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ACETAMINOPHEN POISONING: A COMPREHENSIVE REVIEW DANA BARTLETT, BSN, MSN, MA, CSPI Dana Bartlett is a professional nurse and author. His clinical experience includes 16 years of ICU and ER experience and over 20 years of as a poison control center information specialist. Dana has published numerous CE and journal articles, written NCLEX material, written textbook chapters, and done editing and reviewing for publishers such as Elsevire, Lippincott, and Thieme. He has written widely about toxicology and was recently named a contributing editor, toxicology section, for Critical Care Nurse journal. He is currently employed at the Connecticut Poison Control Center and is actively involved in lecturing and mentoring nurses, emergency medical residents and pharmacy students. ABSTRACT Acetaminophen toxicity is the most common cause of acute liver failure in the United States, Europe, and Australia. Liver damage after acetaminophen overdose is common but liver failure and death are rare. There is a highly effective antidote available, N-acetylcysteine, and if treated promptly, patient recovery and survival from acetaminophen toxic overdose is almost assured. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 1 Policy Statement This activity has been planned and implemented in accordance with the policies of NurseCe4Less.com and the continuing nursing education requirements of the American Nurses Credentialing Center's Commission on Accreditation for registered nurses. It is the policy of NurseCe4Less.com to ensure objectivity, transparency, and best practice in clinical education for all continuing nursing education (CNE) activities. Continuing Education Credit Designation This educational activity is credited for 3.5 hours. Nurses may only claim credit commensurate with the credit awarded for completion of this course activity. Pharmacology content is 1 hour. Statement of Learning Need In toxic overdosing, acetaminophen can cause liver damage and failure, and can lead to costly medical treatment and transplantation. Health teams need to understand the basis for diagnosis and treatment of acetaminophen overdose, which includes clinical manifestations of toxicity and use of the Rumack-Matthew nomogram to interpret acetaminophen plasma concentrations. Course Purpose To help clinicians identify patients at risk of liver damage and failure due to acetaminophen toxic overdose and to know the appropriate treatment to support full recovery and survival. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 2 Target Audience Advanced Practice Registered Nurses and Registered Nurses (Interdisciplinary Health Team Members, including Vocational Nurses and Medical Assistants may obtain a Certificate of Completion) Course Author & Planning Team Conflict of Interest Disclosures Dana Bartlett, BSN, MSN, MA, CSPI, William S. Cook, PhD, Douglas Lawrence, MA, Susan DePasquale, MSN, FPMHNP-BC all have no disclosures Acknowledgement of Commercial Support There is no commercial support for this course. Please take time to complete a self-assessment of knowledge, on page 4, sample questions before reading the article. Opportunity to complete a self-assessment of knowledge learned will be provided at the end of the course. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 3 1. Most acetaminophen is changed to harmless metabolites by a. b. c. d. conjugation. metabolism by cytochrome P-450 enzymes. elimination in the urine. elimination in the stool. 2. Acetaminophen is converted to a toxic metabolite by a. b. c. d. conjugation. metabolism by cytochrome P-450 enzymes. elimination in the urine. elimination in the stool. 3. The toxic dose of acetaminophen is: a. b. c. d. ≥ ≥ ≥ ≥ 10 grams or 200 mg/kg. 7.5 grams or 150 mg/kg. 15 grams or 150 mg/kg. 20 grams 04 300 mg/kg. 4. The basis of acetaminophen poisoning is a. rate/amount of NAPQI formation greater than glutathione availability. b. rate/formation of conjugation is greater than glutathione availability. c. decrease in glutathione effectiveness. d. increased sensitivity of the liver to the drug. 5. One organ, other than the liver, that is affected by an overdose of acetaminophen is a. b. c. d. the the the the lungs. small bowel. kidneys. thyroid. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 4 Introduction The American Association of Poison Control Centers (AAPCC) publishes annual reports documenting the number and nature of drug overdoses. The AAPCC data from 2014 (the latest available data) was similar to the data from almost every previous year. Acetaminophen was one of the most common drugs taken in an overdose with intent to cause self-harm, accounting for almost 17% of the fatalities,1 and therapeutic errors with acetaminophen that caused liver damage were quite common.1 Acetaminophen (the drug is called paracetamol in Europe) overdose is now the most common cause of acute liver failure in the United States, Europe, and Australia.2 Most patients who have taken an overdose of acetaminophen and who are treated correctly and promptly will survive with no permanent damage; in more than 90% of these cases, the patients will recover completely. However, there are hundreds of deaths every year in the United States caused by acetaminophen poisoning, and the mortality rates for patients with acute liver failure caused by acetaminophen overdose can be as high as 28%.3 Acetaminophen: Pharmacology Acetaminophen is an over-thecounter analgesic used for mild to moderate pain and as antipyretic; it appears to have minimal antiinflammatory action. Although it is ! The name acetaminophen, and the brand name Tylenol®, are both derived from combinations of the letters of the chemical term for acetaminophen, N-acetyl-p-aminophenol.! nursece4less.com nursece4less.com nursece4less.com nursece4less.com 5 not completely understood how acetaminophen works, it is thought to produce its analgesic/antipyretic effects by the following mechanisms of action.4,5 • It inhibits synthesis of prostaglandins in the central nervous system; prostaglandins are hormone-like substances involved in sensitizing some neurons to pain and mediating many physiological functions, i.e., the inflammatory response. • It blocks pain impulse generation peripherally. • It acts as an antipyretic by inhibiting the heat-regulating center of the hypothalamus. In therapeutic doses, the drug is rapidly and completely absorbed from the gastrointestinal tract. The serum concentration of an oral dose peaks within 10 to 60 minutes, the onset of action is within one hour, and the therapeutic concentration is 10 to 20 mcg/ml.4,5 First pass metabolism removes approximately 25% of a therapeutic dose. After absorption, approximately 90% of acetaminophen undergoes hepatic glucuronide and sulfate conjugation; the acetaminophen/sulfate and Conjugation is a process by which the acetaminophen is bound to glucuronic acid and sulfate acetaminophen/glucuronic acid complexes are harmless and are eliminated in the urine. A very small amount of the drug is excreted unchanged in the urine, and the remainder (approximately 2% or less) is metabolized by several enzymes of the cytochrome P450 enzyme system to N-acetylbenzoquinoneimine (NAPQI). This metabolite is toxic to the liver and the kidneys. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 6 However, if acetaminophen is ingested in therapeutic doses, NAPQI is combined with glutathione (also known as GSH) and the NAPQIglutathione complex is converted to Glutathione is a tripeptide synthesized in the liver and in other organs, which acts as an antioxidant and is a very important part of the body’s defense system against free radicals and oxidative stress. non-toxic mercaptine or cysteine, both of which are excreted in the urine and bile.4,5 Dosing, Available Forms, Contraindications, Side Effects, and Drug-Drug Interactions Currently the adult dose of acetaminophen is 325 mg to 650 mg, every 4 to 6 hours, and the total amount for 24 hours should not exceed 4 grams. The dose for children and adolescents > 12 years of age is the same as the adult dose. Children < 12 years of age, the dose is 10-15 mg/kg, every 4-6 hours, and the 24-hour total should not exceed 2.6 grams. Acetaminophen is available in oral tablets, caplets, capsules, and gel tabs, oral suspensions and solutions, rectal suppositories, and in an intravenous (IV) formulation. Acetaminophen is frequently added to over-the-counter cold and cough and allergy relief products, Triaminic), over-the-counter medications used for sleep, and over-thecounter analgesics. Opioid analgesics and acetaminophen are frequently combined, as well. Acetaminophen is contraindicated if the patient has hypersensitivity to the drug or if the patient has severe hepatic impairment or severe active liver disease. It should be used cautiously if the patient has G6PD deficiency, consumes ≥ three alcoholic drinks a day, or has renal impairment. The oral form of nursece4less.com nursece4less.com nursece4less.com nursece4less.com 7 acetaminophen is considered safe to use during pregnancy. Acetaminophen does enter breast milk, and the drug should be used cautiously by nursing mothers. The side effects of acetaminophen are minimal. Common side effects are mild and temporary gastrointestinal distress and rash. Rash is more common in children. Drug interactions between acetaminophen and commonly used medications include: • Aripiprazole: The serum concentration of aripiprazole may be increased. • Barbiturates: The metabolism of acetaminophen may be increased, decreasing the effectiveness of acetaminophen and increasing the risk of liver damage. • Carbamazepine: The metabolism of acetaminophen may be increased, decreasing the effectiveness of acetaminophen. • Isoniazid: May enhance the toxic effects of acetaminophen. • Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 substrates. • Prilocaine: Acetaminophen and prilocaine used together increase the risk of developing methemoglobinemia. • Probenecid: The serum concentration of acetaminophen may be increased. • Warfarin: Acetaminophen may enhance the anticoagulant effect of warfarin if the daily dose of acetaminophen is >1.3 grams for >1 week. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 8 Acetaminophen Toxicity The toxic dose of acetaminophen was for many years considered to be ≥150 mg/kg or ≥7.5 grams, whichever was lower.5 These figures are almost certainly very conservative and the toxic dose may be 10 to 12 grams or more for an adult and >250 mg/kg for children.5 The American Association of Poison Control Centers (AAPCC), in an evidence-based consensus, decided that the toxic dose of acetaminophen for adults is ≥10 grams or 200 mg/kg, whichever is lower, and >200 mg/kg for children.6 The Rumack-Matthew nomogram was developed to ascertain whether a patient who ingested acetaminophen would have liver toxicity. Serum concentration levels of acetaminophen are plotted on a graph against the time that has elapsed since the drug was ingestion. In recent years, concern has been raised that the maximum 24-hour therapeutic amount of acetaminophen and the amount considered to be potentially toxic are both too low. Poison control centers in the United Kingdom (UK) now use ≥75 mg/kg as the toxic dose, and it was decided in the UK that the treatment line on the Rumack-Matthew nomogram (the nomogram will be discussed in more depth later) should be lowered from 200 mcg/mL to 100 mcg/mL.7 The benefits of this approach are uncertain,7,8 and, in the United States the dose that is considered to be toxic and the treatment line on the RumackMatthew nomogram have not been changed. