A Randomized Trial Comparing Physostigmine vs Lorazepam for Treatment of Adolescent Antimuscarinic (Anticholinergic) Toxidrome
Phase: PHASE4
Conditions: Anticholinergics Toxicity
Sponsor: University of Colorado, Denver

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COMIRB #: 16-1730 
PI: George Sam Wang, MD 
Protocol Version: 10/16/19 
 
COMIRB Protocol 
COLORADO MULTIPLE INSTITUTIONAL REVIEW 
BOARD 
CAMPUS BOX F-490    TELEPHONE:  303-724-1055  Fax:  
303-724-0990 
 
 
 
Protocol #: 16-1730 
Project Title: A Randomized Trial comparing Physostigmine vs Lorazepam for 
Treatment of Adolescent Antimuscarinic (Anticholinergic) Toxidrome 
Principal Investigator: George Sam Wang 
Version Date: 10/16/19 
 
 
 
 
 
 
  
 
I. Hypotheses and Specific Aims:   
• Specific Aim 1: Determine the effectiveness of physostigmine as 
compared with lorazepam for control of antimuscarinic agitation. 
• Hypothesis: Physostigmine infusion will decrease agitation more 
effectively than lorazepam bolus 
 
• Specific Aim 2: Determine the effectiveness of physostigmine as 
compared with lorazepam in the reversal of antimuscarinic delirium. 
• Hypothesis: Physostigmine bolus will reverse a greater proportion of 
patients with antimuscarinic delirium compared to lorazepam bolus. 
 
• Specific Aim 3: Demonstrate the safety of physostigmine infusion as 
compared to lorazepam bolus dosing for antimuscarinic toxicity. 
• Hypothesis: The proportion of adverse events will not differ between 
physostigmine infusion compared to lorazepam bolus dosing.  
 
II. Background and Significance:  
Overdose or abuse of xenobiotics, such as antihistamines or Jimson Weed, with 
resulting antimuscarinic toxidrome is a common scenario in medical toxicology.  In 2014, 
National Poison Data System (NPDS) annual report revealed 103,327 antihistamine 
ingestions reported to US regional poison centers, making it the 6th most common human 
exposure.[1]  In addition to antihistamines, several medications are direct muscarinic 
antagonists, including antipsychotics.[2,3]  The result of antagonism of muscarinic 
receptors is a constellation of signs and symptoms (toxidrome) which can consist of 
mydriasis (large pupils), decreased sweat, decreased bowel sounds, agitation, delirium, 
hallucinations, urinary retention, tachycardia, flushed skin and seizures.[2,3]  This 
toxidrome is common after supratherapeutic ingestions (overdoses) of these medications. 
Treatment for antimuscarinic toxidrome consists of supportive medical care 
including hemodynamic support with adequate fluid resuscitation, cooling if hyperthermia 
develops, and treatment of seizures. [4]  In addition to hemodynamic support, the goal of 
therapy is control of agitation and delirium.  Most medical therapy consists of 

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administration of sedative hypnotic pharmaceuticals such as benzodiazepines to achieve 
adequate sedation.[4]  However, significant amounts of benzodiazepines can be required, 
which can be a risk factor for hypotension and over sedation, and in loss of airway 
protection leading to intubation and mechanical ventilation.[5]   Furthermore, 
benzodiazepines do not reverse antimuscarinic delirium, and some patients may have a 
paradoxical worsening of symptoms. 
Physostigmine is a reversible acetylcholinesterase inhibitor that increases the 
concentration of acetylcholine at the synapse. The increase in acetylcholine overcomes the 
competitive antagonism of acetylcholine muscarinic receptor.[2,3]  Physostigmine crosses 
the blood-brain barrier, reversing both the agitation and delirium associated with the 
antimuscarinic toxidrome.[6]  Safe and adequate control of agitation and delirium with 
physostigmine in the setting of antimuscarinic toxicity from various xenobiotics has been 
described. [7-16] Retrospective comparisons of physostigmine to benzodiazepines for 
treatment for antimuscarinic toxicity revealed physostigmine controlled all but 1 of 28 
patients, while 16 of 22 patients still had agitation after benzodiazepine alone.[17]  
Delirium was also reversed in 87% patients receiving physostigmine compared with zero 
with benzodiazepine treatment.  Adverse effects were not different between the treatment 
groups.   
In the absence of high quality randomized trials, physostigmine has not been 
widely adopted for treatment of antimuscarinic toxicity. In 2014, NPDS annual review 
reported only 316 patients received physostigmine, while 35,337 patients received 
benzodiazepines for ingestions and exposures.[1]  Concerns over the use of physostigmine 
stem from concerns of adverse events exist due to two case reports in the setting of 
tricyclic antidepressant overdose complicated by seizures and asystolic arrest.[18,19] 
However, more detailed evidence has shown that physostigmine can be administered safely 
and effectively in antimuscarinic toxicity without development of these severe adverse 
effects.[4,7-16,20-22]  Another criticism of physostigmine is the short duration of action.  
The onset of effect after IV administration is rapid, with reversal or antimuscarinic 
toxidrome within several minutes. The duration of action is also short, lasting typically 30-
60 minutes (elimination half-life is 16 minutes).[6,7]   Even though physostigmine has a 
short duration of action, continuous physostigmine infusion for persistent antimuscarinic 
delirium and agitation of at least 8 hours has been demonstrated to be safe and effective 
even in pediatric patients.[23,24]   
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, we propose a randomized clinical trial of physostigmine 
compared to benzodiazepine for antimuscarinic toxicity.  
 
