Acetaminophen Overdose

Epidemiology

• Most common cause of acute liver failure Liver failure Severe inability of the liver to perform its normal metabolic functions, as evidenced by severe jaundice and abnormal serum levels of ammonia; bilirubin; alkaline phosphatase; aspartate aminotransferase; lactate dehydrogenases; and albumin/globulin ratio. Autoimmune Hepatitis (ALF) in the United States
• At-risk populations:
  • Limited literacy
  • Heavy APAP use
  • APAP/ opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation combination use
• Significant number of overdoses are unintentional:
  • Failure to recognize APAP contents in medication
  • Incorrect understanding of dosing directions
• Early identification Identification Defense Mechanisms of overdose is associated with low mortality Mortality All deaths reported in a given population. Measures of Health Status rates.
• Development of ALF:
  • Associated with 28% mortality Mortality All deaths reported in a given population. Measures of Health Status
  • One-third of cases with ALF require liver transplantation Liver transplantation The transference of a part of or an entire liver from one human or animal to another. Hepatocellular Carcinoma (HCC) and Liver Metastases.

Pathophysiology

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

• APAP is quickly absorbed via the GI tract.
• Therapeutic dose serum concentrations peak after 0.5–2 hours.
• In overdose:
  • Serum concentrations peak within 4 hours.
  • Can be > 4 hours if taken with drugs that delay gastric emptying Gastric emptying The evacuation of food from the stomach into the duodenum. Gastrointestinal Motility
• Therapeutic dose:
  • Children: 10–15 mg/kg every 4–6 hours
  • Adults: 325–1,000 mg every 4–6 hours (maximum: 4 g a day)
• Toxic dose (single ingestion):
  • > 250 mg/kg or > 12 g over a 24-hour period
  • Note: lower dose threshold Threshold Minimum voltage necessary to generate an action potential (an all-or-none response) Skeletal Muscle Contraction for alcoholics/ anticonvulsant Anticonvulsant Anticonvulsant drugs are pharmacological agents used to achieve seizure control and/or prevent seizure episodes. Anticonvulsants encompass various drugs with different mechanisms of action including ion-channel (Na+ and Ca+2) blocking and GABA reuptake inhibition. First-Generation Anticonvulsant Drugs users
  • Ingestion of > 350 mg/kg likely to result in severe livery toxicity Toxicity Dosage Calculation if untreated
  • Severe livery toxicity Toxicity Dosage Calculation: peak AST AST Enzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate. Liver Function Tests or ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests > 1,000 IU/L

Normal metabolism

• About 90% is metabolized in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy to sulfate and glucuronide → excreted in urine
• Remaining undergoes oxidation via hepatic cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-Induced Liver Injury (primarily CYP2E1 CYP2E1 An ethanol-inducible cytochrome p450 enzyme that metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Substrates include ethanol; inhalation anesthetics; benzene; acetaminophen and other low molecular weight compounds. Cyp2e1 has been used as an enzyme marker in the study of alcohol abuse. Ethanol Metabolism)
  • CYP2E1 CYP2E1 An ethanol-inducible cytochrome p450 enzyme that metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Substrates include ethanol; inhalation anesthetics; benzene; acetaminophen and other low molecular weight compounds. Cyp2e1 has been used as an enzyme marker in the study of alcohol abuse. Ethanol Metabolism pathway produces the toxic metabolite N-acetyl-p-benzoquinone-imine ( NAPQI NAPQI Drug-Induced Liver Injury).
  • NAPQI NAPQI Drug-Induced Liver Injury is normally detoxified by glutathione → nontoxic cysteine Cysteine A thiol-containing non-essential amino acid that is oxidized to form cystine. Synthesis of Nonessential Amino Acids and mercaptate compounds → excreted in urine

