Chemical warfare. Nerve agent poisoning.

The threat of civilian and military casualties from nerve agent exposure has become a greater concern over the past decade. After rapidly assessing that a nerve agent attack has occurred, emphasis must be placed on decontamination and protection of both rescuers and medical personnel from exposure. The medical system can become rapidly overwhelmed and strong emotional reactions can confuse the clinical picture. Initially, care should first be focused on supportive care, with emphasis toward aggressive airway maintenance and decontamination. Atropine should be titrated, with the goal of therapy being drying of secretions and the resolution of bronchoconstriction and bradycardia. Early administration of pralidoxime chloride maximizes antidotal efficacy. Benzodiazepines, in addition to atropine, should be administered if seizures develop. Early, aggressive medical therapy is the key to prevention of the morbidity and mortality associated with nerve agent poisoning.

Sulfur mustard: its continuing threat as a chemical warfare agent, the cutaneous lesions induced, progress in understanding its mechanism of action, its long-term health effects, and new developments for protection and therapy.

Although sulfur mustard (SM) has been used as a chemical warfare agent since the early twentieth century, it has reemerged in the past decade as a major threat around the world. SM is an agent that is easily produced even in underdeveloped countries and for which there is no effective therapy. This agent is a potential threat not only on the battlefield but also to civilian populations. The skin and other epithelial surfaces are the first targets as this agent is absorbed, and reactions within the skin are the subject of active research into the mechanism of action of this alkylating agent. The depletion of glutathione, generation of reactive oxygen species, and the formation of stable DNA adducts remain theoretic and demonstrated by-products of SM exposure implicated in the disease produced. However, new findings related to the effects of SM on the basement membrane zone; interest in delayed healing of the lesions induced; the inflammatory mediators, enzymes, and cytokines that result; and cellular typing of the inflammatory infiltrate will increase our understanding of the pathophysiology of the lesions caused by SM. In addition, the recent development of a topical skin protectant for SM and for other chemical warfare agents may have broad applications within dermatology.

Clinical effects of organophosphorus cholinesterase inhibitors.

Nerve agents, highly toxic organophosphorus cholinesterase inhibitors, inhibit acetylcholinesterase and cause an accumulation of acetylcholine. Clinical effects depend on the route and amount of exposure and include miosis, bronchoconstriction, excessive secretions, vomiting, seizures, and cessation of respiratory and cardiac activity. Eye effects include miosis, engorgement of ocular vessels, pain, and decrease in light sensitivity. Therapy consists of atropine, a cholinesterase reactivator (pralidoxime), and ventilation as needed.

A serious skin sulfur mustard burn from an artillery shell.

Despite the Geneva Protocol of 1925 and the Paris Conference on Prohibition of Chemical Weapons in 1989, sulfur mustard and other chemical weapons continue to pose a hazard to both civilians and soldiers. The presence of artillery shells containing sulfur mustard, both in waters where these shells were dumped and in old battlefields, presents a problem in times of peace, especially for those who collect wartime memorabilia. Past literature has reported several hundred incidents involving fishermen who inadvertently pulled leaking shells aboard their fishing vessels, thereby exposing themselves to the vesicant chemical. Other literature reports exposure to children who found the chemical shells in old battlefields. The purpose of this article is to report the first case of a serious sulfur mustard burn that occurred after removing the detonator from an old artillery shell in a historic battle field near Verdun, France. The circumstances surrounding the injury, the diagnosis and management of injuries secondary to sulfur mustard, and the long-term consequences to the patient are presented and discussed. Although skin grafting has been used in the management of other chemical burn injuries, this report is the first to describe the need for split-thickness skin grafts in the management of a patient with sulfur mustard burns.

Chemical warfare agents: II. Nerve agents.

Nerve agents are highly potent and rapidly acting organophosphorus compounds that irreversibly bind and inactive acetylcholinesterase. Only rarely have they been used in warfare, but their great lethality and the threat that they pose have encouraged production and stockpiling in large quantities. They differ in a number of important ways from common agricultural organophosphate insecticides. In light of recent threats of chemical warfare and the possibilities of chemical acts of terrorism, North American physicians should be knowledgeable of the effects of these agents and the care of exposure victims.

Nerve agents: a review.

Nerve agents produce neuromuscular blockade and convulsions in exposed humans. Military personnel in areas of potential exposure take prophylactic pyridostigmine. They are instructed to self-administer atropine and pralidoxime at the first sign of nerve agent toxicity. The key to treatment of nerve agent poisoning is the administration of atropine in doses larger than is customary in most other disorders, repeated as often as needed. Mechanical ventilation may be required. Convulsions are treated with diazepam, but only after atropine has been administered.

Agents of chemical warfare: sulfur mustard.

Sulfur mustard is a chemical warfare agent of historical and current interest. Favored militarily because of its ability to incapacitate rather than its ability to kill, its use results in large numbers of casualties requiring prolonged, intensive care. In light of recent threats of chemical warfare and the possibilities of chemical acts of terrorism, North American physicians should be knowledgeable of its effects and the care of its victims.

A model for carbamate and organophosphate-induced emesis in humans.

