Organophosphate chemicals that affect the cholinergic nervous system are the most potent of the chemical weapons. They are often referred to as nerve gases, but this is a misnomer because they are aerosolized liquids rather than true gasses. The military designation for this group of weapons is nerve agents. The best-known terrorist use of a nerve agent occurred in Tokyo, Japan, in March 1995 when the Aum Shinrikyo cult released a dilute form of sarin in the Tokyo subway. Although they used a very ineffective delivery route for this chemical, the attack affected approximately 5,500 people and resulted in 11 deaths. The nearest hospital received 640 of the victims, and its experience is documented in the medical literature.5 The majority of these patients were not decontaminated before arrival at the hospital; as a result, they subsequently contaminated 23% of the emergency department staff, many of whom required medical attention. Identification of the causative agent took approximately 2 hours, and the delay of appropriate treatment contributed to the morbidity and cross-contamination. This event highlights the dramatic impact of a nerve agent attack on the public and local healthcare systems.
Although nerve agents are similar to organophosphate chemicals that are used as insecticides, they are much more potent and typically delivered as vapors. As a consequence, the clinical presentation of nerve agents is slightly different than that of organophosphate insecticides (see eChap. 10). With a nerve agent release, there will be a highly contaminated area surrounding the point of release, where victims will be affected instantaneously and the probability of survival will be low. The size of this area depends on the type of dispersal device and ventilation of the area. Individuals in this area rapidly lose consciousness and develop seizures and apnea because of the rapid respiratory absorption. On the periphery of the lethal area, there will be a casualty zone, where toxic but potentially survivable exposures will occur. These victims will likely develop sublethal toxicity and likely be able to reach a healthcare facility for treatment.
The most common clinical presentation for victims who arrive at a healthcare facility consists of miosis, rhinorrhea, cough, and mild shortness of breath.8 Sweating or muscle fasciculation may also be seen if droplets have come in contact with the skin. Individuals who had more direct or pronged exposure will have more significant symptoms; including altered mental status, muscle weakness, or seizures. Most victims who reach a healthcare facility will have a low likelihood of dying, but they can experience long-term effects. Infants and young children exposed to organophosphates often have a different clinical presentation than adults; central cholinergic effects predominate, and thus pronounced weakness, and altered mental status are more common.9
Long-term effects of acute nerve agent exposure include an increased incidence of neuropsychiatric problems. Organophosphate insecticides and nerve agents cause behavioral and cognitive dysfunction. Studies of occupational exposure and acute poisoning with organophosphate insecticides further substantiate the likelihood of undesirable changes in cognitive and behavioral function, as well as peripheral neuropathies.10–12 Survivors of terrorism with the nerve agent sarin in Japan reported an increased prevalence of such disorders.13–16 Similarly, a recent study indicates that soldiers who were exposed to very low doses of nerve agents, while burning captured munitions during the 1991 Gulf War, who later died of other causes had decreased white matter and increased brain cavity size.17 Cholinesterase enzyme polymorphisms can influence individual response to different organophosphates and may affect susceptibility to these long-term neuropsychiatric problems and neuropathies.18–21
Sidebar: Clinical Presentation: Nerve Agent Poisoning
- Mild: miosis and rhinorrhea
- Moderate: vomiting, profound sweating, possible altered mental status
- Severe: unconscious or convulsing
- Nausea, vomiting, diarrhea, and dyspnea may be present
- Wheezing, rales, or rhonchi
- Bowel sounds are hyperactive
- Bradycardia or tachycardia
- Muscle fasciculation may be noted
- Acidosis will be present with severe poisoning
- Plasma or red blood cell cholinesterase activity
Nerve agents bind to various cholinesterase enzymes and prevent the breakdown of acetylcholine. The resulting excess of acetylcholine leads to acute hyperstimulation of muscarinic and nicotinic receptors. The different nerve agents have demonstrated marked variability in terms of potency and kinetic parameters. Peripherally the muscarinic excess results in increased secretions, and nicotinic excess leads to muscle weakness and fasciculation. Centrally, the excess nicotinic and muscarinic activity leads to altered mental status and seizures. Rapid fatality with high-dose exposures appears to be the result of centrally mediated seizures, whereas fatalities as a consequence of lower exposure are likely due to hypoxia as a result of noncardiogenic pulmonary edema.22 Over time, the organophosphate binding may become irreversible through a process called enzyme aging in which a covalent bond is formed between the enzyme and the organophosphate molecule. The time required for aging can be as short as a few minutes or as long as a few days, depending on the organophosphate. When aging occurs, the affected cholinesterases will never become functional again, and because the majority of cholinesterases are produced by red blood cells, it will take about 120 days, the typical red blood cell life span, before cholinesterase levels will return toward “normal.” However, within 60 to 90 days, when cholinesterase levels recover to approximately 80% of normal, most individuals are able to function without any clinical consequences.23
Organophosphate chemicals are widely used as insecticides and certain highly toxic organophosphate compounds have been developed for military use. Commercially available insecticides for consumer use are relatively dilute, but more concentrated versions are available to registered pesticide applicators. Insecticides could potentially be used by terrorists as weapons but are difficult to disperse effectively. The nerve agents are classified and differentiated by several properties. The most important of these are aging time, potency, and volatility (eTable 12-2). Nerve agents are liquids at room temperature, but the highly volatile agents are more easily dispersed. The high-viscosity agents tend to be harder to aerosolize. VX is the most potent of these agents, but it has low volatility and a long aging time. As little as 1 drop on the skin can be lethal, but absorption may be delayed and thus allow time for treatment. The rapid aging time associated with the agent soman is very concerning because there is little opportunity for intervention.
eTable 12-2 Properties of Nerve Agents |Favorite Table|Download (.pdf)
eTable 12-2 Properties of Nerve Agents
|Aging time||5 hours||5 minutes||14 hours||48 hours||12–24 hours|
|Dermal LD50||1,700 mg||100 mg||1000 mg||10 mg||>35,000 mg|
|Inhaled LCt50||100 mg/m3||50 mg/m3||400 mg/m3||10 mg/m3||>250 mg/m3|
If the exposure occurs in an enclosed space that is poorly ventilated, the agent will be concentrated and result in increased potential for morbidity and mortality. Outdoor release generally produces less concentrated exposures and the presence of rain, sunlight, or wind reduces the effectiveness of these agents, especially the volatile ones. Individuals who are the most heavily exposed will be at the greatest risk and before decontamination, they pose the greatest risk to first responders and healthcare workers. They can present direct contact hazards but also be a respiratory hazard as vapors are volatilized through a process know as off-gassing. Off-gassing is most likely to be problematic in warm and poorly ventilated spaces. Contaminated victims who present to the hospital with residue on their clothes, hair, or skin also represent a significant risk to healthcare professionals.
