A Review of Chemical Warfare Agents and Treatment Options

Chemical warfare agents (CWAs) are defined as “any toxic chemical or its precursor that can cause death, injury, temporary incapacitation or sensory irritation through its chemical action.”¹

CWAs include five primary categories: nerve agents, asphyxiants, blistering agents, toxic industrial chemicals and blood agents. Non lethal incapacitating agents are sometimes included in this category; these chemical agents won’t be included in this review.²

In this article, we’ll discuss a brief history of CWAs and the critical importance of personal protective equipment and decontamination. Additionally, we’ll review the primary categories of CWAs, clinical symptoms of exposure and recent updates in treatment.

Turkish emergency personnel carry a victim of alleged chemical weapons attacks in Syria. AP Photo

History of Use

Historians cite one of the earliest dedicated, targeted uses of CWAs in warfare as World War I. The French military used tear gas and acetone-based compounds for crowd control; chlorine gas was placed in capsules and released at the Battle of Ypres in 1915, and was used as an alternative weapon after the German military exhausted materials for explosive weapons and began to investigate and use CWAs.³

Later, other agents such as phosgene and cyanide were considered for military use, because these chemicals had more toxic pulmonary effects.³

Nerve agents developed in the 1930s and 1940s were stockpiled during the Cold War. More recently, nerve agents have been used in the Iran—Iraq War in the 1980s, the Japanese terrorist attacks by the Aum Shinrikyo cult in 1995 and attacks in Syria in 2017.

The creation of the Chemical Weapons Ban in 1997 by the Organization for the Prohibition of Chemical Weapons stifled the development, use and stockpiling of these materials for military use across 148 nations.^3,4

Protection & Decontamination

Effective treatment of all patients exposed to CWAs requires use of appropriate personal protective equipment (PPE) and early patient decontamination by first responders. PPE may vary depending on the exposure.

Given the potential for many chemical agents to vaporize, it’s recommended that first responders protect their skin and airways while providing initial evaluation using full-face respirators, self-enclosed breathing devices and full suits that aren’t penetrable by liquid or aerosolized materials.⁵ Although many ambulances carry PPE to protect their skin, few carry full-face respirators.

Early decontamination by first responders with appropriate PPE is essential in the care of patients and emergency personnel with chemical exposure.

Patients should be decontaminated prior to being placed in an ambulance and prior to arrival in a healthcare facility to minimize exposure and risks to health care workers.

Initial decontamination includes removal of all articles of clothing and storage in sealed containers to decrease persistent exposure and aerosolization of the chemical.

Additionally, all patients should be washed thoroughly with water and diluted bleach. Eye wash stations should be used for extensive eye irrigation to remove exposure.

Detoxification agents may be considered in assisting with chemical weapon decontamination. For example, hypochlorite solution may be added to decontaminate from mustard gas exposure.⁶

Maintained by the military, M291 skin decontamination kits and Reactive Skin Decontamination Lotion (RSDL) are also available during exposures; studies have demonstrated superior decontamination with RSDL in animal models exposed to soman, a chemical agent.^7,8

Nerve Agents

Nerve agents include two primary categories of chemical agents: G-agents and V-agents. Developed first, G-agents are sarin, cyclosarin, tabun and soman. V-agents include: VE, VG, VM, VR and VX.

Nerve agents have a chemical structure similar to organophosphates which allows them to covalently bind acetylcholinesterase to deactivate the enzyme.^4,9

The primary mechanism of action for nerve agents is blockage of acetylcholinesterase at the neuromuscular junction of muscarinic and nicotinic receptors. Acetylcholinesterase is the primary degrading enzyme of acetylcholine.

The result of nerve agent blockade is increased acetylcholine availability at the neuromuscular junction. Nerve agents may also have effects at glutamate receptors and direct neurotoxic effects.⁴

Clinical symptoms of nerve agent poisoning are a direct result of muscarinic and nicotinic nerve stimulation. Muscarinic nerve stimulation leads to the clinical symptoms commonly known as SLUDGE:

• Salivation;
• Lacrimation;
• Urination;
• Diarrhea;
• Gastrointestinal distress; and
• Emesis.

Miotic pupils are also common.

Most importantly, nerve agents cause the more life-threatening clinical symptoms:
bradycardia, bronchospasm and bronchorrhea.

