Agent 15 Poisoning

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Background

"Incapacitating agent" is a military term used to denote an agent that temporarily and nonlethally impairs the performance of an enemy by targeting the central nervous system (CNS). Of those substances investigated by the military, anticholinergic agents best fit these criteria and are stable enough for use in war. As far back as 184 BC, Hannibal's army used belladonna plants to induce disorientation in enemies. In 1672, the Bishop of Muenster used belladonna-containing grenades in his campaigns.

Approximately 300 years later, the US Army explored several classes of drugs, as well as noise, microwaves, and photostimulation, and found none to be as promising incapacitating agents as the anticholinergics. Stimulants such as cocaine, amphetamines, and nicotine were tested but did not have the potency to be an airborne threat. Depressants (eg, barbiturates, opiates, neuroleptics) similarly were found to be impractical for battlefield use. The unpredictable behavior incurred by psychedelic agents (ie, lysergic acid diethylamide [LSD], phencyclidine [PCP]) led to an early halt in the testing of that particular class of drugs.

By the mid-1960s, after a decade of tests, the US Army concluded that the long-acting anticholinergic 3-quinuclidinyl benzilate (BZ) was the best candidate for weaponization and deployment. BZ subsequently was stockpiled in American military arsenals from the mid-1960s through the late-1980s. The US military was not alone in its attempt to develop an incapacitating agent in the 20th century. Seven years after the conclusion of the Gulf War, the British Foreign Ministry revealed, in February 1998, the existence of an Iraqi chemical warfare agent believed to be a glycolate anticholinergic, similar, if not identical, to BZ. It was dubbed "Agent 15." Little information is known publicly about Agent 15. For this reason, also refer to CBRNE - Incapacitating Agents, 3-Quinuclidinyl Benzilate .

Pathophysiology

BZ is the North Atlantic Treaty Organization (NATO) code for 3-quinuclidinyl benzilate, a glycolate anticholinergic also known as 3-QNB. Both BZ and its Iraqi look-alike, Agent 15, are competitive inhibitors of the effects of acetylcholine at the postsynaptic muscarinic receptors in the peripheral and central nervous systems. In the peripheral nervous system, this inhibition is observed in the smooth muscle, autonomic ganglia, and exocrine glands. BZ's ability to readily cross the blood-brain barrier allows it to wreak havoc on the CNS, causing mental status changes and delirium.

A common problem in developing a chemical warfare agent is finding an effective and reliable chemical. The glycolate anticholinergics (eg, BZ, Agent 15) fit this description. Extremely stable, these chemicals have a half-life of 3-4 weeks in moist air and even longer on surfaces or in soil. Absorption of glycolates can occur following inhalation, ingestion, or cutaneous exposure. Only small doses of this potent drug are needed to produce delirium. The dose of BZ needed to incapacitate 50% of those exposed is 6.2 mcg/kg, compared to 140 mcg/kg for atropine.

Epidemiology

Frequency

United States

With the exception of Army test volunteers in the 1960s, anticholinergic incapacitating agents have not been used in the US. Although many experts believe that most terrorists would opt for a lethal form of chemical attack (eg, nerve agent), use of incapacitating agents cannot be discounted. Other sources of anticholinergic toxicity include clinical medicines such as atropine, antihistamines, and tricyclic antidepressants.

Numerous plants commonly found in North America also can cause delirium indistinct from exposure to an incapacitating agent. Examples include jimsonweed, nightshade, belladonna, and other members of the Solanaceae family.

International

Iraq is known to possess Agent 15. Other governments accused of possibly possessing incapacitating agents include the former Soviet Union and Bosnia.

Mortality/Morbidity

By definition, incapacitating agents are nonlethal. BZ has a high safety ratio. The dose required to produce incapacitating effects is roughly 40 times less than the fatal dose. Fatalities from this class of drug can result from hyperthermia or from the casualty's delirious behavior. Such a scenario was dramatized in the 1990s movie "Jacob's Ladder," in which a fictitious military unit kills itself after accidental exposure to an incapacitant-type chemical warfare agent.

History

Physical

Remarkably little variation exists among individuals when anticholinergics are administered.

Causes

Laboratory Studies

Prehospital Care

Emergency Department Care

Consultations

Additional advice can be acquired by calling the US Army Medical Research Institute of Chemical Defense at the Aberdeen Proving Grounds, Maryland, at (410) 436-3628.

Medication Summary

In the past, physostigmine was used to reverse the effects of anticholinergic intoxicants. However, numerous adverse effects from its use are reported. For this reason, its role as an antidote is controversial, and benzodiazepines generally are considered to be the safest medications for treating patients with anticholinergic-mediated agitation or delirium. Physostigmine use is reserved for patients with intractable seizures, tachycardia, or agitation. Physostigmine does not shorten the clinical course of anticholinergic toxicity. Neostigmine and pyridostigmine lack the central antimuscarinic activity needed to make them effective antidotes.

Physostigmine (Antilirium)

Clinical Context:  Increased concentration of acetylcholine can improve patient's delirium dramatically; for reasons that are not entirely clear, appears to have less effect if administered within 4 h postexposure.

Class Summary

Physostigmine is a carbamate that increases the concentration of acetylcholine in synapses and neuromuscular junctions through acetylcholinesterase inhibition.

Diazepam (Valium, Diazemuls, Diastat)

Clinical Context:  Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA.

Class Summary

By binding to specific receptor-sites these agents appear to potentiate effects of GABA and facilitate inhibitory GABA neurotransmission and other inhibitory transmitters.

Further Inpatient Care

Complications

Prognosis

Author

Geoffrey M Fitzgerald, MD, Consulting Staff, Concord Emergency Medical Associates

Disclosure: Nothing to disclose.

Coauthor(s)

David P Sole, DO, FACEP, Associate Director of Emergency Medical Service Programs, Clinical Assistant Professor of Surgery (Emergency Medicine), Department of Emergency Medicine & Residency Program, Geisinger Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Suzanne White, MD, Medical Director, Regional Poison Control Center at Children's Hospital, Program Director of Medical Toxicology, Associate Professor, Departments of Emergency Medicine and Pediatrics, Wayne State University School of Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Rick Kulkarni, MD, Attending Physician, Department of Emergency Medicine, Cambridge Health Alliance, Division of Emergency Medicine, Harvard Medical School

Disclosure: WebMD Salary Employment

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Robert G Darling, MD, FACEP, Adjunct Clinical Assistant Professor of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Director, Center for Disaster and Humanitarian Assistance Medicine

Disclosure: Nothing to disclose.

References

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