Procter & Gamble Pharmaceuticals
Management of Malignant Hyperthermia
Action And Clinical Pharmacology: Dantrolene is a muscle relaxant acting specifically on skeletal muscles. In isolated muscle preparations, dantrolene uncouples the excitation and contraction of skeletal muscles, probably by interfering with the release of calcium from the sarcoplasmic reticulum.
In the anesthetic induced malignant hyperthermia syndrome, evidence points to a predisposing intrinsic abnormality of muscle tissue. In affected humans, it has been postulated that “triggering agents” induce a sudden rise in myoplasmic calcium either by preventing the sarcoplasmic reticulum from accumulating calcium adequately, or by accelerating its release. This rise in myoplasmic calcium activates acute catabolic processes common to the malignant hyperthermia crisis.
Dantrolene may prevent the increase in myoplasmic calcium and the acute catabolism within the muscle cell by interfering with the release of calcium from the sarcoplasmic reticulum to the myoplasm. Thus, the physiologic, metabolic and biochemical changes associated with the crisis may be reversed or attenuated.
Based on assays of whole blood and plasma, slightly greater amounts of dantrolene are associated with red blood cells than with the plasma fraction of blood. Significant amounts of dantrolene are bound to plasma proteins, mostly albumin, and this binding is readily reversible. Binding to plasma protein is not significantly altered by diazepam, diphenylhydantoin, or phenylbutazone. Binding to plasma proteins is reduced by warfarin and clofibrate and increased by tolbutamide.
In humans dantrolene metabolism is rapid via hepatic microsomal enzymes. The major metabolites in body fluids are the 5 hydroxy analog and the acetamino analog. Urinary excretion of dantrolene and its metabolites occurs in an initially rapid phase (t1/2, 2.5 to 3 hours) followed by a slower phase over a 24-hour period. Dantrolene is also removed by biliary excretion and through the feces. The mean biologic half-life of dantrolene after i.v. administration is about 5 hours. Based on limited information obtained from study patients with malignant hyperthermia, it is estimated that therapeutic efficacy of the drug is obtained at a serum concentration of dantrolene of about 1 Âµg/mL. No toxic effects have been observed in humans with malignant hyperthermia up to a dose level of 10 mg/kg with serum dantrolene concentrations up to 13.79 g/mL.
Dantrolene causes marked, dose-dependent skeletal muscle relaxation in laboratory animals with a long duration of action. The pharmacologic profile of dantrolene in animals is unlike neuromuscular blocking agents in that total muscle paralysis and/or respiratory depression do not occur.
Various studies in vivo and in vitro demonstrated the apparent selectivity of action of dantrolene for skeletal muscle. There were some non-specific depressant effects seen in several smooth muscle studies and insignificant effects in cardiac muscle in doses which cause skeletal muscle relaxation. Nerve transmission was not affected by dantrolene in several animal studies.
Dantrolene i.v. has no appreciable effect on the cardiovascular system or on respiratory function. A transient inconsistent effect on smooth muscles has been observed at high doses.
It has been shown that dantrolene has no effect on the propagated action potential recorded on the muscle membrane, and the total membrane capacitance is not decreased by the drug, indicating that it does not disrupt the function of the transverse tubular system, and acts at a point beyond the electrically excitable surface membrane. Evidence obtained in vitro with muscle preparations exposed to caffeine, an agent known to cause muscle contractions by releasing internal Ca+stores in muscle, suggests that dantrolene acts on skeletal muscle by altering the Ca+release mechanisms. Such an action could explain the apparent specificity of dantrolene for skeletal muscle.
In dogs approximately 40% of an i.v. dose of dantrolene is excreted as the hydroxylated metabolite in bile whereas only 1% of the dose is excreted in this manner by the rat. High biliary concentrations of this metabolite have also been found in the Rhesus monkey. Total excretion of known metabolites in the urine is estimated at approximately 3% in the dog and approximately 10% in the rat.
Studies with malignant hyperthermia susceptible swine have shown that in the established syndrome of malignant hyperthermia induced by halothane or succinylcholine dantrolene caused: rapid loss of muscle rigor commencing within 5 minutes and usually complete within 20 minutes; immediate cessation of the increase in deep muscle temperature followed by a rapid decrease; termination of the progressive, inexorable acidosis characteristic of the syndrome rendering easy the buffering of acidosis developed until dantrolene administration.
Survival rates with dantrolene sodium were 100% as contrasted with 40% with procaine administration. Untreated, the developed syndrome had a mortality rate of 100%. Procaine administration was associated with profound cardiovascular effects while dantrolene had no effect on the myocardium, a factor that permitted the drug’s use up to the limits of therapeutic effectiveness. Mean doses of dantrolene used to successfully treat these animals were 7 mg/kg.
Indications And Clinical Uses: The management of malignant hyperthermia crisis. As soon as the crisis is recognized (i.e., tachycardia, tachypnea, central venous desaturation, central venous hypercarbia, metabolic acidosis, fever, skeletal muscle rigidity or cyanosis and mottling of the skin) cooling procedures should be instituted and dantrolene i.v. administered. If anesthetic agents are being administered they should be promptly discontinued. It is also important that appropriate supportive measures be instituted for treatment of the physiologic and metabolic abnormalities. Dantrolene i.v., when given early in the malignant hyperthermia crisis, has caused abrupt lowering of body temperature, correction of the respiratory and/or metabolic acidosis, decrease of the heart rate, stabilization of blood pressure, and disappearance of the rigidity and/or fasiculations. Patients who received dantrolene i.v. during the crisis have less evidence of muscle destruction as shown by serum creatinine phosphokinase measurements than those treated by other measures.
