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Anesthesia & Analgesia:
doi: 10.1213/ANE.0b013e3182768f99
Pediatric Anesthesiology: Case Report

Death in the Emergency Department: An Unrecognized Awake Malignant Hyperthermia-Like Reaction in a Six-Year-Old

Lavezzi, Wendy A. MD*; Capacchione, John F. MD; Muldoon, Sheila M. MD; Sambuughin, Nyamkhishig PhD; Bina, Saiid PhD; Steele, Deanna MS, CGC; Brandom, Barbara W. MD§‖

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Author Information

From the *Office of the District 5 Medical Examiner, Leesburg, Florida; Department of Anesthesiology, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Center for Medical Genetics and Department of Anesthesiology, University of Pittsburgh, Pittsburgh, Pennsylvania; and §North American Malignant Hyperthermia Registry (NAMHR) of the Malignant Hyperthermia Association of the United States.

Accepted for publication September 24, 2012.

Supported by the Defense Medical Research and Development Program, award no. W81XWH-10-2-0117.

This report was previously presented, in part, at the ANESTHESIOLOGY 2011 meeting, which was the subject of an article in ASA Daily News at ANESTHESIOLOGY 2011.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to John F. Capacchione, MD, Department of Anesthesiology, Uniformed Services University of the Health Sciences, USUHS4301 Jones Bridge Rd., Bethesda, MD 20814. Address e-mail to jcapacchione@usuhs.mil.

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Abstract

A healthy 6-year-old boy developed lower extremity rigidity, trismus, and fever after playing in a splash pool. On arrival in the emergency department, he appeared to be seizing. An endotracheal tube was emergently placed using succinylcholine. Cardiac arrest followed. He could not be resuscitated. Postmortem genetic analysis found a novel RYR1 variant. Family testing revealed the same variant in his father who also had muscle contracture testing diagnostic for susceptibility to malignant hyperthermia and central core disease diagnosed histologically. Because there was no exposure to volatile anesthetics before the onset of symptoms, this is a case of “awake” malignant hyperthermia worsened by succinylcholine.

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle characterized by a hypermetabolic response to inhaled anesthetics and succinylcholine resulting from increased myoplasmic calcium.1 To some, the concept of MH-like episodes without anesthetic exposure is controversial, despite literature to suggest otherwise.2–4 We describe a case of apparent awake MH that, after succinylcholine administration during resuscitation, led to cardiac arrest and death. Postmortem genetic analysis revealed the presence of a novel variant in the ryanodine receptor type 1 (RYR1) gene, the gene most strongly associated with MH susceptibility.5 This case implies that other health care providers, especially first responders who use succinylcholine, should be more conscious of the risk of succinylcholine administration in patients, particularly children, presenting with muscle rigidity and hyperthermia without exposure to anesthetic drugs.

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CASE DESCRIPTION

A 6-year-old Caucasian boy weighing 20 kg, who was not febrile or acutely ill, was playing outside on a hot, humid day in a splash pool for less than 10 minutes when he suddenly developed an inability to bend his legs. He told his mother that his heart felt like it was pounding out of his chest. His mother measured his temperature at 104°F and tried, unsuccessfully, to cool him with a cold shower, ice packs, and cold oral fluids. She therefore drove the child to the local emergency department (ED). En route, the child, although awake, complained of inability to speak clearly because he was unable to open his mouth. On admission to the ED, his rectal temperature exceeded 108.9°F, and he was sweating profusely. His respiratory rate was 60 breaths per minute, oxygen saturation 99%, arterial blood pressure 99/52 mm Hg, and heart rate 190 beats per minute. He appeared to have generalized seizures.

Benzodiazepine (1 dose of diazepam 5 mg; lorazepam 1 mg 4 times separated by 1 minute each for a 4-mg total dose) and other sedative hypnotics (etomidate 3 mg 2 times separated by 1 minute for a 6-mg total dose; propofol 10 mg 2 times separated by 3 minutes for a 20-mg total dose) were given IV over an 18-minute period without an effect on the presumed seizure activity. At 6 minutes into the 18-minute treatment interval, atropine (0.4 mg IV) was also given, presumably to decrease the oral secretions, which were obvious on admission to the ED. Cooling measures with IV fluids and external ice packs were attempted, but could not reduce the fever. Respiration was assisted and tachycardia continued throughout this period.

