3-Quinuclidinyl Benzilate Poisoning 

Updated: Feb 22, 2021
Author: Christopher P Holstege, MD; Chief Editor: Duane C Caneva, MD, MSc 

Overview

Background

The chemical warfare agent 3-quinuclidinyl benzilate (QNB, BZ) is an anticholinergic agent that affects both the peripheral and central nervous systems (CNS). QNB is classified as an incapacitating agent and is listed in Schedule 2 by the Organization for the Prohibition of Chemical Weapons (OPCW).[1]   It is one of the most potent anticholinergic psychomimetics known, with only small doses necessary to produce incapacitation.[2] 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 longer duration of action.  The median effective dose (ED50) of QNB under field conditions is approximately 60 mg/min/m3 for a man of 75 kg body weight with a volume of respiration of 15 L/min.[2]

Also, see the article Chemical Warfare Agents.

Pathophysiology

QNB acts by competitively inhibiting muscarinic receptors. QNB binds to all subtypes of muscarinic receptors (M1-M5).[2]   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. QNB readily crosses the blood-brain barrier.[2]  

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.

 

Presentation

History

An event involving QNB probably would create confusion, panic, multiple seriously ill or dead victims, and a major emergency medical service, police, and/or military response, as follows:

  • Large numbers of casualties would overwhelm any community's emergency response.

  • Chaos appropriately would describe events following such an event.

  • In the early phases of an emergency response, the toxin's identification would be unknown, and the history would be misleading and inaccurate.

  • Depending on the type of employment (overt or covert) and route of dissemination, cases may be grouped or scattered, have a spectrum of exposure symptoms and variability in severity of symptoms.

Physical examination is the key to diagnosing the causative agent.

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."  Marked variations in absorbed dose would occur following an aersolized release and subsequent potential mass human exposures, with the intensity and duration of physical findings dependent on that absorbed dose and the individual patient's pre-existing health conditions.  

Central nervous system manifestations include the following:

  • Depending on the dose and time postexposure, a number of CNS effects may manifest; restlessness, apprehension, abnormal speech, confusion, agitation, tremor, picking movements, ataxia, stupor, and coma are described

  • Hallucinations are prominent, and they may be benign, entertaining, or terrifying to the patient experiencing them; exposed patients may have conversations with hallucinated figures, and/or they may misidentify persons they typically know well

  • Simple tasks typically performed well by the exposed person may become difficult; motor coordination, perception, cognition, and new memory formation are altered as CNS muscarinic receptors are inhibited

Peripheral nervous system manifestations include the following:

  • Eye: Mydriasis resulting in photophobia is expected. Impairment of near vision occurs because of loss of accommodation and reduced depth of field secondary to ciliary muscle paralysis and pupillary enlargement. If QNB comes into direct contact with the eye, conjunctival injection and eye pain also occur.

  • Cardiovascular system: Tachycardia is a prominent feature of QNB exposure. Heart rates may be rapid but rarely exceed 150 beats per minute. Exacerbated heart rate responses to exertion also are expected. Systolic and diastolic blood pressure may show moderate elevation. A decrease in capillary tone may cause skin flushing.

  • Gastrointestinal: Intestinal motility slows, and secretions from the stomach, pancreas, and gallbladder decrease. Nausea and vomiting may occur. Decreased or absent bowel sounds are noted on examination.

  • Respiratory: All glandular cells become inhibited, and dry mucus membranes of the mouth and throat are noted. Speech may decrease to a whisper. Breath of the exposed patient may develop a foul odor.

  • Skin: Inhibition of sweating results in dry skin. Place hands directly into the axilla of the exposed patient and note the absence of moisture. Red flushed skin also may occur.

  • Urinary: Urination may be difficult or impossible. Subsequent urinary retention may occur, and an enlarged bladder may be palpable on examination.

  • Temperature: The exposed patient's temperature may become elevated from the inability to sweat and dissipate heat. In warm climates such as the desert, this may result in marked hyperthermia.