Pathogenesis

• At therapeutic doses of APAP:
  • NAPQI NAPQI Drug-Induced Liver Injury pathway is relatively underutilized. 
  • NAPQI NAPQI Drug-Induced Liver Injury metabolites are rapidly conjugated to nontoxic compounds.
• At toxic doses:
  • Primary hepatic metabolism pathways become oversaturated.
  • ↑ APAP metabolism via cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-Induced Liver Injury → ↑ NAPQI NAPQI Drug-Induced Liver Injury production
  • ↑ NAPQI NAPQI Drug-Induced Liver Injury depletes glutathione levels and saturate the elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy pathways
  • ↑ Free NAPQI NAPQI Drug-Induced Liver Injury binds with hepatic macromolecules → produce NAPQI-protein adducts (irreversible process) → ↑ oxidative stress Oxidative stress A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products. Cell Injury and Death → hepatocellular necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage

Clinical Presentation

The clinical course of APAP poisoning is often divided into 4 stages that are classified according to duration since time of ingestion.

• Stage I (first 24 hours):
  • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics and vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, malaise Malaise Tick-borne Encephalitis Virus
  • May be asymptomatic
  • Laboratory studies are usually normal.
• Stage II (24–72 hours):
  • Ongoing hepatic necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage results in ↑ transaminases Transaminases A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Autoimmune Hepatitis by 36 hours
  • RUQ pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways and hepatomegaly occur.
  • ↑ Prothrombin time Prothrombin time Clotting time of plasma recalcified in the presence of excess tissue thromboplastin. Factors measured are fibrinogen; prothrombin; factor V; factor VII; and factor X. Hemostasis (PT) and total bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism, oliguria Oliguria Decreased urine output that is below the normal range. Oliguria can be defined as urine output of less than or equal to 0. 5 or 1 ml/kg/hr depending on the age. Renal Potassium Regulation, and abnormal creatinine may occur
• Stage III (72–96 hours):
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy function abnormalities peak.
  • Stage I symptoms return with jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, confusion, and bleeding diathesis Bleeding diathesis Wiskott-Aldrich Syndrome.
  • Severe hepatotoxicity Hepatotoxicity Acetaminophen:
    • ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests, AST AST Enzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate. Liver Function Tests > 10,000 IU/L
    • Prolonged PT/INR
    • Lactic acidosis Lactic Acidosis Oxazolidinones
    • Bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism > 4 mg/dL
  • Possibly complicated with ALF, renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome, and pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis
  • Death often occurs due to multiorgan failure.
• Stage IV (4 days to 2 weeks):
  • If stage III is survived, cases enter a recovery phase.
  • Recovery is typically complete by week 1 (longer if severely ill).
  • Symptoms and laboratory values can take weeks to return to normal.

Diagnosis

Evaluation

• Obtain a thorough history: intent, dose, time of ingestion, coingestants, and comorbidities Comorbidities The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. St. Louis Encephalitis Virus.
• Serum APAP concentration (sAPAP) is the basis for diagnosis.
  • Should be measured in every case
  • Draw 4 hours after time of ingestion (levels < 4 hours may not be indicative of peak values).
  • If time of ingestion > 4 hours or unknown → immediate sAPAP → repeat in 4 hours
  • If initial sAPAP undetectable → observe individual and repeat sAPAP in 4 hours
• Time of ingestion and sAPAP are the best predictors of hepatotoxicity Hepatotoxicity Acetaminophen.
• If toxicity Toxicity Dosage Calculation is confirmed or predicted, additional tests should be ordered:
  • Chemistry panel
  • LFTs
  • PT/INR
  • Urinalysis Urinalysis Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. Urinary Tract Infections (UTIs) in Children

Rumack-Matthew nomogram

• Guides the use of the antidote Antidote An antidote is a substance that counteracts poisoning or toxicity. Substances that can cause poisoning include heavy metals (from occupation, treatments, or diet), alcohols, environmental toxins, and medications. Antidotes of Common Poisonings N-acetylcysteine (NAC) based on sAPAP and hours since ingestion in relation to probability Probability Probability is a mathematical tool used to study randomness and provide predictions about the likelihood of something happening. There are several basic rules of probability that can be used to help determine the probability of multiple events happening together, separately, or sequentially. Basics of Probability of hepatotoxicity Hepatotoxicity Acetaminophen
• Cases that lie above the treatment line are treated with NAC.
• Cannot be used for ingestion that occurred > 24 hours prior to presentation, repeated elevated doses, intravenous overdose, or sustained release dose

