AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• The patient may complain of dry mouth, a hot feeling, or blurred vision.
• Changes in mental status produced by incapacitating agents may leave some patients delirious to the point that they fail to or are unable to report symptoms.

Physical

Remarkably little variation exists among individuals when anticholinergics are administered.

• Following exposure, typically a latent period of 30 minutes to 24 hours occurs before signs and symptoms appear.
• Anticholinergic toxicity caused by BZ or Agent 15 can last up to 3-4 days, depending on the amount of drug absorbed.
• Peripheral effects usually precede CNS effects and can be summarized by the mnemonic "dry as a bone, hot as Hades, red as a beet, and blind as a bat."
• • "Dry as a bone" results from decreased glandular secretions in the oral pharynx, GI tract, and eccrine and apocrine glands. Urinary retention also is common.
  • "Hot as Hades" refers to hyperthermia caused by decreased sweating.
  • The body attempts to maintain thermoregulation via compensatory cutaneous vasodilatation, hence "red as a beet."
  • Decreased cholinergic stimulation of the pupillary sphincter muscle causes mydriasis. Anticholinergic effects on the ciliary muscles inhibit accommodation, hence "blind as a bat."
  • Anticholinergic effects on the heart produce tachycardia. This occasionally is preceded by a bradycardia that results from anticholinergic effects in the brain stem.
• The CNS effects of BZ and Agent 15 make them effective incapacitants.
• • Patients receiving these agents react with mental status changes ("mad as a hatter") in a dose-dependent fashion.
  • After a latent period and following the appearance of the peripheral effects, the casualty's mental status begins to fluctuate between a relatively conscious state and frank delirium.
  • Level of consciousness can range from drowsiness to coma.
  • Disorientation to time and place, decreased social restraint with inappropriate behavior, and decreased short-term memory are common.
  • Speech becomes slurred and indistinct.
  • Poor coordination leads to ataxia and agraphia.
  • Anticholinergic toxicity can produce vivid and realistic hallucinations that tend to decrease in size over time. For example, a polar bear may be replaced by a smaller animal such as a rabbit as the toxidrome clears.
  • When multiple victims of anticholinergic toxicity interact, they may play off each other's delirium. An example is 2 victims playing tennis with imaginary racquets. Another term for this shared hallucination is "folie a deux."
  • Phantom behaviors such as plucking or picking at one's clothes (ie, wool gathering) often were observed in Army test subjects who received BZ.
  • As the BZ victim's delirium clears, paranoid tendencies are not uncommon.
• Of final note on the examination is an increase in deep tendon reflexes. Anticholinergic effects on the Renshaw interneurons in the spinal cord cause hyperreflexia.

Causes

• Consider any cause of delirium. Psychiatric disorders such as anxiety reaction also are in the differential diagnosis.
• The presence of peripheral anticholinergic signs suggests another source of anticholinergic such as scopolamine, atropine, jimsonweed, or other anticholinergic source exposure.
• Usually, 6-7 MARK-1 Autoinjectors (ie, 12-14 mg of IM atropine) are needed to cause a significant degree of confusion.
• Nerve agent poisoning can be differentiated by its hyperstimulation of glands.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Thyrotoxicosis
Neuroleptic malignant syndrome
Serotonin syndrome
CNS infection
Heat stroke
Sedative-hypnotic withdrawal
Anticholinergic "outbreaks" involving jimsonweed abuse by teenagers, scopolamine-tainted heroin, or alcoholic beverages

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The paucity of distinct diagnostic signs and the lack of any sort of field detector make the diagnosis of Agent 15 toxicity extremely difficult.
• Maintain a high index of suspicion in scenarios in which terrorist or enemy chemical attack is possible. Multiple casualties exhibiting delirium indicate this diagnosis.
• Most standard urine toxicology screens do not detect the presence of Agent 15.
• Confirmatory testing is available at select reference laboratories.
• Routine laboratory tests can be helpful in ruling out other causes of delirium. These include a CBC, electrolytes, BUN and/or creatinine, glucose, LFTs, toxicology screen, ABG, ammonia level, thyroid stimulating hormone, and lumbar puncture for cerebral spinal fluid.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

• Protection of medical personnel includes removing weapons from victims and using restraints as necessary.
• Use chemical protective masks if residual aerosolized BZ or Agent 15 is present. The high-efficiency particulate air (HEPA) filter in the gas mask provides adequate protection.
• Protective gowns and gloves are indicated.
• Decontamination of victims is critical and involves removing contaminated clothing and flushing the skin with soap and water. Fine particles can be brushed away gently.
• Anticholinergic poisoning places the victim at high risk for hyperthermia. Thus, remove heavy clothing and initiate intravenous fluids as indicated.

Emergency Department Care

• Ensuring that appropriate decontamination has occurred is paramount to stabilize the patient and to prevent facility contamination. Complete decontamination of the skin and clothing if not already performed in the prehospital setting. Any residual Agent 15 on skin or clothing can be removed effectively with soap and water.
• The 2 greatest risks to the patient are his or her own erratic behavior and hyperthermia.
• • Confiscate weapons and closely observe the patient. Physical restraints may be needed in severely affected patients.
  • Monitor core temperature and maintain adequate fluids orally or intravenously.

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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

Drug Category: Cholinesterase inhibitors

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

Drug Category: Benzodiazepines

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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Monitor victims of Agent 15 or other anticholinergics as inpatients until the drug has cleared from the body. This process can take up to 3-4 days in some patients.

Complications

• Long-term effects from poisoning by Agent 15 or other related glycolate anticholinergics are very unlikely.
• Severe exposures may require several days of observation before the patient is clear of anticholinergic effects.

Prognosis

• Prognosis is excellent, with few neurologic sequelae.

Patient Education

• For excellent patient education resources, visit eMedicine's Bioterrorism and Warfare Center. Also, see eMedicine's patient education articles Chemical Warfare and Personal Protective Equipment.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Administration of physostigmine is routine for anticholinergic toxicity. Using this antidote when clinically indicated is sound medicolegal care.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Bowen TE. Emergency War Surgery. Revisionist Press;1988:93-94.
• Burns MJ, Linden CH, Graudins A, et al. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med. Apr 2000;35(4):374-81. [Medline].
• Goldfrank L, Flomenbaum N, Lewin N, et al. Anticholinergic poisoning. J Toxicol Clin Toxicol. Mar 1982;19(1):17-25. [Medline].
• Goldfrank LR, Flomenbaum NE. Goldfrank's Toxicologic Emergencies. Appleton & Lange;1998.
• Ketchum JS, Sidell FR. Incapacitating agents. In: Textbook of Military Medicine, Warfare, Weaponry and the Casualty: Medical Aspects of Chemical and Biological Warfare. United States Government Printing Office;1997:287-306.
• Schneir AB, Offerman SR, Ly BT. Complications of diagnostic physostigmine administration to emergency department patients. Ann Emerg Med. Jul 2003;42(1):14-9. [Medline].
• Shannon M. Toxicology reviews: physostigmine. Pediatr Emerg Care. Jun 1998;14(3):224-6. [Medline].
• Tintinalli JE. Anticholinergic toxicity. In: Emergency Medicine: A Comprehensive Study Guide. McGraw-Hill;2000:1182-1185.

Article Last Updated: Jun 19, 2006