Because the child was in respiratory distress, succinylcholine (20 mg IV) was administered to place an endotracheal tube 19 minutes into the treatment. Jaw relaxation did not occur as anticipated, and another dose of succinylcholine (20 mg IV) was given 1 minute later. An acetaminophen suppository (360 mg) was also given at the same time as the second dose of succinylcholine. Bradycardia occurred almost immediately, then asystole. Advanced cardiac life support was instituted (25 minutes after the onset of treatment with diazepam) with atropine (0.6 mg IV) given 5 minutes after the second dose of succinylcholine. A ceftriaxone (1 g IV) infusion was started at the same time. A second dose of atropine (0.6 mg IV) was given 6 minutes into the resuscitation (beginning of advanced cardiac life support). Bicarbonate (20 mEq IV) was given at 4, 8, and 17 minutes into the resuscitation, and another 40 mEq was given 3 minutes later. Epinephrine (0.2 mg IV) was administered at 14, 15, and 21 minutes into the resuscitation. His laboratory values were significant for plasma potassium 9.4 mEq/L (10 minutes after the second dose of succinylcholine, and 5 minutes into the resuscitation), total creatine kinase 981 U/L with 19.1 U/L MB creatine kinase, and white blood cell count of 10.4 × 103/μL. (Other laboratory values 5 minutes into resuscitation were sodium 140, chloride 101, glucose 163, calcium 8.0, magnesium 2.5, blood urea nitrogen 20, creatinine 1.0.) Despite the multiple doses of atropine, epinephrine, and bicarbonate, a spontaneous cardiac rhythm never returned, and the arterial blood gases at 32 minutes into the resuscitation were pH 7.155, PCO2 166, and PO2 15.9. The rectal temperature was still 108°F.

Death was pronounced 1 hour after arrival in the ED, and 2 hours after his first presenting symptoms. An autopsy was performed within 24 hours. There were no gross pathologic findings or obvious signs of infection. Blood and tissue cultures were negative for significant organisms, microscopic studies were unremarkable, and toxicologic studies were negative for alcohol and drugs, other than what was administered in the ED. Vitreous electrolytes showed mild dehydration.

A retrospective review of the pediatrician’s records of the decedent revealed that he did not walk until 17 months of age, and that he had prominent lumbar lordosis; however, no muscle disorder was ever diagnosed. A genetic consultation at 3 years of age found no evidence for spinal muscular atrophy. Approximately 2 to 3 weeks before his death, the decedent experienced “overheating” and stomach cramps while playing outdoors in the heat. This resolved with rest and drinking cold water. Otherwise, he was well with no febrile illnesses. He periodically complained of leg pain. Two of his siblings and his father also had lumbar lordosis and did not walk until age 17 months. A 10-month-old female sibling had no lordosis and normal motor milestones. The family denied a history of MH, heat intolerance, or exercise intolerance. However, based on the negative autopsy and postmortem studies, the presence of muscle rigidity with extremely high temperature and adverse response to succinylcholine, the forensic pathologist determined MH to be the cause of death. As a result, the family was referred for further MH-related diagnostic testing.

A postmortem liver specimen was analyzed for RYR1 mutations. A novel RYR1 variant, Gly4820Arg, was found in exon 100. The decedent’s parents, grandparents, and siblings were screened for the same variant. The same RYR1 variant was only found in blood samples from the decedent’s father and 2 siblings with lumbar lordosis. The decedent’s father underwent a muscle biopsy and caffeine-halothane contracture test (CHCT), which was strongly positive for MH: mean contracture response of 3.85 g in the presence of 3% halothane and 1.32 g in the presence of 2 mM caffeine. Histology of the father’s muscle sample revealed central core disease (CCD).

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DISCUSSION

This child presented to the ED with rapidly increasing core temperature, profuse sweating, increased minute ventilation, tachycardia, trismus, and extremity rigidity. Attempts to break the presumed fever-induced seizure with benzodiazepines, other sedatives, and external cooling proved unsuccessful. Neurologic disease, including seizures, could produce these signs. Severe rigidity can be neurologic or muscular in origin. If seizures are not easily treated, pharmacologic intervention to control the airway may be needed. Airway intervention is also necessary for respiratory distress. This child’s signs and symptoms were similar to those of status epilepticus, but they were also very similar to the much less common condition, acute fulminant MH, which is typically associated with the administration of potent volatile inhaled anesthetics and/or succinylcholine.

Because the respiratory rate of 60 breaths per minute and heart rate of 190 beats per minute persisted despite attempts to stop the presumed seizures, the ED personnel determined it necessary to secure the child’s airway. The rapidity with which the temperature increased (not suggestive of an infectious etiology), and the history that the child was delayed in reaching the usual motor milestones and potentially myopathic, went unappreciated. Although succinylcholine is an appropriate drug to facilitate the emergent placement of an endotracheal tube, succinylcholine also has a Food and Drug Administration Black Box Warning because of potential hyperkalemic cardiac arrest for children (especially males) younger than 8 years, due to unrecognized myopathies.6 Given the extreme temperature increase, coupled with the other signs and symptoms, dantrolene therapy as part of the resuscitation would have been appropriate and potentially life-saving. It was the combination of hyperthermia and rigidity that was most concerning for possible MH. Unlike MH, exertional or environmental heat stroke does not typically present with muscle rigidity; however, dantrolene administration in environmental heat stroke cases refractory to conventional cooling therapy may be useful.

