TAAT: Treatment of Adolescent Antimuscarinic (Anticholinergic) Toxidrome

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT03090620
• Collaborator: American Academy of Clinical Toxicology (Other)
• Enrollment: 19
• Location: 1
• Arms: 2
• Actual Duration (Months): 41.1
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Anticholinergics Toxicity	Drug: Physostigmine; Drug: Lorazepam	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized Trial Comparing Physostigmine vs Lorazepam for Treatment of Adolescent Antimuscarinic (Anticholinergic) Toxidrome
• Actual Study Start Date: Mar 30, 2017
• Actual Primary Completion Date: Jul 31, 2020
• Actual Study Completion Date: Aug 31, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Comparison of RASS Score Between Physostigmine and Lorazepam: Before Bolus [Baseline, immediately 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.

2. Comparison of RASS Score Between Physostigmine and Lorazepam: After Bolus [Immediately after bolus, up to 10 minutes post-Baseline]

   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.

3. Comparison of RASS Score Between Physostigmine and Lorazepam: 4 Hours [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. Comparison of the Effectiveness in Control of Delirium Between Physostigmine and Lorazepam: Before Bolus [Baseline, immediately 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.

5. Comparison of the Effectiveness in Control of Delirium Between Physostigmine and Lorazepam: After Bolus [Immediately after bolus, up to 10 minutes post-Baseline]

   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.

6. Comparison of the Effectiveness in Control of Delirium Between Physostigmine and Lorazepam: 4 Hours [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.

Secondary Outcome Measures

1. Safety and Effectiveness of Physostigmine Infusion in the Setting of Antimuscarinic Toxidrome. [Up to 4 hours]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 10 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Anschutz Medical Campus, Children's Hospital Colorado	Aurora	Colorado	United States	80045

Sponsors and Collaborators

• University of Colorado, Denver
• American Academy of Clinical Toxicology

Investigators

• Principal Investigator: George S Wang, MD, University of Colorado, Denver

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 16, 2019

More Information

Publications

None provided.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT03090620
• Other Study ID Numbers: 16-1730
• First Posted: Mar 27, 2017
• Last Update Posted: Aug 23, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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
• Additional relevant MeSH terms: Lorazepam; Physostigmine

Study Results

Participant Flow

Arm/Group Title	Physostigmine	Lorazepam
Arm/Group Description	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. Physostigmine: Administration of physostigmine bolus followed by an infusion	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. Lorazepam: Administration of lorazepam bolus followed by normal saline infusion
Period Title: Overall Study
STARTED	9	10
COMPLETED	9	10
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Physostigmine	Lorazepam	Total
Arm/Group Description	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. Physostigmine: Administration of physostigmine bolus followed by an infusion	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. Lorazepam: Administration of lorazepam bolus followed by normal saline infusion	Total of all reporting groups
Overall Participants	9	10	19
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	13.4 (1.4)	14.4 (1.3)	13.9 (1.3)
Sex: Female, Male (Count of Participants)
Female	5 55.6%	7 70%	12 63.2%
Male	4 44.4%	3 30%	7 36.8%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United States	9 100%	10 100%	19 100%
Mean Heart Rate (Beats per minute) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Beats per minute]	127 (18)	117 (10)	122 (14)
Mean Temperature (Celsius) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Celsius]	37.3 (0.6)	37.1 (0.5)	37.2 (0.5)
Mean Respiratory Rate (Respirations per minute) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Respirations per minute]	29 (7)	24 (4)	27 (5)
Mean Systolic Blood Pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	131 (12)	127 (14)	129 (13)
Mean Diastolic Blood Pressure (nnHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [nnHg]	80 (11)	88 (17)	84 (14)
Mean Oxygen Saturations (%Oxygen) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [%Oxygen]	96 (2)	97 (3)	96 (2)

Outcome Measures

1. Primary Outcome

Title	Comparison of RASS Score Between Physostigmine and Lorazepam: Before Bolus
Description	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.
Time Frame	Baseline, immediately before bolus