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.

 

DDx

Diagnostic Considerations

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

  • Thyrotoxicosis

  • Neuroleptic malignant syndrome

  • Serotonin syndrome

  • CNS infection

  • Heat-related illness (e.g., heat stroke)

  • Sedative-hypnotic withdrawal

  • Hallucinogenic indolealkylamines, which are unique analogues of 5-hydroxytryptamine (eg, the psilocybin-containing mushrooms, ibogaine, bufotenine, dimethyltryptamine, lysergic acid).[3]   

  • Anxiety - An important, sometimes overlooked cause of similar symptoms, which can manifest with such findings as dizziness, tachycardia, sweating, headache, and even loss of sensation or ability to move parts of the body. This cause is a diagnosis of exclusion.[3]

  • Anticholinergic "outbreaks" from other substances, such as from specific plants (eg, Datura stramonium) and numeorus pharmaceuticals (eg, diphenhydramine, scopolamine, atropine).[4]

Differential Diagnoses

 

Workup

Laboratory Studies

No rapid tests enable a health care provider to diagnose exposure to 3-quinuclidinyl benzilate (QNB). New testing techniques are being trialed, but are not readily available to treating clinicians.[5, 1, 6] 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 kidney 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.[7]

Imaging Studies

See the list below:

  • A patient exposed to QNB who is comatose may be at risk for aspiration pneumonia; obtain a chest radiograph.

  • If the etiology of the altered mental status is uncertain, obtaining a head CT scan to exclude other intracranial processes is reasonable.

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.

 

Treatment

Prehospital Care

See the list below:

  • Prehospital care providers must place their personal safety before the treatment of potentially contaminated patients.[8]

    • The US military recommends wearing maximum protection when in contact with QNB contamination. These recommendations include wearing an M9 mask and hood, an M3 butyl rubber suit, M2A1 butyl boots, and M3 or M4 butyl gloves.[9]

    • For civilian first responders, decontamination of the exposed patients prior to transfer must occur. 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.

    • Removal from contaminated areas and careful disrobing of victims is, by far, the most effective component to decontamination.

    • Off gassing may occur, and paramedics are at risk for toxicity in the closed confines of an ambulance. Caution must be exercised especially for flight crews, since toxicity of the pilot during mid flight can lead to impaired vision and judgment and subsequent risk of aircraft mishaps.

  • Water can be used for decontamination. Warm, soapy water is generally preferred as the common, standard approach to casualty decontamination.[10]

  • After the patients have been decontaminated, transport them to the nearest hospital facility.

  • Perform general supportive measures (eg, intravenous access, airway management) and monitoring.

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.

  • In patients who are not protecting their airway, perform intubation and mechanical ventilation.

  • Apply soft restraints to patients at risk of harming themselves or health care workers.

  • Intravenous hydration may be necessary; maintain adequate urinary output. If urinary retention is suggested, place a Foley catheter.

  • For patients experiencing marked agitation, consider benzodiazepine administration.[11]

  • In patients with hyperthermia, cooling measures may be necessary.

    • Completely remove the patient's clothing.

    • Insert a Foley catheter.

    • Consider a rectal temperature probe.

    • Administer adequate intravenous fluids.

    • Cooling measures such as evaporative cooling using skin wetting with directed circulating fans, ice water immersion, ice packs, and cooling blankets may be necessary.

  • Include continuous cardiac and core temperature monitoring.

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

Consultations

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

  • Consult with your local or regional poison control center early for any poisonings.  The poison centers work with public health officials for rapid surveillence of sentinal events and to help coordinate a rapid response from local and/or federal agencies.   

  • If the cause of the exposure is a terrorist act against civilians, contact the local health department and law enforcement agency immediately. Also contact federal agencies, such as the US Federal Bureau of Investigation (FBI).

  • If a patient sustained eye contact with QNB and subsequently developed eye pain, change in vision, or marked conjunctival injection, consultation with an ophthalmologist may be necessary.

