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FAQs - Chloroquine and Hydroxychloroquine > What is the rationale for use of high dose diazepam in treating life-threatening chloroquine/hydroxychloroquine cardiac toxicity?

What is the rationale for use of high dose diazepam in treating life-threatening chloroquine/hydroxychloroquine cardiac toxicity?

posted on 7:42 PM, April 14, 2020

The mechanism of diazepam effect in chloroquine or hydroxychloroquine overdose cardiotoxicity remains unclear. There are multiple postulated theories which include a) central antagonistic effect; b) anticonvulsant effect, c) antidysrhythmic effect by an electrophysiologic action inverse to chloroquine’s effect; d) pharmacokinetic interaction between diazepam and chloroquine; and e) decrease in chloroquine-induced vasodilation. In one randomized placebo-controlled study of adults with a suspected “moderate severity” ingestion (>2g, <4g chloroquine), a loading dose of 0.5mg/kg diazepam followed by 1mg/kg over 24 hours did not influence outcome (Clemessy et al; 1996); this limited evidence supports limiting benzodiazepine therapy to treatment of seizures or in acute overdoses with severe cardiotoxic effects.

 

  • WHAT IS THE RECOMMENDED DOSE OF DIAZEPAM IN SEVERE CHLOROQUINE OR HYDROXYCHLOROQUINE OVERDOSE? The recommended dose of diazepam is 2mg/kg IV over 30 minutes followed by 1-2 mg/kg/day for 2-4 days or 005-0.01 mg/kg/hr.

 

  • IF DIAZEPAM IS NOT AVAILABLE, ARE OTHER BENZODIAZEPINES OR BARBITURATES LIKELY TO BE EFFECTIVE? There have been no studies comparing various benzodiazepines in the treatment of the cardiovascular and neurological toxicity resulting from acute chloroquine or hydroxychloroquine overdose. Other benzodiazepines can certainly be used for sedation or to treat seizures in the setting of an acute chloroquine or hydroxychloroquine overdose. Common equivalent drugs with parenteral dosing equivalent approximations are: lorazepam 1mg IV, diazepam 5mg IV, and midazolam 2mg IV. One experimental study documented similar efficacy of phenobarbital and diazepam in seizure control following chloroquine overdose.

 

  • WHAT ARE THE RISKS OF HIGH DOSE BENZODIAZEPINE THERAPY? Treatment with high dose benzodiazepines will be associated with an increased risk for adverse effects of benzodiazepines. Though typically associated with a favorable side effect profile, large benzodiazepine doses, especially when given parenterally, have been associated with decreased heart rate and blood pressure, as well as impaired mentation and ventilation. High doses of diazepam and lorazepam can cause lactate accumulation and metabolic acidosis from the metabolism of the diluent propylene glycol which is present at 40% concentration. Parenteral midazolam also contains 1% benzyl alcohol, which could contribute to hypotension and bradycardia in very large doses in neonates and those patients with severe hepatic dysfunction.

 

References:

Clemessy J-L, Angel G, Borron SW, Ndiaye M, Le Brun F, et al. Therapeutic trial of diazepam versus placebo in acute chloroquine intoxications of moderate gravity. Intensive Care Med 1996;22:1400-1405. 

Leeuwin RS, et al. PK 11195 antagonizes the positive inotropic response of the isolated rat heart to diazepam but not the negative inotropic response. Eur J Pharmacol 1996;299:149–152.

Riou B, Rimailho A, Galliot M, et al. Protective cardiovascular effects of diazepam in experimental acute chloroquine poisoning. Intensive Care Med 1988;14:610-616.

Riou B, et al. Treatment of severe chloroquine poisoning. N Engl J Med 1988; 318:1-6.

Wilson KC, Reardon C, Theodore AC, Farber HW. Propylene glycol toxicity: a severe iatrogenic illness in ICU patients receiving IV benzodiazepines: a case series and prospective, observational pilot study. Chest 2005;128(3):1674-81.