General Approach to Treatment
The initial goals of treatment of nerve agent poisoning are mitigating ongoing exposures; stabilizing immediate threats to the airway, breathing, and circulation; and initiating appropriate antidotal therapies. After stabilization, the patient should be monitored for ongoing antidote needs. Followup evaluation is needed to ascertain if long-term neuropsychiatric problems will need to be treated.
Decontamination of nerve agent exposure victims is of critical importance. Exposed victims should not be allowed to enter the emergency department of a hospital or any other healthcare facility until they have been decontaminated. Personnel working around contaminated victims need to wear protective equipment that at a minimum complies with Occupational Safety and Health Administration’s level C requirements.2 This includes a respiratory protection device (powered air purifying respirator), chemical-resistant suit, double-layered gloves, and boots. For victims of a vapor exposure who have minimal symptoms, removal of their clothes is likely all that will be needed to prevent contamination of others. However, because it is unlikely that the specific agent will be known at the time the person arrives at a healthcare facility, wet decontamination also should be initiated. Wet decontamination consists of washing from head to toe with water and mild soap.
There are three primary reasons to use pharmacologic therapy for the management of acutely exposed people: to treat excessive secretions, to control seizures, and to protect cholinesterase enzymes from aging. The standard antidotes, which include atropine, a muscarinic antagonist; pralidoxime, a peripheral nicotinic antagonist and cholinesterase protectant; and benzodiazepines, for seizure control are discussed in detail in eChapter 10.
Although the general approach to treatment of individuals who have been exposed to a nerve agent as the result of a terrorist action on a large population are the same as those for insecticide poisoning, there are a few subtle differences. Particularly, life-threatening vapor exposures can result in more seizure activity than secretory effects. Nerve agent exposures paradoxically require lower total doses of atropine than insecticides. Also, because nerve agents may rapidly “age,” the use of pralidoxime is more urgent than in insecticide poisonings.
Drug Treatments of First Choice
Currently, the standard antidote regimen for organophosphate poisoning used in the United States includes atropine, pralidoxime, and benzodiazepines, if needed, for seizure control. Atropine competitively antagonizes muscarinic cholinergic receptors to relieve symptoms of cholinergic excess and a starting dose of 2 mg IV should be promptly administered and then rapidly titrated upward until secretions stop and the patient can easily be ventilated.24 Because it freely crosses the blood–brain barrier, atropine acts both centrally and peripherally. In the central nervous system (CNS), atropine blocks muscarinic receptors but simultaneously stimulates acetylcholine release. Pralidoxime is a nucleophilic oxime that acts as a reversible inhibitor of acetylcholinesterase that can also bind peripheral nicotinic cholinergic receptors. By binding to acetylcholinesterase, it can prevent or displace organophosphate from binding to the enzyme and prevent enzyme aging. By binding to peripheral nicotinic cholinergic receptors, pralidoxime is thought to improve muscle weakness within minutes of administration. Pralidoxime, however, has poor CNS penetration and primarily acts only on peripheral enzymes.25 Other oxime compounds, such as obidoxime, that offer greater CNS penetration are used in other countries but are not approved by the Food and Drug Administration (FDA).25 When used alone, pralidoxime offers a limited survival benefit. However, in combination with atropine, it offers a synergistic effect that improves survival beyond that associated with either agent alone.24 By preventing enzyme aging, the combination is also thought to greatly reduce the duration of atropine therapy. The major limitation of such treatment is that central nicotinic receptors are unprotected. This gap in protection may contribute to the long-term neuropsychiatric problems that have been observed.
Alternative Drug Treatments
Pyridostigmine is an ideal pretreatment that would offer peripheral and CNS protection without disrupting cognition or enhancing toxicity however it is currently not available. When there may be a high risk of exposure, such as military operations or for first responders entering a contaminated environment, pretreatment of individuals can be considered. A pretreatment regimen of oral pyridostigmine 30 mg administered every 8 hours in humans can protect the acetylcholinesterase enzyme from organophosphate binding and aging. This therapeutic regimen blocks 20% to 40% of peripheral cholinesterase enzymes.26 As such, this blockade protects a critical mass of acetylcholinesterases against nerve agent binding. In animal studies, pretreatment with pyridostigmine followed by postexposure therapy with atropine and pralidoxime improved survival against high doses of nerve agents.27 Although pyridostigmine appears to improve survival against lethal doses of all nerve agents, its most dramatic effect is against the rapidly aging agent soman. For soman, it improved the protective ratio almost 40-fold in rhesus monkeys versus treatment with atropine and pralidoxime alone.27 Against other nerve agents, pyridostigmine offered more modest benefits, increasing protective ratios by approximately 50%. The benefit of pyridostigmine is somewhat limited because it does not cross the blood–brain barrier and offers no CNS protection. Additionally, it is theoretically possible that pyridostigmine may actually potentiate acute toxicity with low-dose organophosphate exposures.27–29 Central-acting agents are impractical because they can impair cognition. Recent work has focused on developing a prophylactic transdermal patch that continuously delivers subclinical doses of pyridostigmine and procyclidine. This combination has been shown to reduce the lethality of the nerve agent soman in nonhuman primates alone and in combination with traditional postexposure antidotes.30 There is also interest in developing novel treatment using enzymes and proteins as bioscavengers for use as prophylactic and acute treatments, but work with these agents is still in early preclinical phases.31
Young children exposed to organophosphates often have an unusual clinical presentation compared with adults—the degree of emesis and other excess secretions is markedly reduced. Rather, they often present with profound weakness and altered mental status. Their appearance is often described as “floppy” or like a rag doll. However, after being appropriately diagnosed, the treatment is the same as in adults. Pediatric autoinjectors with smaller needles containing 0.5 or 1 mg of atropine are available. Pediatric atropine autoinjectors may offer enhanced safety in small children, but if they are not available, adult-size autoinjectors can be used in life-threatening situations.9 It is important to remember that dosing in these situations is based on neutralizing the excess acetylcholine and not on body weight, so dosing should be titrated in the same manner as in adults and requires similar total doses.