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 9 Is the Therapeutic Dose Toxic? There has been long-term concern that the 4-gram maximum recommended daily dose of acetaminophen may be too high and potentially harmful. In 2011, the Food and Drug Administration (FDA) asked manufacturers to limit the amount of acetaminophen to 325 mg in prescription combination drugs by January 2014, but no request was made to lower the 4-gram limit. In April 2014, the FDA recommended that a pharmacist who receives a prescription for a combination product with more than acetaminophen 325 mg per dosage unit should contact the prescriber to determine if a product with a lower dose of acetaminophen would be acceptable. McNeil Pharmaceuticals, the manufacturer of the Tylenol® brand, has decreased the 24-hour maximum recommended dose of its acetaminophen-containing products to 3000 mg of the 500 mg preparations and 3250 mg of the 325 mg preparations. However, other manufacturers of acetaminophen products continue to use 4 grams as the limit and this is the maximum dose that will be found in pharmaceutical references. There is evidence that 4 grams of acetaminophen can elevate the serum transaminases in both healthy individuals and in people who might be at risk for liver damage.9-19 These systematic reviews, metaanalyses, and prospective studies have shown that a daily 4 gram dose of acetaminophen can cause abnormally high serum transaminases, however: 1) The transaminase levels were not excessively high; 2) The transaminase levels were not excessively high; 3) The transaminase levels returned to normal in almost every case; 4) There was no association between elevation of transaminase levels in these nursece4less.com nursece4less.com nursece4less.com nursece4less.com 10 cases and not associated with death, liver failure, or permanent liver damage; 5) These findings were derived from studies that in some cases examined over 30,000 patients, 6) Some patients in the case reports had risk factors which have been associated with an increased susceptibility to liver damage from acetaminophen; and, 7) Many people who received a 4 gram daily dose or daily doses of 8 to 12 grams did not develop elevated transaminases. The studies are not conclusive, and there could certainly be outliers of individuals that could be harmed by ingesting 4 grams of acetaminophen in a 24-hour period. But available evidence suggests that 4 grams of acetaminophen ingested over a 24-hour period will not cause serious or permanent harm to the liver and in most cases, will cause no damage at all.5 It should be noted, however, that an elevation of serum transaminases that is temporally related to ingestion of acetaminophen is concerning. But serum transaminase levels are influenced by age, body mass index, gender, race, and the time of day at which they are measured. It has also been shown that serum transaminase levels of both healthy individuals and people with stable liver disease can vary by 10-30% from day to day.16 Someone whose serum transaminase is typically near the top level of normal may have periods in which the level is abnormally high. The Toxic Process Of Acetaminophen Poisoning And Liver Damage When acetaminophen is taken in therapeutic amounts, the pathways of glucuronidation and sulfation effectively metabolize 90% of the dose and there are sufficient stores of glutathione available in the liver to nursece4less.com nursece4less.com nursece4less.com nursece4less.com 11 effectively bind and neutralize the NAPQI. But when acetaminophen is taken in toxic amounts, the conjugation pathways become saturated, and a larger proportion of the ingested dose is metabolized to NAPQI. The rate of formation of NAPQI and the amount of NAPQI produced depletes the liver’s glutathione stores and outstrips the liver’s ability to make more glutathione. When hepatic glutathione stores have been depleted to approximately 70% of pre-exposure levels - a process that takes approximately about 8 hours - NAPQI covalently binds to hepatocytes and liver damage will occur.3,5 The precise mechanisms by which NAPQI damages the hepatocytes are not known. It may cause oxidative stress, it may cause mitochondrial dysfunction, or it may be that high amounts of NAPQI can alter the The primary effect of acetaminophen poisoning is liver damage. But the renal parenchyma can also from NAPQI and kidney injury is a very unusual but well documented effect of acetaminophen poisoning. immune function of the liver, producing an abnormal immune response with inflammation that can irreversibly damage hepatocytes.2,5,20 Despite the uncertainty as to exactly how an acetaminophen overdose and excess NAPQI can cause liver damage, there is no doubt that acetaminophen poisoning and liver damage occur when the rate of formation of NAPQI outstrips the liver’s ability to make glutathione and the amount of NAPQI formed is greater than the amount of available glutathione stores in the liver. That is the basis of acetaminophen poisoning. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 12 Clinical Presentation Of Acetaminophen Overdose The clinical presentation of acetaminophen poisoning has traditionally been described as having four phases.5,20,21 There can be individual variation in the presentation but in most cases, these four phases are easily identifiable and follow each other predictably. Phase I This phase occurs from 0 to 24 hours post-ingestion. Nausea, vomiting, abdominal pain, and anorexia are commonly observed but occasionally the patient may be asymptomatic and there are no signs or symptoms that are specific to acetaminophen poisoning. There is usually no laboratory evidence of liver damage. However, the serum transaminases can begin to rise as early as eight hours and as late as 36 hours after ingestion,22-24 Phase II This phase occurs from 24 hours to 72 hours post-ingestion. The gastrointestinal signs and symptoms typically diminish or disappear, but some patients develop right upper quadrant pain. Serum aspartate aminotranferase (AST) and alanine aminotransferase (ALT) (together, the AST and ALT are AST and ALT are enzymes contained in hepatocytes. If the AST and ALT are elevated, that indicates liver damage. The INR and the PT are measures of the liver’s ability to produce clotting factors; the INR provides information about the liver’s functional ability. commonly called liver function tests or LFTs) may begin to rise above normal levels; levels at or above 10,000 IU/L are common. A very high AST level soon after overdose indicates potential for serious poisoning.5 The international normalized ratio nursece4less.com nursece4less.com nursece4less.com nursece4less.com 13 (INR), and prothrombin time (PT) may also begin to rise above normal levels. Occasionally, serum blood urea nitrogen (BUN) and creatinine will also become elevated. Phase III This phase develops from 72 hours to 96 hours after ingestion, and it is characterized by recovery or progression to liver failure. Most patients, even those who do not receive treatment, will have a mild to moderate degree of liver damage but this resolves. Other patients develop fulminant hepatic failure and either recover or succumb. Patients with fulminant hepatic failure may develop metabolic acidosis, acute respiratory distress syndrome (ARDS), coagulopathies, coma, hypoglycemia, cerebral edema, and renal failure. Phase IV Phase IV is from 96 hours after ingestion to approximately two weeks later, and it is characterized by return of liver function. Patients who have survived Phase III, hepatic damage and function are completely healed. It is important for clinicians to be aware that if the patient has ingested a massive amount of acetaminophen, he/she may not present with the normal progression through the phases. These patients will rapidly become comatose and acidotic and may need a liver transplant. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 14 Renal Damage Acute renal failure happens in <2% of all cases of acetaminophen poisoning.5,25 Most cases of renal impairment caused by acetaminophen happen because of repeated excessive dosing5 and the patients have acute kidney injury, hepatic damage, or fulminant liver failure,5,25 but renal damage can occur (very infrequently) in the absence of liver damage.5,25 The onset of renal failure caused by acetaminophen typically begins after liver damage and liver failure; it does not appear that there is a reliable way to predict which patients with acetaminophen overdose will develop renal failure, and the peak serum creatinine levels may not be seen until two to seven days after the ingestion.5 Other Organ Damage Coma, hypotension, and metabolic acidosis can occur very rapidly in patients who ingest massive amounts of acetaminophen, i.e., 75-100 grams or when the acetaminophen level is very high, i.e., >800 mcg/mL.26-30 Cardiac damage and dysrhythmias,31-33 acute pancreatitis, and elevated serum amylase 34,35 have been reported after acetaminophen overdose, the last being very common.35 Aside from elevations of serum amylase these effects are rare and are unlikely to be directly caused by acetaminophen. They are probably sequelae of hepatic failure, an idiosyncratic response, unrelated to the overdose, or due to exacerbation of pre-existing medical problems from acetaminophen-induced hepatic failure.5 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 15 High Risk Patients For Acetaminophen Poisoning Acetaminophen poisoning represents a balance between the amount and rate of NAPQI formation and the amount of available glutathione and the ability of the liver to produce more; and, the primary toxic effect of acetaminophen poisoning is liver damage. It may be assumed then that anything which: 1) increases the amount or rate of NAPQI formation, 2) decreases the amount and rate of glutathione formation, or 3) increases the liver’s vulnerability to injury, might increase the risk of liver damage from an acetaminophen overdose. Researchers have speculated that there are diseases, medical conditions, and medications which if present or prescribed will increase the risk for liver damage after an acetaminophen overdose; these are listed in Table 1. The prescribing information for acetaminophen states that acetaminophen is contraindicated in patients who have severe hepatic impairment or severe active liver disease, chronic daily use may cause liver damage in some patients, and acetaminophen should be used cautiously in patients who have alcoholic liver disease and/or consume ≥three alcoholic drinks a day. Table 1: Risk Factors for Liver Damage after Acetaminophen Overdose5,20,21 Liver disease, specifically hepatitis C Chronic alcohol abuse or acute alcohol intoxication Medications that increase the activity and/or production of cytochrome p450 enzymes, i.e., antiepileptics or antitubercular drugs Cigarette smoking Genetic polymorphisms in drug metabolizing enzymes Age Poor nutrition status nursece4less.com nursece4less.com nursece4less.com nursece4less.com 16 These (possible) risk factors can increase NAPQI formation, decrease glutathione stores, and increase the vulnerability of the liver to damage. But there is no definitive evidence that any of them, except for alcohol, increase susceptibility for liver damage after an acetaminophen overdose5,21 and the treatment protocol would not be changed if one or more of these risk factors were present.5,21 Alcohol and Acetaminophen Poisoning The effect of alcohol as a risk factor in relation to acetaminophen is complicated, not completely understood, and situational.5,21 Acute Alcohol Ingestion/Acute Overdose Acute alcohol ingestion does not increase the risk of developing liver damage from acetaminophen overdose and alcohol may protect in these situations by competing for the activity of the CYP2E1 enzyme. Chronic Alcohol Use/Acute Overdose The combination of chronic alcohol use and acute acetaminophen overdose may slightly increase risk for liver damage but the risk, if any, appears to be small and clinically insignificant. Chronic Alcohol Use/Therapeutic Doses Chronic alcohol users may develop a slight elevation of transaminases after therapeutic doses of acetaminophen but there is no evidence that chronic alcohol use and therapeutic doses of acetaminophen together will cause liver damage. