History

Fact Explanation
Patients may be brought to medical attention within few hours of ingestion with a history of paracetamol overdosing. Patients are usually asymptomatic in the initial 24 hours until manifestations of end organ damage appear.[1] Upon presentation it is important to conduct a detailed assessment to establish the quantity and timing of paracetamol ingestion. It is important to differentiate whether the patient had being taking an overdose paracetamol over a long period of time or whether this is a single event.
Nausea and vomiting/ abdominal pain The patient may experience minor gastrointestinal symptoms within the first 24 hours.
Confusion/ coma Patients may develop encephalopathy. Patients who have ingested massive amounts of paracetamol are prone to develop a coma.[2]
Right hypochondrial pain Due to hepatic necrosis in established liver damage.
Presentation with features of liver failure: jaundice, impaired consciousness, fetor hepaticus, bleeding[2] Paracetamol is mainly metabolized by the liver by conjugation to inactive metabolites. The reactive metabolite – N-acetyl-p-benzoquinoneimine (NAPQI) generated in this process is toxic to the liver. Liver injury will result if NAPQI is generated at an excess rate than its neutralization by glutathione.[1]
Low urine output Patients who ingest massive amounts of paracetamol are prone to develop renal failure secondary to hepatic dysfunction. The risk is exaggerated in patients with pre-existing renal disease and who are dehydrated.[2]
Syncope Patients with paracetamol poisoning are prone to develop hypoglycemia due to liver damage.
References
  1. BOON N.A, COLLEDGE N.R, WALKER B.R, HUNTER J.A.A ed. Davidson's principles and practice of medicine. 21st ed. Edinburgh : Churchill livingstone, 2010.
  2. FERNER R. E., DEAR J. W., BATEMAN D. N.. Management of paracetamol poisoning. BMJ [online] December, 342(apr19 2):d2218-d2218 [viewed 05 June 2014] Available from: doi:10.1136/bmj.d2218

Examination

Fact Explanation
General examination – Conscious level The patient may present in an altered level of consciousness. This may range from a confused state to coma. Altered level of consciousness may be due to hypoglycemia, hepatic encephalopathy, shock etc.
General examination – Features of liver failure The patient present with jaundice and bleeding manifestations. Features of hepatic encephalopathy include asterixis, constructional apraxia, hyper-reflexia and bilateral extensor plantar responses.[1] Fetor hepaticus is a sweet musty odor to the breath which is associated with hepatic failure.
General examination – cachexia, malnourished Identification of malnourishment indicates a higher risk of developing hepatic injury due to depleted glutathione stores.
Abdominal examination Right upper quadrant tenderness may be elicited in the presence of hepatic damage. A tender hepatic edge may also be palpated.[2]
Cardiovascular system examination – Tachycardia and hypo tension Will indicate dehydration and fluid loss.
References
  1. BOON N.A, COLLEDGE N.R, WALKER B.R, HUNTER J.A.A ed. Davidson's principles and practice of medicine. 21st ed. Edinburgh : Churchill livingstone, 2010.
  2. FERNER R. E., DEAR J. W., BATEMAN D. N.. Management of paracetamol poisoning. BMJ [online] December, 342(apr19 2):d2218-d2218 [viewed 05 June 2014] Available from: doi:10.1136/bmj.d2218

Differential Diagnoses

Fact Explanation
Toxin or drug induced hepatotoxicity Various drugs and toxins are known to be toxic to the liver. Toxins such as carbon tetrachloride, benzene derivative, mushroom poisoning and drugs such as anticonvulsant medication, anti-tuberculosis treatment, antiarrhythmics, methotrexate etc may present with symptoms and signs of hepatic damage and hepatic failure.
Alcoholic hepatitis Alcoholic hepatitis is a condition of the alcoholic liver disease spectrum. Chronic inflammation and fibrosis of the liver results from long term alcohol consumption with gradual progression to cirrhosis. The presentation can be with non-specific symptoms such as nausea, vomiting, malaise, and low-grade fever.[1] Acute presentation with symptoms of liver failure can be also be seen. The patient may also present with complications associated with cirrhosis such as upper gastrointestinal bleeding, ascites etc. A diagnosis of alcoholic hepatitis is supported in patients with a long term history of alcohol consumption and by assessment of liver function tests, ultrasound scan examination of the abdomen.
Viral Hepatitis Inflammation of the liver due to infection from the Hepatitis virus group and other rare viruses. Transmission of hepatitis can be sexually, faeco-orally or through other body fluids. Clinical presentation is with non-specific symptoms such as fatigue, anorexia, nausea, and vomiting. The patient will be febrile and will develop jaundice with the onset of the cholestatic phase. Fulminant hepatic failure can develop in a few patients, especially with Hepatitis A and B infections. The patient will present with hepatic encephalopathy. Diagnosis of viral hepatitis is by serological studies which can be used to identify the viral type. Liver function tests - transaminase levels, bilirubin level, alkaline phosphatase can be used as supportive tests for the diagnosis.[2]
References
  1. WOODS SE, HITCHCOCK M, MEYER A. Alcoholic hepatitis. Am Fam Physician [online] 1993 Apr, 47(5):1171-8 [viewed 05 June 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/8465712
  2. PRAMOOLSINSUP C. Management of viral hepatitis B. J Gastroenterol Hepatol [online] 2002 Feb:S125-45 [viewed 05 June 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/12000599