Evaluation of Therapeutic Outcomes
As described earlier, atropine dosing should be titrated to drying of secretions and ease of ventilation. Frequent assessments should be made to determine the required duration of atropine therapy. If atropine cannot be weaned within the first 48 hours, it is likely that enzyme aging has occurred or there is ongoing exposure because of incomplete decontamination. If muscle weakness persists or returns, additional pralidoxime (1 g) is warranted. Routine laboratory studies, such as electrolytes, glucose, and blood cell counts, should be followed daily in patients who require hospitalization. These studies and blood gasses may be performed more frequently based on the patient’s clinical condition. Measurement of serum and red blood cell cholinesterase function may assist in developing a prognosis for moderate to severely poisoned patients. Unfortunately, these tests are not universally available and may be difficult to obtain during mass casualty incidents.
Cyanide and Associated Agents
Cyanide compounds comprise the group of chemical weapons known as blood agents that impair oxygen use for aerobic energy production.4,32 Cyanide salts have been used as oral poisons in numerous cases of suicide and mass poisoning. In 1980, cyanide was inserted into Tylenol products in the Chicago area by an unknown terrorist. This event led to requirements for tamper-evident packaging. Hydrogen cyanide gas, noted for its rapid lethality, has been used to execute condemned prisoners and was used in the Nazi death chambers. Cyanide gas is released in smaller, but still toxic, amounts during fires when plastics and other types of organic materials are burned. Cyanide has become a sought-after chemical weapon by terrorist groups. Terrorists attempting to kill a large number of people with cyanide will most likely use the gaseous form. Similar to the nerve agents, there will be a zone of high lethality at the release site. Victims outside this zone are likely to present to healthcare facilities. Most victims who are able to transport themselves to a healthcare facility or a hospital have a low likelihood of morbidity or mortality.
The clinical presentation of cyanide poisoning can vary in severity depending on dose, time since exposure, and route of exposure. Signs and symptoms are consistent with global hypoxia, ranging from headache to convulsions. Inhaling concentrated cyanide gas results in rapid loss of consciousness and death within in a few minutes. Most victims who survive to the hospital will be unlikely to die from cyanide poisoning. Some may have a noticeable odor of “bitter almonds” that is frequently described as a musty odor. Because approximately 40% of the population does not carry the gene necessary to detect this odor, it is not a reliable sign.4 If ingested, the onset of toxicity may be delayed, and the early signs and symptoms may mimic anxiety. Dizziness, headaches, weakness, flushing, diaphoresis, dyspnea, hyperventilation, and tachypnea are also commonly seen in those with moderate to severe exposures.4 Various cyanide gases may also cause mucus membrane irritation. As cellular hypoxia worsens, victims experience loss of consciousness with fixed, dilated pupils; hemodynamic compromise; arrhythmias; seizures; apnea; secondary cardiac arrest; and finally death. Organs with high oxygen demands are the most sensitive to cyanide poisoning (eFig. 12-1). The most prominent laboratory finding in cyanide toxicity is metabolic acidosis with dramatically elevated lactate levels. Cyanide blocks mitochondrial oxygen use, causing a shift from aerobic to anaerobic metabolism, increasing lactate production and resulting in a high anion gap metabolic acidosis. As the mitochondria cease to use the supplied oxygen, it builds up in the venous blood supply. In the case of an unknown exposure, elevated venous oxygen content along with elevated lactate would strongly indicate cyanide toxicity.33
Signs and symptoms of cyanide poisoning. (↓, Decrease; ↑, increase; ATP, adenosine triphosphate; BP, blood pressure; CNS, central nervous system; CO, carbon monoxide; SA, sinoatrial.) (From Baskin et al.34)
Long-term neuropsychiatric effects from an acute exposure are not frequently addressed but are associated with marked morbidity. These effects are similar to carbon monoxide-induced neuropsychiatric disorders that arise from oxidative stress and lipid membrane peroxidation.4 Chronic low-level cyanide exposure is thought to contribute to or cause several neurologic disorders. Although management of an acute exposure is well defined, little is known about prevention of long-term effects from low-dose cyanide exposure.
Sidebar: Clinical Presentation: Cyanide Poisoning
- Mild: headache, dizziness, possible vomiting
- Moderate: agitation or lethargy
- Severe: unconscious, convulsing
- Rapid heart rate
- Rapid respiratory rate
- Skin will be normal color to flushed
- Arrhythmias may be present
- Metabolic acidosis will be present with poisoning
- Serum lactate will be elevated
- Venous oxygen will be elevated
- Plasma cyanide concentration, if available
Cyanide is known to inhibit many metabolic processes, but the most notable toxic effects seem to originate from the inhibition of the terminal enzyme in the respiratory chain.4 Normally, sulfane and cyanocobalamin reactions rapidly metabolize endogenously produced cyanide. The body can detoxify about 0.017 mg of cyanide/kg/min.34 When these pathways of metabolism are overwhelmed and conjugate substrates depleted, cyanide accumulates, resulting in toxicity. The accumulated “free” cyanide binds cytochrome oxidase within the mitochondria, resulting in abrupt cessation of aerobic metabolism (eFig. 12-2).