The ED physicians taking care of this child were placed in an unenviable situation. They needed to act quickly to secure the airway of a rigid, hyperthermic, apparently seizing child in respiratory distress who was refractory to antiseizure medications. For unknown reasons, the child’s history of motor delay was missed. The administration of succinylcholine likely increased rigidity and precipitated hyperkalemic cardiac arrest. It is unlikely that these ED physicians were aware that MH-like reactions could occur in the absence of anesthesia. Confirmation of an RYR1 variant in the decedent, as well as in the father (de novo mutation) and 2 siblings, who likewise had histories of developmental motor delays, raised the suspicion that this tragic episode was an “awake MH reaction.”

Although the RYR1 variant identified in this case had not been reported or characterized as pathogenic, a different amino acid substitution (Gly4820Trp) at the same locus in a known “hot spot” region (exon 100) of the RYR1 had been described in association with CCD.7 The father’s CCD histopathology and strongly positive CHCT (North American MH protocol) confirmed the diagnosis.7,8 CCD is a known MH-associated myopathy. Furthermore, heat and/or exercise stress trigger nonanesthetic-related MH-like reactions in mouse and swine models of MH.9–11 Finally, it should be noted that the lack of MH family history is not a guarantee for lack of proband MH sensitivity, because de novo mutations, as in this case, do rarely occur.

Given that the RYR1 variant identified in this case shared the same locus as a previously described mutation in an unrelated proband, and given that the decedent’s father, who shared the same variant, also had a strongly positive CHCT and CCD histopathology, the variant should be considered a mutation causal for MH. Although the decedent’s father denied a history of complications during general anesthesia or history of muscle weakness or pain, his wife reported that he could not complete any routine gardening or yard work without taking an unusual number of rest periods. It seemed that over the course of his lifetime he had learned to modulate his fatigue during physical activities, which for him, at least, was not unusual. These parents have appropriate concerns for their 2 children who carry the same mutation, and they have been educated regarding MH signs, symptoms, and triggers. All MH-susceptible family members now wear medical alert bracelets, and the children’s school nurse has been informed of their MH susceptibility and how their brother died.

The incidence of MH during anesthesia is rare, estimated between 1 in 4200 and 250,000 general inhaled anesthetics.12 However, the predicted incidence of MH-causative genetic variants in the general population is estimated at 1 in 2000 to 3000.13,14 This is more than one would expect based on the clinical occurrence of MH during anesthesia.15 Because of variable expression and penetrance, people who are MH susceptible may undergo anesthesia with MH-triggering drugs but still not experience an MH reaction. In fact, Larach et al.16 reported that 50.7% of subjects in a cohort of subjects in the North American MH Registry had 2 or more unremarkable anesthetics before experiencing an MH reaction. These data suggest that the risk of MH in the general population is far greater than one would expect based solely on clinical presentation during anesthesia. In fact, similar cases of awake MH in children, with and without recognized myopathies, have been described.3,4

Because MH is a genetic disorder of skeletal muscle calcium regulation, it might be naive to assume that potent volatile inhaled anesthetics and succinylcholine are the only drugs that precipitate MH episodes. Succinylcholine should not be used in patients who present to the ED with rigidity and hyperthermia unrelated to anesthesia. It is possible that anesthetic drugs are just one of many environmental factors that can precipitate MH reactions. A broader definition of the MH syndrome to include nonpharmacologic environmental triggers is critical because health care professionals who do not practice anesthesia may be called upon to treat MH-related crises that occur without anesthetic exposure. Medical examiners need to consider MH when dealing with deaths marked by hyperthermia, rhabdomyolysis, and acidosis in young, healthy patients with the suggestion of underlying myopathies. Finally, it is critical for the anesthesia community to provide MH-related educational programs with guidelines to ED physicians and others who administer succinylcholine in emergent situations and to make them aware of the possible dangers of administering succinylcholine to patients who are hyperthermic and rigid.

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DISCLOSURES

Name: Wendy A. Lavezzi, MD.

Contribution: This author helped analyze the data and write the manuscript.

Attestation: Wendy A. Lavezzi approved the final manuscript.

Name: John F. Capacchione, MD.