In human volunteers, studies to assess the adverse effects of the carbamate anticholinesterase physostigmine showed that the intramuscular dose observed to induce emesis in 50% of subjects tested (ED50) was 28.1 (23.5-120.7) micrograms/kg. This dose reduced whole blood cholinesterase (ChE) activity to 60% of control values. Studies in marmosets to assess the behavioural toxicology of physostigmine showed that the corresponding ED50 and ChE activity values were 34.3 (21.5-55.8) micrograms/kg and 66% respectively. Sarin was also shown to induce emesis in marmosets, but only at doses that reduced erythrocyte ChE activity to 12% of control values. These data seem also to correspond with reports of organophosphate poisoning in humans. It is concluded that the marmoset may be a very good model of both carbamate and organophosphate-induced emesis in humans.

What to do in case of an unthinkable chemical warfare attack or accident.

Successful management of casualties in a toxic chemical attack or accident depends on planning, preparation, and training. In many communities, physicians join other emergency rescue personnel to take part in periodic exercises and drills. In case of a large-scale attack or accident, all medical care providers will be needed to care for casualties. Chemical warfare agents are generally considered to be highly toxic, exotic materials, but most are not. Nerve agents are similar to, although more potent than, commonly used insecticides; cyanide and phosgene are widely available; the incapacitating agent BZ has effects identical to those of scopolamine; and most physicians with knowledge of chemotherapy are familiar with the effects of mustard. Although a chemical attack might be perceived as an uncontrollable disaster, the guidelines for successful management are the same as for any toxic chemical accident. Medical care of casualties depends on knowledge of the agent and timely intervention, and those responsible for such care must be ready.

Pharmacokinetics of physostigmine intramuscularly administered to guinea pigs.

Physostigmine pharmacokinetics was determined in guinea pigs following im administration of 5-146 micrograms/kg. Eighteen male guinea pigs were divided into three equal groups and given dosages of 5, 27, and 146 micrograms/kg, respectively. Physostigmine was given in the right hind limb and blood samples were collected at various times up to 300 min postinjection via an indwelling carotid catheter. Unbound physostigmine plasma concentrations were analyzed by HPLC. The concentration-time profile for each animal was fitted to standard pharmacokinetic models. A one-compartment open model with first-order absorption and elimination provided the best fit. For all dosage groups, physostigmine concentrations peaked in approximately 30 min. Apparent volumes of distribution (assuming 100% bioavailability) ranged from 1.9 to 2.2 L/kg. Systemic clearances and elimination half-lives were 30-36 mL/min/kg and 40-50 min, respectively. The area under the concentration-time curve and the Cmax were linearly related to the dose, indicating pharmacokinetic linearity. In conclusion, physostigmine, intramuscularly administered to the guinea pig, is absorbed, distributed, and eliminated rapidly, and the pharmacokinetics behave linearly within the 5-146-micrograms/kg dosage range.

Progress in medical defense against nerve agents.

For nearly 50 years, nerve agents have constituted a serious threat that has stimulated extensive efforts to develop effective medical countermeasures. Recent progress in producing pharmacologic defenses suggests that humans can be largely protected from the lethal and prolonged incapacitating effects of these compounds on a chemical battlefield. Current research on new approaches to binding and inactivating nerve agents may further decrease their potential as a threat against protected persons.

Effect of intravenous thiamine on pralidoxime kinetics.

Subjects were given pralidoxime chloride (5 mg/kg, intravenously) alone and again while they were receiving an infusion of thiamine hydrochloride. After the addition of thiamine: (1) overall, the urinary excretion of oxime was the same but the amount excreted in the first three hours was smaller; (2) the plasma half-life of oxime lengthened; (3) the plasma concentrations of oxime rose; and (4) the intercompartmental clearances and rate constant for elimination for oxime fell. These changes suggest that thiamine and oxime compete for a common renal secretory mechanism or that thiamine alters the membrane transport of oxime.

Temporal intrapersonal physiological variability of cholinesterase activity in human plasma and erythrocytes.

Erythrocyte and plasma cholinesterase activities were measured biweekly in one group of 22 subjects for a year and daily for three weeks in another group of nine men. The average range [i.e., (range/mean) X 100] of activity of erythrocyte cholinesterase in men during a year was 8% and during three weeks was 5%. For plasma, the corresponding values were 25% and 12%. The average ranges for erythrocyte and plasma cholinesterase activity in women during a year were 12% and 24%. Erythrocyte cholinesterase activity varies less than do hematocrit, hemoglobin, or erythrocyte count.

Influence of age, sex, and oral contraceptives on human blood cholinesterase activity.

We estimated cholinesterase (EC 3.1.1.8) activities in erthrocytes and plasma of 443 men, 188 women not taking oral contraceptives, and 70 women who were taking oral contraceptives. Men in the first six decades of life had higher plasma cholinesterase activity than did women who were not taking oral contraceptives, and these women had higher plasma cholinesterase activity than women taking oral contraceptives. After the age of 60 there was no intersex difference. Activity of erythrocytes from the oral contraceptive group was higher than in the other groups, men had the lowest activity, and there was an increased activity with age in both sexes until the age of 60. These findings suggest that there is no single "normal" value for cholinesterase activity for adults.