DANTROLENE

….DANTROLENE [yellow powder, Dantrium, 1967; used in Malignant Hyperthermia (MH) 1975 by Gaisford Harrison; earlier Procaine was used for MH with 60-80% mortality, now <10%], though difficult to dissolve for intravenous administration through blood filter but quicker in warm sterile water (20 mg in 60 ml; incompatible with normal saline or 5% Dextrose), capsules can be given orally or via nasogastric tube additionally since its bioavailability is 70%; it comes in capsule form also, which can be opened; in susceptible cases Dantrolene capsules 4-8 mg/kg/day orally started 1-2 days preoperatively but the risk of muscle weakness persisting over two days, liver toxicity, dizziness, confusion and drowsiness deters from prophylactic use!

P.S. ….AZUMOLENE (bromine replaces nitro group; equipotent to Dantrolene) is 30 times more water soluble than Dantrolene but still under development; another formulation is lyophilized lecithin coated microcrystal of sodium dantrolene, which can be dissolved within a minute but causes severe pulmonary hypertension if not filtered before use and it is expensive!

Ideally, each hospital is recommended to have 36 vials (20 mg in each) Dantrolene, which can suffice for 70 kg patient (720 mg i.e. 10 mg/kg).

Malignant Hyperthermia Association of the United States (MHAUS) allows patients of MH to donate blood or organ, implying that it is not transferable by blood transfusion or organ donation!

Dantrolene (structurally similar to hydantoin like phenytoin but not anticonvulsant; metabolites excreted in bile and urine) is a post synaptic excitation-contraction uncoupler through inhibition of calcium ion release from sarcoplasmic reticulum (SR) by antagonising RYANODINE receptors in muscle cells causing direct muscle relaxation; it cannot be achieved by depolarising or non depolarising muscle relaxant because these block action potential build up at acetylcholine receptors and not blocks ryanodine receptors responsible for excess release of calcium causing severe muscles contracture at actin-myosin level!

Malignant Hyperthermia, a hyper metabolic state, is manifested by tachycardia, increase in temperature, supraventricular and ventricular arrhythmia, high EtCO2 in ventilated; masseter spasm, generalised rigidity, skin redness, cyanosis and profuse sweating after succinylcholine must raise alarm to stop these triggers including inhalationals; and, hyperventilate with 100% oxygen with non depolarisers only, opioids, intravenous hypnotics and abandon surgery; start Dantrolene!

Usual dose of intravenous 2.4 mg/kg (repeated every 5 minutes) achieves 4.2 ug/ml plasma concentration to block three-fourth of the muscle contraction, but never blocks hundred percent; continuous infusion 10 mg/kg/day thereafter for at least 24 hours; if Dantrolene >20 mg/ kg used without improvements, MH diagnosis can be doubted!

Also used in neuroleptic malignant syndrome, spasticity and ecstasy intoxication.

Supportive Measures taken are: Body cooling, arrhythmia control with beta blockers and xylocaine; acidosis correction with sodium bicarbonate; hypercalcaemia, hyperkalaemia and myoglobinuria control by frusemide, glucose and insulin!

In Vitro Contracture Testing:

https://www.emhg.org/…/in-vitro-contracture-testing-ivct

Vapor-Clean Filters for MH Cases:

https://www.pentlandmedical.co.uk/…/vapor-clean…/

Patient Helpline:

https://www.ukmhr.ac.uk/…

Malignant hyperthermia:

https://rarediseases.info.nih.gov/…/maligna…/cases/32204

Dantrolene:

https://en.m.wikipedia.org/wiki/Dantrolene

Dantrolene capsules:

https://www.accessdata.fda.gov/…/017443s043s046s048s049…