3-Quinuclidinyl Benzilate Poisoning

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Background

The chemical warfare agent 3-quinuclidinyl benzilate (QNB, BZ) is an anticholinergic agent that affects both the peripheral and central nervous systems (CNS). It is one of the most potent anticholinergic psychomimetics known, with only small doses necessary to produce incapacitation. It is classified as a hallucinogenic chemical warfare agent. QNB usually is disseminated as an aerosol, and the primary route of absorption is through the respiratory system. Absorption also can occur through the skin or gastrointestinal tract. It is odorless. QNB's pharmacologic activity is similar to other anticholinergic drugs (eg, atropine) but with a much longer duration of action.

Also, see the article Chemical Warfare Agents.

Pathophysiology

QNB acts by competitively inhibiting muscarinic receptors. Muscarinic receptors primarily are associated with the parasympathetic nervous system, which innervates numerous organ systems, including the eye, heart, respiratory system, skin, gastrointestinal tract, and bladder. Sweat glands, innervated by the sympathetic nervous system, also are modulated by muscarinic receptors. Effects of QNB by any route of exposure are slow in onset and long in duration. The onset of action is approximately 1 hour, with peak effects occurring 8 hours postexposure. Symptoms gradually subside over 2-4 days. Most of the QNB that enters the body is excreted by the kidneys, making urine the choice for detection.

Epidemiology

Frequency

United States

Use of QNB against the United States has never been reported. Currently, the US Federal Government conducts chemical defense programs including research and development, training, and stockpiling of supplies and antidotes to prepare the nation for potential chemical terrorist attacks against citizens and the military; however, initial responses are dependent on local emergency response agencies.

International

Use of QNB has been suggested, but not confirmed, in two past international conflicts.

On January 16, 1992, Mozambican government forces (approximately 400 soldiers) attacked one of the largest strongholds of the RENAMO resistance group in southern Mozambique, close to the South African border. As they approached the camp on foot, an unidentified light aircraft was seen flying above the area. They came under limited small arms fire and took cover when an explosion occurred above their heads, releasing a dense cloud of black smoke, which then dissipated. The wind was blowing towards the rear of the formation.

Fifteen minutes later, the first complaints occurred: “It became very hot. Some of us were going crazy.” They felt severe chest pains, were tired and thirsty, and when they drank water the next morning some of them vomited. Others said they had difficulty seeing. As a consequence, the troops became disorganized.

The United Nation’s report on this incident concluded that the effect on the troops was consistent with the use of a chemical warfare agent such as QNB, but that in the absence of analytical data, they could not conclude that a chemical warfare agent was used in the attack because a considerable delay occurred between the attack (January 1992) and the formal investigation (March 1992).

On July 11 of 1995, approximately 15,000 people assembled in the village of Jaglici, situated in the Rebublika Srpska of Bosnia and Herzegovina. This group had fled from Srebrenica (15 km away) after Bosnian Serb forces began to shell the town. In order to flee the Bosnian Serbs, the assembled column started to leave Jaglici on July 12 at 12:30 am, with the last members of the column leaving 12 hours later. The reported progress of the column was slow because of concern for minefields. Individuals were required to walk in single file holding hands to avoid getting lost in the forest at dark and enabling them to walk in each other’s footsteps to avoid landmines. Only a fraction of the members of the column eventually reached safe territory on July 16, after coming under fire from Bosnian Serb forces on a number of occasions.

According to eyewitness accounts, the Bosnian Serbs used different shells, some exploded and others gave out a "strange smoke" that did not rise in the air but rather spread toward the column at the height of a man. Reportedly, a large number of those exposed suffered from hallucinations during the course of the 5-day march. It was subsequently suspected that the Bosnian Serb forces had used a chemical warfare agent to disorient the marchers, prompting Human Rights Watch to visit the location in March of 1996.

During the course of the investigation, marchers were interviewed. Subsequent testimony suggested that unusual munitions may have been used by the Bosnian Serbs, and that those interviewed had experienced themselves or witnessed others with marked hallucinations. The agent suspected to have caused these effects was QNB.

Mortality/Morbidity

The LD50 (lethal dose to 50% of an exposed population) for QNB is estimated to be similar to that of atropine, which is approximately 100 mg; however, QNB causes incapacitation at much lower levels. Other factors, such as the exposed patient's preexisting health status and the time from exposure to medical care, are also important.

History

Physical

After exposure to QNB, the physical examination is consistent with an anticholinergic syndrome. Characteristics of the anticholinergic syndrome have long been taught using the old medical adage, "dry as a bone, blind as a bat, red as a beet, hot as a hare, and mad as a hatter."

