Weapons of Mass Casualties - Part Three

The importance of nerve agent’s peripheral effects is paramount. Acetylcholine is a neurotransmitter that is found throughout the central nervous system, the sympathetic and the parasympathetic autonomic ganglia, the postganglionic parasympathetic nervous system, most sympathetic sweat glands, and the skeletal muscle motor end plates.

There are popular mnemonics for the effects of the nerve agents:

1. Salivation, sweating
2. Lacrimation
3. Urination
4. Defecation, drooling, diarrhea
5. Gastric upset and cramps
6. Emesis

Military mnemonic

1. Diarrhea
2. Urination
3. Miosis
4. Bronchorrhea, bronchoconstriction
5. Emesis
6. Lacrimation
7. Salivation
8. Alternative mnemonic – DUMBELS

Unfortunately, none of the mnemonics cover all of the symptoms that the nerve agent can cause and are particularly lacking in covering the nicotinic symptoms of the nerve agent.

Muscarinic manifestations
Much of the clinical effects of the nerve agents are due to the characteristic muscarine-like signs and symptoms associated with cholinergic excess (muscarinic effects). These include the simulation of the endings of the parasympathetic nerves at the smooth muscle of the iris, the ciliary body, the bronchial tree, gastrointestinal tract, bladder and blood vessel. The patient may have conjunctival injection, lacrimation, miosis, loss of dark adaptation, diminished visual acuity, and ciliary muscle spasm exacerbated by attempting to focus. The respiratory effects due to muscarinic stimulation include rhinorrhea, wheezing, cough, increased bronchial secretions, dyspnea, and apnea. The cardiovascular effects of muscarinic stimulation include bradydysrhythmia, prolongation of the PR interval, and atrioventricular blocks. Sympathetic stimulation includes nerves to the sweat glands and causes flushing and sweating.

Salivation, lacrimation, and involuntary defecation and urination result from these effects of the nerve agent on gastrointestinal and genitourinary muscarinic end organs. The patient may develop crampy abdominal pain or tenesmus. Nausea and vomiting are common effects.

Nicotinic effects

Motor end plates

The accumulation of acetylcholine at the endings of the motor nerves to voluntary muscles and the autonomic ganglia results in nicotinic-like signs and symptoms. For muscle, this would mean the following sequence of events would occur:

1. Spontaneous activation of myofibrils (fasciculations) as acetylcholine accumulates and paralyzes random neuromuscular junctions.
2. Tremors and twitching as entire muscle groups are lost
3. The patient would develop progressive weakness culminating in flaccid paralysis as the muscle group loses the effective function of the neuromuscular junction.

Cardiovascular

The nicotinic mediated sympathetic discharge causes tachydysrhythmia and hypertension.

Metabolic

The metabolic effects of excess acetylcholine on nicotinic receptors cause metabolic abnormalities: hyperglycemia, ketosis, and metabolic acidosis are common.

CNS manifestations

Finally, the accumulation of excessive acetylcholine in the brain and spinal cord is thought to result in central nervous system symptoms of twitching, jerking, staggering gait, convulsions, respiratory depression, and coma. Objective changes in the electroencephalogram may be demonstrated. Early manifestations may include anxiety, restlessness, confusion, and ataxia.

Animal studies suggest that nerve agents may eve

Clinical effects

Individuals poisoned by a nerve agent display similar symptoms regardless of exposure route. The intensity and sequence of the symptoms is, however, influenced by the route of absorption and by individual sensitivity.

Ocular

Eye exposure to the nerve agents may produce and pupillary constriction (miosis), ocular pain, and dimness of vision as first effects of the cholinesterase inhibitors. (The accommodation capacity of the eye is reduced so that the short-range vision deteriorates and the victim feels pain when he tries to focus on a nearby object.)

Miosis (pupillary contraction) causes dimness and impairment of night vision. Miosis appears to be a consistent clinical finding with nerve agent vapor exposure. Ciliary spasm also may cause eye pain. This is most likely from direct effect of the agent on the eye.
Eye findings in patients exposed by skin contact are less common. This is probably because the eye usually is not exposed directly to the agent, unlike with the vapor of the G agents. Miosis may be a delayed in VX exposure, since this agent is most commonly absorbed from the skin..

