Agent 15 Poisoning

Updated: Oct 10, 2022
Author: Geoffrey M Fitzgerald, MD; Chief Editor: Duane C Caneva, MD, MSc 

Overview

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.

For patient education information, see Chemical Warfare and Personal Protective Equipment.

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 with 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.[1] 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.[2]

International

Iraq was known to possess Agent 15. Other governments accused of possibly possessing incapacitating agents include Russia and Bosnia.

 

Prognosis

Prognosis is excellent, with few neurologic sequelae. 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.

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.

 

Presentation

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 Examination

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 brainstem.

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. 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.

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."

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.

 

DDx

Diagnostic Considerations

Other problems to be considered in the differential diagnosis include the following:

  • 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

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,[3]  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.

Differential Diagnoses

 

Workup

Laboratory 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. New testing techniques are being trialed, but are not readily available to treating clinicians.[4]  Confirmatory testing is available at select reference laboratories.

Routine laboratory tests can be helpful in ruling out other causes of delirium. These include the following:

  • Complete blood cell count(CBC)
  • Electrolytes
  • Blood urea nitrogen (BUN) and/or creatinine
  • Glucose
  • Liver function tests
  • Toxicology screen
  • Ammonia level
  • Thyroid-stimulating hormone
 

Treatment

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.

Dermal absorption and subsequent toxicity is a risk from contact with contaminated patients or decontamination runoff. Personal protection levels are determined through the incident command system based on contamination levels, response roles, and standard decontamination procedures.[5]

Decontamination of victims is critical and involves removing contaminated clothing and flushing the skin with soap and water.[6] 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 appropriate decontamination is paramount to stabilize the patient and to prevent facility contamination. Complete the decontamination of the skin and clothing if that was 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 these patients are their 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.

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.

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.

 

Guidelines

Guidelines Summary

The US Department of Health and Human services first published PRISM: Primary Response Incident Scene Management: Guidance for the operational response to Chemical Incidents in 2015.  The second edition of PRISM, published in 2018, has expanded the original guidance which focused on timely decontamination in key areas, including a recommended triple decontamination protocol.[7]

The default option for emergency decontamination should be “dry” decontamination using the application of dry, absorbent materials to exposed areas of skin and hair. This is particularly the case for liquid contaminants such as chemical warfare agents, as the application of water to the skin surface may substantially enhance dermal absorption via a phenomenon known as the “rinse-in” or “wash-in” effect.

The Emergency mnemonic covers the dry decontamination protocol which can be performed while waiting for specialists and additional resources:

  • E:  Evacuate everyone from the contaminated area
  • M: Move patients away from source of contamination, ideally uphill and upwind in a sheltered area away from strong winds or rain
  • E:  Engage with patients and explain what is happening. Focus initial attention on compliant individuals.
  • R:  Remove as much clothing as possible. Where possible, do not remove clothing over the head. Use trauma scissors to cut away clothing.
  • G:  Give any available absorbent material to patients including wound dressings, incontinence pads, toilet paper, diapers and paper towels.
  • E:  Establish dry decontamination as soon as possible. Using a blot and rub motion, start with the head (hair), face, then the hands, then any other exposed skin areas. If availability of material permits, instruct patients to use clean swatches of absorbent material for each body area. Above all, ensure that patients do not re-use material after decontaminating their hair. Encourage patients to repeat the entire process several times, paying particular attention to the hair, face and hands 
  • N:  Note the development of any signs and symptoms. Begin triage to identify priority patients.
  • C:  Communicate constantly with patients to encourage cooperation and reassurance that disrobing and decontamination will remove the vast proportion of any contamination. Confirm to the patients that advanced medical assistance is on its way
  • Y:  Yards not inches: Maintain a safe distance from patients at all times, but close enough so that they can hear instructions.   

The 'Washed' mnemonic covers the wet decontamination protocol and is only used in cases of caustic or particulate (e.g., powder) contaminants:

  • W: Warm water:  Shower with temperatures between 35ºC (95ºF) and 40ºC (104ºF) to ensure optimal removal of contaminants. 
  • A:  Aid: Use of a washing aid (e.g., washcloth or sponge) will improve the removal of contamination by 20% during the showering process. Washing aids should be single-use and considered as hazardous waste after use. 
  • S:  Soap: The use of a detergent has been shown to assist decontamination of lipophilic (oily) substances. Where available, use a metered dosing system to add liquid detergent to shower water at a concentration of 0.1–0.5% (v/v). Alternatively, place ~10 mL of liquid soap or detergent directly onto the washing aid immediately prior to use.
  • H:  Head to toe: Instruct patients to wash from the top of the head down to their feet. The head should be tilted back during hair washing to avoid transfer of contamination onto the face. 
  • E:  Expedite: In order to avoid the “wash-in” effect (which can enhance dermal absorption of certain contaminants), shower for no longer than 90 seconds. Ideally, 1 minute with soapy water followed by ½ minute of rinsing with water only. 
  • D:  Drying: active drying with a towel or other appropriate material is a critical step for removing many chemical contaminants. 

 

 

Medication

Medication Summary

In the past, physostigmine was used to reverse the effects of anticholinergic intoxicants. However, because of the numerous adverse effects reported with its use, its role as an antidote is controversial. Instead, 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.

Cholinesterase inhibitors

Class Summary

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

Physostigmine (Antilirium)

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.

Benzodiazepines

Class Summary

By binding to specific receptors, these agents appear to potentiate effects of GABA and facilitate inhibitory GABA neurotransmission and other inhibitory transmitters.

Diazepam (Valium, Diazemuls, Diastat)

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