Treatment of Adolescent Antimuscarinic (Anticholinergic) Toxidrome

Study Overview
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Brief Summary
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Overdose of xenobiotics (antihistamines, antipsychotics, or Jimson Weed) with resulting antimuscarinic toxidrome is a common scenario in medical toxicology. The result of antagonism of muscarinic receptors is a constellation of signs and symptoms (toxidrome): mydriasis, decreased sweat, decreased bowel sounds, agitation, delirium, hallucinations, urinary retention, tachycardia, flushed skin and seizures. Two treatment options are physostigmine or benzodiazepines. Although the antimuscarinic toxidrome occurs commonly, physostigmine has been used sparingly despite evidence of safety and efficacy. To demonstrate the utility and safety of physostigmine, the investigators propose a randomized clinical trial of physostigmine compared to benzodiazepine for antimuscarinic toxicity.

Official Title
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A Randomized Trial Comparing Physostigmine vs Lorazepam for Treatment of Adolescent Antimuscarinic (Anticholinergic) Toxidrome

Conditions
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Anticholinergics Toxicity

Intervention / Treatment
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* Drug: Physostigmine
* Drug: Lorazepam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >=10 and < 18 years Present to the Emergency Department or Intensive Care Unit for an antimuscarinic toxidrome from either a pharmaceutical agent such as antihistamine overdose, or natural toxins or products such as Datura stramonium Antimuscarinic toxidrome will be defined with at least one central nervous system agitation effect (agitation, delirium, visual hallucinations, mumbling incomprehensible speech), and at least 2 peripheral nervous system adverse effect (mydriasis, dry mucus membranes, dry axillae, tachycardia, decreased bowel sounds). Patients will also be required to have a RASS score of +2 to +4 on initial assessment. Exclusion Criteria: History of seizures or seizure during acute clinical course History of asthma or wheezing during clinical course Bradycardia (Heart Rate <60) Concomitant use of atropine or choline ester or depolarizing neuromuscular blocker during present illness and hospital course Diabetes gangrene, known intestinal obstruction or urogenital tract, vagotonic state QRS interval > 120 ms on electrocardiogram Known to be pregnant at the time of enrollment Known ward of the state

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Physostigmine<br>Physostigmine 0.02 mg/kg IV bolus (max of 2 mg), which can be repeated at 10 minutes, followed by a 0.02 mg/kg/hr (max of 2 mg/hr) infusion for 4 hours. | Drug: Physostigmine<br>* Administration of physostigmine bolus followed by an infusion<br>|
| Experimental: Lorazepam<br>Lorazepam 0.05 mg/kg IV bolus (max 2 mg), which can be repeated at 10 minutes if inadequate patient response, followed by a Normal Saline infusion for 4 hours. | Drug: Lorazepam<br>* Administration of lorazepam bolus followed by normal saline infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of RASS Score Between Physostigmine and Lorazepam: Before Bolus | Determine the effectiveness of physostigmine as compared with lorazepam for control of antimuscarinic agitation. Richmond Agitation Sedation Scores (RASS) will be compared throughout treatment protocol. The Richmond Agitation-Sedation Scale (RASS) measures sedation and agitation. Possible scores range from -5 (unarousable) to 0 (alert & calm) to +4 (combative). Scores closer to 0 indicate a better outcome for this measurement. | Baseline, immediately before bolus | 
| Comparison of RASS Score Between Physostigmine and Lorazepam: After Bolus | Determine the effectiveness of physostigmine as compared with lorazepam for control of antimuscarinic agitation. Richmond Agitation Sedation Scores (RASS) will be compared throughout treatment protocol. The Richmond Agitation-Sedation Scale (RASS) measures sedation and agitation. Possible scores range from -5 (unarousable) to 0 (alert & calm) to +4 (combative). Scores closer to 0 indicate a better outcome for this measurement. | Immediately after bolus, up to 10 minutes post-Baseline | 
| Comparison of RASS Score Between Physostigmine and Lorazepam: 4 Hours | Determine the effectiveness of physostigmine as compared with lorazepam for control of antimuscarinic agitation. Richmond Agitation Sedation Scores (RASS) will be compared throughout treatment protocol. The Richmond Agitation-Sedation Scale (RASS) measures sedation and agitation. Possible scores range from -5 (unarousable) to 0 (alert & calm) to +4 (combative). Scores closer to 0 indicate a better outcome for this measurement. | 4 hours | 
| Comparison of the Effectiveness in Control of Delirium Between Physostigmine and Lorazepam: Before Bolus | Determine the effectiveness of physostigmine as compared with lorazepam in the reversal of antimuscarinic delirium. Confusion Assessment Method for the ICU (CAM-ICU) scores will be evaluated throughout the study. This measurement is a dichotomous outcome (yes or no for presence of delirium is indicated rather than a score). The number of participants exhibiting delirium is reported. | Baseline, immediately before bolus | 
| Comparison of the Effectiveness in Control of Delirium Between Physostigmine and Lorazepam: After Bolus | Determine the effectiveness of physostigmine as compared with lorazepam in the reversal of antimuscarinic delirium. Confusion Assessment Method for the ICU (CAM-ICU) scores will be evaluated throughout the study. This measurement is a dichotomous outcome (yes or no for presence of delirium is indicated rather than a score). The number of participants exhibiting delirium is reported. | Immediately after bolus, up to 10 minutes post-Baseline | 
| Comparison of the Effectiveness in Control of Delirium Between Physostigmine and Lorazepam: 4 Hours | Determine the effectiveness of physostigmine as compared with lorazepam in the reversal of antimuscarinic delirium. Confusion Assessment Method for the ICU (CAM-ICU) scores will be evaluated throughout the study. This measurement is a dichotomous outcome (yes or no for presence of delirium is indicated rather than a score). The number of participants exhibiting delirium is reported. | 4 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Effectiveness of Physostigmine Infusion in the Setting of Antimuscarinic Toxidrome. | Evaluation of clinical antimuscarinic symptoms, along with presence of any adverse effects, during the infusion to report tolerability, safety profile, and effectiveness of the infusion. the number of participants exhibiting adverse events will be reported, by type. | Up to 4 hours |