Pathophysiology

Absorption of salicylate may be delayed or erratic, depending on the product. After ingestion of large amounts of non-enteric-coated ASA, absorption from the gastrointestinal (GI) tract may be slowed because of the inhibitory effect of ASA on gastric emptying and the impaired dissolution of tablets in gastric fluids at high concentrations. Peak serum salicylate levels may not be reached for 18 to 24 h, although toxic levels are usually evident within 6 h. Methyl salicylate is a liquid that produces peak levels earlier, whereas peak levels following enteric-coated or sustained-release ASA overdose have been reported to occur 10 to 60 h after ingestion.2 Some formulations of ASA may coalesce to form a gelatinous gastric mass, and significant amounts of ASA may remain in the stomach long after an intentional overdose, providing a source for continued absorption.

After absorption, ASA is hydrolyzed to salicylic acid (salicylate) and is distributed throughout body tissues. The severity of toxicity depends on the cellular salicylate concentration. Salicylate is responsible for both the therapeutic and the toxic effects of ASA. At higher salicylate concentrations, a lesser percentage of the drug is protein bound and more free drug is available to diffuse into tissues and cause toxicity. The p Ka of salicylate is 3.0 and, at physiologic pH (7.40), almost all salicylate molecules are ionized. If the systemic pH decreases, the change in equilibrium will form a greater portion of nonionized molecules. This is an important concept because nonionized molecules will cross cellular membranes, such as the blood-brain barrier. Thus, for a given salicylate level, brain salicylate levels will be substantially higher in the presence of acidemia.3 Although the precise mechanism remains to be determined, the concentration of salicylate in the brain is correlated directly with mortality rate.3

The ionized state of salicylate can be used to enhance its elimination. If the urine pH is above 8.0, more salicylate molecules in the urine will be ionized compared with the renal tubular cell pH of 7.4 and reabsorption across the urinary tubule will be reduced. 4

Acute salicylate overdose may produce nausea and vomiting as a result of local gastric irritation and stimulation of the chemoreceptor trigger zone. 5 Vomiting may result in volume depletion, which reduces renal perfusion and urine flow, adversely affecting renal salicylate elimination and contributing to acid-base and electrolyte disturbances.

Salicylate initially increases respiratory rate through a direct stimulatory effect on the medullary respiratory center in the central nervous system (CNS), 6 but very high levels of salicylate depress respiration, a finding usually seen later in the course. Salicylate also stimulates skeletal muscle metabolism, which causes an increase in oxygen consumption and carbon dioxide production.6 The clinical manifestation of the initial respiratory center stimulation (the dominant component) and the increase in carbon dioxide production causes an increased respiratory rate resulting in respiratory alkalosis. 6 Initially, this will counter the enduring metabolic acidosis. If ventilatory compensation fails to keep pace with increased carbon dioxide production, respiratory acidosis will develop and will compound the metabolic acidosis.

The loss of the respiratory buffering effect is very dangerous, because the kidneys, even under ideal conditions, cannot react with sufficient rapidity to counter the acidosis meaningfully. Also, the critical alkalemia seen early when respiratory alkalosis predominates causes the kidneys to increase bicarbonate and potassium excretion. The urinary bicarbonate loss will eventually decrease the body's bicarbonate stores and impair compensation for the metabolic acidosis of salicylism.

Salicylate enhances lipolysis, uncouples oxidative phosphorylation, and inhibits various Krebs cycle enzymes involved in energy production and amino acid metabolism, resulting in (1) increased catabolism that leads to increased carbon dioxide production, (2) increased heat production, (3) increased glycolysis and peripheral demand for glucose, and (4) production of metabolic intermediaries (organic acids, lactate, pyruvate, and keto acids), which contribute to the metabolic acidosis of salicylate toxicity.7 Overall, the acid-base disturbance associated with salicylate poisoning is mixed and includes respiratory alkalosis, metabolic alkalosis (due to volume contraction) and a wide-anion-gap type metabolic acidosis.

Salicylate-induced noncardiogenic pulmonary edema has been observed in humans89,,10 and 1! and studied in animals. Salicylate toxicity causes increased pulmonary vascular permeability, whereas pulmonary vascular pressures and cardiac performance are unaffected. This vascular injury may also involve the kidneys. Proteinuria is a prominent early finding in salicylate toxicity, starting at a serum salicylate level greater than 30 mg/dL, and it is directly related to salicylate levels. 9

Salicylate also affects both central and peripheral glucose homeostasis. Salicylate causes mobilization of glycogen stores, resulting in hyperglycemia. However, salicylate is also a potent inhibitor of gluconeogenesis. Therefore, normoglycemia, hyperglycemia, or hypoglycemia may occur in salicylate toxicity. The brain involves a unique problem with glucose delivery. Animal studies demonstrate that toxic doses of salicylate produce a profound decrease in brain glucose concentration despite normal serum glucose levels.12 This finding suggests that the supply of glucose to the brain in salicylate poisoning may be inadequate, even though serum glucose levels are normal.

Antiplatelet activity is a well-known effect of ASA, but hemorrhage is a rare complication of acute, single, massive overdose of salicylate. Salicylate has a molecular structure similar to both vitamin K and dicumarol. Chronic administration of large doses of salicylate may cause significant hypoprothrombinemia when the serum salicylate concentration exceeds 60 mg/dL.13 This is presumably due to salicylate's competitive inhibition of the vitamin K effect.

Salicylate ototoxicity is characterized by a reversible sensorineuronal hearing loss, which is not idiosyncratic; it is related to serum salicylate concentrations. 14 When serum salicylate concentrations exceed 40 mg/dL, hearing loss reaches its maximum of 40 decibels.14

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