III. Preliminary Studies/Progress Report:   
From August 1, 2013 through January 31, 2016, 56 patients were 
evaluated by a medical toxicology consultation at Children’s Hospital 
Colorado for antihistamine overdose. Several more were evaluated for 
antimuscarinic toxidrome from other ingestions (antipsychotics and Datura).  
Of the antihistamine overdose patients, 8 received physostigmine with 
complete reversal of agitation and delirium and no reported side effects; the 

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remaining received benzodiazepines.  Twenty-seven patients were admitted to 
the intensive care unit, with the remaining being admitted to the inpatient ward 
or observed in the emergency department.  There were no cardiac 
dysrhythmias or seizures from physostigmine, and no deaths. 
 
IV. Research Methods 
A.  Outcome Measure(s):   
Primary outcome measures for this study include evaluation and assessment of 
delirium and agitation, as measured by the Richmond Agitation-Sedation Score (RASS) 
and modified 3D-Confusion Assessment Delirium (CAM) scores.  Secondary outcomes 
include adverse effects, which include the following: seizures, bradycardia, dysrhythmias, 
bronchospasm, increased secretions, diaphoresis, vomiting, intubation, and over-sedation.  
We will also evaluate treatment satisfaction scores from treating physicians, nursing staff, 
and parents.  Total benzodiazepine doses given will be recorded for each patient enrolled.  
The total time requiring physical restraints will also be collected. 
Immediately prior to study treatment, after each medication bolus, and during every hour 
of treatment, the following will be obtained: vital signs, RASS, determination of delirium, 
adverse effects (seizures, bradycardia (<60), bronchorrhea, bronchospasm, diaphoresis, 
vomiting, intubation and over-sedation) and clinical examination (specifically, symptoms 
of antimuscarinic toxicity: flushed skin, dry axillae, dry mucous membranes, mydriasis, 
decreased bowel sounds, seizures, tachycardia, hyperthermic (>38.0C)).   
Previously validated RASS score will be used to assess agitation: -5 (nonarousable) 
to 0 (alert and calm) to +4 (combative).[25](Table 1) Two separate providers (MD or RN) 
will provide assessment of agitation score.  Modified 3D-CAM score will be used to assess 
delirium.[26]  All patients meeting inclusion criteria for RASS scores will automatically 
have the first 2 criteria for 3D-CAM met: fluctuating course of mental status and 
inattention.[26]  Thus, questions on disorganized thinking will be asked to further assess 
for delirium: 1) Will a stone float on water? 2) Are there fish in the sea? 3) Does one-pound 
weight more than two? 4) Can you use a hammer to pound a nail? Reversal of delirium 
will be defined as ability to correctly answer at least 3 of 4 questions.  Sensitivity analysis 
will be performed to compare 2-3 questions correct.  At the end of the treatment protocol, 
the study will terminate and treating physicians can medically treat patient at their 
discretion.  A urine sample from either a pre-existing foley catheter bag collection, or 
volunteer void, will be sent for a comprehensive urine drug screen.[27]   
 

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B. Description of Population to be Enrolled:   
Inclusion Criteria:  
• >=10 and < 18 years of age  
• Present to the Children’s Hospital Colorado Emergency Department or 
Intensive Care Unit for an antimuscarinic toxidrome from either a 
pharmaceutical agent such as antihistamine overdose (diphenhydramine, 
chlorpheniramine, doxylamine, cyclobenzaprine), or natural toxins/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 systems adverse 
effect (mydriasis, dry mucus membranes, dry axillae, tachycardia, decreased 
bowel sounds).   
• If the patient has one IV, does the medical team deem it appropriate to 
discontinue IVF during the 4-hour infusion period (due to drug compatibility)  
• Patients will also be required to have a RASS score of ≥ +1 AND have a 
positive delirium score on the modified 3D CAM Score on initial assessment. 
• Parent/legal guardian providing consent for the subject is >18 and <85  
Exclusion Criteria: 
• History of epilepsy or seizures 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 
• History of current overdose of tricyclic antidepressant 
• Child is known to be pregnant at the time of enrollment 
• Known ward of the state 
• Child has a history of developmental delay 
• Previous administration of physostigmine during the current illness*   
*(Previous benzodiazepine administration does not exclude subjects as long as 
agitation score meets inclusion criteria.) 
 