Nicotinic nerve stimulation leads to the clinical symptoms of muscle spasms/fasciculations, weakness, flaccid paralysis and tachycardia. Seizures are common in patients who have been exposed to nerve agents.

There’s high mortality associated with nerve gas exposure, which primarily occurs from respiratory failure secondary to bronchospasm and bronchorrhea, or from status epilepticus.

Nerve agents also demonstrate clinical latency periods. Latency depends on the route of exposure. Inhalational exposures generally have near immediate symptom onset. However, cutaneous exposure may have a latency period of minutes/hours until symptoms manifest.

The pharmacology of nerve agents is key to understanding treatment options. Nerve agents phosphoylate acetylcholinesterase to inactivate the enzyme. The acetylcholinesterase-nerve agent complex will undergo a process called aging, in which the nerve agent permanently binds to the enzyme, rendering acetylcholinesterase completely inactivated. The time to aging depends on the nerve agent: Soman has one of the fastest aging times of 1—2 minutes, while VX’s aging time is 30 hours.^4,9

 

Treatment

There’s no single antidote to nerve agent poisoning. Treatment for nerve agent poisoning is a multimodal therapy with three primary components: 1) atropine; 2) a benzodiazepine; and 3) an oxime.

Atropine is a competitive antagonist to the acetylcholine receptor that produces anticholinergic effects. It helps treat the clinical symptoms associated with nerve agent poisoning but has no direct effect on the nerve agent. Healthcare providers should administer 2 mg of atropine every 5—10 minutes by IV; doses can be doubled if there’s no improvement in clinical symptoms.

An atropine infusion can also be started and should be titrated to respiratory effects (e.g., respiratory secretions, tachypnea), not to pupillary constriction.

Early intubation and ventilator use is essential to caring for patients with nerve agent poisoning and may be necessary until additional therapies are given. Benzodiazepines are included in the autoinjectors and treatment regimens to manage seizures.

Oximes are nucleophiles that bind the phosphoryl component of nerve agents, consequently releasing the nerve agent from acetylcholinesterase. They include pralidoxime (2-PAM), hagedorn oxime (HI-6), obidoxime and MMB-4.

Pralidoxime is a common oxime used to treat organophosphate poisoning, but has limited effectiveness in nerve agent poisoning. Several studies have compared the effectiveness of various oximes. In both in vitro and in vivo animal models, for soman, cyclosarin and VX exposures, HI-6 is a superior treatment compared to other oximes.¹⁰

Multiple victims of a suspected sarin gas chemical attack lie on the ground in
Khan Sheikhoun, in Idlib, Syria in April 2017. AP Photo/Alaa Alyousef via AP

Other studies have demonstrated that the optimal regimen includes HI-6, procyclidine and keppra. In rat models, this “triple regimen,” when administered at one and five minutes, prevented or ended seizures and had improved mortality with lethal and supralethal doses of soman, sarin and cyclosarin.

For tabun exposure, there’s some evidence suggesting a quadruple therapy of HI-6, keppra, procyclidine and obidoxime will help treat supralethal exposure to tabun.^11-13

Another promising therapy is organophosphate hydrolyzing enzymes (OPHEs). OPHEs are enzymes that directly hydrolyze nerve agent—acetylcholinesterase complexes. At this time, human butyrylcholinesterase (BChE) is the most promising OPHE.

However, these molecules currently have limited catalytic capacity and biologic stability. Further research is required to optimize their development for human use.^14,15

Finally, pyridostigmine has been used by the military as prophylaxis for nerve agent poisoning in high risk areas, most notably for potential soman exposure. Pyridostigmine is a carbamate which reversibly inactivates acetylcholinesterase.

Therefore, prophylactic pyridostigmine temporarily occupies acetylcholinesterase binding sites, preventing nerve agent binding.¹⁵

Prophylactic dosing is 30 mg every eight hours by mouth. However, the key limitation to pyridostigmine is its inability to cross the blood-brain barrier, leaving central acetylcholinesterase susceptible to nerve agents.

Blistering Agents

Nitrogen mustard and sulfur mustard, more commonly known as mustard gas, were developed and used as chemical weapons during World War I. Today, nitrogen mustard derived compounds are used as chemotherapy for leukemia and lymphoma.

