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Dantrolene—An Update

  • Chapter
Malignant Hyperthermia

Abstract

Dantrolene sodium, a hydantoin derivative, relaxes skeletal muscle by a peripheral rather than a central action by inhibiting release of calcium from the sarcoplasmic reticulum (SR). Both resting and twitch tensions are decreased in the presence of dantrolene. The action of dantrolene on the SR may be indirect rather than direct. Thus in both isolated SR preparations and in skinned fibre preparations dantrolene does not greatly alter caffeine, calcium or chloride induced calcium release from the SR.

Dantrolene prolongs the action potential duration and effective refractory period of normal polarized Purkinje muscle. Dantrolene also blocks calcium release from vascular smooth muscle. Dantrolene depresses canine urethral and bladder pressures and reduces the amplitude of calcium induced contractions of rabbit jejunum.

Dantrolene is formulated in 70 cc bottles which contain 20 mg of dantrolene, 3.0 grams of mannitol and enough sodium hydroxide to raise the pH to 9.5 when the material is reconstituted with 60 ml of water. This rather unusual formulation is necessary because of the relative water insolubility of dantrolene. Care must be taken not to allow extravasation of dantrolene into the tissues because the high pH of the solution would be injurious to the tissues. The vein site should be changed every few hours to avoid serious thrombophlebitis.

Since the introduction of dantrolene a marked improvement in survival from malignant hyperthermic (MH) reactions has occurred. While some of this improvement has probably been due to other factors (better monitoring and better education of anaesthetists about the diagnosis and management of MH reactions) a considerable portion of the improvement must be attributed to the use of dantrolene.

The dose of dantrolene required to successfully resuscitate patients from MH reactions has varied from less than 1.0 to 17 mg/kg. All patients who have received, early in the reaction, at least 6.0 mg/kg of the official formulation have survived. The drug is administered as a bolus at a maximal rate of I mg/kg/minute up to a maximum of 10 mg/kg under EKG control. This bolus may be repeated every 15 minutes. Once temperature, heart rate and muscle stiffness have begun to decline, an IV drip containing 1–2 mg/kg of dantrolene may be administered over a three to four hour period.

In patients dying in spite of the use of dantrolene, one or more of the following has usually been present: use of a non-official formulation; delay in commencing dantrolene; use of an insufficient amount of dantrolene; concomitant use of contraindicated drugs; true diagnosis not malignant hyperthermia. In pigs dantrolene has been effectively used prophylactical ly, to prevent halothane induced MH reactions, in doses ranging from 5 to 24 mg/kg in up to four divided doses. Dantrolene has also been used in MH humans prior to elective anaesthesia. Because deliberate halothane challenge is impossible in human patients its efficacy in this species is difficult to determine.

In some, but not all, MHS patients, dantrolene has reduced the severity of the skeletal muscle aches, pains and cramps from which these individuals not infrequently suffer. Dantrolene is also useful in certain other situations involving non MH patients. For instance, dantrolene is valuable in the management of heat stroke, neuroleptic malignant syndrome, cerebral palsy, Parkinsons disease, chorea, athetosis, spinal cord injury, multiple sclerosis, myotonia and tetanus. Dantrolene also attenuates succinylcholine induced muscle fasciculations, postoperative muscle pains and rises in serum potassium.

Early undesirable but transient effects of dantrolene include dizziness, diplopia, dysarthria, sensations of muscle weakness and swelling of the eyeballs and tongue. These symptoms disappear a few hours after discontinuation of the drug. Liver damage, chronic pleural effusion, acute pericarditis and lymphocytis have rarely been reported but their true relationship to dantrolene ingestion has not been well documented. Long term high dose dantrolene therapy rather consistently causes a fine cuneiform rash over the face and back.

Dantrolene is metabolized through reductive and oxidative pathways. The nitro group of dantrolene is reduced to amino-dantrolene. The amine group is acetylated. Oxidation of dantrolene produces 5-OH dantrolene.

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Authors and Affiliations

  1. Department of Anaesthesia and Pharmacology, University of Toronto, Toronto, Ontario, M5G 2C4, Canada

    B. A. Britt

  2. Toronto General Hospital, Toronto, Ontario, M5G 2C4, Canada

    B. A. Britt

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  1. Department of Anaesthesia and Pharmacology, University of Toronto, Toronto, Ontario, M5G 2C4, Canada

    Beverley A. Britt (Associate Professor, Senior Staff Anaesthetist) (Associate Professor, Senior Staff Anaesthetist)

  2. Toronto General Hospital, Toronto, Ontario, M5G 2C4, Canada

    Beverley A. Britt (Associate Professor, Senior Staff Anaesthetist) (Associate Professor, Senior Staff Anaesthetist)

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© 1987 Martinus Nijhoff Publishing, Boston

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Britt, B.A. (1987). Dantrolene—An Update. In: Britt, B.A. (eds) Malignant Hyperthermia. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-2079-1_14

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