Mechanisms of cyanide toxicity. (ATP, adenosine triphosphate; CN-, cyanide; cyt a3, cytochrome a3; MetHgb, methemoglobin; OxyHg, oxyhemoglobin.) (From Gracia and Shepherd.4)
Essentially, the body can no longer use oxygen to make energy. Cyanide has a high binding affinity for the ferric ion (Fe3+) on the cytochrome (cyt a3) aa3 complex. This effectively stops electron transport. Because cyanide is occupying the binding site, oxygen no longer is able to reoxidize the reduced cyt a3. This uncoupling of oxidative phosphorylation terminates the synthesis pathway of adenosine triphosphate. Although the mitochondria continue to be exposed to an adequate oxygen supply, there is impaired oxygen extraction and use. This disruption of aerobic metabolism leads to increased glycolysis via anaerobic pathways.
Binding to the mitochondrial cytochromes often takes several minutes to occur, but early signs of cyanide poisoning are seen within seconds. This observation leads to the theory of additional mechanisms of toxicity. Because cyanide exists predominately in the unionized form within the body, it readily diffuses across membranes. Rapid effects seen after inhalation may be a result of the near instantaneous diffusion across the blood–brain barrier. Cyanide appears to alter neuronal transmission after absorption into the CNS, possibly through a glutamate pathway. It also appears to increase vascular resistance early in poisoning, which increases cerebral blood flow, thereby enhancing CNS penetration.
Cyanide is both widely available and easily accessible in a variety of forms. Historically, cyanide was used as a warfare agent in the volatile, water-soluble, liquid forms of hydrogen cyanide and cyanogen chloride. Potassium cyanide and sodium cyanide are highly reactive salts that are used in many industrial applications ranging from photograph developing solution to gold mining to production of explosives. Mixing these salts with a strong acid produces hydrogen cyanide gas.4 The plant-derived cyanide precursor amygdalin is an unlikely source of mass exposures but is reported to cause acute toxicity if eaten in very large quantities.
A more frequently encountered source of cyanide exposure is fires. Cyanide gas may be released in the combustion of many synthetic polymers and natural materials. Any material that contains carbon and nitrogen is a potential source of cyanide during a fire. Victims of smoke inhalation are also at high risk for both carbon monoxide and cyanide poisoning.4 Both carbon monoxide and cyanide cause hypoxic damage, and the effects are additive and possibly synergistic. Some studies even suggest that the toxicity from cyanide may be more contributory to death in some fire victims than carbon monoxide.4
Incidence and Risk Factors
Suicide attempts and smoke inhalation are the primary events associated with the development of cyanide toxicity. In these situations, the number of individuals affected has usually been small. An act of terrorism using cyanide gas could harm a much larger group of people and strain or overwhelm community resources. Such an attack would likely occur by releasing cyanide gas into a building or crowded public place.
Treatment: Cyanide Poisoning
General Approach to Treatment
The initial goals for treatment of cyanide poisoning are detecting the exposure; mitigating ongoing exposures; stabilizing immediate threats to the airway, breathing, and circulation; and using antidotal therapies appropriately. After stabilization, the patient should be monitored for sequelae of hypoxic injury.
All patients should undergo decontamination appropriate to the type of exposure. For ingestions, the victim’s clothing should be removed, orogastric lavage should be initiated, and activated charcoal should be administered for patients presenting within 1 hour of ingestion. Although activated charcoal poorly binds cyanide, administration may be helpful because of the relatively small lethal dose.4 Dangerous amounts of cyanide may be exhaled from the affected individual’s lungs or emanate from heavily soaked clothing, skin, or toxic vomitus. For inhalation victims, simply disrobing is appropriate decontamination.
Supplemental oxygen is a crucial part of supportive care in cyanide poisoning. Ventilation with 100% oxygen increases delivery to tissues but does not improve utilization by poisoned cytochromes. However, even in a case of normal measured Po2, supplemental oxygen may enhance antidote efficacy. Oxygen may serve to increase respiratory excretion of cyanide, restore the cytochrome oxidase activity by displacing cyanide, stimulate activation of other oxidative systems (e.g., enzymes not yet poisoned by cyanide), and perhaps facilitate the rhodanese enzyme indirectly.
Additional supportive therapies included initiating treatment for acidosis, hemodynamic compromise, and seizures as needed throughout the clinical course. Seizures resulting from cyanide poisoning require aggressive management and in some cases can be refractory to standard benzodiazepine therapy.4
In the United States, two different cyanide antidotes are approved by the FDA. Two three-part antidotes consisting of nitrates and thiosulfate or hydroxocobalamin are available. Both antidotes have proven to be effective for treating acute cyanide poisoning. No clinical trials have compared the two antidotal regimens in humans, so it is unclear if one has superior efficacy. Antidotes should be used in case of suspected cyanide exposure or an unknown exposure resulting in rapid onset of respiratory and neurologic symptoms. The differential diagnosis for acute cyanide poisoning is relatively small (see eFig. 12-1), and the antidote should be administered empirically to patients with hypoxic symptoms but lacking pallor. Initial studies with the nitrite–thiosulfate combination found that patients were responsive to therapy up to 2.5 hours after the exposure.35
The nitrate–thiosulfate antidote kit contains amyl nitrite, sodium nitrite, and sodium thiosulfate. Nitrites are used to induce methemoglobinemia (metHb). Cyanide preferentially binds to the ferric iron of the metHb rather than in the mitochondria. It is thought that an increased amount of cyanide will then transfer to the extracellular space and be displaced from the cytochrome. The mitochondria can then reactivate electron transport.34 Amyl nitrite is packaged in crushable glass vials for inhaled administration and generates approximately 5% (0.05) metHb. Next, sodium nitrite 300 mg (10 mL of a 3% solution) is given IV and increases metHb to between 15% (0.15) and 20% (0.20) in adults. In children, sodium nitrite requires a dose adjustment based on hemoglobin concentration to prevent excessive methemoglobin formation.4 Doses range from 5.8 to 11.6 mg/kg for hemoglobin concentrations ranging from 7 to 14 g/dL (70–140 g/L; 4.34–8.69 mmol/L). This is often impractical, so the sodium nitrite component may be omitted or the other antidote used, if available.
