of his dantrolene administration during his surgery, but it is unclear if the postoperative dantrolene was administered via this IV. Of note, the patient’s twin had also been diagnosed with an upper extremity clot after an admission for rhabdomyolysis. Neither brother has had a hypercoagulability workup.

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DISCUSSION

Our patient took oral dantrolene chronically to prevent exertional rhabdomyolysis, but this case can be instructive for intraoperative management of patients taking oral dantrolene for other indications. According to the FDA, oral dantrolene is indicated in controlling the manifestations of chronic but presumably reversible spasticity resulting from upper motor neuron disorders (eg, multiple sclerosis, stroke, cerebral palsy, or spinal cord injury) to restore residual function. On the other hand, oral dantrolene should not be used for the management of neuroleptic malignant syndrome or in the treatment of skeletal muscle spasm resulting from rheumatic disorders.

It is unclear whether a “prophylactic dose” of IV dantrolene was necessary for this patient. MHAUS states that dantrolene prophylaxis is not recommended for most MH patients.4 However, there are no published recommendations for whether to administer dantrolene prophylaxis in patients on chronic oral dantrolene. The 2 additional IV doses were chosen based on the 70% bioavailability of oral dantrolene and its somewhat shorter mean biologic half-life (orally, per os : 8.7 hours versus IV: 10–12 hours). The perioperative administration of dantrolene may cause muscle weakness and a delay in the recovery of muscle relaxation, leading to prolonged neuromuscular blockade5; however, the availability of sugammadex may alleviate this concern.

The patient’s postoperative complication of brachial vein thrombosis was possibly associated with IV dantrolene. Phlebitis is a known complication of dantrolene infusion and reported in up to 9% of dantrolene use.6 In addition, the presence of phlebitis has been demonstrated as an independent risk factor for the development of thrombosis.7 Grodofsky et al8 describe a case of a man treated with IV dantrolene for an MH episode who develops a right basilic and cephalic thrombus. Our case and the case of the patient’s twin, who developed an upper extremity deep venous thrombosis (DVT) after being administered IV dantrolene, provide 2 additional cases linking dantrolene administration to DVT formation. It is unclear if our patient’s postoperative dose of IV dantrolene was injected into the arm in which he later developed a DVT.

It still remains unclear whether it is the actual IV dantrolene administration or the underlying condition of MH susceptibility that leads to an increased risk of DVTs. It is also possible that the DVTs in these patients are coincidental. There is no evidence in the literature linking MH susceptibility to increased risk of DVTs.

Another interesting aspect of this case is that induction of pneumoperitoneum with CO2 in laparoscopic surgery causes elevated end-tidal CO2, one of the early findings of MH. The use of CO2 alternatives (eg, room air, nitrogen, nitrous oxide, helium, or argon) may mitigate this problem; however, their risk and benefit profiles are yet to be established.9

Finally, MH susceptibility is a disqualifying condition for entry into military service or continued active duty status.10 Our patient and his brother were unaware of their MH susceptibility and both completed military training without an episode of MH. Both could have suffered from a nonanesthesia-related MH-like episode triggered by exertion or heat. Screening for MH susceptibility and other family history–related conditions may be considered to avoid putting our soldiers in harm’s way. E

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DISCLOSURES

Name: Emily P. Nelson, MD.

Contribution: This author helped write the article.

Name: Margaret E. Dorlon, MD.

Contribution: This author helped perform the surgery and write the article.

Name: Tamas A. Szabo, MD, PhD.

Contribution: This author helped write the article.

Name: Jonathan B. Trollinger, CRNA.

Contribution: This author helped conduct the anesthetic and edit the article.

Name: Crystal Johnson-Mann, MD.

Contribution: This author helped perform the surgery and edit the article.

Name: Gearin Broderick, MD.

Contribution: This author helped perform the preanesthesia evaluation and write the article.

Name: Robert D. Warters, MD.

Contribution: This author helped conduct the anesthetic and edit the article.

This manuscript was handled by: Mark C. Phillips, MD.

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REFERENCES

1. Potts LE, Longwell JJ, Bedocs P, et al. Improving awareness of nonanesthesia-related malignant hyperthermia presentations: a tale of two brothers. A A Case Rep. 2014;3:2326.
2. Kraeva N, Sapa A, Dowling JJ, Riazi S. Malignant hyperthermia susceptibility in patients with exertional rhabdomyolysis: a retrospective cohort study and updated systematic review. Can J Anaesth. 2017;64:736743.
3. Warren JD, Blumbergs PC, Thompson PD. Rhabdomyolysis: a review. Muscle Nerve. 2002;25:332347.
4. MHAUS website. Available at: http://www.mhaus.org/faqs/dantrolene. Accessed June 8, 2017.
5. Jeon J, Song S, Kim MC, Kim KM, Lee S. The effect of long-term oral dantrolene on the neuromuscular action of rocuronium: a case report. Korean J Anesthesiol. 2014;66:153156.
6. Brandom BW, Larach MG, Chen MS, Young MC. Complications associated with the administration of dantrolene 1987 to 2006: a report from the North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States. Anesth Analg. 2011;112:11151123.
7. Jorgensen JO, Hanel KC, Morgan AM, Hunt JM. The incidence of deep venous thrombosis in patients with superficial thrombophlebitis of the lower limbs. J Vasc Surg. 1993;18:7073.
8. Grodofsky S, Levitt C, Schlichter RA, Stanton DC, Liu R, Chen L. Upper extremity deep vein thrombosis in a patient treated for malignant hyperthermia. J Clin Anesth. 2013;25:350352.
9. Yu T, Cheng Y, Wang X, et al. Gases for establishing pneumoperitoneum during laparoscopic abdominal surgery. Cochrane Database Syst Rev. 2017;6:CD009569.
10. Lee MA, McGlinch EB, McGlinch MC, Capacchione JF. Malignant hyperthermia susceptibility and fitness for duty. Mil Med. 2017;182:e1854e1857.
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