What evidence is available regarding the use of dantrolene for malignant hyperthermia?

Comment by InpharmD Researcher

Dantrolene is the only medication known to specifically treat malignant hyperthermia (MH) and is recommended for use by various societal guidelines. Notably, no preferences are provided regarding dantrolene formulations for MH reversal (i.e., Dantrium®, Revonto®, and Ryanodex®). While guideline-recommended dosing regimens for intravenous dantrolene may vary, shortened time-to-administration windows following confirmed or suspected MH are heavily emphasized as a key factor that impacts patient morbidity and mortality outcomes, with drug preparation time and product availability cited as limiting components to timely dantrolene administration. Overall, dantrolene demonstrates efficacious reversal of MH when used in combination with other temperature control methods and supportive care, such as active body cooling and management of hyperkalemia. However, available data are primarily limited to observational studies and anecdotal reports.

Background

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]

References:

[1] JSA guideline for the management of malignant hyperthermia crisis 2016. J Anesth. 2017;31(2):307-317.
[2] Glahn KPE, Girard T, Hellblom A, et al. Recognition and management of a malignant hyperthermia crisis: updated 2024 guideline from the European Malignant Hyperthermia Group. Br J Anaesth. 2025;134(1):221-223. doi:10.1016/j.bja.2024.09.022
[3] Hopkins PM, Girard T, Dalay S, et al. Malignant hyperthermia 2020: Guideline from the Association of Anaesthetists. Anaesthesia. 2021;76(5):655-664. doi:10.1111/anae.15317
[4] Carlson B, Wormuth L. Malignant Hyperthermia: An Overview. US Pharm. 2019;44(1):HS2-HS6.
[5] Litman RS, Smith VI, Larach MG, et al. Consensus Statement of the Malignant Hyperthermia Association of the United States on Unresolved Clinical Questions Concerning the Management of Patients With Malignant Hyperthermia. Anesth Analg. 2019;128(4):652-659.
[6] Urman RD, Rajan N, Belani K, Gayer S, Joshi GP. Malignant Hyperthermia-Susceptible Adult Patient and Ambulatory Surgery Center: Society for Ambulatory Anesthesia and Ambulatory Surgical Care Committee of the American Society of Anesthesiologists Position Statement. Anesth Analg. 2019;129(2):347-349.
[7] Mcavoy JC, Brodsky JB, Brock-utne J. Pennywise and a Pound Foolish: The Advantage of Dantrolene Nanosuspension (Ryanodex) in the Treatment of Malignant Hyperthermia. Anesth Analg. 2019;129(6):e201-e202.
[8] Riazi S, Larach MG, Hu C, Wijeysundera D, Massey C, Kraeva N. Malignant hyperthermia in Canada: characteristics of index anesthetics in 129 malignant hyperthermia susceptible probands. Anesth Analg. 2014;118:381–387.
[9] Schütte JK, Becker S, Burmester S, et al. Comparison of the therapeutic effectiveness of a dantrolene sodium solution and a novel nanocrystalline suspension of dantrolene sodium in malignant hyperthermia normal and susceptible pigs. Eur J Anaesthesiol. 2011;28(4):256-64.

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What evidence is available regarding the use of dantrolene for malignant hyperthermia?

Level of evidence

D - Case reports or unreliable data  Read more→



Please see Tables 1-2 for your response.


Comparison of Therapeutic Effectiveness of Dantrolene and Ryanodex in Porcine Malignant Hyperthermia (Abstract)

Design

Comparative animal study

N=10

Objective

To compare the therapeutic management and effectiveness of dantrolene and Ryanodex in MH susceptible (MHS) swine.

Study Groups

Dantrolene (n=5)

Ryanodex (n=5)

Inclusion criteria

Not defined

Exclusion criteria

Not defined

Methods

Malignant hyperthermia susceptible swine were divided to receive either dantrolene (5 mg/kg) or Ryanodex (5 mg/kg) via venous 22 G cannula in the ear vein. Malignant hyperthermia was induced by anesthetic administration of fentanyl, propofol and flunitrazepam. Therapy was monitored every 24 minutes (Tn).

Duration

N/A

Outcome Measures

Pharmacokinetic (PK) factors of arterial pH, arterial pCO2, and temperature at T0, T4, and T7.

Time needed to establish an aqueous solution and inject in seconds.

