Acetaminophen 18.May.2012-Expires: 7 days - Do not archive DESCRIPTION SUBSTANCE NAME Acetaminophen (Paracetamol)   SUBSTANCE CLASS Para-Aminophenol Derivative INTERVENTION CRITERIA Intervention Level Acute Exposure Investigate those:[1]   6 years or under ingesting 200 mg/kg acetaminophen (paracetamol) or more over a period of less than 8 hours Older than 6 years ingesting At least 10 g or 200 mg/kg (whichever is lower) over a period of less than 8 hours Also investigate if: The dose or timing of ingestion is uncertain, or; The patient is symptomatic   Time of Ingestion Unknown If the time of ingestion is unknown and the dose is above the acute intervention level or unknown: commence an N-acetylcysteine infusion and investigate.   Chronic Exposure Investigate those:[1]   Aged 6 years or under ingesting - 200 mg/kg acetaminophen (paracetamol) or more over a single 24-hour period; - 150 mg/kg or more per 24-hour period for the preceding 48 hours; - 100 mg/kg or more per 24-hour period for the preceding 72 hours; - Blood acetaminophen (paracetamol) >120 umol/L (>20 mg/L) or ALT greater than normal   Aged older than 6 years ingesting - At least 10 g or 200 mg/kg (whichever is lower) over a single 24-hour period; - At least 6 g or 150 mg/kg (whichever is lower) per 24-hour period for the preceding 48 hours; - More than 4 g per day or 100 mg/kg (which ever is less) in patients with predisposing risk-factors; - Blood acetaminophen (paracetamol) >120 umol/L (>20 mg/L) or ALT greater than normal.   Predisposing risk factors[2][1] Chronic alcohol abuse Patients on microsomal inducing drugs such as: barbiturates, carbamazepine, rifampicin, isoniazid Glutathione deficient patients: recent prolonged fasting, acute illness, prolonged vomiting/dehydration, anorexia nervosa, bulimia malnutrition, malignancy, HIV Patients suffering liver injury: viral hepatitis, alcoholic hepatitis Also investigate if: The dose or timing of ingestion is uncertain, or; The patient is symptomatic.   Investigation and Initial Management Acute Ingestion (Link to acute ingestion management flow-chart)   1 to 8 hours post-ingestion   Administer activated charcoal to co-operative adults if within 2 hours of overdose of a solid formulation.[3]   Measure Plasma acetaminophen (paracetamol) level; At 2 hours, or immediately if presenting after this, for pediatric patients ingesting liquid formulations,[4] or; At 4 hours, or immediately if presenting after this, for adults and following ingestion of a solid formulation by any age group. In the case of ingestion of sustained release paracetamol formulations a second plasma acetaminophen (paracetamol) level should be measured 4 hours after the first level.[5][6][7]   The Plasma acetaminophen (paracetamol) level should then be plotted on the treatment nomogram to determine if treatment with the antidote N-acetylcysteine is indicated. In the case of sustained release formulations treatment with the antidote N-acetylcysteine should be commenced if either level falls above the paracetamol treatment nomogram line.[5][6][7]   NOTE: In cases where a 2 hour pediatric level is taken this should be plotted against the 4 hour line on the treatment nomogram   If the plasma acetaminophen (paracetamol) level will NOT be available within 8 hours: Immediately commence an N-acetylcysteine infusion If the plasma acetaminophen (paracetamol) level will be available within 8 hours: Only commence N-acetylcysteine if indicated by the nomogram   If the acetaminophen (paracetamol) level is below the nomogram line, then medical treatment is not required and any N-acetylcysteine infusion can be stopped.   If the acetaminophen (paracetamol) level is above the nomogram line, then commence or continue a full course of N-acetylcysteine.   8 to 24 hours post-ingestion   Immediately commence an N-acetylcysteine infusion Measure: Plasma acetaminophen (paracetamol) level and plot on the treatment nomogram Alanine aminotransferase (ALT)   If the plasma acetaminophen (paracetamol) level is below the nomogram line and the ALT is normal, then the N-acetylcysteine infusion can be halted and no further medical treatment is necessary.   If the plasma acetaminophen (paracetamol) level is above the nomogram line or the ALT is elevated, then complete a full course of N-acetylcysteine.   