CBRNE - Vomiting Agents - Dm, Da, Dc 

Updated: Jan 27, 2020
Author: Christopher P Holstege, MD; Chief Editor: Zygmunt F Dembek, PhD, MPH, MS, LHD 

Overview

Background

The chemical warfare agents diphenylchlorarsine (Da), diphenylcyanoarsine (Dc), and diphenylaminechlorarsine (Dm, adamsite) are classified as vomiting agents. Da appears as colorless crystals, Dc as a white solid, and Dm as light yellow-to-green crystals. Da and Dm are odorless, and Dc reportedly has an odor similar to garlic or bitter almonds. All three agents are insoluble in water.

The synthesis of these agents dates back to the early 20th century. In 1915, Wieland, a German chemist involved in weapons research, synthesized the agent Dm. Three years later, a US chemist, Robert Adams, independently developed this same compound and named it adamsite. These agents have since been produced for two purposes: as riot-control agents and as emesis-inducing agents to promote removal of personal protective gear, thereby increasing susceptibility to subsequent chemical warfare agent exposure.

After World War II, large quantities of chemical weapons, including vomiting agents, were disposed of at various dumping sites in Europe and Japan. The majority of dumping sites are located at sea, since this strategy was deemed more cost effective and facile than land storage or incineration.[1] However, ocean currents and human activity, such as fishing, have disturbed these deposits. Though chemical warfare agent disposal at sea has since been outlawed, concerns remain regarding the potential environmental impact from contamination at previous dumping locations.

Pathophysiology

Vomiting agents typically are disseminated as aerosols. Therefore, the primary route of absorption is through the respiratory system, but exposure also can occur by ingestion, dermal absorption, or eye impact.

Regardless of the route of exposure, the onset of the effects of the vomiting agents are slower in onset and longer in duration than typical riot control agents (eg, tear gas [CS]).[2, 3] On initial exposure, vomiting agents are irritants. This irritation is delayed for several minutes after contact, resulting in less early warning properties being present for those exposed. By the time symptoms of irritation occur and personnel consider donning their protective equipment, significant contamination already may have occurred. Systemic signs and symptoms follow the initial irritation and consist of headache, nausea, vomiting, diarrhea, abdominal cramps, and mental status changes. Symptoms typically persist for several hours after exposure. Death has been reported with excessive exposure.

Recently, concerns have arisen regarding the potential environmental and human health impact of chronic exposure to vomiting agents due to contamination at sites where these chemicals were dumped following WWII. Sanderson and colleagues have documented that approximately 11,000 tons of chemical warfare agents, including  adamsite, were dumped into the Baltic Sea during the disarmament of Germany following WWII, and have resulted in extensive environmental contamination.[4, 5, 6, 7, 8, 9] Because the vomiting agents Da, Dc, and Dm contain arsenic, there is concern regarding potential long-term environmental toxicity from contamination of sea water and adsorption into sediment.  There is a signficant risk of bioccumulation into fish.  No significant human illness has been reported from this region.

However, a recent case series from Japan describes a syndrome of cerebellar symptoms including tremors, myoclonus, memory impairment, and sleep disturbances associated with consumption of well water contaminated with diphenylarsinic acid (DPA), a byproduct from the degradation of diphenylchloroarsine or diphenylcyanoarsine.[10]  Central nervous system damage 3 years after cessation of exposure to DPA appears to be persistent.[11] Other investigators from Japan have attempted to study the effect of DPA in mice and have discovered the possibility for injury to Purkinje cells due to oxidative and nitrosative stress following exposure to DPA, which may lead to cerebellar symptoms.[12] Further study is needed to better assess the health risks of exposure to water contaminated with DPA.

Epidemiology

Frequency

United States

There are no reported instances of the use of vomiting agents within the United States against civilians.  In 1932, adamsite was suspected to have been laced into riot control gas deployed in Washington D.C. against the Bonus Army, which was composed of World War I veterans, civilian members of their families, and affiliated groups, who were demanding financial compensation for their service certificates.

Currently, the US government is funding numerous programs to prepare the nation for potential chemical terrorist attacks against its citizens and military.