 
C. Study Design and Research Methods   
This is a double-blinded, randomized clinical trial, comparing physostigmine and 
benzodiazepines for treatment for antimuscarinic toxicity.  The study will be registered 
with Clintrials.gov. Patients will be initially screened by research assistants (RA) or by 
primary medical treatment team by chief complaint of “Ingestion,” “Overdose,” “XXXX,” 
or “Altered Mental Status” via EPIC electronic medical record.  The diagnosis of 
antimuscarinic toxidrome will also be verified by the medical toxicology service. 

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After signed or verbal phone consent from the child’s parent/legal guardian, 
randomization will be performed by the pharmacy to determine the treatment protocol.  
Investigational pharmacy will be notified by the RA and the initial pharmaceutical 
treatment regimen will be provided to the treatment team.  The patient, caregiver, nursing 
staff, and treating physician will be blinded to the treatment.  To maintain blinding, the 
bolus and infusion medications will only be labeled with a study protocol identifier.  
Physostigmine and lorazepam are both clear, and the bolus and infusion volumes will be 
similar and syringe will be covered to allow for adequate blinding.  Patients will be on 
continuous cardiorespiratory monitoring, receive intravenous fluid resuscitation, laboratory 
assessment (basic metabolic panel, acetaminophen and salicylate concentrations, and 
electrocardiogram) and urine foley placement (if needed) per standard treatment protocol 
for their presenting diagnosis.  They will be allowed to receive other medications, 
including antipsychotic or other benzodiazepines, during their treatment timeline while in 
the study.  They will not be excluded from the study if they have received these 
medications prior to enrollment, as long as they have otherwise met study criteria. 
 
Enrolled patients will be randomized to a treatment arm of: 
• 
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. 
OR 
• 
Lorazepam 0.05 mg/kg IV bolus (max 2 mg), which can be repeated at 10 minutes 
if inadequate patient response, followed by a NS infusion for 4 hours. 
 
During either treatment arm, lorazepam 0.05 mg/kg IV bolus (max 2 mg) can be 
administered every 2 hours as needed for continued elevated agitation scores. 
 
Urine samples will be obtained (10-30ml), and sent to LabCorp for analysis using the 
TOXASSURE Comprehensive Drug Analysis which includes 26 drug categories and 180 
compounds using UPLC/MS-MS analysis platform.  They will be stored at the Research 
Institute Freezer at < 20C until sent to LabCorp for analysis. 
 
D. Description, Risks and Justification of Procedures and Data Collection Tools: 
Human subjects included in our study will consist of patients greater than or equal 
to 10 years and less than 18 years of age. Our study does not involve fetuses, prisoners, 
institutionalized individuals, neonates, or pregnant women.  This study will include 
women, minorities, and children. Parent/Legal Guardian consent will be obtained prior to 
study procedures being performed. Each patient enrolled will be given a unique study 
identifier which will be used for the laboratory samples and data collection.  Any and all 
protected health information and data obtained will be stored in a password-secured, 
REDCap data system.   
 
• Intravenous (IV) administration of medications: These patients will have existing 
IV’s for their standard care and treatment. Risks of this procedure include pain, 
infection, local redness and irritation.  Physostigmine, lorazepam, nor normal saline 
can lead to caustic injury with IV infiltration. 

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• Urine Sample: If a foley is being placed for their standard care, urine sample will 
be obtained from foley bag.  If the patient can void, they will voluntarily void into a 
collection cup.    
• There is a slight but unlikely risk of loss of confidentiality.  To help protect against 
this, a password-protected REDCap database will be used to collect and store all 
data. Only study team members will have access to the database.   
• Reports of seizures and cardiac dysrhythmias have rarely been reported with the 
use of physostigmine and from anticholinergic toxicity.  Other rare but potentially 
serious side effects can include bronchospasm, bradycardia, and bronchorrhea.  
Standard label contraindications will be used for physostigmine (as listed in the 
exclusion criteria) to avoid these complications, and atropine will be at bedside to 
reverse any potential clinical effects which may occur. Adverse effects from 
lorazepam include over sedation and respiratory depression. Supportive care will be 
used for any adverse effects from lorazepam.  Patients will be on a full 
cardiorespiratory monitor for their diagnosis per standard protocol, and will be 
constantly monitored for adverse events associated with their diagnosis, in addition 
to their treatment protocol.    
• Stopping/Exit Criteria during study protocol: 
o Physician discretion 
o Bradycardia (HR <60) 
o Seizures 
o Cardiac Dysrhythmias 
o Wheezing 
o Intubation 
 
Any possible adverse events reported by the research staff or parent/legal guardians that 
might occur from the urine collection or from medications received during their visit will 
be documented and reported to the primary investigator and appropriate IRB authorities in 
real time.  They will be reviewed and determined if any immediate action will need to be 
taken.   
    
