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 as 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 nerve agent in the Tokyo subway system. Although they used a very ineffective delivery route for this chemical, the attack affected approximately 5,500 victims and resulted in 11 deaths. The nearest hospital received 640 of the victims and their experience is documented in the medical literature.5 The majority of these patients were not decontaminated prior to arrival at the hospital, and, 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 Chap. 14). 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 will depend on the type of dispersal device and ventilation of the area. Individuals in this area will rapidly loose consciousness and develop seizures and apnea due to 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.
Sidebar: Clinical Presentation of 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
The most common clinical presentation for victims who arrive at a healthcare facility consists of miosis, rhinorrhea, cough, and mild shortness of breath.7 Sweating or muscle fasciculation may also be seen if droplets have come in contact with the skin. Those 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 will have a different clinical presentation than adults; central cholinergic effects predominate and thus pronounced weakness, altered mental status, and fewer secretions are more common.8
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.9–11 Survivors of terrorism with the nerve agent sarin in Japan reported an increased prevalence of such disorders.12–15 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 and who later died of other causes had decreased white matter and increased brain cavity size.16 Cholinesterase enzymepolymorphisms can influence individual response to different organophosphates and may affect susceptibility to these long-term neuropsychiatric problems and neuropathies.17–20
Nerve agents bind to various cholinesterase enzymes and prevent the breakdown of acetylcholine (see Fig. 16–5). 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, while 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.21 Over time the organophosphate binding may become irreversible through a process called enzyme aging where 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. Once 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 approximately 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.22
Destructive ranges for various sizes of nuclear weapons. (kt, Kilotons [equivalent to 9.07 × 105 kg]) 500 rad is equivalent to 5 Gy. (From reference 51.)
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 different properties. The most important of these are aging time, potency, and volatility. Table 16–2 lists the characteristics of common organophosphate insecticides used in the home. 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 one 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.
TABLE 16-2 Properties of Nerve Agents |Favorite Table|Download (.pdf)
TABLE 16-2 Properties of Nerve Agents
|Aging time||5 h||5 min||14 h||48 h||12–24 h|
|Dermal LD50||1,700 mg||100 mg||1,000 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 prior to 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 that present to the hospital with residue on their clothes, hair, or skin also represent a significant risk to healthcare professionals.
Desired Outcome and General Approach to Treatment
The initial goals for treatment of nerve agent poisoning are; mitigating ongoing exposures, stabilizing immediate threats to the airway, breathing, or circulation, and initiating appropriate antidotal therapies. After stabilization, the patient should be monitored for ongoing antidote needs. Follow-up 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 the 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 Chapter 14.
Although the general approach to treatment for individuals who have been exposed to 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. 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.23 Because it freely crosses the blood—brain barrier, atropine acts both centrally and peripherally. In the 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.24 Other oxime compounds, such as obidoxime, that offer greater CNS penetration are used in other countries but are not FDA approved.24 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.23 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
In situations where 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.25 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.26 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.26 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.26–28 Central-acting agents are impractical because they can impair cognition. An ideal pretreatment that would offer peripheral and CNS protection without disrupting cognition or enhancing toxicity is currently not available.
Young children exposed to organophosphates often will have an unusual clinical presentation as 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, once 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.8 It is important to remember that dosing in this situation is based on neutralizing the excess acetylcholine and not on body weight, so dosing will be titrated in the same manner as adults and will require similar total doses.
The Strategic National Stockpile and CHEMPACK programs (which are discussed below in detail in the section Strategic National Stockpile/CHEMPACK Program) may augment local supplies of antidotes but will take hours to days to arrive and be distributed. Thus plans need to be made at the local level for responding to the initial need for antidotes. Antidote stocking of an initial cache for nerve agent exposures can be quite expensive. Given the infrequency of such events, stocking the drugs with appropriate expiration dates may be problematic. Several authors suggest keeping a stock of powdered atropine on hand for rapid reconstitution. Powdered atropine can be used to rapidly prepare several hundred doses of atropine at a very low cost.29–31 Prefilled autoinjector syringes containing atropine, pralidoxime, and diazepam are available for use in the prehospital and decontamination settings. They are included as part of the strategic national stockpile and CHEMPACK programs. Pralidoxime from autoinjectors appears to be stable if reformulated for intravenous use.32
Evaluation of Therapeutic Outcomes
The assessment of nerve agent exposures is mainly clinical. As described above, 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 due to 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 patients 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.