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 17 Chronic Alcohol Use/Supra-therapeutic Doses Chronic alcohol users who take repeated supra-therapeutic doses of acetaminophen are at risk for liver damage. Chronic use of alcohol unlike acute use – increases the activity of CYP2E1, thus increasing the amount of NAPQI that is formed. Chronic alcoholic users may also have decreased glutathione stores caused by malnutrition. Children and Acetaminophen: Is There Less Risk? Children appear to be less at risk for acetaminophen-induced liver damage after an overdose. Significant liver damage or death is almost unheard of after a single, unintentional, pediatric overdose or exposure. Some of the reasons why this occurs are obvious. Young children do not try and cause self-harm. A child will seldom swallow tablets; he/she chew them and the bitter taste acts as a deterrent. And parents almost always find the child with the medication, stopping the child before a toxic dose can be consumed and if a toxic dose is taken, the child is brought to an emergency department for treatment. There has been speculation that children are inherently resistant to acetaminophen because the amount of acetaminophen metabolized to NAPQI was proportionately less in children, that children had greater glutathione stores, or that they had another way of detoxifying large amounts of acetaminophen not evident in adults. None of these proposed protective mechanisms has been verified, however, and children are inherently more resistant to acetaminophen toxicity than adults because they are smaller than adults. The size of the pediatric liver is proportionately bigger than that of adults, so children have bigger stores of glutathione and metabolize acetaminophen faster.36,37 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 18 Acute Acetaminophen Overdose And Deciding Treatment Unlike many drugs and toxins for which supportive care is the basis of treatment, there is a highly effective antidote that can be used to treat cases of acetaminophen poisoning: N-acetylcysteine (NAC). Although administering NAC many hours or even days after an ingestion of an acetaminophen overdose may be helpful, NAC is most effective if it is given ≤8-10 hours after the ingestion.5,21,38,39 After 8-10 hours from the time of ingestion has passed, the effectiveness of NAC begins to decline so prompt identification of patients at risk is very important. To identify which patients are at risk and need antidotal treatment, the health team members need to know 1) the dose that was ingested and when it was ingested, 2) the serum acetaminophen level, 3) the results of pertinent laboratory tests, and 4) the signs and symptoms the patient is having. These important aspects of the patient’s history are discussed further below. Acetaminophen Ingestion: Dose and Time The toxic dose of acetaminophen is ≥10 grams or ≥200 mg/kg. Unfortunately, many patients do not or cannot recall how much acetaminophen they ingested or when, or they might give the clinician inaccurate information. Evaluation of patients who had taken medications with intent to cause self-harm found that as many as 8.4% who did not self-report ingestion of acetaminophen had a measurable serum level and up to 2.2% had a level that indicated the need for antidotal therapy.40-42 Every effort should be made to obtain this information and it is also critical to determine the pattern of ingestion. If the amount taken was consumed in eight hours of less nursece4less.com nursece4less.com nursece4less.com nursece4less.com 19 this is considered an acute ingestion,6 and acute and chronic ingestions are treated differently. The time of ingestion is used to interpret the serum level and this factor will be discussed in the next section. Acetaminophen Serum Level A serum acetaminophen level should be obtained four hours or later after the ingestion. A therapeutic dose of acetaminophen is quickly absorbed and the peak serum level is reached within two hours, but after overdose the absorption can be delayed and the level must be obtained four hours or later after ingestion. An acetaminophen level measured four hours or later after the ingestion that is ≥150 mcg/mL indicates the potential for hepatotoxicity and the need for antidotal therapy. But what if an acetaminophen level done three hours after ingestion is 31 mcg/mL? How likely is it that a level measured ≥four hours after the ingestion will be ≥150 mcg/mL? Hendrickson (2015) notes that if the acetaminophen level is measured between one and three hours postingestion and the level is undetectable “... significant APAP overdose can likely be excluded.”5 However, research has shown that acetaminophen levels measured before the four-hour mark cannot be used to determine risk and will miss potentially toxic exposures.43-46 The level is then plotted on the Rumack-Matthew nomogram.5,21 The Rumack-Matthew nomogram was developed through examining acetaminophen levels and AST and ALT results after acute overdose, and the data revealed a consistent trend. If the patient had ingested a toxic amount of acetaminophen and the time of ingestion was known nursece4less.com nursece4less.com nursece4less.com nursece4less.com 20 with certainty, an acetaminophen level that was measured ≥four hours after ingestion could be used to predict which patients would develop liver injury. The following case scenario helps to elucidate the value of the nomogram to help determine the probability of liver damage following acetaminophen toxic overdose. Case Example: A patient reported ingestion of 10 grams of acetaminophen eight hours prior to arrival to the emergency department, and a reliable witness confirmed the ingestion time. The acetaminophen level was reported to be 160 mcg/mL. The level was placed on the nomogram and clearly above the line labeled probable hepatotoxicity. In almost all cases of acetaminophen overdose only one level is needed to use the nomogram and to determine the need for treatment. (Exceptions are discussed below). Serial, declining levels document metabolism of the drug, which is to be expected, and there is no value in trending the acetaminophen levels. Also, levels that are within the range of normal values should not be considered nontoxic if the time of ingestion is not known or if the level is toxic when it is plotted on the nomogram. A level has clinical value only if the time of ingestion is known. The Rumack-Matthew nomogram was developed to identify patients that would develop hepatoxicity (defined as a transaminase level >1000 IU/L) after taking an acute overdose of acetaminophen. The nursece4less.com nursece4less.com nursece4less.com nursece4less.com 21 nomogram cannot be used if the time of ingestion is not known; and, it cannot be used if the overdose is chronic. Further, the nomogram does not predict which patients will develop liver failure. Using the Rumack-Matthew nomogram and a single acetaminophen level measured at ≥fours post-ingestion has been shown to be a highly effective way to identify which patients are at risk for liver damage after an acute acetaminophen overdose. Nomogram failures are rare and probably represent incorrect use of the nomogram, inaccurate ingestion histories, or outliers in terms of unidentified risk factors.5 Situations that may require multiple measurements or further assessment are highlighted below. Slowed Peristalsis Antihistamines and opioids can slow gut peristalsis and delay absorption, and several case reports have documented a delayed peak acetaminophen level caused by a co-ingestion of diphenhydramine or an opioid.47-52 Delayed peak serum levels have also been reported after massive ingestions.53,54 Extended Release Acetaminophen Extended release (XR) acetaminophen has 325 mg that is immediately available and 325 mg that is absorbed more slowly. In most cases, the peak serum level occurs within four hours, but in patients who have taken an overdose of XR acetaminophen up to 15% of them had a first acetaminophen level that was non-toxic but subsequent levels were toxic.55-57 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 22 Elevated Serum Bilirubin Significant elevations of serum bilirubin can cause a false positive serum acetaminophen level.58-60 Laboratory Tests Liver transaminases, BUN, creatinine, INR, and PT should be measured. Elevations of AST and ALT represent liver damage and these will occur first. An elevation of INR represents damage to the liver’s functional ability and will occur after AST and ALT have risen. Acetaminophen overdose can cause minor prolongations of the PT and INR in the first 24 hours after ingestion61,62 and N-acetylcysteine can also increase PT and INR.63-67 The INR in these cases is typically between 1.5 and 2.0. These effects can occur in patients who do not have liver damage, and the coagulation prolongations are temporary and of no clinical significance.5,68 Normal laboratory values may indicate that a toxic ingestion has not occurred, but may also reflect an ingestion that recently happened. If the AST, ALT, or INR are above the normal range, if the patient has (or may have taken) an overdose of acetaminophen, and there is no other reason for the laboratory abnormalities, this is a strong indication of a need for treatment. Signs and Symptoms of Acetaminophen Toxicity Abdominal pain, nausea, and vomiting are common signs and symptoms of acetaminophen overdose. But these gastrointestinal complaints are nonspecific, and they may be absent or greatly nursece4less.com nursece4less.com nursece4less.com nursece4less.com 23 diminished 24 hours or so after the ingestion, but their presence or absence could be a factor in determining who has acetaminophen toxicity. Making the Decision: Who Should be Treated with NAC When the serum acetaminophen level and the laboratory test results are known, and the history and physical examination are completed, a decision regarding treatment can be made. A patient is at risk and should receive antidotal therapy for the following findings: • The acetaminophen level is above the treatment line on the Rumack-Matthew