Mustard gas is an alkylating agent that crosslinks DNA and blocks cellular replication. Although not technically a gas agent, exposure occurs via inhalation when the liquid evaporates or is aerosolized.

Although mustard gas is generally not a fatal chemical agent, it causes both acute and chronic medical injury to those exposed to it.

In the acute phase, mustard gas exposure results in skin, eye and lung damage.

Depending on the exposure dose, patients may have only an erythematous rash (low dose) or large, painful blisters that may become necrotic (high dose).

Additionally, there’s also latency in appearance of skin blistering that can delay decontamination and medical care. Skin blistering can result in long-term skin hypopigmentation, permanent scarring and increases the risk of infection.

Patients should be treated at a dedicated burn center for wound care and fluid management. Additionally, there’s some evidence that using povidone iodine solution can decrease damage to non-blistering areas if applied immediately after exposure.¹⁶

Initial symptoms of eye injury secondary to mustard gas exposure including pain, photophobia, scleral injection and lacrimation.

Corneal ulceration can result if significant high-dose exposure occurs.^17,18

For eye injury and exposure, supportive care, including initial eye decontamination with water, darkened glasses for photophobia management and avoiding eye bandaging are all recommended.¹⁶

Lung damage from mustard gas exposure also results in both acute and chronic lung injury; however, long-term, lung-associated sequelae of mustard gas exposure are severe and debilitating. In the acute phase, lung injury from mustard gas includes pulmonary edema and pulmonary hemorrhage.

Late sequelae include chronic obstructive pulmonary disease (COPD), asthma and bronchiolitis obliterans (BOOP), which are caused by the fibrotic changes that occur.^16,19

Some patients with mustard gas exposure will suffer from neutropenia or pancytopenia. Similar to pulmonary symptoms, there’s often a latent period of 4—24 hours before presentation of this lab abnormality.¹⁶ Patients may require treatment with colony-stimulating factor for management and recovery of white blood cell counts.¹⁶

Treatment

Supportive measures are generally indicated for acute lung injury secondary to mustard gas exposure. Patients may require supplemental oxygen, intubation and mechanical ventilation. Additionally, there’s limited evidence in animal models that N-acetylcysteine (NAC) is an effective therapy for respiratory injury due to mustard gas. Due to its antioxidant and radical scavenger properties, research studies in both animal and human models suggest that NAC is an effective treatment.^16,20

In both the acute and long-term treatment phases, NAC helped decrease respiratory symptoms associated with mustard gas inhalation. Additionally, NAC alone or combined with clarithromycin improved pulmonary function in patients with BOOP secondary to mustard gas exposure.²⁰

Asphyxiants

Common chemical asphyxiants include carbon monoxide, chlorine, phosgene and hydrogen sulfide gases. As described above, chlorine and phosgene gases were one of the earliest CWAs used by Germany in World War I. Both of these gases exert their toxic effects on the respiratory system.

Chlorine is an asphyxiant gas used in various industries including polyurethane and polychloroethene (PVC) production, chemical solvent production and water sterilization. Its toxic effects are primarily localized to the upper airways and occur immediately after exposure. Chlorine gas can also cause skin and eye irritation.

In addition to decontamination, some studies have trialed the use of nebulized sodium bicarbonate; results suggested improved lung function based on lab studies but overall no improved survival.²¹

Phosgene is also an asphyxiant gas used in the pesticide and plastics industries. Phosgene has direct toxic effects on the lungs and exposure results in fatal pulmonary edema and acute respiratory distress syndrome (ARDS).²²

Treatment

Pulmonary edema is often delayed up to 24 hours and carries high mortality. Treatment options in addition to general supportive
care, IV diuretics and mechanical ventilation are limited and have only been evaluated in animal models. They include IV corticosteroids, nebulized N-acetylcysteine, and nebulized bronchodilators.^23,24

Blood Agents

Emergency providers often encounter cyanide exposure when caring for patients in house fires, but it’s also a CWA. Cyanide, or hydrogen cyanide, is a weak acid that blocks cytochrome C oxidase and shuts down mitochondrial respiration. Exposure to cyanide can occur via ingestion, skin absorption and inhalation.

Patients with cyanide poisoning present in severe distress with tachycardia, cyanosis and hypotension. The most notable and life-threatening lab abnormality is severe metabolic acidosis. Seizures are common and cardiac arrest may occur.