International

The use of vomiting agents has been reported during international conflicts. Da first was used by German troops in 1917. Since Da was not well filtered by the standard-issue gas masks at that time, troops inhaled Da and experienced nausea and vomiting. As a result of emesis, soldiers removed their gas masks, which made them vulnerable to subsequent attacks by other highly toxic chemical warfare agents, including phosgene and chlorine gas. The Germans also produced Dc and Dm, but limited documentation exists for use of these agents during World War I. Questionable reports exist of vomiting agents used in other countries as riot control agents.

In June 2003, letters containing Dm (adamsite) were sent to the United States, British, and Saudi Arabian Embassies, Belgium’s Prime Minister Guy Verhofstadt, the Court of Brussels, a Belgian ministry, the Oostende airport, and the Antwerp port authority. At least two postal workers and five police officers were hospitalized with symptoms of skin irritation, eye irritation, and breathing difficultly after exposure to the substance. Three people who were exposed in Oostende were also hospitalized. Belgium police suspected a 45-year-old Iraqi political refugee opposed to the US Iraq War. Upon searching his residence, antiterrorism investigators found a plastic bag containing powder. The investigators suffered symptoms similar to those who were exposed to the letters, and the Iraqi was charged with premeditated assault. No other instances of vomiting agent use have been reported, although buried adamsite has been found in one of many chemical weapons dumping sites in Shikhany, Russia. North Korea has been suspected of synthesizing and stockpiling adamsite (DM) at its Aoji-ri chemical complex. 

Mortality/Morbidity

Dm is the most toxic agent of this group, with an estimated LCt50 of 11,000 mg·min/m3 (ie, an estimated 50% lethality for a group of patients breathing air with a concentration of 11,000 mg/m3 for 1 min). Other factors also are important, such as the exposed patient's preexisting health status and the time from exposure to medical care. The dose at which vomiting reportedly begins for Dm is estimated as 370 mg·min/m3.

Race-, Sex-, and Age-related Demographics

No published studies demonstrate a significant difference in the effects of vomiting agents on various races or either sex. Intuitively, persons at the extremes of age would be less tolerant of exposure to these three chemical agents. However, no published studies prove this.

In a case series from Japan describing cerebellar symptoms associated with drinking well water contaminated with diphenylarsinic acid (DPA), a degradation product of diphenylchloroarsine or diphenylcyanoarsine, an infant presented with cognitive impairment and developmental delay with mild cerebral atrophy documented by magnetic resonance imaging.[10] These signs and symptoms improved when the patient was no longer exposed to the contaminated water.

 

Presentation

History

A history of exposure to an aerosolized substance that resulted in ophthalmic and pulmonary irritation and then progressed to nausea, vomiting, abdominal cramps, and headache suggests exposure to a vomiting agent. In the early phases of an emergency response, the toxin's identity would be unknown and the history misleading and inaccurate.

Fear, anxiety, and mistrust are likely to affect victims, emergency responders, bystanders, and the entire community after such an incident. Overwhelming emotions in some patients, rescuers, and hospital staff are likely to cause acute anxiety reactions and mass psychogenic illness. Patients truly suffering from vomiting-agent poisoning and those suffering from mass psychogenic illness would be difficult to separate, because the symptoms are similar. Patients with either condition may complain of the following:

  • Nausea
  • Vomiting
  • Diarrhea
  • Abdominal cramping
  • Headache
  • Tearing
  • Dizziness
  • Chest tightness
  • Shortness of breath

Because differentiating mass hysteria from a true vomiting-agent poisoning may be difficult, treat all patients experiencing symptoms as true toxic emergencies. The potential exists for patients with mass psychogenic illness to overwhelm the entire emergency response system and hinder timely treatment of those with true toxic emergencies.

