According to the Japanese Society of Anesthesiologists (JSA), malignant hyperthermia (MH) develops in one to two patients in every 100,000 general anesthesia cases. Prevalence in males is more common at a 3:1 ratio in comparison to females. Mortality has been less than 10% since the year 2000 in patients treated with dantrolene. Treatment with dantrolene is recommended, and it should be administered immediately if symptoms of MH are suspected. Evidence suggests dantrolene ≥1 mg/kg is necessary to resolve muscle rigidity and prevent recurrence, and the JSA guidelines recommend 2 mg/kg over 15 minutes through a large-bore intravenous (IV) line. Doses may be repeated and adjusted up to a maximum of 7 mg/kg until the patient’s condition improves. [1]
Per European Malignant Hyperthermia Group guidelines on the management of malignant hyperthermia crisis, it is recommended to give dantrolene at a dose of 2-2.5 mg/kg IV. The dose of dantrolene should be based on the patient’s actual body weight up to a maximum of 300 mg per dose. It is also recommended that the initial dose of dantrolene be repeated every 10 minutes (or as often as possible if administration takes >10 minutes). Infusions should be repeated until the partial pressure of carbon dioxide in arterial blood is <6 kPA (45 mm Hg) with normal minute ventilation and a decreasing core body temperature. [2]
The 2020 Association of Anaesthetists of Great Britain guidelines recommend IV dantrolene as a key component in managing and reversing a MH state. It should be administered concurrently with active body cooling, starting with an initial dose of 2-3 mg/kg, followed by 1 mg/kg every 5 minutes until end-tidal carbon dioxide (ETCO2) is less than 6 kPa, normal minute ventilation is observed, and the core body temperature drops below 38.5°C. Notably, additional doses of dantrolene may be necessary if ETCO2 or temperature increases after the initial treatment. [3]
Intravenous dantrolene is the only FDA-approved pharmacologic therapy for MH. No evidence of other pharmacologic strategies for primary MH therapy could be found. Dantrolene sodium is the generic formulation for Dantrium and Revonto ®. Ryanodex® (dantrolene nanosuspension) is the concentrated form of dantrolene, which has a more convenient preparation method and lower mannitol content per vial. [4]
A Canadian study on MH epidemiology found complication rates increased between the first adverse clinical sign and dantrolene treatment. Therefore, the time of administration may be a factor in patient morbidity and mortality. McAvoy et al. further describe the potential advantage of Ryanodex® in terms of time and resources based on their small trial to justify a formulary change. Anesthesiology residents, faculty, and registered nurses attempted to reconstitute either Dantrium or Ryanodex®. Twenty paired reconstitution trials showed that reconstituting a single vial of Dantrium had a mean time of 189 seconds (95% confidence interval [CI] 163 to 215) and Ryanodex® had a mean time of 53.9 seconds (95% CI 43.3 to 64.4) (p<0.01). The mean difference was 135.1 seconds. A 70 kg adult would require a Dantrium preparation time of 28.4 minutes (2.5 mg/kg or 175 mg = 9 vials). [5], [6]
The 2019 Consensus statement from the Malignant Hyperthermia Association of the United States recommends either the dantrolene or Ryanodex® formulation for MH, based on each individual's institution to prepare the dantrolene product in the event of a crisis. The 2019 Society for Ambulatory Anesthesia/Ambulatory Surgical Care Committee position statement also recommends dantrolene but does not have a preference for either product. It is assumed that both societies believe the two products have similar efficacy. [7], [8]
An animal study was conducted to measure the effects of a novel nanocrystalline dantrolene sodium suspension (DSS) on clinical and laboratory variables in MH normal pigs and to compare the therapeutic management and clinical effectiveness of DSS with standard dantrolene sodium in a MH crisis in susceptible pigs. After administration of DSS (5 mg/kg IV bolus injection twice at a 24-minute interval), arterial pH, arterial pCO2, mean arterial pressure, and arterial lactate concentration remained stable in MH normal pigs. In the comparison of standard dantrolene sodium versus DSS in a fulminant MH crisis, the therapeutic effects of both formulations were comparable, resulting in decreased pCO2, muscle temperature, heart rate, and arterial lactate concentration. However, preparation and administration time taken for DDS (51 ±9 sec and 4 ±2 sec) was significantly faster than those taken for standard dantrolene sodium (860 ±202 sec and 472 ±51 sec); thus, DDS may provide a clinically significant advantage in the treatment of malignant hyperthermia. [9]