Nitrites do cause significant adverse side effects, namely vasodilation and hypotension. These side effects can be problematic, especially if compounded by coingestants or preexisting medical conditions. Although metHb is the desired end point to therapy, it may exacerbate the condition of certain patients, including those with poor cardiopulmonary reserve and those with concomitant carbon monoxide poisoning. It is recommended to avoid nitrites in smoke inhalation victims as a result of the risk of worsening the oxygen-carrying capacity deficit. The antidote for metHb is methylene blue, which will counteract excess metHb formation but may subsequently release bound cyanide.4
The third component of the cyanide antidote kit is sodium thiosulfate. This agent enhances clearance of cyanide by acting as a sulfur donor. Thiosulfate reversibly combines with cyanide in the extracellular space to form the minimally toxic and renally excreted thiocyanate. It may also augment mitochondrial sulfurtransferase reactions. The enzyme rhodanese is the catalyst for the direct conversion of cyanide to thiocyanate. The effectiveness of sodium thiosulfate as monotherapy is limited by its delayed onset of action, short half-life, and small volume of distribution. However, in smoke inhalation cases with a suspected cyanide component, thiosulfate can be used without nitrite therapy to avoid hemoglobin problems.
Sodium thiosulfate as a short-term therapy has very few side effects. The only significant adverse reactions are idiopathic hypersensitivity and infusion rate–related hypotension. If hypertension occurs during administration, the infusion rate should be reduced. Chronic exposure to thiocyanate can cause toxicity because thiocyanate and cyanide exist in equilibrium. Toxic effects from acute treatment of cyanide exposure are rare but may occur more frequently in the setting of severe renal failure.4
Hydroxocobalamin is a vitamin B12 precursor and acts as a chelating agent to bind cyanide in equimolar amounts directly forming cyanocobalamin (vitamin B12).36 It is available as a lyophilized powder and forms a clear red liquid when reconstituted. This antidote has proven to be highly effective as a result of its increased affinity for cyanide compared with the cytochrome oxidase moiety. The recommended starting dose is 5 g IV over 15 minutes.36 Additional doses of 2.5 g may be given if needed to control symptoms. No dosing adjustments are required for children.
Adverse reactions to hydroxocobalamin are rare and generally not severe. At recommended doses, it has very low toxicity.36–38 The most commonly reported adverse effect is reddening of the skin, which can last for several days. Allergic reactions are rarely reported.38 The compound’s usefulness is only limited by the large dose required and its relatively short 30-month shelf life because of light instability. An additional advantage of this agent is that pediatric dosing does not have to be based on hemoglobin concentration like sodium nitrite, and thus it is a better option for empiric use in children. There may be a synergistic protection if the hydroxocobalamin therapy is augmented by sodium thiosulfate. Because of its low toxicity and its efficacy, it is ideal when the diagnosis is uncertain or when the induction of metHb may be detrimental.
Some clinicians have advocated combining hydroxocobalamin with thiosulfate. However, results of a comparative trial of hydroxocobalamin, sodium thiosulfate and the combination of the two in a swine model of severe cyanide poisoning revealed that thiosulfate alone did not reverse cyanide-induced shock, and the combination of the two drugs did not provide synergy.39
Sidebar: Clinical Controversy…
The use of hyperbaric oxygen for cyanide toxicity is controversial. The literature offers little corroboration because some investigations find positive effects and other studies fail to demonstrate correlations with improved clinical status.4
Evaluation of Therapeutic Outcomes
The assessment of cyanide-induced hypoxia is complicated by the lack of cyanosis. Improvements in mental status and normalization of the respiratory and heart rates after oxygen or antidotes are indicative of improvement, as well as supportive of the diagnosis. Assessment of mental status, arterial blood gasses with methemoglobin, and lactate guides therapy. Oxygen saturation measurements by pulse oximetry remain high because the blood has good oxygen content; rather, the problem lies in oxygen use and extraction. Of note, after therapy is initiated to induce metHb, the pulse oximetry will depict a higher-than-actual oxygen concentration because oxyhemoglobin and methemoglobin deflect light at similar wavelengths.
Pulmonary agents were the first widely used chemical weapons. During World War I, pulmonary agents were responsible for thousands of casualties and deaths.40 These chemicals are widely used in industry and been exploited by terrorist groups in recent years. In Iraq, terrorists have made crude weapons by attaching explosives to relatively small tanks of chlorine gas.41 Larger quantities such as might be found in rail cars or tanker trucks could be devastating. A recent transportation accident illustrates this vulnerability and the effect on the healthcare system.42
In January 2005, Graniteville, SC was the site of one of the largest hazardous material incidents in the United States.42 Just before 3:00 am, two freight trains collided, releasing 80 tons of chlorine gas. The release required the evacuation of 5,400 people. The exact number of people affected was difficult to determine, but several hundred victims underwent decontamination at secondary facilities and area hospitals. The most commonly reported symptom was minor mucous membrane irritation that rapidly resolved when the individual was removed from proximity to the contaminated area. More than 500 patients were acutely treated in local emergency departments, 69 required hospital admission, and nine people died as a direct result of the exposure. Followup surveys 5 months after the event indicated that approximately half of the victims who initially presented with moderate to severe symptoms were still experiencing pulmonary effects requiring ongoing medical care and posttraumatic stress disorder was also common.42
The biggest clinical challenge for first responders to this event was determining what chemicals were involved and the potential risks associated with the exposure of the community and healthcare professionals. This compromised the ability of physicians to ascertain who had been significantly exposed, to diagnose the initial exposure conditions, and to anticipate sequelae. It also impacted the response of public health officials and pharmacists who were faced with providing immediate specific treatments. Additionally, patients were distributed to hospitals in a random fashion rather than on the basis of hospital resources and capacity. This resulted in several hospitals being overwhelmed and others, such as the regional trauma center, receiving only a small number of the casualties despite having the greatest capacity for casualty decontamination and patient care.
Victims of pulmonary agents present with symptoms ranging from mild mucous membrane irritation to chemical burns and apnea.41 The severity of presentation will vary with different chemical properties, air concentrations, durations of exposure, and the patient’s underlying health status.
