In their zeal to hasten the end of this world, the Japanese Aum Shinrikyo (“Supreme Truth”) doomsday cult repeatedly released anthrax and botulinum spores in the winter of 1993/1994. Failing these attempts at biological mayhem because of insolvable technical glitches, the Aum turned to nerve agent (nerve gas), this time achieving their sinister end (1). An elite strike team first released sarin vapor in the central Japanese city of Matsumoto in June 1994, causing 300 or more casualties and seven deaths. Five two-man teams next (March 1995) deployed nerve gas in Tokyo’s subway cars by puncturing a dozen liquid-sarin-filled plastic bags (1,2). The underground bedlam was unspeakable: of the 5510 injured seeking medical care, more than 1000 were held for observation or treatment, including 17 severe exposures that survived and 12 that did not. To bring home the potential enormity of the chemical threat to civilians, recall the 1984 industrial accident that released a plume of methylisocyanate and chlorine gas over the sleeping Indian city of Bhopal. Of the estimated 38,000 immediate inhalation casualties, some 8000 eventually perished (1).
Terrorists now are targeting Americans at home not only with conventional explosives, but also with nuclear, biological, and chemical weapons of mass destruction (WMD) (2). As security measures tighten, terrorists are bound to turn from overt explosives and guns to covert small-mass, large-yield WMD. Because chemical and biological agents can be prepared in stealth from common commodities and are concealable in personal items (thus, unlike nuclear devices, are virtually undetectable), they have become the “poor man’s atom bomb” of asymmetric conflict.
Although military forces stock a fearsome arsenal of chemical weapons, the ponderous hardware for transport and deployment is readily spied. The pragmatic choice for small-unit terrorist action is the vaporizable G-series of highly toxic volatile agents (Table 1) that can be transported covertly as clear liquids in sealed inconspicuous vials but that vaporize unaided to poison the air when released. Of the four G-agents (Table 1), soman and sarin stand out because of their waterlike volatility at room temperature and the awesome toxicity of the resultant vapor (2,3). The liquid is virtually undetectable, even with full-body searching, because so little is required; air in the <250 m3 passenger compartment of a modern jet, for instance, can be rendered lethal by the vapor from a mere teaspoonful of liquid sarin spilled on the carpeted floor then circulated fore-and-aft throughout the passenger cabin in about 2½ minutes.
The Challenge to Anesthesiologists
Because treatment of nerve gas mass casualties requires not only ventilatory assistance or control, but also acute pharmacologic therapy titrated to a clinical end-point, all in a hostile environment, incident responders must be trained in largely anesthesia-related emergency measures from initial rescue through triage and evacuation to eventual in-hospital stabilization. Short of a major wakeup event, little federal guidance seems forthcoming (see Discussion); yet, prudence suggests that the specter of conflict with a nation known to harbor and use chemical weapons without qualm inevitably will spawn infiltrators to intimidate the United States population. With little effort, anesthesiologists can be prepared for the worst.
The organophosphorus cholinesterase inhibitors, commonly known as nerve agents (gases), were developed in the 1930s from closely related insecticides. However, whereas pesticides are only toxic to humans in large amounts, nerve agents are among the deadliest synthetic chemicals (Table 1). The boiling points of nerve agents separate them into two distinct categories: volatile and nonvolatile. The former, because of rapid absorption by vapor inhalation, are true WMD; the latter, because of prolonged persistence but slower percutaneous absorption, are military target weapons of mass disruption (used to slow an advancing armored column, for instance). High volatility leaves only the volatile liquid nerve gases as expedient weapons for covert terrorist strikes. Critical to rescue workers is not exact agent identification but rather instant recognition of mass nerve agent exposure, including miosis, dim vision, runny nose, difficulty breathing, incontinence, seizures, muscle fasciculation, and weakness.
Although they are liquids with boiling points higher than water, volatile nerve gases vaporize sufficiently at room temperature to yield a highly lethal dense vapor (5). Therefore, even aerosolized droplets on clothing or skin soon evaporate, substantially easing the resource-exhausting casualty decontamination and rescue worker protection required for nonvolatile gases (6,7). The primary absorption route of volatile nerve gas is by inhaling the vapor. However, aerosol droplet or liquid splash absorption from eye and skin, and intestinal absorption from droplet-contaminated food and water, could become troublesome in colder climates (8). The immediate local cutaneous effects of splashed nerve gas droplets manifest as subdermal fasciculation, sweating, and piloerection.