Contra-Indications: There are no known contraindications when used during an acute malignant hyperthermia crisis. tag_WarningWarnings
Manufacturers’ Warnings In Clinical States: Because of the high pH of the i.v. formulation, care must be taken to prevent extravasation of the i.v. solution into the surrounding tissues. Precautions
Precautions: Pregnancy: Safety in women who are or who may become pregnant has not been established; it should be given only when the potential benefits have been weighed against the possible risk to mother and child.
Drug Interactions: The combination of therapeutic doses of i.v. dantrolene and verapamil in halothane/-a-chloralose anesthetized swine has resulted in ventricular fibrillation and cardiovascular collapse in association with marked hyperkalemia. It is recommended the combination of i.v. dantrolene and calcium channel blockers, such as verapamil, not be used during the reversal of a malignant hyperthermia crisis until the relevance of these findings to humans is established.
Adverse Reactions: The more serious reactions reported with repeated doses of oral dantrolene as a muscle relaxant have been hepatitis, seizures and pleural effusions with pericarditis. Cases of fatal hepatitis have been reported in patients who had received dantrolene for 60 days or longer. Symptomatic hepatitis and laboratory evidence of liver dysfunction have also been reported in a number of patients receiving dantrolene as a muscle relaxant. Acneiform skin reactions have also been infrequently reported. For a list of adverse reactions reported with the use of dantrolene as a muscle relaxant, see Dantrium Capsules monograph.
None of these reactions have been reported during clinical trials in patients treated with short-term dantrolene i.v. therapy for malignant hyperthermia.
Symptoms And Treatment Of Overdose: Symptoms: Drowsiness and generalized muscle weakness have been reported following very large doses of oral dantrolene and would be expected as the major symptoms of overdosage.
Treatment: For acute overdosage general supportive measures should be employed. I.V. fluids should be administered in fairly large quantities to avert the possibility of crystalluria. An adequate airway should be maintained and artificial resuscitation equipment made available. ECG monitoring should be instituted, and the patient carefully observed. No experience has been reported with dialysis, hence its value in dantrolene overdosage is not known.
Dosage And Administration: During the crisis: As soon as the malignant hyperthermia reaction is recognized, all anesthetic agents should be discontinued.
Dantrolene i.v. should be administered by continuous rapid i.v. push beginning at a minimum dose of 1 mg/kg, and continuing until symptoms subside or the maximum cumulative dose of 10 mg/kg has been reached.
If the physiologic and metabolic abnormalities reappear, the regimen may be repeated. It is important to note that administration of dantrolene i.v. should be continuous until symptoms subside. The effective dose to reverse the crisis is directly dependent upon the individual’s degree of susceptibility to malignant hyperthermia, the amount and time of exposure to the triggering agent, and the time elapsed between onset of the crisis and initiation of treatment.
Children: Experience to date indicates that the dose for children is the same as for adults.
Preoperatively: If after suitable evaluation of the patient, including family history relative to malignant hyperthermia, it is felt that a malignant hyperthermia crisis may develop during anesthesia and surgery, oral dantrolene may be used prophylactically 1 to 2 days prior to surgery. The dantrolene capsules should be given at a dose of 1 to 2 mg/kg 4 times/day up to 3 to 5 hours prior to surgery.
The following criteria may be used as a general guideline in assessing which individuals are likely to be most susceptible to development of a malignant hyperthermia crisis during anesthesia or surgery:
1. Patients who have survived a malignant hyperthermia crisis or have a positive muscle biopsy.
2. A first-degree relative of anyone known to be malignant hyperthermia susceptible or to have a positive muscle biopsy.
3. A member of a suspected family who has a clinically demonstrable muscle abnormality.
4. A member of a suspected family whose plasma CK value has been found elevated in one or more samples (tested on at least 3 occasions).
Post Crisis Follow-up: The dantrolene capsules should also be administered following a malignant hyperthermia crisis in doses of 4 to 8 mg/kg/day in 4 divided doses, for a 1-to 3-day period to prevent recurrence of the manifestations of malignant hyperthermia.
Reconstitution: Each vial should be reconstituted by adding 60 mL of sterile water for injection USP (without a bacteriostatic agent), and the vial shaken until the solution is clear. The contents of the vial must be protected from light and used within 6 hours after reconstitution. Store reconstituted solution at controlled room temperature 15 to 30°C.
Availability And Storage: Each 70 mL vial contains: a sterile lyophilized mixture of 20 mg dantrolene sodium, 3 000 mg mannitol, and sufficient sodium hydroxide to yield a pH of approximately 9.5 when reconstituted. Bisulfite-, gluten-, lactose-, paraben- and tartrazine-free. These are not multiple dose vials. Cartons of 12 vials. Store below 30°C.
Dantrolene i.v. is available only for use in hospitals or in dental clinics that are equipped to provide the necessary supportive measures used in the treatment of the malignant hyperthermia crisis.
DANTRIUM® INTRAVENOUS Procter & Gamble Pharmaceuticals Dantrolene Sodium Management of Malignant Hyperthermia