Physical

The signs and symptoms encountered in a person exposed to a vomiting agent may vary. Factors that determine clinical effects include the amount of the agent encountered and the route of exposure. Depending on those variables, the progression of signs and symptoms can range from mild mucosal irritation to cardiovascular collapse and death. The following list constitutes findings that may be noted on physical examination following exposure to vomiting agents:

  • Eye - Conjunctival injection, tearing, and blepharospasm

  • Nose - Excessive nasal discharge, sneezing, mucosal injection, and edema

  • Throat - Mucosal injection and edema

  • Lungs - Excessive cough, wheezing, rhonchi, prolonged expiratory phase, and tachypnea

  • Heart - Tachycardia

  • Abdomen - Hyperactive bowel sounds, intestinal cramps, emesis, and diarrhea

  • Skin - Erythema and edema at the site of dermal contact

  • Mental status - Central nervous system depression, syncope, and death (possible with significant exposure)

Causes

Human exposures to vomiting agents rarely have been reported. Potential causes of exposure to these agents are laboratory accidents, terrorist events, or military conflicts.

 

DDx

 

Workup

Laboratory Studies

No rapid tests are available that enable health care providers to definitively determine exposure to vomiting agents. Consider these agents when exposure to an unknown substance inflicts pulmonary and ophthalmic irritation and then progresses to nausea, vomiting, abdominal cramps, and diarrhea.

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

If a patient is markedly agitated or comatose, obtain a urine myoglobin and/or creatine phosphokinase to exclude rhabdomyolysis.

If considering chemical warfare agent poisoning in the differential, obtain extra blood and urine samples for subsequent toxicologic testing.

After absorption, diphenylchlorarsine (Da) and diphenylcyanoarsine (Dc) are rapidly hydrolyzed to diphenylarsinic (DPAA), then conjugated to glutathione (DPAA-GS), and finally excreted. Therefore, blood and urine samples should be collected within 24 hours. Current methods can quantitate DPAA and DPAA-GS levels within hours, using gas chromatography and mass spectroscopy analysis (GC-MS/MS).

Inadequate data are available regarding the metabolic products of diphenylaminearsine (Dm, adamsite), thereby limiting GC-MS/MS methods to the parental Dm molecule and creating a shorter collection window, predominantly from blood samples. The collection window can be widened significantly when measuring organic arsenic levels as opposed to specific metabolites in blood or tissue samples using gas chromatography mass spectroscopy (GC-MS). Arsenic levels in combination with a patient’s cytogenetic profile and clinical presentation may help pinpoint exposure to specific organoarsenic agents.

Imaging Studies

A chest radiograph may need to be obtained to exclude chemical pneumonitis in a patient exposed to vomiting agents who presents with marked pulmonary irritation. Rarely, vomiting agents may cause altered mental status. If the etiology is uncertain, obtain a head computed tomography (CT) scan to exclude other intracranial pathology.

Electrocardiography

Vomiting agents are not reported to cause significant cardiac dysrhythmias. Sinus tachycardia may result from the stress of the event. However, in symptomatic persons at risk for coronary artery disease or in those with preexisting disease, obtain an electrocardiogram (ECG) to exclude evidence of ischemia. When the causative agent is not identified definitively, obtaining an ECG is a reasonable approach to exclude conductive disturbances induced by other toxins.

 

Treatment

Prehospital Care

A military or terrorist event involving the exposure of military personnel or civilians to vomiting agents would create confusion and panic. Large numbers of potential casualties may overwhelm emergency response teams. Chaos may occur. (See Disaster Planning and Medscape's Bioterrorism and Disaster Medicine resource center.)

Prehospital care providers must place their personal safety first before the treatment of potentially contaminated patients. However, with aerosolized exposure, secondary contamination of health care providers is unlikely.

Perform general supportive measures such as obtaining intravenous access and administering oxygen to those with signs of respiratory irritation.

Emergency Department Care

The initial care of patients exposed to vomiting agents primarily is supportive. No specific antidotes are available. Fewer than 1% of those exposed to diphenylaminechlorarsine (Dm, adamsite) will have severe or prolonged effects warranting medical care. Focus care on relieving irritant and systemic effects.

