Understanding Malignant Hyperthermia and the Role of Dantrium

1. Understanding Malignant Hyperthermia and the Role of Dantrium Malignant hyperthermia (MH) is a pharmacogenetic disorder of the skeletal muscles, which is triggered by specific medications. MH becomes apparent when a susceptible individual is exposed to certain types of anesthesia, especially potent halogenated inhaled anesthetics or the muscle relaxant succinylcholine.1 What triggers malignant hyperthermia? In most cases, MH is triggered during or after the administration of general anesthesia. Common anesthetic agents associated with MH include isoflurane, sevoflurane, desflurane, and halothane, along with the muscle relaxant succinylcholine.1 Once exposed, individuals who are genetically susceptible may experience a cascade of symptoms known as "MH crisis" due to uncontrolled calcium release within muscle cells.2 Interestingly, though rare, MH can also be triggered by other non-pharmacological stressors such as extreme heat exposure or strenuous physical exertion.1 This highlights the importance of genetic susceptibility and the potential unpredictability of an MH episode in those undiagnosed. The challenge of diagnosis One of the most challenging aspects of MH is that people who are genetically susceptible typically show no symptoms unless exposed to a trigger. This makes it nearly impossible to identify at-risk individuals without either a known family history or specialized diagnostic testing.1 Diagnostic tests include: • Caffeine-halothane contracture test– performed on a muscle biopsy to evaluate contracture response.1 • Genetic testing – used to identify mutations in the RYR1 gene.1 Clinicians may suspect MH during surgery if certain signs are observed. These include1: • A sudden and unexplained increase in expired carbon dioxide • Rapid rise in body temperature • Muscle rigidity • Rhabdomyolysis (breakdown of muscle tissue) • Acidosis (low blood pH) • Hyperkalemia (elevated potassium levels) Without prompt treatment, MH can lead to serious complications such as cardiac arrhythmia, organ failure, or death.1 How common is malignant hyperthermia? MH is considered a rare condition, with incidence estimates ranging from 1 in 10,000 to 1 in 250,000 anesthetic procedures. The incidence is highest among young individuals, with the average age of affected patients being 18.3 years. However, the risk is present across all ethnicities and geographies.1

2. Awareness and preparedness among healthcare providers are essential to identify and manage it effectively. Dantrium: A cure for MH When a malignant hyperthermia crisis occurs, the only effective antidote is Dantrium (generic name: dantrolene sodium). Dantrium is a muscle relaxant used in both anesthesiology and neurology. Its FDA- approved indication for adults and children is specifically for the treatment of MH, and it has become the standard of care in emergency settings.3 How does Dantrium work? To understand how Dantrium works, we need to look at what happens in the muscles during an MH episode. In healthy muscle cells, calcium release is tightly regulated and is responsible for muscle contraction.4 In MH-susceptible individuals, the ryanodine receptor (RYR1) in muscle cells becomes abnormally sensitive, leading to an excessive and uncontrolled release of calcium. This causes sustained muscle contractions and the rapid generation of heat.5 Dantrium works by binding to this ryanodine receptor, thereby blocking calcium release within the muscle cells. This helps relax the muscles and improve the symptoms of MH.6 Dosage and administration of Dantrium Dantrium is available in two forms: an intravenous (IV) injection and an oral capsule. The IV formulation is the preferred method for treating acute episodes of malignant hyperthermia and is typically administered in a hospital or surgical setting.3 • Initial dose: 2.5 mg/kg of IV dantrolene should be administered immediately once MH is suspected.3 Ongoing dosing: If symptoms persist, additional doses of 1–2.5 mg/kg may be given, up to a total maximum of 10 mg/kg.3 Maintenance: After the initial crisis is managed, 1 mg/kg IV dantrolene every 6 hours for 24 hours is recommended to prevent recurrence.3 • • Oral use and maintenance While oral dantrolene is not used for acute MH treatment, it may be prescribed in other neuromuscular conditions, such as chronic muscle spasticity.3 Safety, side effects, and precautions Like any medication, Dantrium may cause side effects, most of which are consistent with its muscle- relaxing properties. Common side effects of IV Dantrium includesmuscle weakness, respiratory muscle weakness, or decreased inspiratory capacity.3 These effects are typically short-lived and manageable in a monitored setting. Contraindications and cautions There are no contraindications to the use of IV Dantrium in the treatment of malignant hyperthermia.3 However, oral Dantrium is contraindicated in patients with pre-existing liver disease, including cirrhosis, non-alcoholic steatohepatitis (NASH), and hepatitis B or C.3 Use in pregnancy and lactation

