Dantrolene Dose Response in Awake Man: Implications for Management of Malignant Hyperthermia


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Abstract

Dantrolene sodium was administered intravenously to 12 adult volunteers to assess muscular and cardiopulmonary response. Pharmacokinetic results were obtained from whole blood drug concentration. Indirectly evoked thumb adduction was quantitated. Handgrip strength and subjective weakness score (10 equal to full strength, 0 equal to paralyzed) were assessed. Cardiopulmonary variables included forced vital capacity (FVC), peak expiratory flow rate (PEFR), percentage of end-tidal carbon dioxide (ETCO2), indirect mean arterial pressure (MAP), and heart rate (HR). Commercially available dantrolene for intravenous administration 0.33 mg/ml was administered in bolus doses of 0.1 mg/kg every 5 min until a plateau in twitch depression was achieved. Monitored variables were assessed either after each dose or following each cumulative 0.2 mg/kg dose over approximately 2 h. Intermittently during the subsequent 46 h, grip strength, subjective weakness, and blood levels were assessed. An average maximal twitch depression of 75% was reached at 2.2–2.5 mg/kg cumulative dantrolene dose. Significant depression of grip strength was observed after a dantrolene dose of 1.0 mg/kg and remained for 20 h. Subjective weakness score was 4.7 after dantrolene and slowly returned to 10 by 48 h. FVC and PEFR were not depressed significantly from control levels. ETCO2, MAP, and HR were unchanged. Maximum dantrolene blood level was 4.2 μg/ml at 2.9 h after the initial dantrolene dose. A near steady state existed for 5.5 h following the last dantrolene dose with a blood level of 3.6 μg/ml. Then blood levels declined slowly following first-order kinetics with a t 1/2 elimination of 12.1 h. Based on these results, the authors predict that the acute intravenous administration of dantrolene, 2.4 mg/kg, will achieve MH prophylaxis or therapeusis in humans.

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