nomogram. • It has been confirmed that the patient has taken a toxic amount of acetaminophen. • It is suspected or possible that the patient has taken a toxic amount of acetaminophen and there is a measurable acetaminophen level. • There is a measurable acetaminophen level but the time of ingestion is not known. • There is a measurable level but no reported/witnessed history of acetaminophen ingestion. • It is suspected or possible that the patient has taken a toxic amount of acetaminophen and there is laboratory or clinical evidence of liver damage. If the data, i.e., amount ingested and when, and laboratory results are definitive then the decision to treat or not to treat is simple. If the patient has a toxic level and he/she took a toxic amount - treat the patient. If there is no measurable serum acetaminophen and the nursece4less.com nursece4less.com nursece4less.com nursece4less.com 24 laboratory studies are normal, do not treat the patient, even if there is a report of a toxic amount ingested. But in many cases the information needed to make a treatment decision will be unobtainable, ambiguous, or difficult to interpret. Example: A patient reports that she ingested 10 grams of acetaminophen but she cannot remember when she did so and there are no witnesses. There is no measurable serum acetaminophen. She is complaining of abdominal pain and nausea and she has vomited three times. The AST and ALT are slightly elevated (82 IU/L and 105 IU/L, respectively), she has no history of liver disease, and there are no previous measurements of her transaminases. Should she receive antidotal therapy? The example of the patient above should be treated because of what is known, even if some of that data is ambiguous and/or unreliable. There is no measurable serum acetaminophen level but we know this could simply mean the ingestion could have occurred 24 hours or more prior to the measurement. We know that the patient reported taking a toxic dose. That may not be true and it can’t be confirmed but it can’t be disproved either, and the patient’s report is the only known data about the amount taken. Further, elevations in the AST and ALT were found; however, these may be due to a medical problem that has not yet been diagnosed. The elevated AST and ALT could also indicate the early stage of liver damage from an acetaminophen overdose. The nursece4less.com nursece4less.com nursece4less.com nursece4less.com 25 patient reported gastrointestinal complaints. These are nonspecific but are also a common feature of acetaminophen overdose. Initial Care For Acetaminophen Overdose In the initial care for individuals with acetaminophen overdose, the health team should assess the patient’s airway, breathing, and circulation (ABCs). If there are significant derangements in the ABCs, it is possible that the patient has taken an acetaminophen overdose as a massive amount of acetaminophen can cause coma and metabolic acidosis shortly after the ingestion. These cases are rare so it would be prudent to consider other medications as the cause. Nevertheless, acetaminophen overdoses are common so acetaminophen overdose should be considered in the differential diagnosis if a patient has taken an unwitnessed overdose and he/she is acidotic, comatose, and hypotensive. Gastric Decontamination Activated charcoal is the preferred method of gastric decontamination. Gastric lavage and whole bowel irrigation have no place in the treatment of acetaminophen overdose. Activated charcoal binds avidly to acetaminophen and prompt administration of activated charcoal can prevent acetaminophen from being absorbed and converted to NAPQI and reduce the need for antidotal therapy.5,69-71 A single dose of activated charcoal should be administered if:5,20,71 1. A toxic amount of acetaminophen has been ingested. 2. The ABCs are normal. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 26 3. The patient is awake, alert, and has a normal gag reflex. 4. He/she has not taken a co-ingestant that may rapidly cause depressed consciousness. 5. The patient has a functioning gastrointestinal tract. 6. The patient presents ≤one hour after the ingestion. The one hour time window is the accepted standard for administration of activated charcoal.72 However, there is some evidence that activated charcoal given beyond the one hour window may be beneficial;73 certain co-ingestants can decrease peristalsis and increase the possibility that there is acetaminophen in the gut that can be adsorbed by charcoal. Administration of charcoal up to four hours after an acetaminophen overdose has been recommended.20,71 Each case should be considered individually. Charcoal adsorbs oral NAC but this is not clinically important. The use of oral NAC is increasingly uncommon; it would be unusual to need to use them at the same time, and the adsorption is not considered clinically important.5,74 Laboratory Studies or Diagnostic Tests An acetaminophen level and salicylate level should be measured; patients occasionally confuse aspirin and acetaminophen and may use the terms interchangeably. The acetaminophen level should be measured four hours or later from the time of ingestion and if the time is unknown, a level should be obtained at time of arrival and four hours from time of arrival. Coagulation tests, blood urea nitrogen (BUN), creatinine, serum transaminases should also be measured. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 27 Other laboratory tests and diagnostic studies can be done as the situation dictates Hemodialysis Hemodialysis can remove acetaminophen, and using hemodialysis can be considered if the patient’s acetaminophen level is extremely high. However, the antidote is safe and easy to administer and extracorporeal removal is rarely needed. Antidotal Therapy: N-Acetylcysteine The antidote for acetaminophen poisoning is N-acetylcysteine, which is highly effective. If NAC is given within eight hours of an overdose, serious liver damage is very unlikely and death is rare.71 NAC can prevent liver damage, and it can decrease the severity of liver damage through the following means.5,20,68,75,76 • Increasing formation of glutathione. • Binding to NAPQI • Increasing the amount of acetaminophen that is conjugated to sulfate. • Improving blood flow and oxygen delivery to tissues. • Acting as anti-inflammatory. There are two important functions of NAC: 1) it prevents liver damage and 2) it treats liver damage after the damage has begun. It is very effective and if NAC is given within eight hours after the ingestion, there is almost no risk that a patient will develop hepatic failure. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 28 N-acetylcysteine is most effective when it is given within eight hours of an acetaminophen overdose, but NAC given after that point is beneficial and should be given if patients are late presenters.75,76 The standard recommendation is that NAC is most effective when given within eight hours of an overdose, as previously mentioned.71 However, the prescribing information notes that Acetadote should be given 8-10 hours after an overdose,39 and Hendrickson (2015) recommends that NAC therapy should not be unnecessarily delayed past 6 hours if it can safely be administered earlier.5 An explanation of these discrepancies would be very lengthy and would not add significantly to the understanding of NAC therapy. The most important points are that early administration of NAC is better than providing it late, and the effectiveness of the antidote diminishes with time. N-acetylcysteine can be given orally or intravenously and both routes are equally effective at preventing and treating liver damage from acetaminophen overdose.5,68 The oral and intravenous forms have not been directly compared in controlled studies so this information is based on case studies, theoretical data, and observation. Oral NAC In oral NAC the patient is given a loading dose of 140 mg/kg. Seventeen doses of 70 mg/kg are then given, one dose every four hours. If the patient vomits within an hour of administration of the dose, a repeat dose is given. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 29 Monitoring of the patient during treatment includes laboratory testing of the AST, ALT, INR, BUN, and creatinine, which should be checked every day. Adverse effects of oral NAC are primarily nausea and vomiting. Oral NAC smells like rotting eggs and does not taste good so these effects are very common, 20% and higher).5,71,77 These side effects can be prevented by diluting oral NAC with juice or soda, serving it cold in a cup with a lid, and instructing the patient to sip it slowly. If needed oral NAC can be given through a nasogastric tube. Also, pre-treatment with an antiemetic may also be helpful; ondansetron or metoclopramide are more effective than traditional antiemetics such as prochlorperazine. Contradictions to using oral NAC include sensitivity to NAC, the inability to use the gut, or persistent vomiting. Oral NAC is as effective as intravenous administration but the course of the therapy is 72 hours versus 21. Oral NAC cannot be given to patients who do not have a functioning gastrointestinal tract and it cannot easily (or at times safely) be given to patients who have an altered mental status. Disruption of treatment because of nausea and vomiting is common and patients may refuse to drink oral NAC because it is so noxious. Oral NAC may be more effective than when given intravenously if a patient presents late, i.e., 16 hours or more, after an ingestion,78-80 but there is no definitive proof of this.68 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 30 Intravenous NAC Intravenous NAC can be used for any patient who has acetaminophen poisoning, but NAC given intravenously should be used if the patient is pregnant, if he/she has hepatic failure, or the oral form cannot be used, i.e., intractable vomiting and non-functioning gastrointestinal tract.5 Intravenous (IV) dosing is as follows: • Patients >40 kg are given three doses: 1) 150 mg/kg of Acetadote diluted in 200 mL of 5% dextrose in water (D5W), infused in over 60 minutes, followed immediately by 2) 50 mg/kg of Acetadote diluted in 500 mL of D5W, infused in over four hours, followed immediately by 3) 100 mg/kg of Acetadote, diluted in 1000 mL of D5W, infused in over 16 hours. • The maximum doses of Acetadote are 15,000 mg, 10,000 mg and 5,000 mg for the three respective infusions and these correspond to a patient who weighs 100 kg. There are no clinical studies that have investigated higher doses, but as liver size does not differ significantly between obese and non-obese patients, no dosage adjustments are necessary for the patient who weighs >100 kg.5,68 Monitoring of patients receiving intravenous NAC generally involves: 1) 1-2 hours before the 16 hour infusion will be finished, an acetaminophen level, AST, ALT, and INR should be measured, 2) if no acetaminophen is detected and the AST, ALT, and INR are normal, the infusion can be finished and treatment is complete, and 3) if there is measurable acetaminophen (and with this the possibility of further formation of NAPQI) or the AST, ALT, or INR are elevated (evidence of nursece4less.com nursece4less.com nursece4less.com nursece4less.com 31 hepatotoxicity), the patient may need more NAC.5 This issue will be discussed later in this section. Adverse reactions have been