Management

Treatment approach

Entails supportive care, limiting drug absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption, and treatment of toxic effects:

• Initial management: secure airway Airway ABCDE Assessment, breathing, and circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment
• GI decontamination: activated charcoal Charcoal An amorphous form of carbon prepared from the incomplete combustion of animal or vegetable matter, e.g., wood. The activated form of charcoal is used in the treatment of poisoning. Antidotes of Common Poisonings to all adults presenting within 4 hours of ingestion
  • More effective than induced emesis and gastric lavage
  • Do not give if individual is sedated or unable to manage their airway Airway ABCDE Assessment.

N-acetylcysteine (NAC)

• Antidote Antidote An antidote is a substance that counteracts poisoning or toxicity. Substances that can cause poisoning include heavy metals (from occupation, treatments, or diet), alcohols, environmental toxins, and medications. Antidotes of Common Poisonings for APAP, given to all individuals at risk for hepatotoxicity Hepatotoxicity Acetaminophen
• Repletes glutathione stores and subsequently decreases NAPQI NAPQI Drug-Induced Liver Injury production
• Indications for NAC:
  • History of APAP ingestion and evidence of any liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy injury
  • sAPAP (drawn at ≥ 4 hours) above nomogram treatment line
  • Unclear time of ingestion and serum drug level of > 10 µg/mL
  • Suspected single dose of > 7.5 g or 150 mg/kg (if sAPAP unavailable > 8 hours after ingestion)
  • > 24 hours after ingestion with evidence of liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy injury
• If given within 8 hours, serious hepatotoxicity Hepatotoxicity Acetaminophen is prevented and death is rare.
• Treatment protocol and duration:
  • Can vary based on individual case and clinical judgment Judgment The process of discovering or asserting an objective or intrinsic relation between two objects or concepts; a faculty or power that enables a person to make judgments; the process of bringing to light and asserting the implicit meaning of a concept; a critical evaluation of a person or situation. Psychiatric Assessment
  • Cases are generally treated for 20–72 hours.
• Available in oral and IV forms
  • In general, both are acceptable. 
  • Use IV for:
    • Cases with intractable vomiting Intractable Vomiting Pediatric Vomiting
    • Hepatic failure Hepatic failure Severe inability of the liver to perform its normal metabolic functions, as evidenced by severe jaundice and abnormal serum levels of ammonia; bilirubin; alkaline phosphatase; aspartate aminotransferase; lactate dehydrogenases; and albumin/globulin ratio. Autoimmune Hepatitis
    • Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation to oral: pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis, ileus Ileus A condition caused by the lack of intestinal peristalsis or intestinal motility without any mechanical obstruction. This interference of the flow of intestinal contents often leads to intestinal obstruction. Ileus may be classified into postoperative, inflammatory, metabolic, neurogenic, and drug-induced. Small Bowel Obstruction, bowel obstruction Bowel obstruction Any impairment, arrest, or reversal of the normal flow of intestinal contents toward the anal canal. Ascaris/Ascariasis/injury
• Adverse reactions:
  • Anaphylaxis Anaphylaxis An acute hypersensitivity reaction due to exposure to a previously encountered antigen. The reaction may include rapidly progressing urticaria, respiratory distress, vascular collapse, systemic shock, and death. Type I Hypersensitivity Reaction: 10%–20% develop a hypersensitivity reaction.
  • Vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia: About 33% of cases develop nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics and vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia.
    • If vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia occurs ≤ 1 hour after NAC administration → repeat dose
    • If vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia persistent → administer IV formation