Nasal and oral

Rhinorrhea is most common after a vapor exposure but also can be observed with exposures by other routes.
The patient will have increased secretions and salivation early in the exposure. These increased secretions may complicate airway management of the patient.

Pulmonary

The respiratory effects of the nerve agents are ultimately responsible for most deaths due to these chemicals. The nerve agents cause respiratory failure in three ways: increased airway resistance, weakness and paralysis of the muscles of respiration, and central depression of the respiratory drive.
Patients may describe shortness of breath, chest tightness, respiratory distress, or gasping. These sensations are caused by bronchoconstriction and increased intrabronchial secretions. The patients often develop prolonged expiration, cough, and wheezing. Patients with asthma or chronic obstructive pulmonary disease may be at significant increased risk due to their increased sensitivity and potentially diminished reserves.

The respiratory paralysis caused by the nerve agents was originally thought to be the major cause of respiratory arrest. Weakness of the diaphragm and accessory muscles of respiration does occur; however respiratory arrest will often occur prior to neuromuscular blockade and is not always due to muscle paralysis. The patient may develop weakness of the muscles of the upper airway resulting in obstruction from the tongue within the oral pharynx. Laryngeal muscle paralysis may cause vocal cord dysfunction and subsequent stridor.

With severe intoxication, the patient may rapidly develop centrally mediated apnea. Multiple animal studies have shown that the respiratory depression occurs before the neuromuscular blockade and the bronchoconstriction have reached significant proportions . These studies support the contention that a major contribution to respiratory failure is central nervous system rather peripheral toxicity.

Fortunately the need for ventilatory support and intensive care for Sarin casualties treated in Tokyo was only 24-48 hours when both atropine and an oxime were given. Even patients with severe signs of poisoning recovered completely if adequate supportive therapy and antidotes were given early.

Muscle

Fasciculations are often seen with these agents. The fasciculation is often confined to the area of exposure early in the intoxication; they then spread to cause generalized involvement of the entire musculature. Myoclonic jerks (twitches) may be observed. Eventually, muscles fatigue and a flaccid paralysis ensues. This includes the muscles of respiration.

When exposed to a high dose of nerve agent, the muscular symptoms are more pronounced. The victim may rapidly suffer convulsions and lose consciousness. The process of intoxication may be so rapid that the patient does not have time to develop the minor symptoms before respiratory arrest occurs.

Skin

Most of the sweat glands are controlled by sympathetic cholinergic receptors. Skin exposure may produce localized sweating and fasciculations as the first effect. Generalized diaphoresis can be observed with larger exposures and with systemic absorption.

Gastrointestinal

The muscarinic receptors stimulate secretion from the salivary glands, the gastric parietal cells, goblet cells, chief cells. In addition the muscarinic receptors contract the gallbladder, increase gastric and intestinal motility and relax the anal sphincter. The stimulation of these receptors results in the Salivation, Defecation, Emesis, and Gastric cramping described in the mnemonic SLUDGE. This is true even when the nerve agent is inhaled. The time of onset and the severity of the gastrointestinal symptoms is related to the duration of exposure, amount of exposure (C—t) and the route of exposure.

Cardiac

The patient intoxicated with a nerve agent may present with either bradycardia or tachycardia. The cardiac rate of the intoxicated patient depends on the predominance of adrenergic stimulation (resulting in tachycardia) or of the parasympathetic tone (causing bradycardia via vagal stimulation).

These cardiac toxicities from the anticholinesterase inhibitors can be divided into three phases: Tachycardia and hypertension may result from the initial intense sympathetic activity. The victims then develop bradydysrhythmia, prolongation of the PR interval, atrioventricular blocks, and hypotension as the parasympathetic stimulus predominates. The final phase is QT prolongation and possible torsades de pointes. (It should be noted that Torsade de pointes has been noted with the organophosphate insecticides, but not yet with the nerve agents.)

At least one patient had marked ST-segment elevation in leads V2-6 on presentation to the ED following Sarin intoxication. This ischemic change was related to coronary vasospasm.

Heart blocks and premature ventricular contractions can be observed after intoxication with the nerve agents, although these are also often seen with hypoxia.

Among the delayed effects are sudden cardiac failure in patients who have apparently recovered from the effects of organophosphate exposure. Cardiomyopathy has been reported in animals exposed to Sarin, but no human cases have been noted in the literature.

