Acetaminophen Overdose (Clinical)

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^[1,2,4,13]
• At-risk populations:
  • Limited literacy
  • Heavy APAP APAP Acetaminophen (APAP) is an over-the-counter nonopioid analgesic and antipyretic medication. Acetaminophen is the most commonly used analgesic worldwide. Acetaminophen overdose is also one of the most common causes of medication poisoning and death. Acetaminophen Overdose use
  • APAP APAP Acetaminophen (APAP) is an over-the-counter nonopioid analgesic and antipyretic medication. Acetaminophen is the most commonly used analgesic worldwide. Acetaminophen overdose is also one of the most common causes of medication poisoning and death. Acetaminophen Overdose/ 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 APAP Acetaminophen (APAP) is an over-the-counter nonopioid analgesic and antipyretic medication. Acetaminophen is the most commonly used analgesic worldwide. Acetaminophen overdose is also one of the most common causes of medication poisoning and death. Acetaminophen Overdose 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^[1,12]

• APAP APAP Acetaminophen (APAP) is an over-the-counter nonopioid analgesic and antipyretic medication. Acetaminophen is the most commonly used analgesic worldwide. Acetaminophen overdose is also one of the most common causes of medication poisoning and death. Acetaminophen Overdose is quickly absorbed via the GI tract.
  • Food may delay 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.
  • Intake of opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics or anticholinergics Anticholinergics Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs also makes 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 unpredictable, owing to delayed gastric emptying Gastric emptying The evacuation of food from the stomach into the duodenum. Gastrointestinal Motility.
• Therapeutic dose serum concentrations peak after 0.5 to 2 hours.
  • Therapeutic serum concentrations: 10–20 µg/mL (65–130 µmol/L)
• 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 to 6 hours (maximum dose, 80 mg/kg/day)
  • Adults: 325–1000 mg every 4 to 6 hours (maximum dose, 4 g/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
    • Chronic alcohol users have enhanced 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 activity.
    • Anticonvulsants (e.g., carbamazepine Carbamazepine A dibenzazepine that acts as a sodium channel blocker. It is used as an anticonvulsant for the treatment of grand mal and psychomotor or focal seizures. It may also be used in the management of bipolar disorder, and has analgesic properties. First-Generation Anticonvulsant Drugs, phenytoin Phenytoin An anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. First-Generation Anticonvulsant Drugs) and antituberculosis drugs (e.g., isoniazid Isoniazid Antibacterial agent used primarily as a tuberculostatic. It remains the treatment of choice for tuberculosis. Antimycobacterial Drugs), also alter 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 activity.
  • 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 > 1000 IU/L

Normal metabolism^[1,2,4,12]

• 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 conjugates → 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 N-Acetyl-P-Benzoquinone-Imine Acetaminophen Overdose ( 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^[1,2,4,12]

• At therapeutic doses of APAP APAP Acetaminophen (APAP) is an over-the-counter nonopioid analgesic and antipyretic medication. Acetaminophen is the most commonly used analgesic worldwide. Acetaminophen overdose is also one of the most common causes of medication poisoning and death. Acetaminophen Overdose:
  • 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 APAP Acetaminophen (APAP) is an over-the-counter nonopioid analgesic and antipyretic medication. Acetaminophen is the most commonly used analgesic worldwide. Acetaminophen overdose is also one of the most common causes of medication poisoning and death. Acetaminophen Overdose 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 APAP Acetaminophen (APAP) is an over-the-counter nonopioid analgesic and antipyretic medication. Acetaminophen is the most commonly used analgesic worldwide. Acetaminophen overdose is also one of the most common causes of medication poisoning and death. Acetaminophen Overdose poisoning is often divided into 4 stages, which are classified according to duration since time of ingestion.^[12]

• Stage I (1st 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.
  • An anion gap Anion gap Metabolic Acidosis metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis may be seen (rare) after a massive overdose.
• 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.
  • Stage I symptoms tend to resolve.
  • 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.
  • Subclinical elevations of 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 and ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests
  • ↑ 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, 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 often > 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, 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. (Most common in stage III.)
• Stage IV (4 days to 2 weeks):
  • If stage III is survived, cases enter a recovery phase.
  • Clinical recovery is typically complete by 1 week (longer if severely ill).
  • Symptoms and laboratory values can take weeks to return to normal.
  • Long-term sequelae (i.e., chronic hepatic dysfunction) are not typically associated with acetaminophen overdose Acetaminophen Overdose Acetaminophen (APAP) is an over-the-counter nonopioid analgesic and antipyretic medication. Acetaminophen is the most commonly used analgesic worldwide. Acetaminophen overdose is also one of the most common causes of medication poisoning and death. Acetaminophen Overdose.

