1506 SECTION XII I Pediatric Critical Care Pharmacology and Toxicology Acetaminophen (Paracetamol) Although it does not cause a toxidrome per se, acetaminophen is the most commonly ingested drug in in[.]
1506 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology Acetaminophen (Paracetamol) Although it does not cause a toxidrome per se, acetaminophen is the most commonly ingested drug in intentional overdose It may cause fulminant hepatic failure and therefore admission to the pediatric intensive care unit Major routes of elimination of acetaminophen are through glucuronidation or sulfation followed by excretion in the urine A minor pathway is via CYP2E1 to produce N-acetyl-p-benzoquinone-imine (NAPQI), a toxic metabolite capable of binding to hepatocytes and causing cell death With therapeutic doses of acetaminophen, NAPQI is rapidly detoxified by glutathione In overdose, larger amounts are formed and may overwhelm the available glutathione stores, resulting in a centrilobular hepatic necrosis QT interval nomogram QT interval (msec) 600 550 Increased risk of TdP 500 450 400 350 No increased risk of TdP 300 Patients can initially present with nausea and vomiting More often, they have no symptoms or signs; thus, laboratory detection is important because treatment is most effective if administered early after ingestion Transaminases begin to rise at approximately 18 to 24 hours after ingestion, peaking between 48 and 72 hours Patients progress either to fulminant hepatic failure or to complete recovery N-acetylcysteine (NAC) reduces the incidence of hepatotoxicity through several suggested mechanisms, including enhanced synthesis of glutathione and free radical scavenging.130 Although it is most efficacious when administered within 10 hours of ingestion, studies have shown benefit when administered to patients presenting after this window of time In one study, intravenous NAC decreased the risk of death from acetaminophen-induced fulminant hepatic failure even in patients who presented with already established hepatic encephalopathy.131 The decision to treat an acute ingestion is based on plotting a single acetaminophen blood level at least hours after ingestion on the Rumack-Matthew nomogram (Fig 126.2) Before hours and after 24 hours, the nomogram is not useful An acetaminophen level should be measured and liver function analyzed to assess the patient’s risk for development of toxicity and potential prognosis The nomogram has not been validated in chronic ingestion or multiple, staggered ingestions In these cases, the nomogram should not be relied on for an assessment of toxicity A poison control center should be consulted for specific treatment advice 250 200 20 40 60 80 100 Heart rate (bpm) 120 140 160 • Fig 126.1 QT interval nomogram for determining at-risk QT TdP, Torsades de pointes An approach to management of acute acetaminophen overdose Draw blood for acetaminophen plasma assay or more hours post-ingestion PLOT ON NOMOGRAM If the acetaminophen level, determined at least hours following an overdose, falls above the broken line, administer the entire course of acetylcysteine treatment If the acetaminophen level, determined at least hours following an overdose, falls below the broken line, acetylcysteine treatment is not necessary or if already initiated may be discontinued Serum levels drawn before hours may not represent peak levels Acetaminophen plasma concentration USE OF NOMOGRAM IN MANAGEMENT OF ACUTE ACETAMINOPHEN OVERDOSE gmol µmol 300 2000 200 150 1300 1000 900 800 700 600 500 100 90 80 70 60 50 40 30 20 400 300 250 200 Potential for toxicity Toxicity unlikely 100 90 80 70 60 50 40 30 Recommended treatment if level is above broken line 20 Take level at least hours post-ingestion 12 16 20 24 28 Hours post-ingestion • Fig 126.2 Use of a nomogram in the management of acute acetaminophen overdose 32 36 CHAPTER 126 Toxidromes and Their Treatment Key References Bowdle AT Adverse effects of opioid agonists and agonist-antagonists in anesthesia Drug Saf 1998;19:173-189 Forti RJ Opiate overdose Pediatr Rev 2007;28:35-36 Ghoneim M, Dhanaraj J, Choi W Comparison of four opioid analgesics as 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