  • For patients requiring intensive care monitoring, consider early consultation with a physician trained in critical medicine.

  • Useful resources for chemical exposures include the Chemical Hazards Emergency Medical Management (CHEMM), TOXNET, ATSDR ToxFAQs and WISER.

 

Medication

Medication Summary

No specific antidote has been found to reverse the action of QNB definitively. Peripherally acting anticholinesterase drugs that do not cross the blood-brain barrier (eg, pyridostigmine, neostigmine, pilocarpine) are ineffective against the central effects of QNB.[2]

Physostigmine does cross the blood-brain barrier and can be used to reverse the effects of anticholinergic agents. Use of physostigmine in QNB poisoning has been studied.[3]  However, its efficacy in QNB intoxication and its adverse effect potential have not been delineated definitively. A number of other compounds have been considered for treatment, including 7-methoxytacrine, which was one of the most widely investigated potential antidotes for QNB.[2]  

Supportive care is the mainstay of therapy. The patient is at risk for injuries from erratic, agitated behavior. QNB casualties may act on their delusions, so they must be kept safe from harming themselves or others.[2]  If the exposed patient is markedly agitated, consider administration of a benzodiazepine to calm. 

QNB poisoned patients are also at risk for hyperthermia, especially in hot and/or humid environments.  This significant complication arises due to the suppression of the ability to secrete sweat, which, along with agitation and warm ambient temperatures, can give rise to fatal hyperthermia.[3] Management of heat stress assumes a high priority in patients poisoned with QNB, including appropriate rehydration. 

 

Benzodiazepines

Class Summary

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

Diazepam (Valium, Diastat)

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

Antidote, anticholinergic agents

Class Summary

These agents prolong the central and peripheral effects of acetylcholine.

Physostigmine

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

 

Follow-up

Further Inpatient Care

See the list below:

  • Inpatient care is no different than that discussed in Emergency Department Care. Keep symptomatic patients who were exposed to QNB in a monitored setting until their symptoms completely resolve. Use of maintenance intravenous fluids and sedatives such as benzodiazepines may be necessary. Prolonged intoxication may occur depending on the dose of QNB absorbed.

Transfer

See the list below:

  • Any health care facility that is unable to adequately monitor a patient intoxicated with an anticholinergic should consider transfer to a facility that can care for such patients.

  • Smaller health care facilities may be overwhelmed if a large-scale terrorist attack with multiple victims occurs. Disaster plan implementation and appropriate transfer of patients to less stressed facilities may be necessary.

Complications

See the list below:

  • Rhabdomyolysis: If a person exposed to QNB develops marked agitation or profound somnolence, tissue necrosis may occur and rhabdomyolysis may develop. If this remains undiagnosed, myoglobinuric renal failure may develop.

  • Anoxic brain injury: If an exposed person becomes comatose and loses his or her ability to maintain ventilatory function, hypoxia may develop and lead to anoxic brain injury.

  • Aspiration pneumonia: Inability of exposed patients to maintain their airway may result in aspiration of gastric contents into the lungs.

  • Ileus: The prolonged anticholinergic effects of QNB may lead to development of an ileus.

  • Angle-closure glaucoma: Those patients predisposed may be at risk due to the mydriasis induced by QNB.

  • Bleeding diathesis: Disseminated intravascular coagulation may develop in patients with shock and marked hyperthermia.

  • Hepatic injury: Hepatic injury may accompany antimuscarinic agent toxicity that involves hyperthermia or shock.

Prognosis

See the list below:

  • The prognosis is good for QNB-exposed patients if they do not develop a secondary injury such as the complications noted above. Once they are removed from the exposure and the absorbed QNB is metabolized, they should become more lucid. Full recovery is expected within 4 days. No long-term effects are expected from QNB itself.

Patient Education

See the list below:

  • For patient education resources, see the Bioterrorism and Warfare Center, as well as Chemical Warfare and Personal Protective Equipment.