Contribution: This author helped analyze the data and write the manuscript.

Attestation: John F. Capacchione approved the final manuscript.

Name: Sheila M. Muldoon, MD.

Contribution: This author helped analyze the data and write the manuscript.

Attestation: Sheila M. Muldoon approved the final manuscript.

Name: Nyamkhishig Sambuughin, PhD.

Contribution: This author helped analyze the data and write the manuscript.

Attestation: Nyamkhishig Sambuughin approved the final manuscript.

Name: Saiid Bina, PhD.

Contribution: This author helped analyze the data and write the manuscript.

Attestation: Saiid Bina approved the final manuscript.

Name: Deanna Steele, MS, CGC.

Contribution: This author helped analyze the data and write the manuscript.

Attestation: Deanna Steele approved the final manuscript.

Name: Barbara W. Brandom, MD.

Contribution: This author helped analyze the data and write the manuscript.

Attestation: Barbara W. Brandom approved the final manuscript.

This manuscript was handled by: Peter J. Davis, MD.

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REFERENCES

1. Nelson TE. Malignant hyperthermia: a pharmacogenetic disease of Ca++ regulating proteins. Curr Mol Med. 2002;2:347–69

2. Gronert GA, Thompson RL, Onofrio BM. Human malignant hyperthermia: awake episodes and correction by dantrolene. Anesth Analg. 1980;59:377–8

3. Tobin JR, Jason DR, Challa VR, Nelson TE, Sambuughin N. Malignant hyperthermia and apparent heat stroke. JAMA. 2001;286:168–9

4. Groom L, Muldoon SM, Tang ZZ, Brandom BW, Bayarsaikhan M, Bina S, Lee HS, Qiu X, Sambuughin N, Dirksen RT. Identical de novo mutation in the type 1 ryanodine receptor gene associated with fatal, stress-induced malignant hyperthermia in two unrelated families. Anesthesiology. 2011;115:938–45

5. MacLennan DH, Duff C, Zorzato F, Fujii J, Phillips M, Korneluk RG, Frodis W, Britt BA, Worton RG. Ryanodine receptor gene is a candidate for predisposition to malignant hyperthermia. Nature. 1990;343:559–61

6. Larach MG, Rosenberg H, Gronert GA, Allen GC. Hyperkalemic cardiac arrest during anesthesia in infants and children with occult myopathies. Clin Pediatr (Phila). 1997;36:9–16

7. Robinson R, Carpenter D, Shaw MA, Halsall J, Hopkins P. Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mutat. 2006;27:977–89

8. Larach MG. Standardization of the caffeine halothane muscle contracture test. North American Malignant Hyperthermia Group. Anesth Analg. 1989;69:511–5

9. Durham WJ, Aracena-Parks P, Long C, Rossi AE, Goonasekera SA, Boncompagni S, Galvan DL, Gilman CP, Baker MR, Shirokova N, Protasi F, Dirksen R, Hamilton SL. RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knockin mice. Cell. 2008;133:53–65

10. Chelu MG, Goonasekera SA, Durham WJ, Tang W, Lueck JD, Riehl J, Pessah IN, Zhang P, Bhattacharjee MB, Dirksen RT, Hamilton SL. Heat- and anesthesia-induced malignant hyperthermia in an RyR1 knock-in mouse. FASEB J. 2006;20:329–30

11. Fujii J, Otsu K, Zorzato F, de Leon S, Khanna VK, Weiler JE, O’Brien PJ, MacLennan DH. Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia. Science. 1991;253:448–51

12. Ording H. Incidence of malignant hyperthermia in Denmark. Anesth Analg. 1985;64:700–4

13. Monnier N, Krivosic-Horber R, Payen JF, Kozak-Ribbens G, Nivoche Y, Adnet P, Reyford H, Lunardi J. Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. Anesthesiology. 2002;97:1067–74

14. Ibarra M CA, Wu S, Murayama K, Minami N, Ichihara Y, Kikuchi H, Noguchi S, Hayashi YK, Ochiai R, Nishino I. Malignant hyperthermia in Japan: mutation screening of the entire ryanodine receptor type 1 gene coding region by direct sequencing. Anesthesiology. 2006;104:1146–54

15. Tammaro A, Di Martino A, Bracco A, Cozzolino S, Savoia G, Andria B, Cannavo A, Spagnuolo M, Piluso G, Aurino S, Nigro V. Novel missense mutations and unexpected multiple changes of RYR1 gene in 75 malignant hyperthermia families. Clin Genet. 2011;79:438–47

16. Larach MG, Gronert GA, Allen GC, Brandom BW, Lehman EB. Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg. 2010;110:498–507

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