The high boiling point, hence low vapor pressure in temperate climates, of VX (Table 1) makes it a weak inhaled toxin compared with the G-agents; its oily consistency conversely favors transcutaneous absorption. VX is an extremely lethal, insidiously slow-onset, droplet agent that clings tenaciously to skin and clothing demanding total body protection of rescuers and exhaustive decontamination of victims and environment (9,10). Its lethality hit home when VX leaked from a remote Army depot, killing some 6000 sheep in Utah’s Skull Valley (11). As a terrorist weapon however, the bulky missile or artillery dispersion system makes VX a most unlikely candidate for inflicting toss-and-run mass casualties (12).
Clinical Presentation of Nerve Agent Exposure
Acetylcholinesterase (AChE), one of nature’s most efficient enzymes, hydrolyzes approximately 10,000 acetylcholine (ACh) molecules per second to inactive products. Predictably (4), its inhibition causes near-instant endogenous ACh flooding that presents as a fulminating cholinergic crisis composed of: (a) muscarinic effects at cholinergic end-organs such as secretory glands (rhinorrhea and bronchorrhea), smooth muscle contraction (miosis, asthmatic wheezing, and bladder and bowel hyperactivity), and cardiac pacemaker (vagal bradycardia); (b) nicotinic effects at the neuromuscular junction (skeletal muscle fasciculation, weakness, and eventual depolarization paralysis); and (c) central manifestations of neurotransmitter accumulation (convulsions and respiratory center depression). The proximate cause of death is respiratory, due to a combination of massive airway flooding, intense bronchospasm, progressive ventilatory muscle paralysis, and impaired respiratory center drive (9,13).
Exposure Classification (Triage)
First responders must be trained to recognize the clinical manifestations of nerve agent exposure in humans so as to quickly make informed triage and decontamination decisions.
This group includes subjects near to, but outside of, the vapor flume. Many in this category present with anxiety or panic reactions that may mimic classic vapor exposure symptoms such as visual disturbance, headache, or nausea. Absent miosis or blood cholinesterase depression (see Moderate Exposure), swift evacuation from the scene, and self-observation should suffice.
Minimal to Mild Exposure.
The ambulatory casualties in this group may experience miosis, rhinorrhea, or both, possibly with moderate eye or head pain. The important triage decision here is to sort the mildly sick from the mostly scared, i.e., to ensure that minimally exposed victims are directed to proper medical care while steering the unexposed “worried well” away from swamped rescue personnel.
The casualties in this group ambulate with some difficulty because of visual disturbance, muscle weakness, or both and may complain of dyspnea, chest pain, or both. Miosis (if exposed to vapor) is seen in many if not most; nausea is frequent and vomiting common. Facial, lingual, or superficial muscle groups may fasciculate randomly; generalized convulsions would place the casualty in the next higher triage category. Heart rate and blood pressure are unpredictable. Blood cholinesterases (erythrocyte or plasma) assayed by rapid microcolorimetry often are depressed below 50%(14).
Casualties experience pronounced respiratory difficulty with drooling, miosis, rhinorrhea, and asthmalike wheezing. The skin is damp with sweat, pale, and dusky. Heart rate and blood pressure are unpredictable; hypotension could presage circulatory failure. Profuse upper and lower airway secretions severely impair gas flow, and apnea may be imminent. Patients may be semicomatose, convulsing intermittently, or both. Jerking random contractions of large skeletal muscle groups and tongue should be differentiated from true convulsions (coordinated muscle contractions with loss of consciousness) that require anticonvulsant treatment. The patient may already be comatose, apneic, and pulseless by the time rescuers arrive, and convulsions may no longer be manifest because of flaccid muscle paralysis.
The largely empirical and experimental foundations for the medical management of chemical casualties (9,15) have matured to evidence-based medical practice by blending the hard-earned lessons of recent nerve gas terrorism in Japan and the Middle East with existing doctrine (5,16–18).
It is imperative that rescue personnel be protected at the least with chemical filter respirator (gas mask) and butyl rubber gloves before entering a chemical vapor-contaminated incident scene. If VX droplet spray or liquid spill are suspected, the complete protective suit, butyl rubber boots, gloves, and hooded mask ensemble (so-called MOPP gear) must be donned.