Genitourinary

Cholinergic stimulation causes contraction of the detrusor muscle of the bladder and relaxation of the trigone and sphincter muscles. This leads to the involuntary Urination described in the mnemonic SLUDGE.

Central nervous system

There are cholinergic receptors throughout the central nervous system with the highest concentrations within the reticular activating system, the basal ganglia, the limbic system, the cortex, the cerebellum, and the synapses found in the ventral and dorsal spinal cord. Since there are so many CNS cholinergic receptors, there are a wide variety of symptoms and signs caused by intoxication with a cholinesterase inhibitor.

Minor exposures to the nerve agents may result in behavioral changes such as anxiety, psychomotor depression, intellectual impairment, and unusual dreams.

Large exposures to the nerve agents result in rapid loss of consciousness and seizures.

Organophosphate exposure can produce both central and peripheral nervous system signs and symptoms if the patient survives the respiratory failure and other immediately lethal events. These symptoms may include impaired memory, hallucinations, fatigue, balance problems, confusion, and concentration deficits. Signs may include both central and peripheral neuropathies and late seizures. Severely intoxicated patients may remain unconscious for hours or days.

Other effects and complications include hypoxia, ischemia, acidosis, hyperthermia, hypothermia, peripheral neuropathy and cerebral edema. These have been seen in patients who have received convulsive doses of nerve agents. It is obvious that many of the longer term effects are directly related to the problems of providing adequate ventilation to the contaminated, seizing patient who has copious airway secretions.

There is animal evidence that prolonged nerve agents-induced toxic convulsions produce irreversible brain damage. Benzodiazepine anticonvulsants appear to reduce the morbidity associated with these convulsions.

Recent work has proposed that the sole toxic effect of the nerve agents is not just the inactivation of acetylcholinesterase. Albuquerque and associates have described agonistic effects at the nicotinic cholinesterase receptor sites from Tabun, Sarin, and Soman . These agents are capable of activation of the ionic channel in a manner similar to acetylcholine. He also noted that VX prevents ionic conductance through the channel, even if acetylcholine binds to the nicotinic receptor site. This means that there is no single site of treatment for an antidote for the CNS effects.

Laboratory Findings

Laboratory findings are useless to the clinician and prehospital provider. There is no measurement clinically available of the serum or urine concentration of any nerve agent that would help differentiate nerve agent intoxication from other cholinergic excess syndromes.

The only “useful” measurement is the concentration of plasma and erythrocyte cholinesterase. The erythrocyte cholinesterase is similar to the cholinesterase at the synapse and is deactivated by the nerve agents. It is replaced at a slower rate than the normal regeneration of the enzyme at the synapse. Plasma cholinesterase or “pseudocholinesterase” is made in the liver and is also rapidly inactivated by nerve agents.
When the patient has vapor exposure, local effects on the eyes and upper airway may result from this topical vapor contact without any significant effect on the RBC or plasma cholinesterase.

When systemic symptoms are produced, no matter by what route of exposure, the red blood cell and/or plasma cholinesterase activity will be depressed, usually to below 30% of baseline levels. This depends partly upon which agent is used. With mild to moderate exposure nerve agents tend to inhibit RBC cholinesterase more than that found in plasma. (VX 70% RBC inhibition, 20% plasma inhibition, Sarin 80% RBC inhibition, 30% plasma inhibition.) This selective inhibition is lost during severe exposures and activity of both the RBC and plasma cholinesterase will be near zero.
In general, plasma cholinesterase levels may be more useful for monitoring of the recovery of the patient during the weeks after exposure. The RBC cholinesterase may be more useful in detecting mild exposure as noted above.

As a guide, in the absence of other causes, a cholinesterase activity of less than 50% of baseline would indicate exposure to an anticholinesterase agent. Again, this measurement is not readily available in the field or emergency department and the clinician must depend on clinical analysis for diagnosis of this intoxication.

Nerve gases also result in a number of delayed toxicities. The inhibition of cholinesterase enzymes is irreversible once aging occurs, so effects may be prolonged. Until the tissue cholinesterase enzymes are restored to normal levels, there is a period of increased susceptibility to another exposure of any nerve agent. This regeneration of enzyme levels may take as long as 2-3 months. During this period of regeneration of enzyme, the effects of repeated exposures are cumulative.