24 plus hours post-ingestion, or time of ingestion or dose are unknown   Immediately commence an N-acetylcysteine infusion Measure: Plasma acetaminophen (paracetamol) level Alanine aminotransferase (ALT) INR/prothrombin time Creatinine and urea Glucose Arterial Blood Gas Platelet count   If the plasma acetaminophen (paracetamol) level is non-detectable and the ALT is normal, then the infusion can be halted and no further medical treatment is necessary.   If plasma acetaminophen (paracetamol) is detectable or ALT is elevated, then complete a full course of N-acetylcysteine.   The other measurements are used as baseline values to guide future management.   Time of Ingestion Unknown Immediately commence an N-acetylcysteine infusion Measure: Plasma acetaminophen (paracetamol) Alanine aminotransferase (ALT)   If plasma acetaminophen (paracetamol) is not detectable and ALT is normal, the infusion may be halted immediately.   Otherwise, complete the infusion and re-measure plasma acetaminophen (paracetamol) and ALT. If plasma acetaminophen (paracetamol) is <120 umol/L (<20 mg/L) and ALT is normal or declining continued N-acetylcysteine infusion is not necessary.   Chronic Ingestion (Link to repeated supratherapeutic ingestion management flow-chart)   In patients meeting intervention criteria for chronic ingestion   Measure: Plasma acetaminophen (paracetamol) level Alanine aminotransferase (ALT)   If plasma acetaminophen (paracetamol) is <120 umol/L (<20 mg/L) and ALT is normal, then no medical treatment is necessary.   If plasma acetaminophen (paracetamol) is >120 umol/L (>20 mg/L) or ALT greater than normal, then commence an N-acetylcysteine infusion.   If an N-acetylcysteine infusion has been started, then measure plasma acetaminophen (paracetamol) and ALT 8 hours from start of infusion: If plasma acetaminophen (paracetamol) is <120 umol/L (<20 mg/L) and ALT is normal, static or declining, then the N-acetylcysteine can be halted and no further medical treatment is required.   Otherwise continue infusion and re-measure plasma acetaminophen (paracetamol) and ALT 12 hourly until:   Plasma acetaminophen (paracetamol) is <120 umol/L (<20 mg/L) and ALT is normal, static or declining, then the N-acetylcysteine can be halted and no further medical treatment is required.   Observation Period Observation at Home No observation is required for those patients with ingested doses or plasma acetaminophen (paracetamol) determinations below the intervention levels. However, review is warranted should nausea, vomiting, or abdominal pain occur after discharge, particularly if within 24 to 48 hours after the ingestion.   Medical Observation Medical observation of asymptomatic patients is not required provided plasma acetaminophen (paracetamol) investigation is undertaken and levels are below the appropriate intervention level.   Admission Criteria Patients requiring intervention for acute acetaminophen (paracetamol) overdose should be appropriately decontaminated and managed in a medical facility able to rapidly determine plasma acetaminophen (paracetamol) and provide N-acetylcysteine.   Referral to an intensive care unit and/or liver transplant unit may be required in severe poisoning.   TREATMENT TREATMENT SUMMARY Decontamination with activated charcoal is effective within 2 hours of ingestion of non-liquid forms of acetaminophen (paracetamol).[3][8] It is indicated for cooperative adult patients only. Rapid measurement of plasma acetaminophen (paracetamol) level is necessary to determine if an antidote is required. N-acetylcysteine is a life-saving antidote, and while its efficacy declines after approximately eight hours of the acetaminophen (paracetamol) ingestion,[9] it should be administered to all patients with a potentially toxic overdose, regardless of time,[10] and in all cases where there is uncertainty.   Supportive care includes the continued use of N-acetylcysteine, monitoring of major organ function, and further management as indicated. Use of sedating drugs is not recommended due to their impact on the assessment of mental function/encephalopathy. Acute hepatic and renal failure are well recognized concerns. Most complications are a consequence of hepatic failure and rarely occur in its absence.   