Results

Endpoint

Dantrolene

(n=5)

Ryanodex

(n=5)

PK factors at T0

Arterial pH

Arterial pCO2

Temperature

 

7.46

40.0

38.6

 

7.46

40.8

38.5

PK factors at T4

Arterial pH

Arterial pCO2

Temperature

 

7.20

65.2

39.1

 

7.20

69.2

39.5

PK factors at T7

Arterial pH

Arterial pCO2

Temperature

 

7.43

46.4

39.8

 

7.47

44.8

39.9

Time needed to establish an aqueous solution, seconds

860.3 50.6

Injection time, seconds

471.5 4..2

Adverse Events

N/A

Study Author Conclusions

Course of MH-crises and therapeutic effects were comparable between the groups. Normalisation of heart rate, blood pressure and lactate were similar (data not shown).

Therapeutic action of ryanodex is comparable to dantrolene. Yet, preparation and administration of the ryanodex solution was faster. Therefore, ryanodex seems to be a promising agent in treatment of MH.

InpharmD Researcher Critique

This was an animal study based on a poster presentation which may not reflect the human population. 

Only the abstract was available. However, the information appeared to be complete including pharmacokinetic table results per a standard poster presentation.

References:

Gerbershagen M, Becker S, Burnester S, et al. Comparison of Therapeutic Effectiveness of Dantrolene and Ryanodex in Porcine Malignant Hyperthermia. Poster presented at: American Society of Anesthesiologists; October 17, 2007. New Orleans, LA.

 

Management of Suspected Malignant Hyperthermia With Dantrolene: Clinical Insights From 2 Case Reports in a Single-Center Experience

Design

Case report

Case presentation 1

A previously healthy 4-year-old female developed an acute malignant hyperthermia (MH) crisis during an adenotonsillectomy under general anesthesia with sevoflurane. Ten minutes into the procedure, she exhibited a rapid increase in EtCO₂ (peaking at 101 mmHg), a swift temperature rise from 37.5°C to 39.9°C within 5 minutes, progressive tachycardia (HR 150-180 bpm), hypertension (BP 145/90 mmHg), masseter muscle rigidity, and generalized tonic rigidity. Lab results confirmed metabolic acidosis (pH 7.20, BE -14.7 mEq/L, pCO₂ 68 mmHg) and elevated creatine kinase (CK 478 U/L).

An MH emergency was declared. Sevoflurane was discontinued, and anesthesia was switched to propofol. Cooling measures were initiated, including ice packs, cold intravenous normal saline, and cold saline irrigation of the bladder and stomach. Bicarbonate was administered for acidosis, along with hyperventilation and diuresis. Four hours after the onset of signs, intravenous dantrolene 2.5 mg/kg (50 mg;Revonto) was administered, leading to a rapid decrease in temperature and normalization of EtCO₂ within 30 minutes. Dantrolene was continued at 1 mg/kg every 6 hours for two days. The patient was extubated on postoperative day 2, with gradual resolution of lab abnormalities (peak CK 10458 UI/L). She was discharged on hospital day 7. Genetic analysis identified a novel RYR1 gene variant (c.11947C>T, p.R3983C), classified as a variant of uncertain significance, but highly suggestive of MH given the strong clinical presentation.

Case presentation 2

A 13-year-old female undergoing pedicle screw fixation for congenital scoliosis developed an acute MH crisis during sevoflurane-maintained general anesthesia. After 120 minutes of anesthesia, she exhibited tachycardia (HR 140 bpm progressing to 160 bpm), hypertension (BP 145/70 mmHg to 160/90 mmHg), elevated EtCO₂ (60 mmHg to 94 mmHg), and a rapid temperature increase (37.6°C to 40.1°C). Generalized tonic rigidity with limb extension was also observed, and arterial blood gas revealed respiratory acidosis (pH 7.13, pCO₂ 61 mmHg).

MH was promptly suspected. Fortunately, dantrolene (Revonto) was immediately available. Dantrolene 2.5 mg/kg was administered intravenously approximately 10 minutes after the initial signs, along with supportive interventions, including cooling measures and acidosis correction. The patient's condition gradually improved in the ICU. Dantrolene was continued at 1 mg/kg every 6 hours for 12 hours. Her peak CK level was 1417 UI/L, with no subsequent renal or liver dysfunction. She was discharged after 10 days, having made a full recovery with no residual muscle weakness or renal issues. She received extensive counseling on avoiding MH triggering agents, was provided with documentation for her medical records, and advised to wear a medical alert bracelet. Genetic testing was not performed for this patient.

Study Author Conclusions

Early recognition of symptoms and prompt administration of dantrolene are critical for effective management of malignant hyperthermia. Delays in treatment can lead to more severe muscle damage and complications.
References:

Trung Kien N, Nguyen Nhat T, Dinh Tung D, et al. Management of Suspected Malignant Hyperthermia With Dantrolene: Clinical Insights From 2 Case Reports in a Single-Center Experience. Clin Med Insights Case Rep. 2025;18:11795476251349345. Published 2025 Jun 14. doi:10.1177/11795476251349345