There’s currently no rapid cyanide blood test to detect exposure; thus, diagnosis is based on context, clinical symptoms and clinical suspicion.

Treatment

There are several antidotes currently available for treatment of cyanide poisoning. Due to the risk of large-scale poisonings that require immediate treatment, much research is working towards finding antidotes that can be administered intramuscularly (IM) in the field by first responders and have immediate treatment effects.

The Lily kit, also known as Nithiodote, contains three essential medications: amyl nitrite, sodium nitrite and sodium thiosulfate. Most often, sodium nitrite is administered at a dose of 300 mg IV, which causes methemoglobinemia.

Cyanide has a higher binding affinity for methemoglobin compared to the oxidative phosphorylation enzymes, and helps restore cellular respiration. The risk associated with nitrite administration is the formation of
methemoglobin, which has no oxygen carrying capacity.

In patients exposed to house fires, who may already suffer from hypoxia due to smoke inhalation or lung injury, administration of nitrite therapy carries significant risk. Sodium thiosulfate acts to increase enzymatic activity of rhodanase, an enzyme that metabolizes thiocyanate by products.

Increasing this enzyme’s activity helps to remove cyanide more rapidly. It’s recommended to give 12.5 g of sodium thiosulfate IV for severe cyanide toxicity.^25,26

Hydroxocobalamin is a newer therapy for cyanide intoxication. Although first developed and tested in 1952, hydroxocobalamin was not approved for use in the United States until 2006.

Hydroxocobalamin has a strong binding capacity for cyanide and forms cyanocobalamin or vitamin B12. Cyanokits contain 5g of hydroxocobalamin which is reconstituted in 100 mL of normal saline or lactated ringer’s solution and administered IV over 7.5 minutes.

Similar to the cyanokit, the prolonged administration time and need for IV access are two limitations associated with this drug’s use in first responder settings.^25,26

More recently, nitrocobinamide and sulfanagen have be tested in animal models as possible intramuscular antidotes. Nitrocobinamide is a precursor to cobalamin that has demonstrated rescue capability in animal models; it has even greater rescue capacity when combined with thiosulfate.²⁷

When compared to hydroxocobalamin, IV cobinamide as equally effective in rescuing swine models.²⁸

This molecule contains two moieties of 3—mercaptopyruvate; 3—mercaptopyruvate monomers can inactivate cyanide to produce thiocyanate and pyruvate.

Some animal studies testing sulfanagen and sulfanagen combined with nitrocobinamide have shown improved mortality, suggesting sulfanagen is also a promising future therapy.²⁹

Hydrofluoric Acid

Not commonly used as a weapon, hydrofluoric acid is an industrial chemical used in electronics, glass etching and other chemical industries. However, unprotected exposure to hydrofluoric acid can pose severe health risks.

Hydrofluoric acid is a weak acid easily absorbed by the skin that binds and depletes calcium and magnesium stores. Calcium-fluoride and magnesium-fluoride complexes deposit in the soft tissues.

Clinical symptoms of local hydrofluoric acid poisoning include severe pain in the exposed area. Patients with systemic toxicity usually have gastrointestinal distress, vomiting and cardiac arrhythmias.

Systemic toxicity usually occurs with large body surface area exposures, inhalation and ingestion exposures.

Cardiac arrhythmias may result from hypocalcemia and hyperkalemia, a lab abnormality associated with hydrofluoric acid exposure.³⁰

Treatment

Treatment of hydrofluoric acid includes IV calcium to restore these ion stores. Providers can administer IV calcium gluconate or IV calcium chloride, along with IV magnesium.

Topical calcium gluconate gel can be applied directly to the area or calcium gluconate can be locally infiltrated.³⁰ Hyperkalemia should be managed with standard regimens, including IV insulin/glucose, albuterol, sodium bicarbonate and/or a binding agent.

Conclusion

Although CWAs continue to pose a threat to human health, ongoing research demonstrates promising treatment options for first responders and emergency healthcare providers.

New therapies that may be used in the field and without IV access will be crucial to protecting patients and military personnel from
large-scale chemical weapon threats.

Additional research should also continue to evaluate the long-term health outcomes of patients who endure chemical agent exposures.

References

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