Treatment of Adolescent Antimuscarinic (Anticholinergic) Toxidrome (TAAT)

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

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.

Study Overview

• Status: Completed
• Conditions: Anticholinergics Toxicity
• Intervention / Treatment: Drug: Physostigmine; Drug: Lorazepam

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Anschutz Medical Campus, Children's Hospital Colorado

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Physostigmine; 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; Administration of physostigmine bolus followed by an infusion
Experimental: Lorazepam; 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; Administration of lorazepam bolus followed by normal saline infusion

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: American Academy of Clinical Toxicology
• Investigators: Principal Investigator: George S Wang, MD, University of Colorado, Denver

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2017
• Primary Completion (Actual): July 31, 2020
• Study Completion (Actual): August 31, 2020

Study Registration Dates

• First Submitted: March 10, 2017
• First Submitted That Met QC Criteria: March 20, 2017
• First Posted (Actual): March 27, 2017

Study Record Updates

• Last Update Posted (Actual): August 23, 2021
• Last Update Submitted That Met QC Criteria: July 28, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Enzyme Inhibitors; Antiemetics; Gastrointestinal Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anticonvulsants; Cholinesterase Inhibitors; Miotics; Lorazepam; Physostigmine
• Other Study ID Numbers: 16-1730

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No