Advice should be sought from a specialist liver transplant unit: If  The International Normalized Ratio (INR) is greater or equal to 2 at 24 hours or 3 at any time after overdose Or Creatinine is greater or equal to 200 umol/L (2.2 mg/dL) Or pH is less than or equal to 7.3 or bicarbonate less than or equal to 18 mmol/L (18 mEq/L) Or Blood pressure is low after volume loading (mean arterial pressure less than or equal to 60 mmHg) Or The patient becomes encephalopathic   Early discussion with a liver transplant unit is essential. Advice may be given and a decision to transport dependent upon results. In general it is considered desirable to transport patients prior to development of grade 2 encephalopathy.   Emergency Stabilization Emergency stabilization should not be required Decontamination Single dose activated charcoal Antidote(s) N-acetylcysteine Enhanced Elimination Not recommended Supportive Care Monitoring Hepatic Acute hepatic failure Renal Acute renal failure Metabolic Metabolic acidosis Hypoglycemia Hypophosphatemia Cardiovascular Hypotension Cardiotoxicity Hematologic Coagulopathy Thrombocytopenia Hemolysis Respiratory Pulmonary edema Gastrointestinal Pancreatitis EMERGENCY STABILIZATION Emergency Stabilization Should Not Be Required Emergency stabilization of patients following recent ingestion of acetaminophen (paracetamol), solely, is highly unlikely to be necessary. If stabilization is required, then carefully consider co-ingestants or non-toxicological causes. In massive overdoses coma has been associated with acidosis.[11]   DECONTAMINATION Ingestion Single Dose Activated Charcoal Gastrointestinal decontamination is not indicated in any pediatric patient following acetaminophen (paracetamol) overdose.   Gastrointestinal decontamination with activated charcoal is only indicated:[1][3] In co-operative adult patients Within 2 hours of the overdose If at least 10 g or 200 mg/kg (which ever is lower) is ingested If the formulation is a solid (i.e. tablets, capsules)   Further decontamination with activated charcoal may be necessary for co-ingestants.   Induction of emesis and gastric lavage are both contra-indicated.   Single dose activated charcoal[12] CHILD 1 to 2 g/kg orally ADULT 50 to 100 g orally   SIGNS AND SYMPTOMS Initial manifestations of acetaminophen (paracetamol) intoxication may be absent or may only include gastrointestinal effects, malaise, pallor, and diaphoresis.[13][14] Rarely, following massive overdose, there may be an initial metabolic acidosis and coma.[11][15]   Hepatic damage is a common feature of acetaminophen (paracetamol) toxicity and further signs and symptoms become apparent if hepatotoxicity develops. As time after overdose increases signs and symptoms associated with acute hepatic failure including right upper quadrant tenderness, hypotension, acidosis, coagulopathy, encephalopathy, and hypoglycemia may develop.[14][16][17] Jaundice is not evident as an early sign but develops as hepatic failure progresses.[14] Additionally, an initial increase in INR can be seen in the first 24 to 48 hours which appears to result from an inhibition of the activation of vitamin K dependent coagulation factors.[18] Later, coagulopathy is typically a result of liver failure.   Renal failure associated with acetaminophen (paracetamol) overdose may rarely appear acutely, or more usually over a period of days and in association with hepatotoxicity/failure.[19] Cardiovascular concerns are rarely an acute consequence of poisoning, but hypotension and myocardial injury may appear in patients with fulminant hepatic failure as part of multisystem organ failure.[20]   Onset/Duration of Symptoms Four phases of acute acetaminophen (paracetamol) toxicity have been described.[13]   Phase 1 (0.5 to 24 hours after overdose): During the first 24 hours following acute overdose a patient may have few if any signs or symptoms. However, they may demonstrate malaise, anorexia, nausea, vomiting, pallor, and diaphoresis.[13][14]Rarely, following massive overdoses, metabolic acidosis and coma may occur in this phase as a direct toxic effect.[11][15]   Phase 2 (24 to 72 hours after overdose): Previous symptoms subside. Right upper quadrant pain may appear indicating hepatic damage with associated raised hepatic transaminases. International Normalized Ratio (INR) increases. Renal function may begin to deteriorate, however blood urea may remain low due to decreased hepatic urea formation.