identified as anaphylactoid, occurring in 18% (some sources report a slightly higher incidence) of patients who are given intravenous NAC.81,82 These reactions are mostly mild to moderate,68,81,82 and the patients have flushing, itching, and rash. Severe reactions characterized by angioedema, bronchospasm, and hypotension can happen,68,81,82 but they are rare.39 Anaphylactoid reactions are more likely to happen with the initial, one hour infusion,39,83 if a patient has a lower acetaminophen level than a higher (>300 mcg/mL) level,68,81,84 in women and if the patient has previously been given NAC,85 and if a patient has asthma.39,86,87 If the patient has a minor anaphylactoid reaction with erythema and flushing the intravenous NAC infusion can be continued and the patient closely monitored. Other possibilities are if the patient has urticaria (administer diphenhydramine), if a severe reaction occurs (stop the infusion and administer (as needed) standard symptomatic treatment, i.e., adrenaline, antihistamines, inhaled β2 agonists, and corticosteroids).68,88,89 If signs or symptoms resolve, NAC can be restarted. If they do not the patient should be switched to oral NAC.68 Duration of Therapy If at the end of the 24 hour IV NAC there is measurable acetaminophen, elevations of AST, ALT, or INR, or clinical evidence of hepatic encephalopathy the patient needs more IV NAC: begin a fourth bag, 100 mg/kg in 1000 mL, and infuse over 16 hours. Intravenous venous NAC should then be continued until there is no measurable nursece4less.com nursece4less.com nursece4less.com nursece4less.com 32 acetaminophen and laboratory test values and the patient’s clinical status are improving. The need for IV NAC beyond the standard three bag protocol is not uncommon, and this approach is universally agreed upon.68,71,90 The endpoint of extended IV NAC therapy is less clear (note the previous use of imprecise and undefined term improving) and there are no consensus protocols for this situation.68,71,91 Many clinicians feel that if the patient’s clinical condition is normal, the AST has been steadily declining and is below 1000 IU/L and the INR is <2.0 it is safe to discontinue the NAC.5,71 Each case should be considered and treated individually and a clinical toxicologist consulted if needed. The IV NAC protocol has been in place for over 40 years and it has been highly successful. But the protocol is applied to every patient, without consideration of the acetaminophen level or the amount of drug ingested, and there is evidence that for some patients 21 hours of IV NAC is not needed and that patients who have very high acetaminophen levels or have taken a massive amount of acetaminophen need higher doses of NAC.92,93 Multiple approaches for decreasing or increasing the amount of NAC and the duration of therapy have been tried but there is no conclusive data that supports changing the standard protocol. Hendrickson,5 Howland68 and Heard, et al.,71 note that if the patient has taken a massive overdose, increasing the IV NAC dose can be considered. Chronic Ingestion Of Excess Acetaminophen Chronic ingestion of an excess amount of acetaminophen - often called repeated supra-therapeutic ingestion - is a common and potentially nursece4less.com nursece4less.com nursece4less.com nursece4less.com 33 serious problem.94-97 The U.S. Acute Liver Failure Multicenter Prospective Study found that unintentional overdoses accounted for 48% of all cases of acetaminophen-related acute liver failure,98 doses that are not far above the accepted maximum have caused serious harm,99 and supra-therapeutic acetaminophen ingestions will often cause hepatoxicity. 95,100 Assessment of a patient who has taken repeated supra-therapeutic ingestions is challenging. Most people cannot accurately remember the pattern of use. The Rumack-Matthew nomogram cannot be used to determine if the serum acetaminophen level is toxic or non-toxic, and there may not be a detectable level. The serum transaminases may/may not be elevated and the patient may be asymptomatic. The AAPCC has provided a guideline for assessment and treatment of chronic, supra-therapeutic acetaminophen ingestions.6 1. Patients <6 years of age should be referred to an emergency department if they have ingested: • 200 mg/kg or more over a single 24-hour perio. • 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 or longer 2. Patients 6 years of age or older should be referred to an emergency department if they have ingested: • at least 10 g or 200 mg/kg (whichever is less) over a single 24-hour period • at least 6 g or 150 mg/kg (whichever is less) per 24-hour period for the preceding 48 hours or longer nursece4less.com nursece4less.com nursece4less.com nursece4less.com 34 3. If the patient has risk factors that may make them susceptible to acetaminophen toxicity (i.e., history of alcohol use, alcoholism, isoniazid use, prolonged fasting), the dose of acetaminophen considered potentially toxic should 4 grams or 100 mg/kg (whichever is less) per day. The acetaminophen level, AST, ALT, INR, BUN, and creatinine should be checked. If the patient has signs or symptoms of liver damage, has ingested a toxic amount, has a measurable acetaminophen level, or has abnormal laboratory values, the patient should be considered at risk and treated with NAC. If the patient reportedly ingested a toxic amount of acetaminophen, but the physical exam is unremarkable, the acetaminophen level is zero, and the laboratory values are normal, the patient would not be considered at risk. Pregnancy and Acetaminophen Overdose Acetaminophen does cross the placenta to the fetus,5 and there is evidence that the fetal liver can synthesize a toxic metabolite and the fetal liver can be injured.5,20 Assessment and treatment of women who are pregnant and have taken an overdose of acetaminophen should be done using standard protocols.5,20,71 Intravenous NAC is preferred to avoid vomiting and interruptions in treatment and to (possibly) increase the amount of NAC that crosses the placenta, and IV NAC appears to be safe for the fetus. In most cases the pregnancy and delivery are uneventful,5,71 but overdose with acetaminophen by pregnant women has been associated with spontaneous abortion and fetal death.5,71 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 35 Liver Failure and Transplantation Liver transplantation can be the only effective therapy in certain cases of acetaminophen overdose, and the King’s College Hospital Criteria have traditionally been used to identify patients who need transplantation.5 These criteria are highlighted below. • Serum pH is < 7.30 despite fluid resuscitation • The prothrombin time is > 100 seconds • The serum creatinine is >3.3 mg/dL • Grade III-IV encephalopathy The APACHE II (Acute Physiologic and Chronic Health Evaluation), MELD (Model for End-stage Liver Disease), SOFA (Sequential Organ Failure Assessment) assessment tools and measurement of serum lactate have also been used in these clinical situations.5 Each of these and the Kings College Criteria offer differing levels of sensitivity and specificity.5 Summary Acetaminophen is the drug most commonly taken with intent to cause self-harm. Therapeutic errors with acetaminophen are very common as well, and intentional or accidental acetaminophen overdose is the most common cause of acute liver failure. Acetaminophen overdose can also cause renal damage but this is rare, and damage to other organ systems has been reported but it is unclear if these case reports are describing an effect of acetaminophen. If acetaminophen is ingested in massive amounts a rapid onset of acidosis, coma, and hypotension is possible. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 36 In order to determine if a patient has taken a toxic dose of acetaminophen the health team needs to know: 1) how much acetaminophen has been ingested, and the time taken, 2) the serum acetaminophen level, 3) the LFTs, BUN, creatinine, and coagulation studies, and 4) the patient’s health history and the physical assessment. The toxic dose of acetaminophen after an acute ingestion is ≥10 grams or ≥200 mg/kg. After chronic overdose, the toxic dose of acetaminophen depends on how long the patient has been taking the drug and the presence of risk factors. The serum level must be done at four hours or later after ingestion and it is plotted on the RumackMatthew nomogram and will be toxic or non-toxic. If the laboratory studies were abnormally high this would indicate a possible acetaminophen overdose, but laboratory evidence of liver damage typically is not evident for 24 hours after ingestion. The same basic assessment should be used for chronic ingestions of acetaminophen. However, the Rumack-Matthew nomogram was designed to evaluate serum acetaminophen levels from acute ingestions and cannot be used to determine if a serum acetaminophen level is toxic or non-toxic if the ingestion was chronic. An acetaminophen level should be measured in these cases and if acetaminophen is detected then this would be an indication for treatment, but the nomogram cannot be used. The treatment for acetaminophen overdose is N-acetylcysteine. Nacetylcysteine is highly effective if it is given within 8-10 hours of the ingestion. The antidote can and should be given if patients present after that time but its efficacy is reduced. N-acetylcysteine can be given orally or intravenously. No direct comparisons between the two nursece4less.com nursece4less.com nursece4less.com nursece4less.com 37 forms have been done, but the evidence suggests that they are equally effective. If patients are treated promptly and correctly, survival is virtually assured and the liver will completely recover. There are certain conditions that may or may not increase a patient’s susceptibility to liver damage from excess acetaminophen, but even if these potential risk factors are present, the standard treatment protocol should be used. Patients who present late or have taken a massive ingestion lead to poor outcomes, liver failure, and death. Antidotal therapy should still be used but liver transplantation may be the only hope. Please take time to help NurseCe4Less.com course planners evaluate the nursing knowledge needs met by completing the self-assessment of Knowledge Questions after reading the article, and providing feedback in the online course evaluation. Completing the study questions is optional and is NOT a course requirement. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 38 1. Most acetaminophen is changed to harmless metabolites by a. b. c. d. conjugation. metabolism by cytochrome P-450 enzymes. elimination in the urine. elimination in the stool. 2. Acetaminophen is converted to a toxic metabolite by a. b. c. d. conjugation. metabolism by cytochrome P-450 enzymes. elimination in the urine. elimination in the stool. 3. The toxic dose of acetaminophen is: a. b. c. d. ≥10 grams or 200 mg/kg. ≥7.5 grams or 150 mg/kg. ≥15 grams or 150 mg/kg. ≥20 grams 04 300 mg/kg. 4. The basis of acetaminophen poisoning is a. rate/amount of NAPQI formation greater than glutathione availability. b. rate/formation of conjugation is greater than glutathione availability. c. decrease in glutathione effectiveness. d. increased sensitivity of the liver to the drug. 5. One organ, other than the liver, that is affected by an overdose of acetaminophen is a. b. c. d. the the the the lungs. small bowel. kidneys. thyroid. