Ver el código de «Acetaminophen toxicity»

==Background==
*Includes Tylenol and numerous brands and products including [[acetaminophen]]
*Now the most common cause of acute liver failure in the US<ref>Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med. 2002 Dec 17; 137(12): 947-54.</ref>

===Maximal acetaminophen daily doses===
*Adults: 4 g/day
*Peds: 75 mg/kg/day

===Toxic dose===
*>10 g or >200 mg/kg as single ingestion or over 24hr period '''OR'''
*>6 g or >150 mg/kg per 24hr period x 2days
*200 mg/kg in healthy children 1-6 years of age

===The 150 Rule===
*Toxic dose is 150 mg/kg
*Give [[NAC]] if level is >150 mcg/mL four hours post-ingestion
*Initial loading dose of [[NAC]] is 150 mg/kg IV (140 mg/kg PO)

===Mechanism of action===
*Poorly understood
*Possibly through inhibition of Cyclooxygenase-3 (COX-3)
**Decreases synthesis of prostaglandins
*Antipyresis through inhibition of hypothalamic heat center

===Pharmacokinetics===
*A - Rapid and near complete absorption
*D - Vd = 0.95 L/kg
*M - T 1/2 = 1.5-2 hrs
**40-60% - Glucuronidation 
**20-40% - Sulfuronidation
**5-10% - Metabolism through CYP450/CYP2E1 '''(Forms NAPQI)'''<ref>Hendrickson RG, Bizovi KE. Acetaminophen. In: Flomenbaum NE, Goldfrank LR, Hoffman RS, et al, eds. Goldfrank’s Toxicologic Emergencies. 8th ed. New York: McGraw-Hill; 2002:523-543. (Textbook chapter)</ref>
**Metabolized by first-order kinetics
*E - Conjugated and unconjugated excreted through kidneys

===Toxicologic Pathophysiology===
*Acetaminophen is metabolized by sulfation and glucuronide conjugation. This process becomes overwhelmed in overdose and metabolism is shifted to the CYP 450 pathway generating toxic NAPQI.
*APAP toxic metabolite NAPQI usually quickly detoxified by glutathione stores in liver
**In overdose, glutathione runs out, NAPQI accumulates → liver injury
*[[NAC]] increases availability of glutathione
**[[NAC]] is a precursor

==Clinical Features==
===Stage 1 (first 24hr)===
*Mild nausea and vomiting/malaise
*[[Hypokalemia]] (associated with  high 4-hr level)
*[[Acetaminophen_toxicity#Massive Ingestion|Massive Ingestion]] (>500 mg/kg) may present with acidemia, coma, hemodynamic changes shortly after ingestion and prior to hepatic necrosis <ref name = “Roth”> Roth B, Woo O, Blanc P. Early Metabolic Acidosis and Coma After Acetaminophen Ingestion. Ann Emerg Med. 1999;33(4):452-456. </ref> <ref> Zein JG, et al. Early anion gap metabolic acidosis in acetaminophen overdose. Am J Emerg Med. 2010;28:798-802. </ref>

===Stage 2 (days 2-3)===
*Improvement in symptoms
*[[RUQ abdominal pain]]
*Elevated transaminases
*Elevated bilirubin, PT (if severe)

===Stage 3 (days 3-4)===
*Recurrence of [[nausea and vomiting]]
*Acute liver necrosis → liver failure
*[[Jaundice]]
*[[Coagulopathy]]
*Encephalopathy (esp with massive ingestions)
*[[Acute renal failure]] (1-2%; usually after hepatic failure is evident)
*[[Pancreatitis]] (rare)

===Stage 4 (after day 5, up to 2 weeks)===
*Clinical improvement and recovery (7-8 d) '''OR'''
*Deterioration to multi-organ failure and death '''OR'''
*Continued deterioration