Diagnosis

Evaluation^[1,2,3,9,12]

• Obtain thorough history: intent, dose, time of ingestion, co-ingestants, 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.^[2]
• Serum APAP APAP Acetaminophen (APAP) is an over-the-counter nonopioid analgesic and antipyretic medication. Acetaminophen is the most commonly used analgesic worldwide. Acetaminophen overdose is also one of the most common causes of medication poisoning and death. Acetaminophen Overdose concentration (sAPAP) is the basis for diagnosis.^[1]
  • 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 (to determine degree of hepatic and other organ injury).
  • Chemistry panel
  • LFTs
  • PT/INR
  • Amylase Amylase A group of amylolytic enzymes that cleave starch, glycogen, and related alpha-1, 4-glucans. Digestion and Absorption
  • 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
• Additional tests may include, but are not limited to:^[1]
  • Urine toxicology
  • CBC
  • Arterial blood gas Arterial blood gas Respiratory Alkalosis
  • Lactic acid
  • CK
  • Serum salicylate
  • Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance
  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care test in women of childbearing age
  • ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Electrocardiogram (ECG) and cardiac lab workup as indicated
  • Imaging (chest X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests, 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 US)
  • Other tests based on 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

Rumack-Matthew nomogram Rumack-Matthew nomogram Guides the use of the antidote n-acetylcysteine (NAC) based on sapap and hours since ingestion in relation to probability of hepatotoxicity. Acetaminophen Overdose^[1,2,12]

• 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 N-Acetylcysteine Acetaminophen Overdose ( NAC NAC Acetaminophen Overdose) 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 NAC Acetaminophen Overdose.
• Cannot be used for ingestion that occurred > 24 hours prior to presentation, repeated elevated doses, intravenous overdose, or sustained release dose.
• Understanding the nomogram:
  • In the original Rumack-Matthew nomogram Rumack-Matthew nomogram Guides the use of the antidote n-acetylcysteine (NAC) based on sapap and hours since ingestion in relation to probability of hepatotoxicity. Acetaminophen Overdose:
    • NAC NAC Acetaminophen Overdose is given to those with a sAPAP above the line joining 200 µg/mL at 4 hours and 25 µg/mL at 16 hours (probable toxicity Toxicity Dosage Calculation).
    • sAPAP above the line joining 300 µg/mL at 4 hours and 37.5 µg/mL at 16 hours is regarded as high toxicity Toxicity Dosage Calculation.
  • In the modified Rumack-Matthew nomogram Rumack-Matthew nomogram Guides the use of the antidote n-acetylcysteine (NAC) based on sapap and hours since ingestion in relation to probability of hepatotoxicity. Acetaminophen Overdose, the treatment line is 25% lower than the probable toxicity Toxicity Dosage Calculation line.
    • Considers the differences in sAPAP measurements among laboratories
    • Also takes into account the imprecise timing of ingestion
    • Probable toxicity Toxicity Dosage Calculation line (treat with NAC NAC Acetaminophen Overdose): line joining 150 µg/mL at 4 hours and 18.8 µg/mL at 16 hours

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 N-Acetylcysteine Acetaminophen Overdose ( NAC NAC Acetaminophen Overdose)

• 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 APAP Acetaminophen (APAP) is an over-the-counter nonopioid analgesic and antipyretic medication. Acetaminophen is the most commonly used analgesic worldwide. Acetaminophen overdose is also one of the most common causes of medication poisoning and death. Acetaminophen Overdose, 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 NAC Acetaminophen Overdose:
  • History of APAP APAP Acetaminophen (APAP) is an over-the-counter nonopioid analgesic and antipyretic medication. Acetaminophen is the most commonly used analgesic worldwide. Acetaminophen overdose is also one of the most common causes of medication poisoning and death. Acetaminophen Overdose 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 NAC Acetaminophen Overdose administration → repeat dose
    • If vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia persistent → administer IV formation