Respiratory irritation is managed as follows:

  • These effects typically are transient and resolve soon after exposure ceases; duration of irritation depends on the dose of agent inhaled and the premorbid status of the patient

  • Patients with preexisting lung disease (eg, asthma, emphysema) may develop exacerbations of these diseases that are slow to resolve

  • If a patient has dyspnea with wheezing, treatment with nebulized albuterol may be necessary; steroids may be considered

  • In most patients without preexisting lung disease, symptoms abate spontaneously

Ophthalmic irritation is managed as follows:

  • Consider eye irrigation in patients sustaining chemical exposure and subsequent ocular irritation; appropriate irrigant choices include water, normal saline, and lactated Ringer solution; perform irrigation with 1-2 L of irrigant per affected eye

  • Examine the eyes using a slit lamp and fluorescein; if a corneal abrasion is noted, consider cycloplegics and topical antibiotics

Treat patients who are experiencing repetitive emesis with intravenous hydration and antiemetics. Numerous antiemetics are available, and no specific agent is documented as superior.

Acute mental status changes rarely have been reported. One death after Dm exposure is documented, but complete information on this fatality has not been released. If a patient presents in marked respiratory distress with mental status changes, intubation and mechanical ventilation may be necessary.

Late-onset erythema caused by a larger exposure to Dm in a hot and humid atmosphere is often more severe and less likely to resolve rapidly. It may require the use of soothing compounds such as calamine, camphor, and mentholated creams. Small vesicles should be left intact, but larger ones will ultimately break and should be drained. Irrigation of denuded areas several times a day should be followed by the application of a topical antibiotic. Large, oozing areas respond to compresses containing substances such as colloidal oatmeal, Burow's solution, or other dermatologic preparations.

Consultations

The following consultations may be necessary:

  • Intensivist: In the rare event that a patient exposed to vomiting agents presents with acute respiratory distress or acute mental status changes, early consultation with a physician trained in critical care medicine may be necessary.

  • Poison control center and/or local health department: Report adverse events caused by toxins to the local poison control center and health department. This allows coordination of information with other health care facilities and expedites assistance in determining the etiology of the poisoning.

  • Law enforcement: If the cause of the exposure is unknown or believed to be a terrorist act, contact local and federal law enforcement.

  • Ophthalmologist: If significant eye exposure has occurred and the patient develops persistent ophthalmologic signs and symptoms or evidence of corneal damage, contact an ophthalmologist.

 

Medication

Medication Summary

Medical therapy focuses on controlling the emesis induced by vomiting agents. Initial antiemetic therapy may begin with routine doses of drugs commonly used to combat vomiting, such as promethazine, prochlorperazine, or droperidol. High doses of metoclopramide may be administered. If these agents are unsuccessful, 5-HT3 receptor antagonists may be administered to control nausea and vomiting. This class of drugs is comparatively expensive but well tolerated with few adverse effects. These agents include dolasetron, ondansetron, and granisetron.

Antiemetics

Class Summary

A common effect of diphenylchlorarsine (Da), diphenylcyanoarsine (Dc), and diphenylaminearsine (Dm, adamsite) is emesis. Consider antiemetics in patients with persistent vomiting.

Prochlorperazine (Compazine)

May relieve nausea and vomiting by blocking postsynaptic mesolimbic dopamine receptors through anticholinergic effects and depressing reticular activating system. In addition to antiemetic effects, has advantage of augmenting hypoxic ventilatory response, acting as a respiratory stimulant at high altitude.

Promethazine (Phenergan)

For symptomatic treatment of nausea in vestibular dysfunction. Antidopaminergic agent effective in treating emesis. Blocks postsynaptic mesolimbic dopaminergic receptors in brain and reduces stimuli to brainstem reticular system.

Droperidol (Inapsine)

Neuroleptic agent that may reduce emesis by blocking dopamine stimulation of chemoreceptor trigger zone.

Metoclopramide (Reglan, Clopra, Maxolon)

Dopamine antagonist that stimulates acetylcholine release in myenteric plexus. Acts centrally on chemoreceptor triggers in floor of fourth ventricle, which provides important antiemetic activity.

5-HT3 receptor antagonists

Class Summary

A more expensive drug category compared to the other available antiemetics noted above. These agents typically are reserved for severe cases of emesis not responsive to the above medications.