==Differential Diagnosis==
{{Acute hepatitis causes}}

==Evaluation==
[[File:APAP_nomogram.jpg|thumb|Rumack-Matthew Nomogram '''(use correct units!)''']]
===Work-Up===
*Acetaminophen (APAP) level
**Obtain 4 hrs post-ingestion and compare level to Rumack-Matthew nomogram  
**Obtaining level between 2-4 hrs post ingestion is helpful if level is undetectable (essentially zero risk of progressing to toxic levels), but anything other than undetectable requires a repeat draw at 4 hrs<ref>https://www.ncbi.nlm.nih.gov/pubmed/27788602</ref>
**Obtaining multiple levels is rarely indicated in the absence of hepatotoxicity
*Chemistry
**[[Metabolic acidosis]] seen with extremely large ingestion
**Lactic acid and blood gas<ref>Zein JG, Wallace DJ, Kinasewitz G, Toubia N, Kakoulas C. Early anion gap metabolic acidosis in acetaminophen overdose. Am J Emerg Med. 2010;28:798-802.</ref>
*LFT
**AST and ALT elevation more specific than GGT and alkaline phosphatase
**AST levels > 1000 IU/L are more likely to result from acetaminophen poisoning than from chronic hepatitis or alcoholic liver disease<ref>By, O’Malley GF, O’Malley R. Acetaminophen Poisoning - Injuries; Poisoning. Merck Manuals Professional Edition. https://www.merckmanuals.com/professional/injuries-poisoning/poisoning/acetaminophen-poisoning?query=acetaminophen+poisoning. Published April 2020. Accessed July 15, 2021.</ref>
*PT/PTT/INR
*[[Aspirin]] levels and other co-ingestants

===Rumack-Matthew Nomogram===
*Only indicated for single, acute ingestion occurring <24 hr prior to presentation
**Not useful for chronic ingestion (patients who take supratherapeutic doses for several days) or if time of ingestion is unknown
*'''Make sure you use the correct units!'''
*Dotted line should be used for those at higher-risk of liver toxicity (eg alcoholics, those on enzyme-inducing drugs)
*Co-ingestion of drugs that reduce GI motility should prompt repeating acetaminophen level at 8 hrs:
**Opiates
**Anticholinergics ([[diphenhydramine]], etc.)

==Management==
;''Very important to identify time of ingestion.  The Rumack-Matthew Nomogram is only for acute acetaminophen ingestions and not useful for chronic ingestions''

===<4 hr after ingestion===
*GI decontamination
**[[Activated Charcoal]] if <3 hr post-ingestion (no role for [[multidose activated charcoal]])
**[[Gastric Lavage]] if high-morbidity coingestants and <1 hr post-ingestion
*Send 4hr APAP level
**Toxic level: Give [[NAC]]
**Nontoxic level: No treatment necessary

===Between 4-24 hr after ingestion===
*Send APAP level
**If level will be available within 8hr post-ingestion: wait for level before treating
**If level will not be available within 8hr post-ingestion: do not wait for level before treating
***Discontinue treatment if level returns non-toxic

===Unknown or >24 hr after ingestion===
*Consider GI decontamination for unknown ingestion time
*Give 1st dose of [[NAC]]
*Send APAP level, LFT, coags
**APAP level >10 '''OR''' elevated transaminases? If yes then continue [[NAC]]
***pH <7.3 or PT >100 or creatinine >3.3 or [[altered mental status]]? If yes refer to liver transplant unit
**APAP level <10 and LFT both normal? If yes then stop [[NAC]] (treatment not indicated)

===Chronic Ingestion===
*Initiate [[NAC]] in any patient with evidence of ongoing hepatotoxicity (lft abnormalities) '''OR''' 'positive' tylenol level (>20 mcg/mL) 
*If patient has normal LFT and 'negative' tylenol level (<20 mcg/mL), NAC treatment NOT required

===Overdose in Pregnancy===
{{NAC use in pregnancy}}

===Extended release overdose===
*Extended-release acetaminophen (Tylenol ER) consists of acetaminophen 325 mg in immediate release (IR) form surrounding a matrix of acetaminophen 325mg
**Several studies show that the elimination of ER and IR APAP preparations is nearly identical after 4 hours. However, some case reports have documented APAP levels that are above the potential toxicity and treatment line on the nomogram as late as 11-14 hours after the ingestion of the ER preparation. 
**Recommended management includes the measurement of 4-, 6-, and 8-hour APAP concentrations. Begin [[NAC]] therapy if any level crosses above the nomogram treatment line. If the 6-hour level is greater than the 4-hour level, begin [[NAC]] therapy.