[13][14]   Phase 3 (72 to 96 hours after overdose): Continuing hepatic centrilobular necrosis with associated coagulation defects, hypoglycemia, metabolic acidosis, and jaundice. Renal failure and cardiac complications frequently occur. Hepatic encephalopathy and death may ensue.[13][14]   Phase 4 (4 days to 2 weeks after overdose): If phase 3 is survived complete resolution of hepatic and renal function is usual.[13][21]   Severity of Poisoning Mild Acetaminophen (Paracetamol) Toxicity Moderate Acetaminophen (Paracetamol) Toxicity Severe Acetaminophen (Paracetamol) Toxicity Malaise Nausea Vomiting Pallor Diaphoresis Upper right quadrant pain Increased INR Metabolic acidosis Hypoglycemia Jaundice Renal failure Fulminant hepatic failure Hepatic encephalopathy   REFERENCES [1] Daly FF, Fountain JS, Murray L, Graudins A, Buckley NA. Guidelines for the management of paracetamol poisoning in Australia and New Zealand - explanation and elaboration. Med J Aust 2008 Mar 3; 188 (5): 296-301. [2] Dart RC, Erdman AR, Olson KR, Christianson G, Manoguerra AS, Chyka PA, Caravati EM, Wax PM, Keyes DC, Woolf AD, Scharman EJ, Booze LL, Troutman WG. Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2006; 44 (1): 1-18. [3] Buckley NA, Whyte IM, O'Connell DL, Dawson AH. Activated charcoal reduces the need for N-acetylcysteine treatment after acetaminophen (paracetamol) overdose. J Toxicol Clin Toxicol 1999; 37 (6): 753-7. [4] Anderson BJ, Holford NH, Armishaw JC, Aicken R. Predicting concentrations in children presenting with acetaminophen overdose. J Pediatr 1999 Sep; 135 (3): 290-5. [5] Graudins A, Chiew A, Chan B. Overdose with modified-release paracetamol results in delayed and prolonged absorption of paracetamol. Intern Med J 2010 Jan; 40 (1): 72-6. [6] Graudins A, Pham HN, Salonikas C, Naidoo D, Chan B. Early presentation following overdose of modified-release paracetamol (Panadol Osteo) with biphasic and prolonged paracetamol absorption. N Z Med J 2009 Aug 7; 122 (1300): 64-71. [7] Tan C, Graudins A. Comparative pharmacokinetics of Panadol Extend and immediate-release paracetamol in a simulated overdose model. Emerg Med Australas 2006 Aug; 18 (4): 398-403. [8] Yeates PJ, Thomas SH. Effectiveness of delayed activated charcoal administration in simulated paracetamol (acetaminophen) overdose. Br J Clin Pharmacol 2000 Jan; 49 (1): 11-4. [9] Prescott LF, Illingworth RN, Critchley JA, Proudfoot AT. Intravenous N-acetylcysteine: still the treatment of choice for paracetamol poisoning. [Letter] Br Med J 1980 Jan 5; 280 (6206): 46-7. [10] Keays R, Harrison PM, Wendon JA, Forbes A, Gove C, Alexander GJ, Williams R. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ 1991 Oct 26; 303 (6809): 1026-9. [11] Zezulka A, Wright N. Severe metabolic acidosis early in paracetamol poisoning. Br Med J (Clin Res Ed) 1982 Sep 25; 285 (6345): 851-2. [12] Fountain JS, Beasley DM. Activated charcoal supercedes ipecac as gastric decontaminant. N Z Med J 1998 Oct 23; 111 (1076): 402-4. [13] Linden CH, Rumack BH. Acetaminophen overdose. Emerg Med Clin North Am 1984 Feb; 2 (1): 103-19. [14] Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975 Jun; 55 (6): 871-6. [15] Roth B, Woo O, Blanc P. Early metabolic acidosis and coma after acetaminophen ingestion. Ann Emerg Med 1999 Apr; 33 (4): 452-6. [16] Dargan PI, Jones AL. Acetaminophen poisoning: an update for the intensivist. Crit Care 2002 Apr; 6 (2): 108-10. [17] Bernal W, Auzinger G, Dhawan A, Wendon J. Acute liver failure. Lancet 2010 Jul 17; 376 (9736): 190-201. [18] Whyte IM, Buckley NA, Reith DM, Goodhew I, Seldon M, Dawson AH. Acetaminophen causes an increased International Normalized Ratio by reducing functional factor VII. Ther Drug Monit 2000 Dec; 22 (6): 742-8. [19] Jones AL, Prescott LF. Unusual complications of paracetamol poisoning. QJM 1997 Mar; 90 (3): 161-8. [20] Lip GY, Vale JA. Does acetaminophen damage the heart? J Toxicol Clin Toxicol 1996; 34 (2): 145-7. [21] Hamlyn AN, Douglas AP, James OF, Lesna M, Watson AJ. Liver function and structure in survivors of acetaminophen poisoning. A follow-up study of serum bile acids and liver histology. Am J Dig Dis 1977 Jul; 22 (7): 605-10. Do Not Archive. This document is current on day of issue, NZ: 18.May.2012

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