Ondansetron (Zofran)

Selective 5-HT3 receptor antagonist that blocks serotonin both peripherally and centrally.

Dolasetron (Anzemet)

Selective 5-HT3 receptor antagonist that blocks serotonin both peripherally and centrally.

Granisetron (Kytril)

At chemoreceptor trigger zone, blocks serotonin peripherally on vagal nerve terminals and centrally.

Bronchodilators

Class Summary

Acute bronchospasm may result when exposure occurs to aerosolized chemicals. Bronchodilators are administered to attempt to alleviate bronchospasm that causes decreased pulmonary airflow and wheezing.

Albuterol (Ventolin, Proventil)

Beta-agonist for bronchospasm refractory to epinephrine. Relaxes bronchial smooth muscle by action on beta2-receptors with little effect on cardiac muscle contractility.

Cycloplegics

Class Summary

Eye muscarinic antagonists that cause mydriasis and alleviate ciliary spasm. May alleviate symptoms in patients who develop a chemical conjunctivitis caused by eye exposure.

Cyclopentolate (Cyclogyl, AK-Pentolate)

Prevents muscle of ciliary body and sphincter muscle of iris from responding to cholinergic stimulation. Induces mydriasis in 30-60 min and cycloplegia in 25-75 min.

 

Follow-up

Further Outpatient Care

Most patients exposed to vomiting agents recover within the first few hours postexposure and demonstrate no further toxicity. If marked ocular toxicity occurs and corneal injury is documented, obtain follow-up care with an ophthalmologist to ensure that healing is progressing. Schedule this follow-up visit within 24 hours of discharge.

Further Inpatient Care

Inpatient care for patients exposed to vomiting agents is no different than the care discussed in Emergency Department Care. Symptomatic patients exposed to these agents should remain in a health care setting until signs and symptoms abate and they are able to take adequate fluid by mouth without repeat emesis. Continued use of IV fluids and antiemetics may be necessary. Patients who demonstrate marked bronchospasm may need repeated nebulized albuterol as necessary.

Transfer

A health care facility that is unable to adequately provide care for a patient intoxicated with a vomiting agent should consider transfer to a facility that can care for such patients. Health care facilities may be overwhelmed quickly if a large-scale exposure occurs with multiple casualties. Disaster plan implementation and appropriate transfer of patients to less stressed facilities may be necessary.

Complications

Complications are expected to be rare in persons exposed to vomiting agents if rapid and adequate supportive care is initiated. Exceptions are as follows:

  • If significant ocular exposure occurs, corneal chemical burns may develop
  • In persons with preexisting lung disease, exacerbation of the lung disease may occur
  • If a patient sustains a large exposure, coma may develop, with subsequent risk of anoxic brain injury and aspiration pneumonia

Corneal chemical burns

Significant exposure to vomiting agents can lead to damage of the cornea. If the patient complains of significant eye discomfort, foreign body sensation, photophobia, or decreased visual acuity, consider eye irrigation. Thoroughly examine the eye and include visual acuity testing. Perform slit lamp examination with fluorescein. If a chemical corneal burn is documented, a cycloplegic may be used to reduce pain; apply topical antibiotic ointment. Arrange follow-up care with an ophthalmologist within 24 hours. For more information, see Ocular Burns.

Acute bronchospasm

As with many types of chemical inhalation exposures, acute bronchospasm may develop in patients exposed to vomiting agents. This is especially true of patients with preexisting lung disease (eg, asthma). If acute bronchospasm occurs leading to respiratory distress, treatment with bronchodilators (eg, albuterol) may be necessary.

Anoxic brain injury

If an exposed person becomes comatose and loses his or her ability to maintain ventilatory function, hypoxia may develop, leading to anoxic brain injury. Unless massive levels are encountered, this complication is exceedingly rare after exposure to vomiting agents.

Inability of exposed patients to maintain their airway may result in aspiration of gastric contents into the lungs, causing aspiration pneumonia

Prognosis

The prognosis is good for persons exposed to vomiting agents if they do not develop secondary injuries. Full recovery is expected in most patients.

Patient Education

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