The immediate rescue scenario merely sorts walking unexposed and mildly exposed subjects from the more severely exposed downed casualties who require medical attention before evacuation. Triage granularity can be refined progressively as medical personnel and materiel converge on the scene.
Decontamination of vapor-exposed casualties requires little more than removal to an airy outside location and, where feasible, perhaps an exchange of clothing (11,19). Conversely, decontamination of liquid droplet exposure to eyes, skin, or clothing becomes a most urgent priority to minimize transcutaneous nerve agent absorption (9,13). (Caution: hot water, scrubbing, and strong detergents or bleaches increase perfusion of abraded skin, thereby hastening chemical agent absorption (8).)
Medical Rescue ABCDs.
Although casualties with respiratory depression or apnea require immediate assistance with ventilation, pulmonary gas exchange must be isolated from chemical vapor-containing ambient air. The urgent rescue tasks of Airway, Breathing, Circulation, and Drugs can be memorized as ABCD, and are treated as follows:
Airway and Breathing: Mouth-to-mouth insufflation is contraindicated because the rescuer not only would inhale toxic air, but also, during exhalation, will pass it on to the casualty (20). A self-inflating (Ambu®) bag and mask open to ambient air, likewise, forces toxin-containing air down the casualty’s lungs. However, adequate lung isolation can be secured by connecting the self-inflating bag’s unidirectional valve tail to an oxygen tank or filtered compressed air source. An oral airway greatly facilitates gas exchange and aids suction access by lifting the tongue from the lax posterior pharynx (21).
Optimally, endotracheal intubation of apneic and near-apneic casualties isolates the lungs from toxic vapor, secretions, and vomitus, forces gas transport through constricted bronchi, and permits suctioning of the deeper airways. (Caution: an intubating neuromuscular blocking drug seldom is called for; if required, titrate small doses to effect, keeping in mind that succinylcholine is two molecules of ACh fused at the choline tails and, thus, will be hydrolyzed very slowly, contributing to prolonged flaccidity (11).)
The cuffed crico-thyroidotomy rescue device offers features comparable to tracheal intubation, but the safety of rescue crico-thyroidotomy is suspect, and its use in nerve agent casualties is undocumented. The laryngeal airway mask seals insufficiently when lung compliance is poor and offers inadequate airway protection from voluminous secretions and vomitus, whereas the esophageal-tracheal CombiTube® precludes suction access to the trachea, according to recent Israeli Defense Force analysis (18).
Apneic oxygenation has the potential for satisfying the short-term oxygen demand of apneic casualties, without further ventilatory assistance, by flowing oxygen at a low rate (approximately twice the metabolic requirement) through a wide-bore transtracheal needle. Apneic oxygenation has been proposed as an expedient alternative to intubation for apneic mass casualties because it can sustain oxygenation for 30–45 min, albeit at the price of progressive hypercarbia, provided that the lower airways have been cleared by lateral positioning and suction, and are kept dry by atropine administration (21).
Circulation and Drugs: Nerve agent antidote administration during the initial rescue phase relies on IM injection because IV lines are far too awkward to insert while wearing a gas mask (let alone clumsy gloves). Auspiciously, therapeutic blood levels of atropine and pralidoxime appear within minutes in fit volunteers injected IM with the Mark-I self-administration kit (9); however, antidote absorption becomes erratic when muscle perfusion declines as circulation falters (13). Large and repeated amounts of atropine, up to 3 separate 2-mg IM doses initially (8,15) and then more after (see below), must be given to block the muscarinic actions of endogenous ACh (secretions, sweating, and wheezing). Pralidoxime (Protopam® [2-PAM]), up to 3 separate 600-mg IM doses initially (8,15), if available to rescuers, is co-administered with atropine to regenerate AChE at the muscle end plate and restore skeletal (respiratory) muscle function.
Comprehensive Medical Care
In the end stage of field casualty care, patient management is transferred from the incident rescue and evacuation teams to a fixed medical care facility, suitably buffered by a hot zone admission interface.
No admitting hospital should take for granted the adequacy of field decontamination; prudence calls for establishing a well-aired hot zone outside the receiving department, perhaps sited in parking lot tents (17,22). In the hot zone, appropriately attired medical personnel provide more individualized attention to the ABCDs and decontamination (8,23). Once decontamination is completed (in case of vapor exposure, it requires no more than the removal of street clothing and, ideally, a shower), casualties are moved into the facility for definitive medical care (22). All other hospital entrances should be secured to prevent inadvertent secondary contamination or entry by unauthorized personnel (19).
