CHAPTER 3-21: DANTROLENE

INTRODUCTION

1. Pharmacology. Dantrolene relaxes skeletal muscle by inhibiting the release of calcium from the sarcoplasmic reticulum, thereby reducing actin-myosin contractile activity. Dantrolene can help control hyperthermia that results from excessive muscle hyperactivity, particularly when hyperthermia is caused by a defect within the muscle cells (eg, malignant hyperthermia). Dantrolene is not a substitute for other temperature-controlling measures (eg, sponging and fanning).

2. Indications

   1. The primary indication for dantrolene is malignant hyperthermia.

   2. Dantrolene may be useful in treating hyperthermia and rhabdomyolysis caused by drug-induced muscular hyperactivity that is not controlled by usual cooling measures or neuromuscular paralysis.

      1. There are a number of case reports suggesting benefit for the management of several conditions associated with muscle hyperactivity or rigidity, including neuroleptic malignant syndrome (NMS); monoamine oxidase (MAO) inhibitor-induced hyperthermia; serotonin toxicity; methylenedioxymethamphetamine (MDMA) overdose; dinitrophenol-induced hyperthermia; muscle rigidity from baclofen withdrawal; hypertonicity from carbon monoxide poisoning; tetanus; thyroid storm; and black widow spider envenomation. It should be noted that a meta-analysis of NMS case reports found that dantrolene use was associated with higher mortality than supportive care alone.

   3. Theoretically, dantrolene is not expected to be effective for hyperthermia caused by conditions other than muscular hyperactivity, such as increased metabolic rate (eg, salicylate or dinitrophenol poisoning); impaired heat dissipation (eg, anticholinergic syndrome); and environmental exposure (heat stroke).

3. Contraindications. No absolute contraindications exist. Patients with muscular weakness or respiratory impairment must be observed closely for possible respiratory arrest.

4. Adverse effects

   1. Muscle weakness, which may aggravate respiratory depression.

   2. Drowsiness, fatigue, dizziness, photosensitivity, and diarrhea.

   3. Black box warning. Potential for fatal hepatotoxicity (hypersensitivity hepatitis) reported after chronic therapy. May also be dose-related (more common with 800 mg/d). Transaminases are elevated in about 10% of patients treated with dantrolene.

   4. Intravenous administration has been associated with pulmonary edema (mannitol may contribute), phlebitis (avoid extravasation), and urticaria.

   5. Use in pregnancy. FDA Category C (indeterminate). This does not preclude acute, short-term use of dantrolene for a seriously symptomatic patient (Introduction).

5. Drug or laboratory interactions

   1. Dantrolene may have additive CNS-depressant effects with sedative and hypnotic drugs.

   2. Dantrolene and verapamil coadministration is associated with hyperkalemia and hypotension (case report).

   3. Each 20-mg vial of Dantrium contains 3 g of mannitol; this should be taken into consideration, as it may have additive effects with any mannitol given to treat rhabdomyolysis. Use only sterile water (without bacteriostatic agent) to reconstitute. Incompatible with D₅W and NS.

6. Dosage and method of administration (adults and children)

   1. Initial dose. Give a minimum of 1 mg/kg and up to 2.5 mg/kg rapidly IV through a secure, free-flowing peripheral or central line; this may be repeated as needed every 5–15 minutes to a cumulative total dose of 10 mg/kg (up to 30 mg/kg has been used). Satisfactory response usually is achieved with an average total dose of 2.5 mg/kg.

   2. Postcrisis maintenance. To prevent recurrence of hyperthermia, administer 1–2 mg/kg intravenously or orally (up to 100 mg maximum) 4 times a day for 1–3 days. Daily dose not to exceed 400 ...