Treatment of Adolescent Antimuscarinic (Anticholinergic) Toxidrome

NCT03090620 | Completed Phase 4 Results FDA Drug

• 1 other identifier: 16-1730
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Anticholinergics Toxicity

Outcome Measures

Primary Outcomes (6)

• 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 Outcomes (1)

• Safety and Effectiveness of Physostigmine Infusion in the Setting of Antimuscarinic Toxidrome.

  Up to 4 hours

Study Arms (2)

Physostigmine

EXPERIMENTAL

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

Lorazepam

EXPERIMENTAL

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

Interventions

Physostigmine DRUG

Administration of physostigmine bolus followed by an infusion

Physostigmine

Lorazepam DRUG

Administration of lorazepam bolus followed by normal saline infusion

Lorazepam

Eligibility Criteria

• Age: 10 Years - 17 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Colorado, Denver: lead
• American Academy of Clinical Toxicology: collaborator

Study Sites (1)

University of Colorado Anschutz Medical Campus, Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

MeSH Terms

Interventions

Physostigmine; Lorazepam

Intervention Hierarchy (Ancestors)

Phenylcarbamates; Carbamates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Benzodiazepinones; Benzodiazepines; Benzazepines

Limitations and Caveats

We had a smaller sample size. All patients in our cohort ingested antihistamines, the majority of which was diphenhydramine. There were no ingestions of other antimuscarinic xenobiotics. Many of the subjects were enrolled during the overnight hours; in addition to the underlying sedation effect of the ingested agent made an assessment of delirium challenging which may have led to more positive delirium scores in both treatment arms. We did not assess efficacy or safety beyond 4 hours.

Results Point of Contact

• Title: Dr. George Sam Wang
• Organization: UColorado

george.wang@childrenscolorado.org

303-724-9967

Study Officials

• George S Wang, MD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 10, 2017
• First Posted: March 27, 2017
• Study Start: March 30, 2017
• Primary Completion: July 31, 2020
• Study Completion: August 31, 2020
• Last Updated: August 23, 2021
• Results First Posted: August 23, 2021

Record last verified: 2021-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)