Low-level exposures can result in minimal irritation to the eyes and airway and may have a delayed onset of initial respiratory toxicity. Low-level exposures can be problematic in victims with preexisting lung disease such as asthma or chronic obstructive pulmonary disease (COPD). Higher doses result in significant toxicity almost immediately and often have effects on the eyes and skin, as well as the lungs. Severe exposures will manifest as upper airway irritation, leading to increased secretions, productive cough, dyspnea, and possibly laryngospasm. Auscultation may reveal rales and crackles as a result of pulmonary edema. After a mass exposure, the majority of victims will present with mild mucous membrane irritation and self-limiting coughing and choking.
Sidebar: Clinical Presentation: Pulmonary Agent Exposure
- Skin is erythematous, and varying sizes of blisters may be present
- Onset is delayed with low-water-solubility agents
- Nonproductive cough to respiratory distress
- Burning of eyes and mucous membranes
- Nausea, vomiting
- Pulmonary: rales, decreased breath sounds, dullness to percussion
- Skin: irritation and mild erythema
- Eyes: irritation, conjunctivitis
- Arterial blood gasses: respiratory acidosis may be present, and oxygen levels may be low in symptomatic patients
- Chest radiography looking for bilateral infiltrates
- Findings may be delayed 12 to 24 hours
Pulmonary agents may cause damage in one or more of the following ways: asphyxiation, allergic reactions, or direct irritant or corrosive effects. Asphyxiation may result from displacement or dilution of oxygen by other gasses. Typically, this only occurs in enclosed spaces or other poorly ventilated areas. Allergic response to an inhaled toxicant may result in a pulmonary or systemic reaction, which may be mediated by one or more of a variety of immunoglobulins.41 Direct irritant effect is the main mechanism of toxicity. Topical damage to the respiratory tract may occur because of direct toxic inhalational injury to the airways or alveoli.41 The chemicals in this class combine with water to produce acids or bases. Cellular damage with consequent airway obstruction, pulmonary interstitial damage, surfactant loss, or alveolar–capillary damage can result in impaired oxygen–carbon dioxide exchange.
The pulmonary agents are grouped below by their water solubility, which impacts where in the airway injury occurs and the rapidity of onset.
Ammonia, formaldehyde, hydrogen chloride, and sulfur dioxide are common examples of highly water-soluble irritant gases. These chemicals react rapidly with moisture in the upper airways to form corrosive compounds. In patients exposed to these agents, chemical burns affecting the upper airway and eyes, as well as laryngospasm, are the primary concerns. These patients often need aggressive airway management. Any hint of airway compromise exhibited by stridor may be an indication of impending airway obstruction.
Intermediate Water Solubility
Chlorine is the prototypical example with intermediate water solubility. When inhaled into the moderately size airways, it combines with the water there to form hydrochloric and hypochlorous acid. Chemicals in this category are capable of affecting the entire respiratory tract. Consequently, the patients have some upper airway involvement but also have significant wheezing and bronchospasm as a result of the moderate-size airway involvement.40,43 Similar to the highly water-soluble agents, irritant effects occur rapidly and are dose dependent.
The low-water-solubility agents penetrate deeper into respiratory tissues because they react slower with water to form corrosive compounds. Examples of low-solubility agents include various oxides of nitrogen and phosgene. Oxides of nitrogen have numerous industrial applications and are produced by crops in silage. These compounds react with water to form nitric acid. Phosgene also has numerous industrial uses relating to plastics and polymer production. Phosgene reacts with water to form modest amounts of hydrochloric acid. Low-level exposures to these agents can result in a significant delay in the onset of toxicity, and progression of the injury may last for several days before reaching a nadir.40,41 After leaving the contaminated area and medical intervention, most patients will have an apparent improvement but are at risk of delayed (up to 24 hours later) worsening of lower airway problems.
Among this group, phosgene is probably the most concerning agent. Toxicity can occur at concentrations below the odor threshold. Because it smells like freshly mown hay even at detectable concentrations, victims often will not recognize the hazard. In addition to poor recognition, phosgene also has additional toxic mechanisms. Besides water, phosgene also reacts with cellular constituents. Acylation reactions occur with sulfhydryls, amines, and hydroxyl groups that produce hydrochloric acid. Additionally, the process of acylation can damage cell membranes, disrupt enzymatic processes, impair energy production, and promote free radical formation.41
Incidence and Risk Factors
Respiratory exposures to irritant chemicals are fairly common. Minor exposures often occur in the home or workplace when cleaning chemicals are inappropriately mixed. Combining household bleach with acidic or ammonia-based chemicals will result in the generation of chlorine or chloramine gas, respectively. Such exposures are usually self-limiting when the victim is removed to fresh air. Large-scale releases resulting in multiple casualties typically are the result of industrial accidents or illegal activity. Whatever the cause, exposures that occur in enclosed spaces with limited ventilation are more likely to produce significant injuries than exposures that occur outside. Victims with preexisting lung disease such as asthma or COPD may have significant problems even with minor exposures.
Treatment: Pulmonary Agents
General Approach to Treatment
The primary goal of therapy is to limit further exposure, maintain respiratory function, and monitor for delayed complications.40,41,43 The initial goals are detection of the exposure source; mitigation of ongoing exposure; stabilization of immediate threats to the airway, breathing, and circulation; and appropriate use of antidotal therapies. After stabilization, the patient should be monitored for the late onset of complications, especially if a poorly water-soluble agent is believed to have been involved. Followup evaluation may be needed to assess for the development of long-term respiratory complications in more severe cases.
Removal from the contaminated atmosphere is the initial priority of therapy. Removal of clothing is usually adequate decontamination for irritant gas exposures unless the victim has skin or mucous membrane irritation. For any patient with significant irritation, water should be applied to affected areas. If there is any doubt, the patient should receive full-body decontamination. The treatment of irritant gas exposure is primarily supportive in nature with aggressive early airway management for patients with high and moderately water-soluble exposures.41 Airway compromise is the most common cause of death in these patients. The method of delivery and flow rate of supplemental oxygen should be modified based on the severity of clinical presentation.
