Anticholinergics Toxicity
Conditions
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.
Interventions
DRUGPhysostigmine
Administration of physostigmine bolus followed by an infusion
DRUGLorazepam
Administration of lorazepam bolus followed by normal saline infusion
Sponsors
American Academy of Clinical Toxicology
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
10 Years to 17 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Physostigmine: Administration of physostigmine bolus followed by an infusion | 9 |
| 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.
Lorazepam: Administration of lorazepam bolus followed by normal saline infusion | 10 |
| Total | 19 |
Baseline characteristics
| Characteristic | Physostigmine | Lorazepam | Total |
|---|---|---|---|
| Age, Continuous | 13.4 years STANDARD_DEVIATION 1.4 | 14.4 years STANDARD_DEVIATION 1.3 | 13.9 years STANDARD_DEVIATION 1.3 |
| Mean Diastolic Blood Pressure | 80 nnHg STANDARD_DEVIATION 11 | 88 nnHg STANDARD_DEVIATION 17 | 84 nnHg STANDARD_DEVIATION 14 |
| Mean Heart Rate | 127 Beats per minute STANDARD_DEVIATION 18 | 117 Beats per minute STANDARD_DEVIATION 10 | 122 Beats per minute STANDARD_DEVIATION 14 |
| Mean Oxygen Saturations | 96 %Oxygen STANDARD_DEVIATION 2 | 97 %Oxygen STANDARD_DEVIATION 3 | 96 %Oxygen STANDARD_DEVIATION 2 |
| Mean Respiratory Rate | 29 Respirations per minute STANDARD_DEVIATION 7 | 24 Respirations per minute STANDARD_DEVIATION 4 | 27 Respirations per minute STANDARD_DEVIATION 5 |
| Mean Systolic Blood Pressure | 131 mmHg STANDARD_DEVIATION 12 | 127 mmHg STANDARD_DEVIATION 14 | 129 mmHg STANDARD_DEVIATION 13 |
| Mean Temperature | 37.3 Celsius STANDARD_DEVIATION 0.6 | 37.1 Celsius STANDARD_DEVIATION 0.5 | 37.2 Celsius STANDARD_DEVIATION 0.5 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment United States | 9 participants | 10 participants | 19 participants |
| Sex: Female, Male Female | 5 Participants | 7 Participants | 12 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 10 |
| other Total, other adverse events | 2 / 9 | 2 / 10 |
| serious Total, serious adverse events | 0 / 9 | 0 / 10 |
Outcome results
Primary
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.
Time frame: 4 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Physostigmine | Comparison of RASS Score Between Physostigmine and Lorazepam: 4 Hours | 0 score on a scale |
| Lorazepam | Comparison of RASS Score Between Physostigmine and Lorazepam: 4 Hours | 0.25 score on a scale |
Primary
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.
Time frame: Immediately after bolus, up to 10 minutes post-Baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Physostigmine | Comparison of RASS Score Between Physostigmine and Lorazepam: After Bolus | 0 score on a scale |
| Lorazepam | Comparison of RASS Score Between Physostigmine and Lorazepam: After Bolus | 1 score on a scale |
Primary
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.
Time frame: Baseline, immediately before bolus
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Physostigmine | Comparison of RASS Score Between Physostigmine and Lorazepam: Before Bolus | 1.5 score on a scale |
| Lorazepam | Comparison of RASS Score Between Physostigmine and Lorazepam: Before Bolus | 1 score on a scale |
Primary
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.
Time frame: 4 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Physostigmine | Comparison of the Effectiveness in Control of Delirium Between Physostigmine and Lorazepam: 4 Hours | 2 Participants |
| Lorazepam | Comparison of the Effectiveness in Control of Delirium Between Physostigmine and Lorazepam: 4 Hours | 10 Participants |
Primary
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.
Time frame: Immediately after bolus, up to 10 minutes post-Baseline
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Physostigmine | Comparison of the Effectiveness in Control of Delirium Between Physostigmine and Lorazepam: After Bolus | 4 Participants |
| Lorazepam | Comparison of the Effectiveness in Control of Delirium Between Physostigmine and Lorazepam: After Bolus | 10 Participants |
Primary
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.
Time frame: Baseline, immediately before bolus
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Physostigmine | Comparison of the Effectiveness in Control of Delirium Between Physostigmine and Lorazepam: Before Bolus | 9 Participants |
| Lorazepam | Comparison of the Effectiveness in Control of Delirium Between Physostigmine and Lorazepam: Before Bolus | 9 Participants |
Secondary
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.
Time frame: Up to 4 hours
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Physostigmine | Safety and Effectiveness of Physostigmine Infusion in the Setting of Antimuscarinic Toxidrome. | Diaphoresis | 0 Participants |
| Physostigmine | Safety and Effectiveness of Physostigmine Infusion in the Setting of Antimuscarinic Toxidrome. | Bradycardia | 0 Participants |
| Physostigmine | Safety and Effectiveness of Physostigmine Infusion in the Setting of Antimuscarinic Toxidrome. | Intubation | 0 Participants |
| Physostigmine | Safety and Effectiveness of Physostigmine Infusion in the Setting of Antimuscarinic Toxidrome. | Seizures | 0 Participants |
| Physostigmine | Safety and Effectiveness of Physostigmine Infusion in the Setting of Antimuscarinic Toxidrome. | Vomiting | 1 Participants |
| Physostigmine | Safety and Effectiveness of Physostigmine Infusion in the Setting of Antimuscarinic Toxidrome. | Bronchorrhea | 0 Participants |
| Physostigmine | Safety and Effectiveness of Physostigmine Infusion in the Setting of Antimuscarinic Toxidrome. | Oversedation | 1 Participants |
| Physostigmine | Safety and Effectiveness of Physostigmine Infusion in the Setting of Antimuscarinic Toxidrome. | Bronchospasm | 0 Participants |
| Lorazepam | Safety and Effectiveness of Physostigmine Infusion in the Setting of Antimuscarinic Toxidrome. | Oversedation | 1 Participants |
| Lorazepam | Safety and Effectiveness of Physostigmine Infusion in the Setting of Antimuscarinic Toxidrome. | Seizures | 0 Participants |
| Lorazepam | Safety and Effectiveness of Physostigmine Infusion in the Setting of Antimuscarinic Toxidrome. | Bradycardia | 0 Participants |
| Lorazepam | Safety and Effectiveness of Physostigmine Infusion in the Setting of Antimuscarinic Toxidrome. | Bronchospasm | 0 Participants |
| Lorazepam | Safety and Effectiveness of Physostigmine Infusion in the Setting of Antimuscarinic Toxidrome. | Diaphoresis | 0 Participants |
| Lorazepam | Safety and Effectiveness of Physostigmine Infusion in the Setting of Antimuscarinic Toxidrome. | Intubation | 0 Participants |
| Lorazepam | Safety and Effectiveness of Physostigmine Infusion in the Setting of Antimuscarinic Toxidrome. | Vomiting | 1 Participants |
| Lorazepam | Safety and Effectiveness of Physostigmine Infusion in the Setting of Antimuscarinic Toxidrome. | Bronchorrhea | 0 Participants |