Investigations - for Diagnosis

Fact Explanation
Serum paracetamol level A history of paracetamol ingestion and determination of paracetamol level is important for diagnosis and management of patients. Whether to commence antidote treatment (N-acetylcysteine) is based on blood paracetamol levels. For accurate estimation of paracetamol levels blood should be collected 4 hours after ingestion. The measurement is less reliable after 15 hours.[1]
References
  1. FERNER R. E., DEAR J. W., BATEMAN D. N.. Management of paracetamol poisoning. BMJ [online] December, 342(apr19 2):d2218-d2218 [viewed 05 June 2014] Available from: doi:10.1136/bmj.d2218

Investigations - Fitness for Management

Fact Explanation
Liver function tests: alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum bilirubin, alkaline phosphatase Evidence for hepatic injury is monitored for by regular liver function tests usually performed 12 hourly. Biochemical evidence of severe liver damage as indicated by Alt > 1000 IU/L may develop 48-96 hours after ingestion.
Prothrombin time with INR To check for bleeding tendency associated with hepatic failure.
Capillary blood glucose Blood glucose levels are monitored regularly due to the risk of hypoglycemia.
Arterial blood gas assessment Patients with paracetamol poisoning may develop lactic acidosis.[1] The development of lactic acidosis is described in two pathways - Due to hepatic failure leading to reduced clearance of lactate & in shocked patients due to peripheral anaerobic respiration. The arterial blood gas assessment will reveal a metabolic acidosis with an increased anion gap.[2]
Serum creatinine level/ Serum electrolytes To monitor renal functions.[3]
References
  1. ZEIN JG, WALLACE DJ, KINASEWITZ G, TOUBIA N, KAKOULAS C. Early anion gap metabolic acidosis in acetaminophen overdose. Am J Emerg Med [online] 2010 Sep, 28(7):798-802 [viewed 05 June 2014] Available from: doi:10.1016/j.ajem.2009.04.005
  2. SHAH AD, WOOD DM, DARGAN PI. Understanding lactic acidosis in paracetamol (acetaminophen) poisoning Br J Clin Pharmacol [online] 2011 Jan, 71(1):20-28 [viewed 05 June 2014] Available from: doi:10.1111/j.1365-2125.2010.03765.x
  3. FERNER R. E., DEAR J. W., BATEMAN D. N.. Management of paracetamol poisoning. BMJ [online] December, 342(apr19 2):d2218-d2218 [viewed 05 June 2014] Available from: doi:10.1136/bmj.d2218

Management - General Measures

Fact Explanation
Regular monitoring of the patient Monitor the patients' vital parameters, urine output and conscious level. Observations should be made to detect features of hepatic dysfunction. Biochemical investigations such as liver function tests, serum creatinine, prothrombin time test & blood glucose levels are also used for monitoring the patient.[1]
Patient counseling and psychiatric referral Following acute phase management, a detailed history should be evaluated with regards to finding the etiology for paracetamol overdose. Patients who have ingested paracetamol with the intention of deliberate self harm or suicide need a risk assessment for future recurrence of similar acts. Patients with a low risk of recurrence need counseling with regards to coping strategies and stress management. High risk patients need psychiatric referral.[2]
References
  1. BOON N.A, COLLEDGE N.R, WALKER B.R, HUNTER J.A.A ed. Davidson's principles and practice of medicine. 21st ed. Edinburgh : Churchill livingstone, 2010.
  2. HAWTON K, WARE C, MISTRY H, HEWITT J, KINGSBURY S, ROBERTS D, WEITZEL H. Paracetamol self-poisoning. Characteristics, prevention and harm reduction. Br J Psychiatry [online] 1996 Jan, 168(1):43-8 [viewed 05 June 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/8770427