Acute overdose

• Management of acute ingestion of acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen (> 7.5-g single dose):
  • 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:^[7,12]
    • Give within 4 hours of ingestion
    • 1 g/kg (maximum dose, 50 g) by mouth
    • Beyond 4 hours, the benefit is questionable.
  • NAC NAC Acetaminophen Overdose can be given orally or intravenously:^[6]
    • IV is preferred in individuals with vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, 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, 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, or bowel obstruction Bowel obstruction Any impairment, arrest, or reversal of the normal flow of intestinal contents toward the anal canal. Ascaris/Ascariasis/ 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.
    • Main adverse effect of oral administration: 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 (up to 33% of individuals) → may lead to inadequate 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
    • Main adverse effect of IV administration: 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 (e.g., pruritus Pruritus An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. Atopic Dermatitis (Eczema), bronchospasm Bronchospasm Asthma Drugs)
  • Antiemetic treatment (e.g., ondansetron Ondansetron A competitive serotonin type 3 receptor antagonist. It is effective in the treatment of nausea and vomiting caused by cytotoxic chemotherapy drugs, including cisplatin, and has reported anxiolytic and neuroleptic properties. Antiemetics)
• NAC NAC Acetaminophen Overdose protocols:
  • Oral (72-hour protocol):^[7,10,12]
    • Loading dose Loading Dose Dosage Calculation: 140 mg/kg by mouth
    • Followed by: 70 mg/kg every 4 hours for 17 doses
  • Standard 20-hour IV protocol:^[7,8,12]
    • Loading dose Loading Dose Dosage Calculation: 150 mg/kg IV given over 15–60 minutes
    • Followed by: 50 mg/kg given over 4 hours (= 12.5 mg/kg/hr)
    • Followed by: 100 mg/kg given over 16 hours (= 6.25 mg/kg/hr)
  • Simplified 20-hour protocol (“two-bag protocol”):^[7,11]
    • Initial dose: 200 mg/kg IV given over 4 hours (= 50 mg/kg/hr)
    • Followed by: 100 mg/kg IV given over 16 hours (= 6.25 mg/kg/hr)
  • “SNAP” regimen:[15]
    • Loading dose Loading Dose Dosage Calculation of 100 mg/kg over 2 hours
    • Followed by 200 mg/kg over 10 hours
  • Shorter protocols have also been developed.
• Monitoring:^[3,8,13]
  • Obtain ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests (checking 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) and sAPAP (verifying undetectable level) prior to end of NAC NAC Acetaminophen Overdose treatment.
  • Other labs:
    • INR
    • Creatinine
    • Sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia
    • Bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes
    • pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance
    • Bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism 
  • Monitor for signs of encephalopathy Encephalopathy Hyper-IgM Syndrome.
• Length of therapy depends on the clinical status of the individual.
• Discontinuation of NAC NAC Acetaminophen Overdose is considered when the risk of developing toxicity Toxicity Dosage Calculation is minimal or low, seen as:
  • Undetectable acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen concentration
  • Normal or significantly decreased ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests (often < 50% of peak values)
  • INR < 2

Rule of 150^[6]

• Toxic dose: 150 mg/kg
• Administer NAC NAC Acetaminophen Overdose if sAPAP is > 150 µg/mL 4 hours post-ingestion (in Rumack-Matthew nomogram Rumack-Matthew nomogram Guides the use of the antidote n-acetylcysteine (NAC) based on sapap and hours since ingestion in relation to probability of hepatotoxicity. Acetaminophen Overdose)
• Initial loading dose Loading Dose Dosage Calculation of NAC NAC Acetaminophen Overdose: 150 mg/kg IV (140 mg/kg by mouth)

Repeated supratherapeutic acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen ingestion^[1]

