Etiology
Salicylic acid is the therapeutic but potentially toxic metabolite derived from salts and esters of salicylate.[1] Although small amounts are found in some plants, medically important amounts of salicylates are found in many households as pharmaceuticals. Poisoning can occur as a result of accidental ingestion, inappropriate dosing in therapeutic use, or intentional self-harm. Incorrect salicylate dosing in children and older people can also result in toxic salicylate exposure. People at extremes of age (children ages 3 years and younger and adults ages 70 years and older) have been shown to be particularly at risk when compared with the general population.[2] Although uncommon, cutaneous absorption of salicylates (particularly methyl salicylate) can also cause toxicity.
The most common source of salicylate poisoning is aspirin (acetylsalicylic acid), which is rapidly hydrolyzed to salicylate in the gastrointestinal tract and bloodstream. The dose of salicylates has been standardized to the equivalent of aspirin. There are many nonprescription analgesics available that contain aspirin. Many cold and influenza preparations also contain salicylates, and consumers may not recognize that they are exposing themselves to a cumulative poisoning. Additional sources of exposure include methyl salicylate (oil of wintergreen), found in some topical liniments, and bismuth subsalicylate, a 50% aspirin equivalent found in some nonprescription antidiarrheal medications.[1][2]
A consensus statement by a panel of experts recognizes that a definite threshold dose for toxicity has not been established and that many exposures are not single-dose exposures.[2] The panel concluded that the acute ingestion of 150 mg/kg or 6.5 g, whichever is less, of aspirin or aspirin equivalent is an indication for emergency evaluation because of the risk of salicylate poisoning. Ingestion of more than a lick or taste of oil of wintergreen (98% methyl salicylate) by children <6 years old, or of >4 mL by patients ages 6 years or older, also carries a risk.[2] The risk of poisoning with chronic salicylate exposure is extremely difficult to predict. Chronic poisoning tends to occur as a result of repeated exposure to high-dose aspirin or equivalent (150 mg/kg/day or more).
Pathophysiology
Salicylate poisoning is characterized by a mixed acid-base disturbance, electrolyte abnormalities, and central nervous system (CNS) effects.[1] In overdose, the initial systemic effect is tachypnea which stems from salicylate-induced direct stimulation of the respiratory center in the brainstem.[1] Early, this results in respiratory alkalosis.[1] As more salicylate is absorbed, an uncoupling of oxidative phosphorylation occurs, and the patient develops concomitant metabolic acidosis.[1] Metabolic acidosis develops more rapidly in children, who have a decreased capacity for respiratory compensation.
The most common source of salicylate poisoning is aspirin (acetylsalicylic acid), which in nontoxic doses is rapidly hydrolyzed to salicylate in the gastrointestinal (GI) tract, liver, and bloodstream (aspirin has a serum half-life of 15 minutes).[2] When salicylate-containing tablets are ingested in overdose, functional bezoars, concretions, and pylorospasm can result in a significant delay of the rate of absorption.[2] As total-body burden of salicylate increases, metabolic pathways exhibit saturation, resulting in further accumulation of salicylate and slower elimination. The serum half-life of salicylate excretion increases from 2 to 4 hours for low-dose aspirin, to 12 hours for anti-inflammatory dosing, to 15 hours or more in overdose.[2] As much as 30% of salicylate is excreted unchanged in the urine, but this proportion is drastically reduced in the presence of acidemia or renal insufficiency. At urine pH <6.0 (marked acidosis), unbound, undissociated salicylate is reabsorbed into the renal tubules by nonionic diffusion. Nonionized salicylates cross the blood-brain barrier and are responsible for increasing CNS toxicity. In addition, the many negative physiologic effects of salicylates include:[1]
Local irritation of the GI tract
Tachypnea due to direct stimulation of the respiratory center in the brainstem, with subsequent respiratory alkalosis
Metabolic acidosis from uncoupling of oxidative phosphorylation
Stimulation of metabolic rate
Disturbance of carbohydrate and lipid metabolism
Interference with hemostasis
Cerebral edema, acute lung injury (pulmonary edema).
Salicylates impair the production of energy in two main ways. Firstly, they interfere with the Krebs cycle, resulting in decreased ATP production. They also uncouple oxidative phosphorylation, which results in pyruvate and lactate accumulation, and the release of energy as heat. These combined effects result in hyperthermia and diaphoresis.
Therefore, salicylate poisoning can paradoxically cause fever and respiratory alkalosis as well as metabolic acidosis, which itself increases toxicity in a vicious cycle.
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