Paracetamol and Salicylate Levels

Paracetamol and salicylate are the two most common drugs for which a serum level changes management after overdose. Paracetamol is metabolised mostly by glucuronidation and sulfation, and a small fraction by cytochrome P450 to the toxic metabolite NAPQI, which is detoxified by glutathione. In overdose the conjugation routes saturate, glutathione is depleted, and NAPQI causes centrilobular hepatic necrosis. Salicylate (aspirin, oil of wintergreen, bismuth subsalicylate) uncouples oxidative phosphorylation and stimulates the respiratory centre.

Levels are measured by enzymatic or colorimetric assay on serum or heparin plasma. Paracetamol level, interpreted against the time since ingestion, is the basis for deciding on acetylcysteine. Salicylate level, repeated, shows whether absorption is continuing and defines the need for alkalinisation and dialysis.

Paracetamol is the most frequent drug involved in intentional overdose in many countries and a leading cause of acute liver failure. Salicylate poisoning is less frequent and carries a mortality of 1 to 2% in acute poisoning, higher in chronic toxicity.

Indications. Any intentional or unintentional overdose, suspected poisoning of uncertain agent, unexplained high anion gap metabolic acidosis with respiratory alkalosis, unexplained raised ALT with an unclear history, tinnitus, vomiting, hyperventilation or confusion in an older adult on aspirin, and children with unwitnessed ingestion.

Specimen. Serum or heparin plasma. A paracetamol level is taken at least 4 hours after a single acute ingestion, because earlier levels are unreliable. For salicylate, two samples 2 to 4 hours apart are taken because absorption may be delayed. Record the time of ingestion and sample.

Local ranges, units and treatment lines apply.

Paracetamol level. Range: under the limit of detection (under 5 mg/L) at therapeutic dosing. Conversion: mg/L multiplied by 6.62 gives micromol/L.

Acute single ingestion, sampled 4 to 24 hours after ingestion: the treatment line starts at 100 mg/L (660 micromol/L) at 4 hours and falls by half every 4 hours, reaching 15 mg/L (100 micromol/L) at 15 hours. Treatment with acetylcysteine is given for a level on or over the line. A line starting at 150 mg/L at 4 hours is used in some countries, and the local line takes precedence.

Treatment does not wait for the level when:

• The patient presents 8 hours or more after ingestion, and a toxic dose (over 150 mg/kg or over 12 g) is possible. Acetylcysteine is started and the level checked when available.
• The ingestion is staggered, taken over more than 1 hour, or the time is unknown. The treatment line does not apply, and any detectable level or a raised ALT calls for treatment.
• There is evidence of hepatic injury (ALT over the reference range, raised INR).

Risk is raised by enzyme inducing drugs (carbamazepine, phenytoin, rifampicin), chronic alcohol use, malnutrition and prolonged fasting, and glutathione depletion, so the treatment line is lowered in some regions for these groups.

Salicylate level. Range: under 30 mg/L (under 0.2 mmol/L) at therapeutic dosing, and up to 300 mg/L in rheumatic doses. Conversion: mg/L divided by 138 gives mmol/L.

• Mild toxicity: 300 to 500 mg/L (2.2 to 3.6 mmol/L) with tinnitus, nausea and vomiting, sweating.
• Moderate toxicity: 500 to 750 mg/L (3.6 to 5.4 mmol/L) with hyperventilation, fever, confusion and acid base disturbance.
• Severe toxicity: over 750 mg/L (over 5.4 mmol/L) with coma, seizures, pulmonary oedema and cerebral oedema.

Symptoms and acid base state matter more than the level. Chronic toxicity causes serious illness at levels of 200 to 400 mg/L, since tissue levels are higher.

Paracetamol toxicity course.

• 0 to 24 hours: nausea and vomiting, or no symptoms.
• 24 to 72 hours: right upper quadrant pain, rising ALT and AST, prolonged INR.
• 72 to 96 hours: peak hepatic injury, with jaundice, encephalopathy, hypoglycaemia, coagulopathy, acute kidney injury and lactic acidosis.
• After 4 days: recovery, or acute liver failure.