• Chronic overdose or repeated supratherapeutic ingestion (RSTI):
  • More than 1 intake (multiple ingestions) of APAP APAP Acetaminophen (APAP) is an over-the-counter nonopioid analgesic and antipyretic medication. Acetaminophen is the most commonly used analgesic worldwide. Acetaminophen overdose is also one of the most common causes of medication poisoning and death. Acetaminophen Overdose over a period > 24 hours that results in a cumulative toxic dose (> 4 g per 24 hours)
  • In comparison:
    • Therapeutic dose: ≤ 4 g per 24 hours
    • Acute overdose: > 4 g in ≤ 8 hours
  • Seen in those ingesting extra doses or multiple analgesics, such as hydrocodone-APAP (or other combination analgesic) + APAP APAP Acetaminophen (APAP) is an over-the-counter nonopioid analgesic and antipyretic medication. Acetaminophen is the most commonly used analgesic worldwide. Acetaminophen overdose is also one of the most common causes of medication poisoning and death. Acetaminophen Overdose
  • Signs and symptoms are often nonspecific.
  • Rumack-Matthew nomogram Rumack-Matthew nomogram Guides the use of the antidote n-acetylcysteine (NAC) based on sapap and hours since ingestion in relation to probability of hepatotoxicity. Acetaminophen Overdose is not applicable.
  • sAPAP is often at therapeutic level.
• Suspect acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen toxicity Toxicity Dosage Calculation in individuals with the following:
  • > 7.5 g intake over 24 hours
  • > 4 g intake over 24 hours PLUS one of the following:
    • Chronic alcohol use
    • Fasting
    • Intake of P450-inducing drugs
  • Symptomatic: RUQ pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, 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
  • ↑ Acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen level (even with normal LFTs)
  • ↑ 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, ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests on presentation (even with normal acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen levels)
• Empirically treat the following with NAC NAC Acetaminophen Overdose:
  • Toxic acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen concentrations (> 20 µg/mL)
  • Clinical toxicity Toxicity Dosage Calculation ( 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, 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 tenderness)
  • ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests or 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 ≥ 50 U/L
  • Risk factors + excessive intake + acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen concentration >10 µg/mL

Other clinical scenarios^[7]

• Massive overdose:
  • Acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen concentration above the nomogram line at 300 µg/mL
  • Involve a medical toxicologist or poison center.
  • No clear guidelines, but higher dose of NAC NAC Acetaminophen Overdose may be required
• Unknown time of ingestion or > 24 hours post-ingestion:
  • Consult with a medical toxicologist or poison center.
  • For a suspected single ingestion, can potentially use the “last known time prior to ingestion” as the “time of ingestion” (a worst-case scenario)
  • Treatment with NAC NAC Acetaminophen Overdose is given in those with:
    • Elevated ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests (even with normal acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen concentration)
    • sAPAP > 10 µg/mL
• Pregnant women:
  • Because acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen crosses the placenta Placenta A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). Placenta, Umbilical Cord, and Amniotic Cavity, fetal death can occur.
  • Management is similar to that for nonpregnant adults using the nomogram.
  • NAC NAC Acetaminophen Overdose:
    • Category B
    • IV NAC NAC Acetaminophen Overdose preferred (↓ risk of vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia)
• 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:[13]
  • Demonstrated by all of the following:
    • Elevated aminotransferases (often with ↑ bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism, ↑ alkaline phosphatase Alkaline Phosphatase An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. Osteosarcoma)
    • Coagulopathy (INR ≥ 1.5)
    • Encephalopathy Encephalopathy Hyper-IgM Syndrome
  • Requires ICU ICU Hospital units providing continuous surveillance and care to acutely ill patients. West Nile Virus management
  • Use IV (rather than oral) NAC NAC Acetaminophen Overdose with the 20-hour IV protocol; however, the NAC NAC Acetaminophen Overdose is continued until:
    • Encephalopathy Encephalopathy Hyper-IgM Syndrome resolves and INR < 2 OR
    • 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 takes place.
  • Prognostic models (which rely on lab tests and clinical status) help select those for 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 (and predict mortality Mortality All deaths reported in a given population. Measures of Health Status):
    • Model for End-stage Liver Disease (MELD) score calculator
    • King’s College Criteria calculator