===Massive Ingestion===
*>500mg/kg
*May have early acidemia, coma, hemodynamic changes (does not necessarily indicate hepatic damage)
**Supportive care (IVF, pressors, intubation PRN)
*Early consultation with poison control, prior to 4 hour level
*May consider early or increased [[NAC]] dosage, dialysis in extreme cases <ref> Gosselin S, et al. Extracorporeal treatment for acetaminophen poisoning:
Recommendations from the EXTRIP workgroup. Clin Tox. 2014;52:856-867.</ref>

===[[NAC]] Treatment===
Should begin if:
*The patient's history suggests:acetaminophen ingestion of ≥ 150mg/kg in children or 7.5 g in adults and the results of blood tests will not be available within 8 hours of the ingestion or
*Serum acetaminophen concentration falls on or above the Rumack-Matthew nomogram treatment line or
*While waiting for AST/ALT levels of a patient with a chronic overdose
**Serum levels may not reach peak until up to 4 hours post-ingestion

===Anaphylactoid reactions to IV NAC===
*Generally the reactions are self limited with symptoms such as pruritis treated with [[Diphenhydramine]]. If angioedema develops NAC infusion should be stopped and restarted an hour after symptom resolution.<ref>Bailey B, McGuigan MA. Management of anaphylactoid reactions to intravenous N-acetylcysteine. Ann Emerg Med. 1998 Jun;31(6):710-5.</ref>

==Adult N-Acetylcysteine Dosing==
''See above guidelines for when to dose [[NAC]]''
{{Adult NAC dosing}}

==Pediatric N-Acetylcysteine Dosing==
{{Pediatric NAC dosing}}

==Disposition==
*Consider discharge for asymptomatic patients who do not require NAC
*Admission if requiring NAC or other ingestions, injuries
*Transfer to transplant center based on above criteria
*Psych consult if patient has suicidal ideation
*In subacute toxicity, AST/ALT ratio of < 0.4 has sen of 99% for resolving hepatic injury<ref>Mcgovern AJ, et al. Can AST/ALT ratio indicate recovery after acute paracetamol poisoning? Clin Toxciol. 2015; 53:164-167.</ref>

===King's College Criteria===
*Criteria for predicting fulminant hepatic failure, and thus referral to transplant center<ref>Bailey B, et al. Fulminant hepatic failure secondary to acetaminophen poisoning: a systematic review and meta-analysis of prognostic criteria determining the need for liver transplantation. Crit Care Med. 2003; 31(1):299-305.</ref>
*PPV 70-90% and sensitivity 69%
*Includes:
**pH<7.3 or lactate>3 at 12hrs after full fluid resuscitation, '''OR''' all of the following:
**Cr>3.4
**INR>6.5
**grade 3 or 4 [[Hepatic Encephalopathy]]

*Other predictors of APAP-induced hepatic failure include:
**lactate >3.5 4hrs after fluid resusciation
**phos >3.8 at 48hrs, '''OR'''
**APACHE II >15

==External Links==
*[http://www.mdcalc.com/acetaminophen-overdose-and-iv-nac-dosing/ MDCalc - Acetaminophen Overdose & NAC Dosing]
*[http://www.mdcalc.com/kings-college-criteria-for-acetaminophen-toxicity/ MDCalc - King's College Criteria for Acetaminophen Toxicity]
*[https://www.merckmanuals.com/professional/injuries-poisoning/poisoning/acetaminophen-poisoning?query=acetaminophen%20poisoning| Merk Manual: Acetaminophen Poisoning]
*[https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2808062 Management of Acetaminophen Poisoning in the US and Canada: A Consensus Statement (2023)]

==References==
<references />

[[Category:Toxicology]]