What is the role of Benzodiazepines in the management of Organophosphate (OP) poisoning?

From the Guidelines

Benzodiazepines are recommended as adjunctive therapy in organophosphate poisoning, alongside primary treatments such as atropine and oximes, to control seizures and agitation, reduce fasciculations, and decrease morbidity and mortality. According to the 2023 American Heart Association focused update on the management of patients with cardiac arrest or life-threatening toxicity due to poisoning 1, benzodiazepines such as diazepam (first line) or midazolam have demonstrated efficacy in patients with organophosphate poisoning. The guidelines recommend administration of benzodiazepines to treat seizures and agitation in the setting of organophosphate or carbamate poisoning 1.

The mechanism of action of benzodiazepines in organophosphate poisoning involves enhancing GABA-mediated inhibition in the central nervous system, which counteracts the excitatory effects of organophosphate poisoning 1. Diazepam is the preferred benzodiazepine, typically administered at 5-10 mg IV in adults (0.1-0.3 mg/kg in children) every 5-15 minutes as needed, with a maximum of 30 mg in an hour. Midazolam (0.1-0.2 mg/kg) or lorazepam (0.05-0.1 mg/kg) can be used as alternatives.

Benzodiazepines should be continued as needed based on clinical response, with close monitoring for respiratory depression, especially when combined with atropine 1. They should be administered early in the treatment course, even prophylactically in severe cases, as they can prevent the development of seizures and subsequent brain damage. The American Heart Association guidelines provide updated guidance for resuscitation of patients with cardiac arrest, respiratory arrest, and refractory shock due to poisoning, including the use of benzodiazepines in organophosphate poisoning 1.

Key points to consider when using benzodiazepines in organophosphate poisoning include:

• Early administration to prevent seizures and brain damage
• Close monitoring for respiratory depression, especially when combined with atropine
• Use of diazepam as the preferred benzodiazepine, with midazolam or lorazepam as alternatives
• Administration of benzodiazepines as needed based on clinical response, with a maximum dose of 30 mg in an hour.

From the Research

Benzodiazepines in Organophosphate Poisoning

• Benzodiazepines, such as diazepam, have been shown to be effective in preventing and treating convulsions produced by organophosphates (OPs) 2
• The use of diazepam is an important part of the treatment regimen of severe OP poisoning as it prevents, or at least reduces the duration of, convulsions 2
• Diazepam has also been shown to ameliorate muscle fasciculation, a subjectively unpleasant feature of OP pesticide poisoning 2
• However, there are no data demonstrating any clear effect of diazepam alone on lethality in OP poisoning, and in one study, diazepam given alone increased lethality 2

Mechanism of Action

• The exact mechanism of OP-induced central respiratory depression is unknown, but it is thought to be mediated through overstimulation of CNS respiratory centers 3
• Diazepam has been shown to inhibit OP-induced central respiratory depression, and when combined with peripherally acting anticholinergic agents, reduces mortality in a rat model of severe acute OP poisoning 3
• Benzodiazepines, such as midazolam, have been shown to prevent the emergence of spontaneous recurrent seizures (SRSs) and chronic epilepsy in rats poisoned with OPs 4

Treatment Guidelines

• Benzodiazepines, such as diazepam, should be given to patients poisoned with OPs whenever convulsions or pronounced muscle fasciculation are present 2
• In severe poisoning, diazepam administration should be considered even before these complications develop 2
• The use of benzodiazepines, such as midazolam, has been recommended as part of the immediate pharmacological treatment of OP poisoning, along with atropine and an oxime 4
• A systematic review of treatments for acute organophosphorus poisoning found that benzodiazepines were effective in reducing seizure activity and mortality 5

Seizure Activity

• Seizures are a common feature of OP poisoning, and can rapidly progress to status epilepticus, contributing to mortality and neurological impairment 6
• Benzodiazepines, such as diazepam, are the treatment currently indicated for control of seizures in OP poisoning 6
• Animal studies have shown that the early phase of seizure activity is purely cholinergic, while the later phase involves mixed cholinergic and noncholinergic modulation 6