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 39 6. A massive overdose of acetaminophen can cause a rapid onset of a. b. c. d. metabolic acidosis and coma. arrhythmias and ARDS. pancreatitis and congestive heart failure. coma and myocardial infarction. 7. The serum acetaminophen level must be measured ________________ after an ingestion. a. b. c. d. 8 hours or more 4 hours or more 2 hours or more 10 hours or more 8. True or False: Organ damage other than hepatic or renal is common after acetaminophen overdose. a. True b. False 9. Laboratory tests used to evaluate cases of acetaminophen poisoning are a. b. c. d. LFTs, BUN, creatinine, INR. AST, CBC, and creatinine. ALT, INR, and TSH. AST, CK, and creatinine. 10. The antidotal therapy for acetaminophen poisoning is a. b. c. d. glucagon. methylene blue. sodium thiosulfate. N-acetylcysteine (NAC). nursece4less.com nursece4less.com nursece4less.com nursece4less.com 40 11. The American Association of Poison Control Centers (AAPCC), in an evidence-based consensus, decided that the toxic dose of acetaminophen for children is: a. b. c. d. >100 >150 >200 >250 mg/kg. mg/kg. mg/kg. mg/kg. 12. After 24 hour IV NAC, if there is measurable acetaminophen, elevations of AST, ALT, or INR, or clinical evidence of hepatic encephalopathy the patient a. b. c. d. needs more IV NAC. should not be administered more NAC. begin a 2nd bad, 50 mg/kg in 1000 mL. infuse a 3rd bag, 100 mg/kg over 4 hours. 13. Drug interaction between acetaminophen and Carbamazepine result in metabolism of acetaminophen that may be a. b. c. d. increased decreased. minimally affected, depending on the patient’s genotype. None of the above: the effectiveness of acetaminophen in not affected. 14. The clinical presentation of acetaminophen poisoning has traditionally been described as having ______ phases. a. b. c. d. Two Three Four Five 15. Administration of activated charcoal up to _______ hours after an acetaminophen overdose has been recommended. a. b. c. d. Three Four Five Six nursece4less.com nursece4less.com nursece4less.com nursece4less.com 41 16. True or False: Acetaminophen is available in oral and rectal forms but NOT in an intramuscular or intravenous formulation. a. True b. False 17. The side effects of acetaminophen are minimal. Common side effects are a. b. c. d. mild and temporary gastrointestinal distress. rash. blurry vision. Answers a., and b., are correct 18. Rash as a side effect of acetaminophen ingestion is more common in a. b. c. d. children. women. elderly. people with preexisting skin disorders. 19. Unintentional overdoses accounted for ____% of all cases of acetaminophen-related acute liver failure. a. b. c. d. 25 33 48 55 20. Phase IV of acetaminophen poisoning is a. b. c. d. 12 hours after ingestion. 96 hours after ingestion to approximately two weeks later. characterized by return of liver function. Answers a., and b., are correct 21. True or False: Acetaminophen is the drug most commonly taken with intent to cause self-harm. a. True b. False nursece4less.com nursece4less.com nursece4less.com nursece4less.com 42 22. A patient reports that she ingested 10 grams of acetaminophen but she cannot remember when she did so and there are no witnesses. There is no measurable serum acetaminophen. She is complaining of abdominal pain and nausea and she has vomited three times. The AST and ALT are slightly elevated (82 IU/L and 105 IU/L, respectively), she has no history of liver disease, and there are no previous measurements of her transaminases. Should she receive antidotal therapy? a. No, she is not at risk of toxic overdose. b. Yes, because of what is known, even if some of that data is ambiguous and/or unreliable. c. No, because the data is ambiguous or unreliable. d. No, because the patient’s report cannot be confirmed. 23. The ________ has provided a guideline for assessment and treatment of chronic, supra-therapeutic acetaminophen ingestions. a. b. c. d. APA AMA AAPCC ALF 24. A woman arrived to the emergency department with a known gastrointestinal surgical resection of a portion of small bowel. She would benefit most from a. b. c. d. a liquid form of NAC. intravenous NAC. oral NAC, crushed. sublingual NAC. 25. NAC side effects of nausea and vomiting can be prevented by a. b. c. d. diluting oral NAC with juice or soda. giving NAC through a nasogastric tube. pre-treatment with an antiemetic. All of the above nursece4less.com nursece4less.com nursece4less.com nursece4less.com 43 26. True or False: Prochlorperaize is more effective than ondansetron or metoclopramide. a. True b. False 27. A patient who has taken repeated supra-therapeutic ingestions a. is said to have acute ingestion of excess acetaminophen. b. must use the Rumack-Matthew nomogram to determine if the serum acetaminophen level is toxic or non-toxic. c. will often cause hepatoxicity. d. will always have detectible levels of serum acetaminophen. 28. Which of the following statements is true regarding oral administration of NAC? a. the course of therapy of oral administration is shorter than IV. b. disruption of administration due to nausea and vomiting is uncommon. c. it is less effective than IV administration of NAC. d. patients may refuse to drink oral NAC because it is so noxious. 29. When a pregnant woman takes acetaminophen, the drug a. b. c. d. does not cross the placenta to the fetus. the fetal liver can synthesize a toxic metabolite. can injure the fetal liver. administration of NAC is contraindicated. 30. True or False: Intravenous administration of NAC to a pregnant woman who has overdosed on acetaminophen appears to be safe for the fetus. a. True b. False 31. Hemodialysis can remove acetaminophen and using hemodialysis to remove acetaminophen may be considered nursece4less.com nursece4less.com nursece4less.com nursece4less.com 44 a. b. c. d. even in mild cases of acetaminophen poisoning. if the patient’s acetaminophen level is extremely high. if a patient refuses to drink oral NAC. in cases of elevated salicylate toxicity. 32. ____________ is the preferred method of gastric decontamination of acetaminophen overdose. a. b. c. d. Whole bowel irrigation. Induced vomiting. Activated charcoal Gastric lavage 33. The IV NAC protocol is applied to every patient a. on a case-by-case basis. b. without regard to acetaminophen levels or amount of drug ingested. c. based on the amount of drug ingested. d. based on the acetaminophen levels. 34. True or False: Significant elevations of serum bilirubin can cause a false positive serum acetaminophen level. a. True b. False 35. Activated charcoal binds avidly to acetaminophen and prompt administration of activated charcoal can prevent acetaminophen from being absorbed and converted to a. b. c. d. NAPQI. cytochrome P450. N-acetylcysteine (NAC). serum acetaminophen. 36. _________________ can slow gut peristalsis and delay absorption of acetaminophen. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 45 a. b. c. d. Activated charcoal. Salicylate N-acetylcysteine (NAC) Antihistamines and opioids 37. Liver transplantation may be the only effective therapy in certain cases of acetaminophen overdose, such as a. b. c. d. with a non-functioning gastrointestinal tract. disruption of administration due to nausea and vomiting. Grade III-IV encephalopathy. with significant elevations of serum bilirubin. 38. If the patient has _______________ with erythema, flushing the intravenous NAC infusion can be continued and the patient closely monitored. a. b. c. d. a severe anaphylactoid reaction nausea a minor anaphylactoid reaction slowed gut peristalsis 39. Extended release (XR) acetaminophen has 325 mg that is immediately available and 325 mg that is absorbed more slowly such that a. b. c. d. with the delayed release, levels do not become toxic. opioids are the first line of defense to slow gut peristalsis. activated charcoal is not effective. first acetaminophen levels may be non-toxic but subsequent levels may be toxic. 40. True or False: Charcoal adsorbs oral NAC but this is not clinically important. The use of oral NAC is increasingly uncommon; it would be unusual to need to use them at the same time. a. True b. False CORRECT ANSWERS: 1. Most acetaminophen is changed to harmless metabolites by nursece4less.com nursece4less.com nursece4less.com nursece4less.com 46 a. conjugation. “After absorption, approximately 90% of acetaminophen undergoes hepatic glucuronide and sulfate conjugation; the acetaminophen/sulfate and acetaminophen/glucuronic acid complexes are harmless and are eliminated in the urine.” 2. Acetaminophen is converted to a toxic metabolite by b. metabolism by cytochrome P-450 enzymes. “A very small amount of the drug is excreted unchanged in the urine, and the remainder (approximately 2% or less) is metabolized by several enzymes of the cytochrome P450 enzyme system to N-acetyl-benzoquinoneimine (NAPQI). This metabolite is toxic to the liver and the kidneys.” 3. The toxic dose of acetaminophen is: a. ≥ 10 grams or 200 mg/kg. “The toxic dose of acetaminophen is ≥10 grams or ≥200 mg/kg.” 4. The basis of acetaminophen poisoning is a. rate/amount of NAPQI formation greater than glutathione availability. “The rate of formation of NAPQI and the amount of NAPQI produced depletes the liver’s glutathione stores and outstrips the liver’s ability to make more glutathione. When hepatic glutathione stores have been depleted to approximately 70% of pre-exposure levels - a process that takes approximately about 8 hours - NAPQI covalently binds to hepatocytes and liver damage will occur.” 5. One organ other than the liver that is affected by an overdose of acetaminophen is c. the kidneys. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 47 “A very small amount of the drug is excreted unchanged in the urine, and the remainder (approximately 2% or less) is metabolized by several enzymes of the cytochrome P450 enzyme system to N-acetyl-benzoquinoneimine (NAPQI). This metabolite is toxic to the liver and the kidneys.” 6. A massive overdose of acetaminophen can cause a rapid onset of a. metabolic acidosis and coma. “If there are significant derangements in the ABCs, it is possible that the patient has taken an acetaminophen overdose as a massive amount of acetaminophen can cause coma and metabolic acidosis shortly after the ingestion.” 7. The serum acetaminophen level must be measured ________________ after an ingestion. b. 4 hours or more “A serum acetaminophen level should be obtained four hours or later after the ingestion.” 8. True or False: Organ damage other than hepatic or renal is common after acetaminophen overdose. b. False “A very small amount of the drug is excreted unchanged in the urine, and the remainder (approximately 2% or less) is metabolized by several enzymes of the cytochrome P450 enzyme system to N-acetyl-benzoquinoneimine (NAPQI). This metabolite is toxic to the liver and the kidneys.” 9. Laboratory tests used to evaluate cases of acetaminophen poisoning are a. LFTs, BUN, creatinine, INR. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 48 “Laboratory Tests: Liver transaminases, BUN, creatinine, INR, and PT should be measured.” 10. The antidotal therapy for acetaminophen poisoning is d. N-acetylcysteine (NAC) “Unlike many drugs and toxins for which supportive care is the basis of treatment, there is a highly effective antidote that can be used to treat cases of acetaminophen poisoning: Nacetylcysteine (NAC).” 