Aetiology

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, self-harm, or attempts to die by suicide. Incorrect salicylate dosing in children and older people can also result in toxic salicylate exposure. Children aged ≤3 years and adults aged ≥70 years have been shown to be particularly at risk when compared with the general population.[5]

The most common source of salicylate poisoning is aspirin (acetylsalicylic acid), which is rapidly hydrolysed to salicylate in the gastrointestinal tract and bloodstream. In the UK, several non-prescription aspirin-containing products are available. Many cold and influenza preparations also contain salicylates, and consumers may not recognise that they are exposing themselves to a cumulative poisoning. Bismuth subsalicylate is another source of salicylate (a 50% aspirin equivalent) found in some non-prescription medications for stomach ailments such as indigestion and diarrhoea.

Although uncommon, cutaneous absorption of salicylates (particularly methyl salicylate) can also cause toxicity. Sources of methyl salicylate exposure include oil of wintergreen, found in some topical liniments.[5]

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.

Pathophysiology

Salicylate poisoning is characterised by a mixed acid-base disturbance, electrolyte abnormalities, and central nervous system effects.[1] In overdose, the initial systemic effect is tachypnoea, because salicylates induce stimulation of the respiratory centre in the brainstem directly.[1] This results in respiratory alkalosis in the early stages after ingestion. As more salicylate is absorbed, an uncoupling of oxidative phosphorylation occurs, and concomitant metabolic acidosis develops.[1] Metabolic acidosis develops more rapidly in children, who have a decreased capacity for respiratory compensation.

In non-toxic doses, acetylsalicylic acid is rapidly hydrolysed to salicylate in the gastrointestinal tract, liver, and bloodstream (aspirin has a serum half-life of 15 minutes).[5] When salicylate-containing tablets are ingested in overdose, the tablets can form functional bezoars or concretions (aggregates of undigested material) in the gastrointestinal tract, which can result in a significant delay of the rate of absorption.[5] 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.[5] As much as 30% of salicylate is excreted unchanged in the urine, but this proportion is drastically reduced in the presence of acidaemia or renal insufficiency. At urine pH <6.0 (marked acidosis), unbound, undissociated salicylate is re-absorbed into the renal tubules by non-ionic diffusion. Non-ionised salicylates cross the blood-brain barrier and are responsible for increasing central nervous system toxicity. In addition, the many negative physiological effects of salicylates include:[1]

  • Local irritation of the gastrointestinal tract

  • Tachypnoea due to direct stimulation of the respiratory centre in the brainstem, with subsequent respiratory alkalosis

  • Metabolic acidosis and hyperthermia from uncoupling of oxidative phosphorylation

  • Stimulation of metabolic rate

  • Disturbance of carbohydrate and lipid metabolism

  • Interference with haemostasis

  • Cerebral oedema

  • Acute lung injury (pulmonary oedema).

Salicylates impair the production of energy in two main ways. Firstly, they interfere with the Krebs' cycle, resulting in decreased adenosine triphosphate 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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