E.   Potential Scientific Problems:   
One potential issue is misclassification of the patient at the time of enrollment. The 
anticholinergic toxidrome is a clinical diagnosis and there are many conditions that may 
mimic parts of this toxidrome.  However, members of the medical toxicology service will 
be evaluating the patients to verify presentation of antimuscarinic toxidrome.  There may 
be provider variability in rating delirium and agitation. We are using standardized scales to 
decrease this variability. Although standard dosing is used, the dose of physostigmine or 
lorazepam used for this study may not be adequate in treatment of delirium or agitation, 
depending on the exposure and amount ingested. 
 
F.   Data Analysis Plan:   
Data will be analyzed by SAS 9.4 (SAS Institute, Cary, NC). Two-tailed Fisher 
exact and Mann-Whitney U tests will be used for independent samples.  McNemar’s and 
Wilcoxon signed rank tests will be used to assess variable change before and after 

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treatment. If continuous or ordinal data is non-normally distributed, non-parametric tests 
will be performed. Due to multiple comparisons, statistical significance will be adjusted 
using Bonferroni’s correction. To compare intergroup changes in agitation score, repeated-
measure analysis of variance will be used. When number of observed events was small, the 
exact binomial distribution was used to compute 95% confidence intervals. Kappa score 
for agreement will be performed for provider determination of agitation score.  Our power 
calculations, based a retrospective study evaluating after initial control of agitation with 
treatment of where 96% of physostigmine and 27 % of benzodiazepine treated patients had 
control of agitation, suggested that 22 subjects (11 in each arm) provides 92% power to 
detect at least 70% difference assuming an alpha of type 1 error rate of 5%.  To account for 
study withdrawal and attrition, study protocol and budget will be prepared for enrollment 
of 28 during the study time period.   
 
G.  Summarize Knowledge to be Gained:   
Our study promotes the study of health effects and treatment of a common 
ingestion (antihistamines) and toxidrome (antimuscarinic), and will ultimately improve 
clinical care and practice of clinical toxicology, specifically in this very common patient 
population.  It will help expand knowledge of safety and efficacy of physostigmine by 
providing top level evidence, and help define the use of this antidote for clinical 
toxicologists and other treating physicians.   
 
H. References: 
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report of the American Association of Poison Control Centers’ National Poison 
Data System (NPDS): 32nd Annual Report. Clin Toxicol (Phila). 
2015;53(10):962-1147. 
2. Rumack BH. Anticholinergic Poisoning: Treatment with Physostigmine. 
Pediatrics. 1973;52(3):449-451. 
3. Lieberman JA. Managing Anticholinergic Side Effects. Prim Care Companion J 
Clin Psychiatry. 2004;6(suppl 2):20-23. 
4. Watkins JW, Schwarz ES, Arroyo-Plasencia AM, Mullins ME; Toxicology 
Investigators Consortium. The Use of Physostigmine by Toxicologists in 
Anticholinergic Toxicity. J Med Toxicol. 2015;11(2):179-84. 
5. Beauchamp GA, Giffin SL, Horowitz BZ, Laurie AL, Fu R, Hendrickson RG. 
Poisonings associated with intubation: US National Poison Data System 
Exposures 2000-2013. J Med Toxicol. 2015. [epub ahead of print]. 
6. Dawson AH, Buckley NA. Pharmacological management of anticholinergic 
delirium- theory, evidence and practice. Br J Clin Pharmacol. 2015. [epub 
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7. Beaver KM, Gavin TJ (1998) Treatment of acute anticholinergic poisoning with 
physostigmine. Am J Emerg Med 16(5):505–507. 
8. Rasimas JJ, Sachdeva K, Salama AM, Helmick TJ, Donovan JW. A review of 
bedside toxicologic experience with physostigmine and flumazenil. Clin 
Toxicol. 2010;48(6):648. 

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9. Crowell EB Jr, Ketchum JS. The treatment of scopolamine induced delirium 
with physostigmine. Clin Pharmacol Ther. 1967. 8(3): 409–414.  
10. Slovis TL, Ott JE, Teitelbaum DT, Lipscomb W. Physostigmine therapy in 
acute tricyclic antidepressant poisoning. Clin Toxicol. 1971;4(3):451–459. 
11. Teoh R, Page AV, Hardern R. Physostigmine as treatment for severe CNS 
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of the Richmond Agitation-Sedation Scale (RASS).  JAMA. 
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