Vomiting, diarrhea and pulmonary edema

Case:

A 40 year old man develops mild abdominal pain and several episodes of emesis thirty minutes after eating a spaghetti meal prepared by his wife. He appears uncomfortable, and has vomited at least once in the ED. He also has a bout of diarrhea which is noted by the patient to be watery. His vital signs are notable for a heart rate of 130 per min, a normal blood pressure, and a respiratory rate of 30 per minute. On physical examination the patient has moist skin and mucous membranes, and his pupils are 2 mm in diameter. In addition, the patient is slightly lethargic but his mentation is clear. His abdomen shows visible peristalsis and hyperactive bowel function, but is soft and nontender. His stool is guiaic negative. The remainder of the neurologic examination is normal. Over the next hour, the patient develops pulmonary edema and requires intubation.

What is the differential diagnosis of this patient's "ingestion"?

Food poisoning is still a common occurrence today despite the advent of refrigeration and food preservatives. The acute nature of this patients symptoms lowers the likelihood of a true gastrointestinal infection such as salmonella, shigella or campylobacter, as does the absence of dysenteric symptoms and bloody diarrhea. The time course of his symptoms is more typical of ingestion of preformed toxin such as is seen with Staphylococcal food poisoning. Alternatively, the etiology of this patients symptoms may not be infectious, but rather toxic.

Toxins may produce acute vomiting and diarrhea for several reasons. A direct irritant effect is responsible for that seen with heavy metals, detergents, solanine-containing plants (unripe tomatoes), and some cathartics (senna). The irritation is usually profound and causes dysenteric symptoms and most produce guiaic positive stool, if not gross blood. Metabolic interruption is the mechanism by which colchicine, podophylline, and chemotherapeutic agents produce gastrointestinal mucosal sloughing. In these patients, the diarrhea is usually severe, and is not generally watery. Stimulation of the chemoreceptor trigger zone in the medulla is responsible for the emesis noted with ipecac, but diarrhea is uncommon. Finally, cholinergic stimulation by cholinergics (pilocarpine, bethanacol) or cholinesterase inhibitors (organophosphates, carbamates) may produce the above syndrome.

How do organophosphates produce toxicity?

Inhibition of cholinesterases result in persistence of acetylcholine (ACh) within the synaptic cleft and repetitive stimulation of the postsynaptic effector organ. Stimulation of muscarinic receptors, found in hollow viscus organs, results in salivation, lacrimation, urination and defecation (SLUD). The pupil (meiosis), the heart (bradycardia) and the bronchi (bronchorrhea and pulmonary edema) are also innervated by muscarinic receptors. Nicotinic receptors within the neuromuscular junction produce muscle fasciculations and depolarizing blockade when hyperstimulated, an effect analogous to succinylcholine. Nicotinic receptors in the autonomic ganglia enhance sympathetic outflow with resultant hypertension, tachycardia and mydriasis. Finally, in the central nervous system, ACh excess produces anxiety, seizures, respiratory depression and coma.

The clinical findings of cholinesterase inhibitor toxicity can be very confusing. For example, direct parasympathetic stimulation to the heart produces bradycardia, whereas autonomic stimulation or bronchorrhea induced hypoxia indirectly leads to tachycardia. Pupil size is also highly variable and results from interplay of the sympathetic and parasympathetic systems. The effects that predominate are difficult to predict but are related to the agent in question (lipid solubility, concentration), route of administration and individual patient variability.

How should patients with organophosphate or carbamate poisoning be treated?

Early intubation and management of pulmonary secretions are essential, as is assessment of oxygenation status. Death is most commonly due to bronchorrhea induced hypoxia or from respiratory failure secondary to neuromuscular blockade. Decontamination, both external and gastrointestinal, are essential. Dermal exposure or inhalation by the physician may lead to secondary toxicity. Atropine, a derivative of many plants including deadly nightshade (Atropa belladona) and Jimsonweed (Datura stramonium) is a competitive muscarinic antagonist. It should be given to symptomatic patients to eliminate continued respiratory secretions or to elevate heart rate. Rapidly escalating doses may be needed, starting with 1 mg in an adult. The clinical endpoint of atropinization is drying of respiratory secretions and improvement in oxygenation status.

Note that respiratory paralysis is related to nicotinic receptor overstimulation a site to which atropine cannot bind. Therefore, pralidoxime must be administered to patients with nicotinic findings. Pralidoxime, also known as 2-PAM, is able to regenerate functional cholinesterase by cleaving the organophosphate from the cholinesterase enzyme active site. Pralidoxime improves function of both muscarinic and nicotinic receptors as it regenerates all cholinesterases, not just those at muscarinic sites. Since it is unknown which patients will develop respiratory weakness, and since pralidoxime is thought to reduce or prevent delayed neuropathy, it should be given to patients who receive more than 1 mg of atropine, even if no nicotinic signs are present. The initial dose of pralidoxime is 1 gram intravenously over 15-30 minutes. Other protocols involve the intravenous infusion of pralidoxime at 500 mg per hour. This may be superior, as serum levels remain in the therapeutic range longer.

Case management: This patient received an initial dose of atropine 1mg intravenously which was doubled every 5 minutes. Resolution of the bronchorrhea occurred after 4 mg. He also received an initial bolus of pralidoxime 1 gram intravenously, followed by an infusion of 500 mg per hour. An atropine infusion was required to prevent recurrent bronchorrhea. The patient received a total of 500 mg of atropine over the next day. Pralidoxime infusion continued for an additional 24 hours after the atropine was stopped and was then discontinued. His cholinesterase levels were consistent with organophosphate poisoning.

Case conclusion: Further testing of the sample could not isolate any toxin, including metals or organophosphate pesticides. However, after further history, it was discovered that the patient worked as a school janitor. He revealed that had spent the day applying a pesticide to the grounds.


Lewis Nelson MD
Medical Toxicology
New York City Poison Center
Bellevue/NYU Medical Center
New York, NY