3. • Pregnancy: Dantrium can be used for MH treatment in pregnant women if clinically necessary. Limited data suggests no significant fetal harm.3 • Breastfeeding: Breastfeeding should be paused during treatment and for 48 hours after the last dose, or alternative therapies should be considered.3 Storage and handling Dantrium IV is typically stored and managed by hospital pharmacies and operating room teams. As a result, patients do not need to worry about storage or disposal. It is vital for healthcare facilities to maintain ready access to dantrolene wherever general anesthesia is administered.3 Dantrium vs. other muscle relaxants Unlike general muscle relaxants used in surgical procedures or for chronic spasticity, Dantrium directly targets calcium regulation within skeletal muscle cells. This unique mechanism makes it the only medication specifically indicated and effective in malignant hyperthermia.6 Accessing Dantrium in India: The Named Patient Program Since Dantrium is not always widely stocked in hospitals across India, patients and physicians may need to access it through special regulatory pathways. One such route is the Named Patient Program (NPP).7 The NPP allows Indian physicians to request access to medicines that are not commercially available in India but are approved elsewhere. Through this program, Dantrium can be imported on a case-by- case basis for patients with documented medical need, such as MH-susceptible individuals or those with a family history. How to Navigate the NPP Process 1.Consultation with a physician – Confirm the need for Dantrium through clinical evaluation. 2.Application submission – The treating doctor submits a request along with a justification for use. 3.Regulatory approval – Indian authorities review and grant permission for the import. 4.Procurement and delivery – The medication is imported and dispensed under supervision. Authorized distributors such as Rx4U help facilitate this process for both healthcare providers and patients. Summary: Quick Facts About Dantrium and MH • Malignant hyperthermia is a rare genetic disorder triggered by anesthesia. • Symptoms include muscle rigidity, high temperature, and acidosis. • Dantrium (dantrolene) is the only FDA-approved treatment for MH. • Mechanism: It blocks calcium release in muscles to halt the MH reaction. • IV formulation is used in emergencies; oral form is used for other conditions. • No contraindications for IV use in MH; oral use is restricted in liver disease. • Access in India is possible via the Named Patient Program.

4. Frequently Asked Questions (FAQs) Q. Is malignant hyperthermia preventable? While the condition itself cannot be prevented, proper screening and avoiding trigger agents can reduce the risk.3 Q. Can someone be tested for MH before surgery? Yes, especially if there is a family history. Genetic testing and muscle biopsy testing can determine susceptibility.3 Q. Is Dantrium available in India? Not readily available in pharmacies, but it can be accessed through the Named Patient Program.7 Q. Can Dantrium be used for other conditions? Yes. It may be used in chronic muscle spasticity under specialist guidance.3 Note: The information provided is for education purpose only and is subjected to prescribing information of the drug and the guidance of your treating physician. Always consult your health care provider before making any medical decision for starting your treatment. Disclaimer: Rx4U procures prescribed medicines directly from manufacturers or authorized distributors. It does not claim ownership of any trademarks and complies with the provisions of the Trademark Act, 1999, particularly Sections 30 and 30(1) concerning ‘Fair Use’. It solely facilitates access to new launches through named patient import. References: 1.Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K. Malignant hyperthermia: a review. Orphanet J Rare Dis. 2015;10:1-9. 2.Schneiderbanger D, Johannsen S, Roewer N, Schuster F. Management of malignant hyperthermia: diagnosis and treatment. Ther Clin Risk Manag. 2014:355-62. 3.Dantrolene. NIH. Upgated April 3, 2023. Accessed July 2, 2025. https://www.ncbi.nlm.nih.gov/books/NBK535398/ 4.Gehlert S, Bloch W, Suhr F. Ca2+-dependent regulations and signaling in skeletal muscle: from electro-mechanical coupling to adaptation. Int J Mol Sci. 2015;16(1):1066-95. 5.Stephens J, Schiemann AH, Roesl C, Miller D, Massey S, Pollock N, et al. Functional analysis of RYR1 variants linked to malignant hyperthermia. Temperature (Austin). 2016;3(2):328-39. 6.Agilus. European Medicines Agency. Updated March 23, 2024. Accessed July 2, 2025. https://www.ema.europa.eu/en/medicines/human/EPAR/agilus 7.Patil S. Early access programs: Benefits, challenges, and key considerations for successful implementation.Perspect Clin Res. 2016;7(1):4-8. doi:10.4103/2229-3485.173779