The receiving area is the focal point for patient examination, documentation, registration, and definitive determination of whether to discharge, to observe, to treat, or to admit. In case of hospitalization, admission triage also determines whether intensive respiratory or circulatory support or both will be required. Fortunately, most spontaneously breathing, otherwise uninjured, patients can be managed with nerve agent antidotes and frequent reassessment in augmented nursing units (23,24).
Nerve Agent Antidotes.
Because of its brief half-life, 2–4 mg of atropine must be re-administered every few hours, easily totaling 20–50 mg/d in fit adults (4,15). Although experience in children is limited to accidental insecticide poisoning, an atropine dose range of 0.02–0.10 mg/kg has been proposed, with the caveat that infants can easily become hyperthermic, dehydrated, or both (18). (Caution: to avoid malignant brady-arrhythmias in adults, delay full atropinization until co-existing hypoxia has been corrected (9,13).) Adequacy of atropine dosing is gauged clinically by easing of breathing (or reduced inspiratory pressure), lessening of wheezing, and drying of secretions. (Note: neither mydriasis (25) nor tachycardia (15) have proven to be reliable indicators of full atropinization [see Convalescence].)
Should dimmed vision secondary to miosis (sunglasses effect) or ciliary spasm cause discomfort, topical homatropine (or equivalent ophthalmic preparation) promptly dilates the pupil, albeit with the unwelcome penalty of photophobia (25). (Caution: although spasm of the eye’s ciliary body is painful and alarming, opioids should be used sparingly to not further depress the respiratory center or aggravate bronchospasm (8).)
2-PAM given before the toxin-AChE complex begins to age (de-alkylates to form an irreversible covalent bond) leaches organophosphate toxin out of the active enzyme gorge (4,10). This uncoupling of the toxin-enzyme bond regenerates the esterase to resume hydrolysis of ACh at the neuromuscular junction, effectively reversing the nicotinic crisis (9,15). Sarin and tabun age so slowly that pralidoxime may still be effective when supplies eventually catch up with demand; soman, conversely, ages within minutes so that only instant self-administration of 2-PAM (feasible in the military but unlikely in the civilian setting) will be effective (4,13). Lacking experience, the IM pralidoxime dose for children is estimated at 15–25 mg/kg, with the caveat of hypotension (18). Because precise nerve agent identification may lag the incident by hours, 2-PAM should be administered regardless (when indicated) as soon as it becomes available (6,23).
Convulsions secondary to nerve agent intoxication respond to benzodiazepine anticonvulsants such as diazepam (Valium®) or midazolam (Versed®) (8,15). Be aware that although the brain continues to fire electrical seizure bursts (as shown by electroencephalography), convulsive motor activity ceases when skeletal muscles become paralyzed (11). Because oxygen consumption of the convulsing brain increases precipitously, adequate oxygenation is vital to this highly vulnerable patient group (21).
Severely exposed patients may require up to several days of assisted or controlled ventilation along with around-the-clock atropinization until freshly synthesized AChE takes over (26). Although complete erythrocyte AChE restoration may take months (red cells are replenished at a rate of 1% per day), recent Japanese experience is encouraging, in that partial AChE regeneration sufficed to restore neuromuscular transmission within days (23,27). Whatever the clinical signs of residual muscarinism (sweating, wheezing, or drooling) or neuromuscular dysfunction may be, they (rather than laboratory numbers) should be treated.
Nerve agents can affect the circulation adversely through vagal stimulation (bradycardia or the pooling of blood in the splanchnic bed) and the substantial quantities of fluids and electrolytes lost in exocrine gland secretions, vomitus, and diarrhea. Because IV fluids readily restore homeostasis, and atropine promptly reverses bradycardia, circulatory collapse has proven much less of a concern in managing adult nerve gas mass casualties than respiratory impairment (15,28,29). However, dehydration and hypotension may prove considerably more troublesome in children, the elderly, and the sick (18). Secondary fragmentation, concussion, thermal injury, or impact injury further complicate the clinical picture and gravely increase the risk of interventional surgery and anesthesia (18).
