Gastroenterology training and education

What is the toxic dose for paracetamol?

At least 12g paracetamol is usually required to produce serious toxicity in adults, unless the patient is at high risk.
High risk patients (>7.5g may produce toxicity):

• Malnutrition/cachexia- e.g. eating disorder, cystic fibrosis, AIDS (causes glutathione depletion)
• Chronic high alcohol consumption (>21 U in males and 14U in females)
• Hepatic enzyme inducing drugs- phenytoin, rifampicin, carbamazepine, barbiturates, primidone

Patients with chronic liver disease who do not regularly ingest alcohol do not appear to be at increased risk for acetaminophen-induced hepatic injury.

What is the mechanism of toxicity?
A fraction of paracetamol is metabolized by the hepatic cytochrome P450 pathway to toxic N-acetyl-p-benzoquinoneimine (NAPQI). This is rapidly detoxified by conjugation with hepatic glutathione and excreted in urine. In overdose, glutathione conjugation is saturated leading to tissue injury by NAPQI
N-acetyl cysteine (NAC) increases glutathione stores and thus enhances nontoxic conjugation. It also combines directly with NAPQI as a glutathione substitute. Once hepatotoxicity is established NAC may be beneficial by other mechanisms.
Discuss the clinical stages of paracetamol toxicity?

The clinical course of paracetamol overdose has 4 stages.

• Stage 1 (time of ingestion to 24 hours) – The patient typically has anorexia, nausea, vomiting, and diaphoresis. The results of laboratory tests are usually normal.
• Stage 2 (24-72 hours) – The patient may actually appear to have improved clinically, but results of laboratory tests begin to be abnormal. Abnormalities include increases in serum transaminases, bilirubin and prothrombin time.  Nephrotoxicity may be evident during this stage.
• Stage 3 (72 to 96 hours) – also known as hepatic stage. Severe signs of hepatotoxicity appear. This include plasma ALT and AST levels that often exceed 10,000 IU/L, prolongation of the PT or INR, hypoglycemia, lactic acidosis, and a total bilirubin concentration above 70umole/l (primarily indirect). Death most commonly occurs in this stage, usually from multiorgan system failure.
• Stage 4 (4 days-2 weeks) – is the recovery stage. Patients who survive stage III enter a recovery phase that usually begins by day 4 and is complete by 7 days after overdose.

What are the indicators of severe paracetamol poisoning and when to contact a specialist liver centre?

• Progressive coagulopathy or INR > 2 at 24 hrs INR > 4 at 48 hours, INR > 6 at 72 hours.
• Renal impairment (creatinine > 200 ?mol/l)
• Hypoglycaemia
• Metabolic acidosis (pH < 7.3, bicarbonate < 18) despite rehydration
• Hypotension despite fluid resuscitation
• Encephalopathy

Discuss the antidote and its doses and side effects?

N-acetylcysteine (NAC) is the antidote. Its dose in adults:

• 150 mg/kg NAC in 200 ml 5% dextrose over 15 minutes followed by
• 50 mg/kg NAC in 500 ml 5% dextrose over 4 hours followed by
• 100 mg/kg NAC in 1000 ml 5% dextrose over 16 hours

Adverse reactions to NAC
Flushing, itching, rashes, angioedema, bronchospasm, and hypertension.
NAC should be stopped and an IV antihistamine given. Once any adverse effects have settled, the NAC can be restarted at a rate of 50 mg/kg over 4 hours

Discuss the general principles of management of paracetamol toxicity?

• Serious hepatotoxicity and mortality is uncommon if NAC is administered within 8 to 10 hours following paracetamol overdose. The efficacy of NAC progressively diminishes as the time interval between ingestion and treatment increases beyond 8 hours.
• Peak serum concentrations are reached within four hours following overdose. So paracetamol levels are checked at or after 4 hours of overdose and plotted on Rumack-Matthew nomogram.
• Without antidotal therapy, patients with paracetamol concentrations above the treatment line at 4 hours and at 16 hours have a significant incidence of severe hepatotoxicity and mortality.
• Peak levels may be delayed beyond four hours when drugs that delay gastric emptying (e.g., opiates, anticholinergic agents) are co-ingested or following overdose of extended releases preparations. In these patients it may be worth checking paracetamol levels at 7-8 hrs if the 4 hour levels are below the treatment line.
• Hepatic failure- NAC should be administered until death or recovery and an INR <2.0.

Discuss the treatment of paracetamol overdose (OD)?

• 50 gm of charcoal orally- If the patient presents within one hour of significant (at least 7.5 gm) overdose.
• If presents within 8 hrs- check levels at or after 4 hrs and treat if the levels are above the treatment line. If paracetamol levels not likely to be available by 8 hrs after OD and the dose ingested is significant, then treatment should be started. The treatment could be stopped, if the levels are below the treatment line.
• If presents 8-24 hrs after significant OD- start treatment immediately. Check bloods for paracetamol levels, INR, LFTs, U&Es and venous bicarbonate (if bicarbonate abnormal- do ABG). Continue treatment if the paracetamol levels are above treatment line or patient is symptomatic or lab results are abnormal. On completion of NAC recheck INR, creatinine and venous bicarbonate. If normal- discharge. If still abnormal- continue with maintenance NAC at a dose of 150 mg/kg over 24 hours and discuss with regional liver centre, if appropriate.
• Presents after 24 hrs- Take bloods for paracetamol levels, INR, LFTs, U&Es and venous bicarbonate (if bicarbonate abnormal- do ABG). If the pt is asymptomatic and lab results are normal- discharge. However if lab results are abnormal or pt is symptomatic- start NAC if not already started.

Discuss the management of staggered or chronic overdose?

• Patients are at increased risk of developing hepatotoxicity if the total dose ingested is more than 12gms (7.5 gms in high risk patients) in 24 hours.
• Start NAC immediately if the total dose ingested is significant or unknown
• Check blood for paracetamol levels, INR, LFTs, U&Es and venous bicarbonate.
• Treatment with NAC is recommended for all patients with liver tenderness, elevations of aminotransferases, supra therapeutic serum paracetamol concentrations (> 10-20 mcg/mL).
• If a patient has a detectable paracetamol concentration but is without signs, symptoms, or risk factors for toxicity and without elevations of aminotransferases, then treatment is not necessary.
• If the serum paracetamol concentration is undetectable and aminotransferases are normal, NAC therapy is not necessary.
• Treatment is clearly recommended if serum paracetamol concentrations are potentially toxic by the nomogram with respect to the time of the last dose.

Discuss paracetamol induced acute renal failure (ARF)?

ARF mostly occurs in association with hepatic injury. However isolated ARF can occur. The mechanism of renal damage is similar to hepatic injury. Paracetamol is metabolized locally by the cytochrome P450 to toxic metabolite NAPQI.  Renal function spontaneously returns to normal within one to four weeks, although dialysis may be required during the acute episode. There is no evidence that NAC has any protective effect on the kidney.