Management - Specific Treatments

Fact Explanation
Treatment with N-acetylcysteine (NAC) The first line treatment for paracetamol poisoning is NAC.[1] The mechanism of action is yet to be fully understood but involves neutralization of N-acetyl-p-benzoquinoneimine and improved synthesis of glutathione.[2] The standard infusion regime of NAC is administered in 3 stages with a total dose of 300 mg/kg: 1. 150 mg/kg over the first hour 2. 50 mg/kg over the next 4 hours 3. 100mg/kg over the next 16 hours NAC infusion is continued at a rate of 150mg/kg/24h in 5% dextrose/ 0.9% saline if features of liver damage manifest. This is continued until liver damage is seen to recover.[3]
Decision on when to administer NAC Treat all patients with a single overdose of more than 10g or 200mg/kg body weight and when the time of ingestion is not reliable. In all other patients treatment is based on the timing of ingestion and plasma paracetamol level. Rumack-Matthew normogram is used to plot plasma paracetamol levels against the timing of ingestion and decide on the need to initiate NAC treatment.[4] Some charts include a separate curve for high risk patients (Patients who are heavy alcoholics, on enzyme inducing drugs, malnourished etc) where the treatment threshold is lower than for a normal healthy individual.
Gastrointestinal decontamination Gastrointestinal decontamination can be used in patients presenting within 2 hours of ingestion. Gastric lavage followed by administering activated charcoal limit absorption of paracetamol via the stomach. Gastrointestinal decontamination is effective for a longer duration if the paracetamol product ingested is a slow release product.
Treatment of patients presenting within 8 hours of ingestion Blood sample is collected for measurement of plasma paracetamol level at 4 hours after ingestion or later and the value obtained is plotted in the normogram. The NAC treatment regime is initiated if the paracetamol level is above the treatment line.[5] Continue monitoring the patient during treatment. Patients with paracetamol level below the treatment threshold could be discharged after arranging appropriate follow-up.
Treatment of patients presenting within 8- 24 hours of ingestion Initiate treatment with NAC pending plasma paracetamol level. The value is plotted in the graph and the NAC infusion is continued if the value is above the treatment threshold. Treatment with NAC is discontinued if the plasma level is below the treatment line.
Treatment of patients presenting after 24 hours of ingestion Assessment of paracetamol level is less reliable at this stage. Examine the patient for evidence for hepatotoxicity and if present NAC is administered. Following the initial dose of 300mg/kg, NAC is continued at a dose of 150mg/kg/24h until features of liver damage show improvement.[5]
Management of complications Observe the patient to detect development of acute renal failure, hypoglycaemia, acute liver failure & lactic acidosis and manage accordingly.
Allergic reaction to NAC Inquire about previous allergic reactions to NAC. NAC can be administered with the cover of hydrocortisone and chlorpheniramine in such situations.
Methionine as an alternative to NAC Methionine is effective if given within 8 hours of ingestion. It is administered at a dose of 2.5g orally every 4 hours.
References
  1. KOZER E, KOREN G. Management of paracetamol overdose: current controversies. Drug Saf [online] 2001, 24(7):503-12 [viewed 05 June 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/11444723
  2. LAUTERBURG BH, CORCORAN GB, MITCHELL JR. Mechanism of Action of N-Acetylcysteine in the Protection Against the Hepatotoxicity of Acetaminophen in Rats In Vivo J Clin Invest [online] 1983 Apr, 71(4):980-991 [viewed 05 June 2014] Available from: doi:10.1172/JCI110853
  3. HEARD KJ. Acetylcysteine for Acetaminophen Poisoning N Engl J Med [online] 2008 Jul 17, 359(3):285-292 [viewed 05 June 2014] Available from: doi:10.1056/NEJMct0708278
  4. MEREDITH TJ, CROME P, VOLANS G, GOULDING R. Treatment of paracetamol poisoning. Br Med J [online] 1978 May 6, 1(6121):1215-1216 [viewed 05 June 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1604216
  5. WALLACE C, DARGAN P, JONES A. Paracetamol overdose: an evidence based flowchart to guide management Emerg Med J [online] 2002 May, 19(3):202-205 [viewed 05 June 2014] Available from: doi:10.1136/emj.19.3.202