Miosis, one of the earliest signs of vapor exposure, also is one of the last to disappear, at times persisting for up to 14 days (25); dim-light vision may remain impaired for several more days (9). Relative progress of AChE regeneration can be documented with blood enzyme assay (14) and that of neuromuscular transmission with a hand-held peripheral nerve stimulator (21). Erythrocyte AChE assay is the more predictive laboratory test to observe recovery from organophosphate exposure than is plasma (butyl) cholinesterase because the former is genetically identical to the cholinergic system’s enzyme (4). Erythrocyte AChE thus provides a window, albeit a cloudy one, on tissue AChE regeneration because it is held back by the slow fixed erythrocyte turnover rate (4,15). Therefore, clinical recovery usually leaps well ahead of laboratory prediction (9,16).
The systematic approach to medical management of mass chemical casualties presented here implicitly assumes that: (a) first responders arriving at the incident scene are properly trained and equipped with protective gear. That assumption may not necessarily hold true, for chemical casualty rescue training will require substantial input from medical experts in this arcane field. The very nature of nerve agent intoxication virtually mandates that anesthesiologists proactively participate in relevant homeland defense exercises and take the lead in hospital mass disaster planning committees. (b) The primary injury is volatile nerve gas exposure from covert vapor release by hit-and-run terrorists. When a chemical agent is dispersed by long-range missile or artillery shell, secondary conventional injuries are to be expected, greatly complicating rescue, decontamination, triage, and anesthesia for surgery. The problem is further compounded when children or infants are injured. Comprehensive guidance for managing the complex interactions of combined injury mass casualties is provided by a timely review article (18).
One impediment to evidence-based disaster planning is that present rescue scenarios remain mired in the venerable Incident Command System protocol that has served well in containing remote industrial chemical spills but is no match in scale for urban mass casualties (2,7,22). In the Tokyo subway sarin strike, for instance, over 5000 civilians had to be triaged within a few hours, resulting in some 700 hospital admissions in short order; worse yet, the casualty toll might have been far graver had the Aum terrorists used full strength rather than diluted (to 30% potency) nerve gas (17). Thus, regional planners must address the disposition of vast numbers of fragile patients and be heedful of the systemic bottlenecks that plagued the Tokyo Metropolitan Disaster Command, including vehicles for casualty evacuation, balancing inter-hospital patient distribution, proportioning hospital bed allocation, maintaining two-way communication between rescuers and hospital staff, and coordinating interoperability among overlapping agencies (16,17). It is a credit to our Japanese colleagues that not only did they correctly diagnose nerve gas poisoning, contrary advisories of acetonitrile exposure notwithstanding, but they also administered state-of-the-art lifesaving treatments to so many in so little time.
I recommend that the local planning processes for managing nerve gas mass casualties be accelerated. Although the Centers for Disease Control (CDC) is the government’s lead agency for biological and chemical incidents, they are far better staffed and funded to deal with the former than the latter threat. Because the unpublished report Recommendations of the CDC Strategic Planning Workgroup (for summary see http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4904a1.htm) offers little more than threat analysis and promises of a nationwide diagnostic network by 2004/2005, a separate national agency tasked with chemical detection and identification technology, as well as rescue personnel protection and chemical casualty management guidance as its primary mission, may be required to coordinate planning, issue treatment protocols, preposition protective gear and hazardous environment ventilators, and stockpile chemical warfare agent antidotes.
Optimizing the limited national pool of anesthesia providers, concentrated in hospitals and ambulatory surgery centers, clearly requires training and exercising first responders in patient survival techniques, and providing a system for evacuating victims to local medical facilities where they can receive definitive medical care. Rather than dispatching medical caregivers to incident sites, it makes far more sense to concentrate anesthesia providers at sites of highest chemical casualty density, i.e., medical center hot zones, provisional emergency rooms, and critical care hospital wards.
Short of a major wakeup incident, little centralized guidance seems forthcoming; yet, prudence suggests that the specter of conflict with a nation known to harbor and use chemical weapons inevitably will spawn infiltrators to intimidate the United States population. Must we wait for a catastrophe before laying the medical groundwork? I hope not, for with little effort and modest expense, anesthesiologists can be ready for the worst. Even if hospital, municipal, or state agencies should prove unresponsive to our call for action (and well they may), each and every anesthesia department should be conversant at the least with the devastatingly rapid toxic properties of nerve agents and the means to treat them, make provision for stocking inexpensive drugs such as atropine, diazepam, and pralidoxime, and look into issuing a properly fitted chemical protective respirator to each staff member.
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