Central nervous system manifestations include the following:

Peripheral nervous system manifestations include the following:

Causes

Human QNB exposures rarely are reported. Potential causes of exposure to this agent are a laboratory accident, a terrorist event, or a military conflict.

Laboratory Studies

No rapid tests enable a health care provider to diagnose exposure to QNB. Consider QNB if a number of persons arrive after an exposure to an unknown substance and manifest an anticholinergic syndrome.

Obtaining a complete blood count, electrolytes, clotting studies, and renal and liver function tests is reasonable in any person who potentially was exposed to a chemical warfare agent.

If the patient is markedly agitated or comatose, obtaining a urine myoglobin and/or creatine phosphokinase is warranted to exclude rhabdomyolysis. Hyperkalemia, hyperphosphatemia, and hypocalcemia may occur in association with rhabdomyolysis. The agitated patient also may develop an elevated lactate.

If QNB is considered in the differential, obtain extra blood and urine samples. Tests have been developed to confirm human exposure to QNB.

Disseminated intravascular coagulation is a potential complication in a patient with marked agitation and/or hyperthermia. Obtain clotting studies (eg, prothrombin time, activated partial thromboplastin time, international normalized ratio) in these patients. If clotting studies are elevated, then fibrinogen, fibrin split products, and a peripheral smear looking for evidence of hemolysis may be necessary.

Most of the QNB that enters the body is excreted by the kidneys, either as the parent compound or as metabolites, making urine the choice for detection. QNB undergoes hydrolysis to produce benzylic acid and 3-quinuclidinyl. A solid-phase extraction of the urine and isotope dilution in conjunction with gas chromatography/mass spectrometry (GC/MS) has been used for detection of QNB.[1]

Imaging Studies

Electrocardiography

QNB is associated with sinus tachycardia. Patients exposed to QNB who have preexisting cardiac disease may be at risk for cardiac ischemia as their heart rates increase. Other anticholinergic agents are associated with QT prolongation, QRS widening, and various tachydysrhythmias. Obtain an ECG to exclude these potential problems.

Prehospital Care

Emergency Department Care

Once decontamination has occurred, the primary emphasis simply is supportive care of exposed patients. Emergency department staff must be certain that proper decontamination has occurred. Dermal absorption and off gassing of QNB does occur and can pose a risk to hospital personnel.

See Medscape's Disaster Preparedness and Aftermath Resource Center for more information.

Consultations

If an exposure to QNB occurs, consider a number of consultations.

Medication Summary

No specific antidote has been found to reverse the action of QNB definitively. In the past, physostigmine was used to reverse the effects of anticholinergic agents. However, numerous adverse effects associated with its use in reversing poisonings are reported in the literature. Subsequently, the use of physostigmine has diminished greatly in the setting of acute anticholinergic toxicity. Use of physostigmine in QNB poisoning has been studied. However, its efficacy in QNB intoxication and its adverse effect potential have not been delineated definitively. At this time, supportive care is the mainstay of therapy. If the exposed patient is markedly agitated, consider administration of a benzodiazepine.

Diazepam (Valium, Diastat)

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

Class Summary

Consider in patients sustaining exposure to QNB and presenting with marked agitation.

Physostigmine

Clinical Context:  Inhibits destruction of acetylcholine by acetylcholinesterase, which facilitates transmission of impulses across myoneural junction.

Class Summary

These agents prolong the central and peripheral effects of acetylcholine.

Further Inpatient Care

Transfer

Complications

Prognosis

Author

Christopher P Holstege, MD, Professor of Emergency Medicine and Pediatrics, University of Virginia School of Medicine; Chief, Division of Medical Toxicology, Center of Clinical Toxicology; Medical Director, Blue Ridge Poison 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

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

Duane C Caneva, MD, Senior Medical Advisor to Customs and Border Protection, Department of Homeland Security (DHS) Office of Health Affairs; Federal Co-Chair, Health, Medical, Responder Safety Subgroup, Interagency Board (IAB)

Disclosure: Nothing to disclose.

References

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  2. US Army Center for Health Promotion and Preventive Medicine. Psychodelic Agent 3 - Quinuclidinyl Benzilate (BZ). The Deputy for Technical Services' Publication: Detailed Chemical Facts Sheets. 1998;
  3. Byrd GD, Paule RC, Sander LC, et al. Determination of 3-quinuclidinyl benzilate (QNB) and its major metabolites in urine by isotope dilution gas chromatography/mass spectrometry. J Anal Toxicol. May-Jun 1992;16(3):182-7. [View Abstract]
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