Hepatotoxicity is usual with a 4 hour level over 150 mg/L, and ALT over 1000 U/L marks significant injury.

Monitoring after acetylcysteine. ALT, INR, creatinine, bicarbonate, lactate, phosphate and glucose are checked at completion of the infusion. If ALT is rising or INR is raised, the infusion continues until improvement.

Markers of poor outcome in paracetamol liver failure. pH under 7.30 after fluid resuscitation, INR over 6.5, creatinine over 300 micromol/L, grade 3 or 4 encephalopathy, lactate over 3 mmol/L after resuscitation, and phosphate over 1.2 mmol/L. These identify patients who need transplant assessment.

Salicylate toxicity.

• Respiratory alkalosis early, then mixed respiratory alkalosis with high anion gap metabolic acidosis, and acidaemia in severe or late poisoning.
• Hypokalaemia, hypoglycaemia (neuroglycopenia with normal blood glucose), raised lactate, ketones, fever, and non-cardiogenic pulmonary oedema.
• A falling pH raises the proportion of unionised salicylate that enters the brain, so acidaemia is dangerous at a given level.

Treatment thresholds.

• Urinary alkalinisation (sodium bicarbonate, aim for urine pH 7.5 to 8.0) for levels over 500 mg/L (3.6 mmol/L) or symptoms, with potassium replacement.
• Haemodialysis for a level over 1000 mg/L (7.2 mmol/L) in acute poisoning, or lower levels with altered mental state, pulmonary oedema, kidney injury, pH 7.20 or less, or failure of alkalinisation.
• Intubation is avoided if possible, since loss of respiratory compensation worsens acidaemia. If needed, ventilate at a high minute volume.

Critical values and findings needing immediate action.

• Paracetamol level on or over the treatment line, or any detectable level with a staggered or unknown time of ingestion.
• ALT over 1000 U/L, INR over 1.5, or encephalopathy after paracetamol overdose.
• Salicylate level over 300 mg/L, or any level with acid base disturbance, confusion, tinnitus or tachypnoea.
• Rising salicylate levels at repeat sampling.
• Mixed overdose with other drugs, especially opioids, sedatives and antidepressants.

Interferences and pitfalls.

• A level taken before 4 hours cannot be interpreted against the treatment line, and must be repeated.
• The line applies only to single acute ingestions. It cannot be used for staggered, chronic or therapeutic excess, or unknown timing.
• Hyperbilirubinaemia and high uric acid can give falsely high values in some enzymatic paracetamol assays, and a high result in a well patient is checked by a second method.
• A second peak in salicylate level occurs from enteric coated tablets, bezoar formation and slowed gut motility, so one low level does not exclude toxicity.
• Therapeutic salicylate use, including topical, causes detectable levels, and a level at therapeutic range does not exclude a recent large ingestion if sampled early.
• Urine ferric chloride testing is a crude screen and is not interpreted without a serum level.
• Acetylcysteine infusion can alter INR measurement slightly, and does not stop treatment decisions.
• Combination products containing paracetamol (with opioids, antihistamines, or cold remedies) cause toxicity from the co-ingestant first.

Special groups.

• Children: unintentional ingestion usually involves liquid preparations, and doses under 150 mg/kg are seldom toxic. The treatment line applies.
• Pregnancy: overdose is treated without delay, since untreated overdose threatens the foetus.
• Older adults: chronic salicylate toxicity presents with confusion and is often missed. Paracetamol therapeutic excess occurs in frail, malnourished patients.
• Malnutrition and prolonged fasting: lower thresholds for treatment.
• Regions: paracetamol availability and pack size affect incidence, and salicylate poisoning from oil of wintergreen and traditional remedies is important in some settings.

Follow up tests. ALT, AST, INR, bilirubin, creatinine, urea and electrolytes, glucose, phosphate, lactate, venous or arterial blood gas, anion gap, osmolar gap, repeat salicylate level at 2 to 4 hours, repeat paracetamol level if the first is early, full blood count, ECG, pregnancy test, and levels of co-ingested drugs.