11. The American Association of Poison Control Centers (AAPCC), in an evidence-based consensus, decided that the toxic dose of acetaminophen for children is: c. >200 mg/kg. “The American Association of Poison Control Centers (AAPCC), in an evidence-based consensus, decided that the toxic dose of acetaminophen for adults is ≥10 grams or 200 mg/kg, whichever is lower, and >200 mg/kg for children.” 12. After 24 hour IV NAC, if there is measurable acetaminophen, elevations of AST, ALT, or INR, or clinical evidence of hepatic encephalopathy the patient a. needs more IV NAC. “If at the end of the 24 hour IV NAC there is measurable acetaminophen, elevations of AST, ALT, or INR, or clinical evidence of hepatic encephalopathy the patient needs more IV NAC: begin a fourth bag, 100 mg/kg in 1000 mL, and infuse over 16 hours.” 13. Drug interaction between acetaminophen and Carbamazepine result in metabolism of acetaminophen that may be a. increased. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 49 “Drug interactions between acetaminophen and commonly used medications include…Carbamazepine: The metabolism of acetaminophen may be increased, decreasing the effectiveness of acetaminophen.” 14. The clinical presentation of acetaminophen poisoning has traditionally been described as having ______ phases. c. Four “The clinical presentation of acetaminophen poisoning has traditionally been described as having four phases.” 15. Administration of activated charcoal up to _______ hours after an acetaminophen overdose has been recommended. b. Four “Administration of charcoal up to four hours after an acetaminophen overdose has been recommended.” 16. True or False: Acetaminophen is available in oral and rectal forms but NOT in an intramuscular or intravenous formulation. b. False “Acetaminophen is available in oral tablets, caplets, capsules, and gel tabs, oral suspensions and solutions, rectal suppositories, and in an intravenous (IV) formulation.” 17. The side effects of acetaminophen are minimal. Common side effects are a. mild and temporary gastrointestinal distress. b. rash. c. blurry vision. d. Answers a., and be are correct [correct answer] “The side effects of acetaminophen are minimal. Common side effects are mild and temporary gastrointestinal distress and rash.” nursece4less.com nursece4less.com nursece4less.com nursece4less.com 50 18. Rash as a side effect of acetaminophen ingestion is more common in a. children. “The side effects of acetaminophen are minimal. Common side effects are mild and temporary gastrointestinal distress and rash. Rash is more common in children.” 19. Unintentional overdoses accounted for ____% of all cases of acetaminophen-related acute liver failure. c. 48 “The U.S. Acute Liver Failure Multicenter Prospective Study found that unintentional overdoses accounted for 48% of all cases of acetaminophen-related acute liver failure …” 20. Phase IV of acetaminophen poisoning is a. 12 hours after ingestion b. 96 hours after ingestion to approximately two weeks later c. characterized by return of liver function. d. Answers a., and be are correct [correct answer] “Phase IV is from 96 hours after ingestion to approximately two weeks later, and it is characterized by return of liver function.” 21. True or False: Acetaminophen is the drug most commonly taken with intent to cause self-harm. a. True “Acetaminophen is the drug most commonly taken with intent to cause self-harm.” 22. A patient reports that she ingested 10 grams of acetaminophen but she cannot remember when she did so and there are no witnesses. There is no measurable serum acetaminophen. She is complaining of abdominal pain and nausea and she has vomited three times. The AST and ALT are slightly elevated (82 IU/L and 105 IU/L, respectively), nursece4less.com nursece4less.com nursece4less.com nursece4less.com 51 she has no history of liver disease, and there are no previous measurements of her transaminases. Should she receive antidotal therapy? b. Yes, because of what is known, even if some of that data is ambiguous and/or unreliable. “The example of the patient above should be treated because of what is known, even if some of that data is ambiguous and/or unreliable.” 23. The __________ has provided a guideline for assessment and treatment of chronic, supra-therapeutic acetaminophen ingestions. c. AAPCC “The AAPCC has provided a guideline for assessment and treatment of chronic, supra-therapeutic acetaminophen ingestions.” 24. A woman arrived to the emergency department with a known gastrointestinal surgical resection of a portion of small bowel. She would benefit most from b. intravenous NAC “Oral NAC cannot be given to patients who do not have a functioning gastrointestinal tract ...” 25. NAC side effects of nausea and vomiting can be prevented by a. diluting oral NAC with juice or soda. b. giving NAC through a nasogastric tube. c. pre-treatment with an antiemetic. d. All of the above [correct answer] nursece4less.com nursece4less.com nursece4less.com nursece4less.com 52 “Adverse effects of oral NAC are primarily nausea and vomiting… pre-treatment with an antiemetic may also be helpful … These side effects can be prevented by diluting oral NAC with juice or soda, serving it cold in a cup with a lid, and instructing the patient to sip it slowly. If needed oral NAC can be given through a nasogastric tube.” 26. True or False: Prochlorperaize is more effective than ondansetron or metoclopramide. b. False “Ondansetron or metoclopramide are more effective than traditional antiemetics such as prochlorperazine.” 27. A patient who has taken repeated supra-therapeutic ingestions c. will often cause hepatoxicity. “Chronic ingestion of an excess amount of acetaminophen often called repeated supra-therapeutic ingestion … and supratherapeutic acetaminophen ingestions will often cause hepatoxicity…. Most people cannot accurately remember the pattern of use. The Rumack-Matthew nomogram cannot be used to determine if the serum acetaminophen level is toxic or non-toxic, and there may not be a detectable level. The serum transaminases may/may not be elevated and the patient may be asymptomatic.” 28. Which of the following statements is true regarding oral administration of NAC? d. patients may refuse to drink oral NAC because it is so noxious. “Oral NAC is as effective as intravenous administration but the course of the therapy is 72 hours versus 21…. Disruption of nursece4less.com nursece4less.com nursece4less.com nursece4less.com 53 treatment because of nausea and vomiting is common and patients may refuse to drink oral NAC because it is so noxious.” 29. When a pregnant woman takes acetaminophen, the drug c. can injure the fetal liver. “Acetaminophen does cross the placenta to the fetus, and there is evidence that the fetal liver can synthesize a toxic metabolite and the fetal liver can be injured.” 30. True or False: Intravenous administration of NAC to a pregnant woman who has overdosed on acetaminophen appears to be safe for the fetus. a. True “Intravenous NAC is preferred to avoid vomiting and interruptions in treatment and to (possibly) increase the amount of NAC that crosses the placenta, and IV NAC appears to be safe for the fetus. In most cases the pregnancy and delivery are uneventful, but overdose with acetaminophen by pregnant women has been associated with spontaneous abortion and fetal death.” 31. Hemodialysis can remove acetaminophen and using hemodialysis to remove acetaminophen may be considered b. if the patient’s acetaminophen level is extremely high. “Hemodialysis can remove acetaminophen, and using hemodialysis can be considered if the patient’s acetaminophen level is extremely high. However, the antidote is safe and easy to administer and extracorporeal removal is rarely needed.” 32. ____________ is the preferred method of gastric decontamination of acetaminophen overdose. c. Activated charcoal “Activated charcoal is the preferred method of gastric decontamination. Gastric lavage and whole bowel irrigation have no place in the treatment of acetaminophen overdose.” nursece4less.com nursece4less.com nursece4less.com nursece4less.com 54 33. The IV NAC protocol is applied to every patient b. without regard to acetaminophen levels or amount of drug ingested. “The IV NAC protocol has been in place for over 40 years and it has been highly successful. But the protocol is applied to every patient, without consideration of the acetaminophen level or the amount of drug ingested,…” 34. True or False: Significant elevations of serum bilirubin can cause a false positive serum acetaminophen level. a. True “Significant elevations of serum bilirubin can cause a false positive serum acetaminophen level.” 35. Activated charcoal binds avidly to acetaminophen and prompt administration of activated charcoal can prevent acetaminophen from being absorbed and converted to a. NAPQI. “Activated charcoal binds avidly to acetaminophen and prompt administration of activated charcoal can prevent acetaminophen from being absorbed and converted to NAPQI and reduce the need for antidotal therapy.” 36. _________________ can slow gut peristalsis and delay absorption of acetaminophen. d. Antihistamines and opioids “Antihistamines and opioids can slow gut peristalsis and delay absorption, and several case reports have documented a delayed peak acetaminophen level caused by a co-ingestion of diphenhydramine or an opioid.” nursece4less.com nursece4less.com nursece4less.com nursece4less.com 55 37. Liver transplantation may be the only effective therapy in certain cases of acetaminophen overdose, such as c. Grade III-IV encephalopathy. “Liver transplantation can be the only effective therapy in certain cases of acetaminophen overdose, and the King’s College Hospital Criteria have traditionally been used to identify patients who need transplantation. These criteria are: … Grade III-IV encephalopathy.” 38. If the patient has _______________ with erythema, flushing the intravenous NAC infusion can be continued and the patient closely monitored. c. a minor anaphylactoid reaction “If the patient has a minor anaphylactoid reaction with erythema and flushing the intravenous NAC infusion can be continued and the patient closely monitored…. if a severe reaction occurs (stop the infusion and administer (as needed) standard symptomatic treatment,….” 39. Extended release (XR) acetaminophen has 325 mg that is immediately available and 325 mg that is absorbed more slowly such that d. first acetaminophen levels may be non-toxic but subsequent levels may be toxic. “Extended release (XR) acetaminophen has 325 mg that is immediately available and 325 mg that is absorbed more slowly. In most cases, the peak serum level occurs within four hours, but in patients who have taken an overdose of XR acetaminophen up to 15% of them had a first acetaminophen level that was non-toxic but subsequent levels were toxic.” 40. True or False: Charcoal adsorbs oral NAC but this is not clinically important. The use of oral NAC is increasingly uncommon; it would be unusual to need to use them at the same time. a. True nursece4less.com nursece4less.com nursece4less.com nursece4less.com 56 “Charcoal adsorbs oral NAC but this is not clinically important. The use of oral NAC is increasingly uncommon; it would be unusual to need to use them at the same time, and the adsorption is not considered clinically important.” References Section The References below include published works and in-text citations of published works that are intended as helpful material for your further reading. 