Age-Specific Clinical Features of Pediatric Malignant Hyperthermia: A Review of 187 Cases Over 60 Years in Japan

Otsuki, Sachiko; Miyoshi, Hirotsugu; Mukaida, Keiko; Yasuda, Tomoo; Nakamura, Ryuji; Tsutsumi, Yasuo M.

doi:10.1213/ane.0000000000005837

Cited by 5 publications

(6 citation statements)

References 23 publications

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“…The symptoms of MH vary according to the age of onset. Otsuki reported a comparison of Japanese pediatric patients with MH stratified by age [ 14 ]. In the younger age group (0–24 months), hyperthermia was the most common first symptom and was a characteristic finding compared with other age groups.…”

Section: Discussionmentioning

confidence: 99%

Pediatric fulminant malignant hyperthermia with severe electroencephalographic abnormality and brain damage: a case report

et al. 2023

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Background Malignant hyperthermia is an extremely dangerous condition that can occur with exposure to volatile inhalant anesthetics and depolarizing muscle relaxants, and that requires immediate intervention. Neurological complications have rarely been reported, with no reports of electroencephalographic abnormalities or encephalopathy. Here, we report a case of severe electroencephalographic abnormality in the acute phase of malignant hyperthermia that eventually led to diffuse cerebral cortical damage. Case presentation A 15-month-old Japanese boy underwent a Rastelli procedure to correct a double-outlet right ventricle and pulmonary atresia. Sevoflurane was used for induction and maintenance of anesthesia during surgery. After withdrawal from the heart–lung machine, his body temperature rose at a rate of 0.1 ℃/minute, and when he left the operating room, his core body temperature had reached 42 ℃. After admission to the intensive care unit, tachycardia, high PaCO2, and progressive metabolic acidosis were observed. A clinical grading scale score of 63 indicated malignant hyperthermia, and dantrolene was administered. The pupils were dilated, and the electroencephalogram showed persistent generalized continuous multifocal spikes. Midazolam, levetiracetam, and fosphenytoin were administered without improvement, and thiamylal and ketamine were infused continuously. After the electroencephalogram shifted to burst suppression, the epileptic firing gradually decreased, and the background electroencephalogram became lower in amplitude. Magnetic resonance imaging of the head performed after the patient was hemodynamically stable suggested diffuse cerebral cortical damage. Severe mental retardation, hypertonia, and quadriplegia were observed as neurological complications. Conclusions In this case, despite the use of high-dose anticonvulsants, the patient showed severe electroencephalogram abnormality, resulting in diffuse cortical damage. Hyperthermia is known to damage the central nervous system by causing increased brain pressure and cerebral edema, which may have triggered the severe neuronal excitation that we observed in this case. The presence of systemic inflammatory response syndrome and the patient’s background, including young age and ethnicity, might also have been factors. Malignant hyperthermia can be complicated by encephalopathy, and continuous electroencephalogram monitoring should be considered.

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Section: Discussionmentioning

confidence: 99%

Pediatric fulminant malignant hyperthermia with severe electroencephalographic abnormality and brain damage: a case report

et al. 2023

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“…the initial dose of dantrolene recommended in some countries (e.g. Japan) and the lower end of EMHG dose recommendation, respectively 6,11 . These doses were set below the maximum tolerability threshold for healthy volunteers reported previously (www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205579Orig1s000SumR.pdf).…”

Section: Methodsmentioning

confidence: 99%

The novel rapid formulation of intravenous dantrolene (NPJ5008) versus standard dantrolene (Dantrium®)