Drug Treatments of First Choice
There is no specific antidote for the treatment of casualties exposed to these agents. The general approach to pharmacotherapy is similar to the treatment of acute asthma (see Chap. 15). Initially, 100% humidified oxygen should be administered and then oxygen concentration should be adjusted downward as tolerated. An oxygen saturation of 90% (0.90) or greater is the usual goal of therapy. β2-Adrenergic agonists should be administered if bronchospasm develops. Typically, albuterol is given as a nebulized solution containing 2.5 mg (0.1–0.15 mg/kg/dose in young children) over 5 to 15 minutes.40,41 Inhaled corticosteroid treatment with budesonide is often used in combination with albuterol for victims with symptomatic chlorine exposures, but clinical data on efficacy are inconclusive.40,41 In a randomized controlled study, pigs were exposed to chlorine gas, and the effects of terbutaline, budesonide, or combination therapy revealed that there was improvement in the terbutaline and the budesonide alone groups, which was enhanced with combination therapy.43
Alternative Drug Treatments
Theoretically, the use of sodium bicarbonate may neutralize the acidic products formed when the chlorine gas reacts with water. There have been no controlled studies in humans evaluating the safety or efficacy of sodium bicarbonate inhalation.43 There is limited evidence to suggest that repletion of glutathione reduces or prevents lung damage by phosgene. This may provide an opportunity for therapeutic intervention with inhaled N-acetylcysteine, 1 to 10 mL of a 20% solution every 2 to 6 hours.40
Evaluation of Therapeutic Outcomes
Victims should be observed for improvements in mucous membrane irritation and respiratory functions. Those who had significant acute injury can have persistent pulmonary abnormalities (e.g., a decrease in total lung capacity, functional residual capacity, and vital capacity and a significant increase in residual volume and airway resistance over several years and persistent reactive airways disease syndrome). After the initial hospitalization follow up for pulmonary function, monitoring and evaluation of the medication regimen should be addressed in the care plan.
The vesicants are often referred to as blistering agents. They have produced more casualties than any other type of chemical weapon. Sulfur mustard was the most widely used vesicant.44,45 Lewisite and phosgene oxime are also classified as vesicants but have never been used. Vesicants have lower lethality than nerve agents but cause injuries that often disable survivors for weeks to months. Often victims have permanent effects such as loss of vision, respiratory problems, and physical disfigurement. Because of the psychological impact of seeing such injuries and the large amount of resources required to care for victims, vesicants are considered ideal terrorist weapons.
The clinical hallmark of the vesicant agents is the formation of fluid-filled blisters and bullae on the skin (eFig. 12-3).44,45
Examples of injury caused by (A) sulfur mustard in the eye, (B) bullae on a patient’s back, and (C) scarring of the arm and hand of a patient of 5 days after exposure. (From McManus et al.45)
The mortality rate is low in victims with only dermal exposure, but they will consume considerable medical resources and require lengthy hospitalization. Inhalation exposures are associated with higher mortality rates. Initial signs of vesicant exposures usually appear within 1 to 2 hours but may be delayed for up to 24 hours depending on the agent and degree of exposure.44,45 Typically, erythema and pain occur first and then rapidly progress to vesicles or bullae. In very large exposures, nausea, vomiting, and CNS depression also may be seen early in the course of the exposure. Patients with very high exposures may develop a central zone of coagulation necrosis in the exposed area. The eyes are very sensitive to vesicants with exposure often resulting in chemosis conjunctivitis. Systemic effects can also be seen with vesicants.44,45 The mustards can produce bone marrow suppression as a delayed consequence. Lewisite contains arsenic, which, when absorbed systemically, can impair cellular energy production. In the long-term vesicants can cause changes in pigmentation or scarring of affected areas. Also, restrictive respiratory disorders may result from inhalation exposures.44,45
Sidebar: Clinical Presentation: Blister Agent Exposure
- Skin will be erythematous, and varying sizes of blisters may be present
- Onset is delayed with low-dose exposures
- Eyes and mucosa are most sensitive
- Burning pain and itching at the affected areas
- Mucosal irritation
- Nausea, vomiting
- Skin: erythema to bullae
- Eyes: irritation, conjunctivitis, ophthalmitis
- Pulmonary: mild cough to respiratory distress
- High fluid and electrolyte loss is not expected
- Immune suppression may occur
- Blood and urinary arsenic concentrations for lewisite exposures, if available
Causative Agents and Mechanism of Toxicity
The vesicants include sulfur mustard, lewisite, and phosgene oxime. Vesicants bind irreversibly to cell structures within minutes of exposure; this process is referred to as “fixing.” The mechanisms of action for the three agents are discussed below.
Mustard is an oily, tan-colored liquid that has low volatility except at high temperatures. Allegedly, mustard received its name from its smell or taste and its color. When vaporized, mustard is approximately five times heavier than air. Pure mustard freezes at 13.9°C (57°F) but can be combined with other chemicals to lower the freezing points. This allows its use in colder environments.
Mustard rapidly penetrates cells and generates toxic intermediates that damage tissues through a poorly understood process.44,45 Within the cells, mustard alkylates DNA, RNA, and proteins. These reactions disrupt cell function by preventing transcription and translation of genetic material to assemble proteins necessary for maintaining cell function. Similar to what is seen with nitrogen mustard chemotherapy, rapidly dividing cells are most susceptible. Mustard also creates stable bonds with thiol and sulfhydryl groups. These reactions may lead to an inability to detoxify free radicals, resulting in lipid peroxidation and impairment of the activity of thiol-containing enzymes.44,45
Lewisite is an arsenical compound with vesicant properties. Lewisite hydrolyzes rapidly and has very limited activity in humid environments. Lewisite is similar to mustard in that it damages the skin, eyes, and airways. However, its clinical effects appear within seconds of exposure.44,45 Fortunately, the recovery time is also faster than for mustard. Lewisite shares many biochemical mechanisms of injury with the other arsenical compounds. It inhibits many enzymes that are important for energy production, particularly those with thiol groups, such as pyruvic oxidase, alcohol dehydrogenase, succinic oxidase, hexokinase, and succinic dehydrogenase.44,45 Inactivation of carbohydrate metabolism, primarily because of inhibition of the pyruvate dehydrogenase complex, is thought to be a key factor.