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Physostigmine	Lorazepam
Arm/Group Description	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. Physostigmine: Administration of physostigmine bolus followed by an infusion	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. Lorazepam: Administration of lorazepam bolus followed by normal saline infusion
Measure Participants	9	10
Median (Inter-Quartile Range) [score on a scale]	1.5	1

2. Primary Outcome

Title	Comparison of RASS Score Between Physostigmine and Lorazepam: After Bolus
Description	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.
Time Frame	Immediately after bolus, up to 10 minutes post-Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Physostigmine	Lorazepam
Arm/Group Description	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. Physostigmine: Administration of physostigmine bolus followed by an infusion	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. Lorazepam: Administration of lorazepam bolus followed by normal saline infusion
Measure Participants	9	10
Median (Inter-Quartile Range) [score on a scale]	0	1

3. Primary Outcome

Title	Comparison of RASS Score Between Physostigmine and Lorazepam: 4 Hours
Description	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.
Time Frame	4 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Physostigmine	Lorazepam
Arm/Group Description	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. Physostigmine: Administration of physostigmine bolus followed by an infusion	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. Lorazepam: Administration of lorazepam bolus followed by normal saline infusion
Measure Participants	9	10
Median (Inter-Quartile Range) [score on a scale]	0	0.25

4. Primary Outcome

Title	Comparison of the Effectiveness in Control of Delirium Between Physostigmine and Lorazepam: Before Bolus
Description	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.
Time Frame	Baseline, immediately before bolus

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Physostigmine	Lorazepam
Arm/Group Description	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. Physostigmine: Administration of physostigmine bolus followed by an infusion	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. Lorazepam: Administration of lorazepam bolus followed by normal saline infusion
Measure Participants	9	10
Count of Participants [Participants]	9 100%	9 90%

5. Secondary Outcome

Title	Safety and Effectiveness of Physostigmine Infusion in the Setting of Antimuscarinic Toxidrome.
Description	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.
Time Frame	Up to 4 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Physostigmine	Lorazepam
Arm/Group Description	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. Physostigmine: Administration of physostigmine bolus followed by an infusion	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. Lorazepam: Administration of lorazepam bolus followed by normal saline infusion
Measure Participants	9	10
Seizures	0 0%	0 0%
Bradycardia	0 0%	0 0%
Bronchorrhea	0 0%	0 0%
Bronchospasm	0 0%	0 0%
Diaphoresis	0 0%	0 0%
Intubation	0 0%	0 0%
Vomiting	1 11.1%	1 10%
Oversedation	1 11.1%	1 10%

6. Primary Outcome

Title	Comparison of the Effectiveness in Control of Delirium Between Physostigmine and Lorazepam: After Bolus
Description	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.
Time Frame	Immediately after bolus, up to 10 minutes post-Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Physostigmine	Lorazepam
Arm/Group Description	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. Physostigmine: Administration of physostigmine bolus followed by an infusion	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. Lorazepam: Administration of lorazepam bolus followed by normal saline infusion
Measure Participants	9	10
Count of Participants [Participants]	4 44.4%	10 100%

7. Primary Outcome

Title	Comparison of the Effectiveness in Control of Delirium Between Physostigmine and Lorazepam: 4 Hours
Description	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.
Time Frame	4 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Physostigmine	Lorazepam
Arm/Group Description	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. Physostigmine: Administration of physostigmine bolus followed by an infusion	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. Lorazepam: Administration of lorazepam bolus followed by normal saline infusion
Measure Participants	9	10
Count of Participants [Participants]	2 22.2%	10 100%

Adverse Events

Time Frame	4 Hours
Arm/Group Title	Physostigmine		Lorazepam
Arm/Group Description	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. Physostigmine: Administration of physostigmine bolus followed by an infusion		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. Lorazepam: Administration of lorazepam bolus followed by normal saline infusion
All Cause Mortality
	Physostigmine		Lorazepam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/10 (0%)
Serious Adverse Events
	Physostigmine		Lorazepam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Physostigmine		Lorazepam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/9 (22.2%)		2/10 (20%)
Gastrointestinal disorders
Vomitnig	1/9 (11.1%)	1	1/10 (10%)	1
Nervous system disorders
Oversedation	1/9 (11.1%)	1	1/10 (10%)	1

Limitations/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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.