Ng Kwet Shing,

Clayton,

Smith

et al. 2024

European Journal of Anaesthesiology

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BACKGROUND Delays in treating anaesthesia-induced malignant hyperthermia increase risks of complications and death. NPJ5008 is a novel formulation of the indicated treatment, dantrolene sodium, developed to shorten preparation and administration times compared with the reference formulation DANTRIUM IV. The two formulations have been compared preclinically. OBJECTIVES Assess bioequivalence of overall dantrolene (free acid) exposure of NPJ5008 versus DANTRIUM IV and ascertain similarities in their pharmacokinetics and safety/tolerability profiles. Evaluate preparation/administration time savings for the new formulation. DESIGN Part 1 of this open-label trial in humans was a 1 : 1 randomised crossover study; part 2 was a single-arm study. Trial pharmacy data and laboratory simulations assessed preparation/administration step timings. SETTING Single clinical centre in the UK, April to July 2021. PARTICIPANTS Twenty-one healthy male and female individuals. INTERVENTIONS Part 1: single intravenous 60 mg dose of NPJ5008 or DANTRIUM IV, sequentially. Part 2: single intravenous 120 mg dose of NPJ5008. Simulation: five vials per formulation using paediatric and adult cannulas. MAIN OUTCOME MEASURES Overall drug exposure to last measurable concentration (AUC0 to last) and extrapolated to infinity (AUC0 to ∞) were primary endpoints. Other pharmacokinetic, clinical and muscle-function parameters, and adverse events, were monitored. RESULTS Adjusted geometric mean ratios of NPJ5008 versus DANTRIUM IV were 90.24 and 90.44% for AUC0 to last and AUC0 to ∞, respectively, with the 90% confidence intervals (CI) within the 80 to 125% acceptance interval, establishing bioequivalence. No new safety issues emerged: any adverse events were of a similar magnitude across treatments and related to pharmacological properties of dantrolene. Pharmacy and simulation data revealed that every step in preparation and administration was 26 to 69% faster for NPJ5008 than DANTRIUM IV. CONCLUSION NPJ5008 showed comparable pharmacokinetic and safety profiles to DANTRIUM IV, while reducing dantrolene dose preparation/administration times, potentially reducing patient complications/healthcare resourcing in malignant hyperthermia. TRIAL REGISTRATION EudraCT Number: 2020-005719-35, MHRA approval.

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“…In addition, this database contains data from another institution, Saitama Medical University, that is used to perform the CICR tests. As a result, Hiroshima University has been collecting data on Japanese patients with MH since 1960, and our database reflects almost all of the MH cases in Japan [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

Rapid Dantrolene Administration with Body Temperature Monitoring Is Associated with Decreased Mortality in Japanese Malignant Hyperthermia Events

Toyota

Kondo

Shorin

et al. 2023

BioMed Research International

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Purpose. Malignant hyperthermia (MH) is a rare genetic disorder but one of the most severe complications of general anesthesia. The mortality rate of MH has dropped from 70% in the 1960s to 15% because of dantrolene, the only currently accepted specific treatment for MH. In this study, we retrospectively identified the optimal dantrolene administration conditions to reduce MH mortality further. Methods. Our database performed a retrospective analysis of patients with MH clinical grading scale (CGS) grade 5 (very likely) or 6 (almost certain) between 1995 and 2020. We examined whether dantrolene administration affected mortality and compared the clinical variables associated with improved prognosis. Furthermore, a multivariable logistic regression analysis was used to identify specific variables associated with improved prognosis. Results. 128 patients met the inclusion criteria. 115 patients were administered dantrolene; 104 survived, and 11 died. The mortality rate of patients who were not administered dantrolene was 30.8%, which was significantly higher than those of patients who were administered dantrolene ( P = 0.047 ). Among patients administered dantrolene, the interval from the first sign of MH to the start of dantrolene administration was significantly longer in the deceased than in the survivors (100 min vs. 45.0 min, P < 0.001 ), and the temperature at the start of dantrolene administration was also significantly higher in the deceased (41.6°C vs. 39.1°C, P < 0.001 ). There was no significant difference in the rate of increase in temperature between the two, but there was a substantial difference in the maximum temperature ( P < 0.001 ). The multivariable analysis also showed that the patient’s temperature at dantrolene administration and interval from the first MH sign to dantrolene administration was significantly associated with improved prognosis. Conclusions. Dantrolene should be given as rapidly as possible once MH has been diagnosed. Beginning treatment at a more normal body temperature can prevent critical elevations associated with a worse prognosis.

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Age-Specific Clinical Features of Pediatric Malignant Hyperthermia: A Review of 187 Cases Over 60 Years in Japan

Cited by 5 publications

References 23 publications

Pediatric fulminant malignant hyperthermia with severe electroencephalographic abnormality and brain damage: a case report

Pediatric fulminant malignant hyperthermia with severe electroencephalographic abnormality and brain damage: a case report

The novel rapid formulation of intravenous dantrolene (NPJ5008) versus standard dantrolene (Dantrium®)

Rapid Dantrolene Administration with Body Temperature Monitoring Is Associated with Decreased Mortality in Japanese Malignant Hyperthermia Events

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