Phosgene oxime is the third chemical designated by the U.S. military as a vesicant agent. It is important to note that phosgene oxime is not the same as phosgene gas that was described earlier. However, it is not a true vesicant because, unlike mustard and Lewisite, it does not produce fluid-filled blisters; rather, it produces solid wheal-like lesions resembling urticaria.44
Phosgene oxime’s exact mechanism of action is unknown.44,45 It might produce biologic damage because of corrosive effects of the chlorine moiety, because of the direct effect of the oxime, or because of the carbonyl group. The skin lesions, in particular, are similar to those caused by a strong acid.
Treatment: Vesicant Agents
General Approach to Treatment
The primary defense against vesicants is protective garments and decontamination. Removal of contaminated clothing and thorough washing need to be initiated as soon as possible. Decontamination is only effective if performed within 2 to 5 minutes of contact with the skin. Unfortunately, in many cases, the exposure will not be recognized in time to perform effective removal.44,45 Recently, there has been work evaluating various creams to protect against sulfur mustard. Although the data are limited, it appears that creams with drugs designed to actively neutralize the agent are superior to simple barrier creams. Experimental studies have found that metal oxide nanocrystals and perfluorocarbon compounds in creams reduced lesion size in exposed animals.45
Drug Treatments of First Choice
Current therapy for vesicant exposures is primarily supportive care.45 For skin lesions less than 1 cm, topical soothing agents, such as calamine, are all that is needed. Larger lesions should be deroofed and treated with topical antibiotic ointment. Victims with large dermal exposures may appear similar to burn victims. However, fluid loss is significantly lower than in burn victims. To prevent overhydration, rehydration should be based on the patient’s fluid and electrolyte status rather than using formulas based on affected surface area.45 Respiratory effects should be treated as described in the section on pulmonary agents. If bone marrow suppression occurs, transfusions or growth factors may be used to treat anemia or immunosuppression.
Ocular exposures should be irrigated with saline for 15 minutes. Lubricating eye drops may be used to reduce discomfort but severe cases may require systemic pain medications. Ophthalmic preparations of antibiotics, such as 10% sulfacetamide ointment three times daily for a week, can be used to prevent secondary infections in the eye. Ophthalmic steroids, such as 0.1% dexamethasone drops twice daily for 2 days, can be used to reduce inflammation early in the course of therapy. Atropine 1% drops four times a day for 2 days can be used to reduce scarring and blepharospasm.
Currently, there is no approved antidote for mustard. Several compounds are under investigation, but they are not yet commercially available; indeed, FDA approval is unlikely within the next 2 to 3 years.45 The one currently approved drug that may offer some benefit is N-acetylcysteine, a glutathione precursor and sulfhydryl donor that has been evaluated as a treatment against sulfur mustard exposure.46 In several animal studies, it appears to minimize lung injury associated with low to moderate exposure to mustard gas, which is believed to be related to glutathione depletion.47,48 In one study, it reduced lung injury by 70% in rats when given 10 minutes before exposure, and administration up to 90 minutes after exposure was also associated with some benefit.48 It is by no means a perfect antidote, but it has a track record of human safety, and further studies may be warranted.
The most common adverse effects after oral administration of N-acetylcysteine are nausea and vomiting, but this is not significantly higher than placebo. The U.S. military recommends prophylactic administration with an oral dose of 1,200 mg four times a day for persons who are likely to have mustard exposure for as long as they are in a high-risk environment.46 For postexposure treatment, either oral or IV N-acetylcysteine may be used. Although there are no human studies, animal data suggest that doses between 50 and 150 mg/kg are a reasonable emergency measure.47,48 The IV route may achieve better tissue penetration and distribution, but currently there are no published data indicating either route is superior. There have been no controlled studies addressing patients with immunosuppression caused by sulfur mustard exposure. However, for such patients, it would be reasonable to follow guidelines for patients receiving alkylating agent chemotherapy.
British anti-Lewisite, also known as dimercaprol, is a chelating agent that contains sulfhydryl groups that bind the arsenic moiety of the lewisite molecule.44 It comes in a peanut oil vehicle and should be avoided in patients with peanut allergy. British anti-Lewisite can be used topically as a barrier or to assist in decontamination. The injectable product can be compounded into topical products for immediate dermatologic or ocular use. When there is greater than 5% body surface area affected or evidence of systemic arsenic poisoning, British anti-Lewisite should be administered intramuscularly (IM).44 Recommended dosing for children and adults is 2.5 to 3 mg/kg IM four times per day for 2 days, twice a day on day 3, and then once daily until recovery. Typically, the course of therapy will last for 7 to 10 days. If renal impairment develops, the drug should be discontinued or the dose reduced if the drug remains clinically necessary. IM administration of British anti-Lewisite is painful because of its peanut oil vehicle. Hypertension, tachycardia, and a sense of chest tightness are common during administration. Other common complaints include lacrimation and rhinitis, headache, paraesthesia, tremor, and gastrointestinal (GI) symptoms.
Succimer may be considered as an alternative to British anti-Lewisite for systemic toxicity. Succimer is a chelating agent that is indicated for pediatric lead poisoning but has been reported to be useful for systemic arsenic poisoning.44 Typical dosing is 10 mg/kg orally every 8 hours for 5 days and then 10 mg/kg every 12 hours for 14 days. Common adverse effects include GI upset, rash, and elevations of aspartate aminotransferase and alanine aminotransferase. Less commonly, significant neutropenia has been reported.
Evaluation of Therapeutic Outcomes
Victims of vesicant exposures should be monitored for resolution of lesions, respiratory function, and resolution of any systemic toxicity. Good wound care and appropriate antibiotic selection are critical for managing vesicant exposures, particularly if immunosuppression occurs. Blood cell counts should be monitored daily, and colony-stimulating factors should be considered for those with severe leucopenia.44