1. 2. 3. 4. 5. 6. 7. Mowry JB, Spyker DA, Brooks DE, McMillan N, Schauben JL. 2014 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 32nd Annual Report. Clin Toxicol (Phila). 2015;53(10):962-1147. Woolbright BL, Jaeschke H. Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure. J Hepatol. 2016 Nov 29. pii: S0168-8278(16)30693-6. doi: 10.1016/j.jhep.2016.11.017. [Epub ahead of print] Bunchorntavakul C, Reddy KR. Acetaminophen-related hepatotoxicity. Clin Liver Dis. 2013;17(4):587-607. Lexicomp®. Acetaminonphen (Lexi-Drugs). November 28, 2016. http://online.lexi.com.online.uchc.edu/lco/action/doc/retrieve/doc id/patch_f/6264. Hendrickson RG. Acetaminophen. In: Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR, Flomenbaum NE, eds. Goldfrank’s Toxicologic Emergencies, 10th ed. McGraw-Hill: New York, NY; 2015. 447-464. Dart RC, Erdman AR, Olson KR, et al., Acetaminophen poisoning: An evidence-based consensus guideline for out-of-hospital management. Clinl Toxicol. 2006;44(1):1-18. Gosselin S, Hoffman RS, Juurlink DN, Whyte I, Yarema M, Caro J. Treating acetaminophen overdose: thresholds, costs, and uncertainties. Clinl Toxicol. 2013; 58(3):130-133. Villeneuve E, Gosselin S, Whyte I. Four-hour acetaminophen concentration after ingested dose based on pharmacokinetic levels. Clin Toxicol. 2014;52(5):556-560. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 57 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. Gelotte CK, Aulier JF, Lynch JM, Temple AR, Slattery JT. Disposition of acetaminophen at 4, 6, and 8 g/day in healthy young adults. Clin Pharmacol Therapeut. 2007;81(6):840-848. Dart RC, Green JL, Kuffner EK, Heard K, Sproule B, Brands B. The effects of paracetamol (acetaminophen) on hepatic tests in patients who chronically abuse alcohol – a randomized study. Aliment Pharmacol Therapeut. 2010; 32(3):478-486. Rumack B. Heard K, Green JL, et al. The effect of acetaminophen on serum alanine aminotranferase activity in patients who consume ethanol: a systematic review and meta-analysis of published randomized, controlled trials. Pharmacotherapy. 2012; 32(9):784-791. Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA. 2006;296(1):87-93. Lavonas EJ, Reynolds KM, Dart RC. Therapeutic acetaminophen is not associated with liver injury in children: a systematic review. Pediatrics. 2010;126(6): e1430-e1444. Heard KJ, Green JL, Dart RC. Serum alanine aminotransferase elevations during10 days of acetaminophen use in non-drinkers. Pharmacotherapy. 2010;30(8):818-822. Kuffner EK, Temple AR, Cooper KM, Baggish JS, Parenti DL. Retrospective analysis of transient elevations in alanine aminotransferase during long-term treatment with acetaminophen in osteoarthritis clinical trials. Curr Med Res Opin. 2006;22(11):2137-2148. Dart RC, Bailey E. Does therapeutic use of acetaminophen cause liver failure? Pharmacotherapy. 2007;27(9):1291-1230. Savino F, Lupica MM, Tarasco V, Locatelli E, Garazzino S, Tovo PA. Fulminant hepatitis after 10 days of acetaminophen treatment at recommended dosage in an infant. Pediatrics. 2011;127(2); e494-e497. Forget P, Wittebole X, Laterre PF. Therapeutic dose of acetaminophen may induce fulminant hepatitis in the presence of risk factors: a report of two cases. Br Journal of Anaesth. 2009;103(60:899-900. Alhelail MA, Hoppe JA, Rhyee SH, Heard KJ. Clinical course of repeated supra-therapeutic ingestion of acetaminophen. Clin Toxicol. 2011;49(2):108-112. Yoon E, Babar A, Choudhary M, Kutner M, Pyrsopoulos N. Acetaminophen-induced hepatotoxicity: a comprehensive update. J Clin Transl Hepatol. 2016;4(2):131-142. Burns, MJ, Friedman, SL, Larson AM. Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, nursece4less.com nursece4less.com nursece4less.com nursece4less.com 58 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. and diagnosis. UpToDate. October 6, 2015. Retrieved online at http://www.uptodate.com/contents/acetaminophen-paracetamolpoisoning-in-adults-pathophysiology-presentation-and-diagnosis. Singer AJ, Carracio TR, Mofenson HC. The temporal profile of increased transaminase levels in patients with acetaminopheninduced liver dysfunction. Ann Emer Med. 1995;26(1):49-53. Green TJ, Silvioti ML, Langman C, et al. When do the aminotransferases rise after acute acetaminophen overdose? Clin Toxicol. 2010;48(8):787-792. Al-Hourani K, Mansi R, Pettie J, Dow M, Bateman DN, Dear JW. The predictive value of hospital admission serum alanine transaminase activity in patients treated for paracetamol overdose. QJM. 2013;106(6):541-546. Chen YG, Lin CL, Dai MS, et al. Risk of acute kidney injury and long-term outcome in patients with acetaminophen intoxication: A nationwide population-based retrospective cohort study. Medicine (Baltimore). 2015 Nov;94(46): e2040. doi: 10.1097/MD.0000000000002040. Kanji HD, Mithani S, Boucher P, Dia VC, Yarema MC. Coma, metabolic acidosis, and methemoglobinemia in a patient with acetaminophen toxicity. J Popul Ther Clin Pharmacol. 2013;20(3): e207-e211. Zell-Kanter M, Coleman P, Whiteley PM, Leikin JB. A gargantuan acetaminophen level in an acidemic patient treated solely with intravenous N-acetylcysteine. Am J Ther. 2013;20(1):104-106. Sivilotti ML, Juurlink DN, Garland JS, et al. Antidote removal during haemodialysis for massive acetaminophen overdose. Clin Toxicol (Phila). 2013;51(9):855-863. Gosselin S, Juurlink DN, Kielstein JT, et al. Extracorporeal treatment for acetaminophen poisoning: recommendations from the EXTRIP workgroup. Clin Toxicol (Phila). 2014;52(8):856-867. Ghannoum M, Kazim S, Grunbaum AM, Villeneuve E, Gosselin S. Massive acetaminophen overdose: effect of hemodialysis on acetaminophen and acetylcysteine kinetics. Clin Toxicol (Phila). 2016;54(6):519-522. Lip GY Vale JA. Does acetaminophen damage the heart? J Toxicol Clin Toxicol. 1996;34(2):145-147. Armour A, Slater SD. Paracetamol cardiotoxicity. Postgrad Med J. 1993;69(807):52-54. Ralapanawa U, Jayawickreme KP, Ekanayake EM, Dissanayake AM. A study on paracetamol cardiotoxicity. BMC Pharmacol Toxicol Jul 2016:14;17(1):30. doi: 10.1186/s40360-016-0073-x. Cavanaugh Z, Naut R. Acetaminophen-induced pancreatic pseudocyst: first case report. 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Value of rapid screening for acetaminophen in all patients with intentional drug overdose. Ann Emerg Med. 1989;18(10):1035-1038. 41. Sporer KA, Khayam-Bashi H. Acetaminophen and salicylate serum levels in patients with suicidal ingestion or altered mental status. Am J Emerg Med. 1996;14(5):443-446. 42. Lucanie R, Chiang WK, Reilly R. Utility of acetaminophen screening in unsuspected suicidal ingestions. Vet Hum Toxicol. 2002;44(3):171-173. 43. Yarema MC, Green JP, Sivilotti ML, et al. Can a serum acetaminophen concentration obtained less than 4 hours postingestion determine which patients do not require treatment with acetylcysteine? Clin Toxicol (Phila). 2016 Oct 28:1-7. [Epub ahead of print] 44. Seifert SA, Kirschner RI, Martin TG, Schrader RM, Karowski K, Anaradian PC. Acetaminophen concentrations prior to 4 hours of ingestion: impact on diagnostic decision-making and treatment. Clin Toxicol (Phila). 2015;53(7):618-623. 45. Froberg BA, King KJ, Kurera TD, et al. Negative predictive value of acetaminophen concentrations within four hours of ingestion. Academ Emerg Med. 2013;20(10):1072-1075. 46. Rhyee SH. Early serum acetaminophen levels: How soon is too soon? Academ Emerg Med. 2013;20(10):1070-1071. 47. Hendrickson RG, McKeown NJ, West PL, Burke CR. Bactrian (“Double hump”) acetaminophen pharmacokinetics: A case series and review of the literature. J Medical Toxicol. 2010;6(3):337344. 48. Ferguson KL, Chan GM, Lee C, Greller HA, Su M. Delayed hepatotoxicity from combined acetaminophen and nursece4less.com nursece4less.com nursece4less.com nursece4less.com 60 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. diphenhydramine despite 21-hour intravenous acetylcysteine. Clin Toxicol. (Abstract) 2007;45(6):615. Ho S, Arellano M, Zolkowski-Wynne J. Delayed increase in acetaminophen concentration after Tylenol PM overdose. Am J Emerg Med. 1999;17(3):315-317. Schwartz EA, Hayes BD, Sarmiento KF. Development of hepatic failure despite use of intravenous acetylcysteine after a massive ingestion of acetaminophen and diphenhydramine. Ann Emerg Med. 2009;54(3):421-423. Chan BS, Graudins A, Chiew A. Acetaminophen poisoning with a difference. (Abstract) Clin Toxicol. 2008;46(7):601-602. Kirschner R, Rozier CM, Smith LM, Jacobitz KL. Nomogram line crossing after acetaminophen combination product overdose. Clin Toxicol (Phila). 2016;54(1):40-46. Bihari S, Verghese S, Bersten AD. Delayed and prolonged elevated serum paracetamol level after an overdose – possible causes and implications. Crit Care and Resusc. 2011;13(4):275277. Smith SW, Howland MA, Hoffman RS, Nelson LS. Acetaminophen overdose with altered acetaminophen pharmacokinetics and hepatotoxicity associated with premature cessation of intravenous N-acetylcysteine therapy. Ann Pharmacother. 2008;42(9):13331339. Graudins A. Overdose with modified-release paracetamol (Panadol Osteo®) presenting to a metropolitan emergency medicine network: a case series. Emerg Med Australas. 2014;26(4):398402. Dougherty PP, Klein-Schwartz W. Unexpected late rise in plasma acetaminophen concentrations with change in risk stratification in acute acetaminophen overdoses. J Emergency Med. 2012;43(1):58-63. Graudins A, Chiew A, Chan B. Overdose with modified-release paracetamol results in delayed and prolonged absorption of paracetamol. Intern Med J. 2010;40(1):72-76. Polson J, Wians FH Jr, Orsulak P, et al. False positive acetaminophen concentrations in patients with liver injury. Clin Chim Acta. 2008; 391(1-2):24-30. Beuhler MC, Curry SC. False positive acetaminophen levels associated with hyperbilirubinemia. Clin Toxicol (Phila). 2005;43(3):167-170. Bertholf RL, Johannsen LM, Bazooband A, Mansouri V. Falsepositive acetaminophen results in a hyperbilirubinemic patient. 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The in vitro effect of Nacetylcysteine on prothrombin time in plasma samples from healthy subjects. Acad Emerg Med. 2011;18(4):351-354. 66. Jang DH, Weaver MD, Pizon AF. In vitro study of N-acetylcysteine on coagulation factors in plasma samples from healthy subjects. J Med Toxicol. 2013;9(1):49-53. 67. Thorsen S, Teisner A, Jensen SA, Philips M, Dalhoff K, Bendtsen F. Effect of N-acetylcysteine on the accuracy of the prothrombin time assay of plasma coagulation factor II+VII+X activity in subjects infused with the drug. Influence of time and temperature. Scand J Clin Lab Invest. 2009;69(6):643-650. 68. Howland MA. N-Acetylcysteine. In: Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR, Flomenbaum NE, eds. Goldfrank’s Toxicologic Emergencies, 10th ed. McGraw-Hill: New York, NY; 2015. 465-472. 69. Buckley NA, Whyte IM, O’Connell DL. Activated charcoal reduces the need for N-acetylcysteine treatment after acetaminophen (paracetamol) overdose. 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Clin Toxicol (Phila). 2008;46(10):927-1057. 100. Lexicomp®. Acetylcysteine (Briggs Drugs in Pregnancy and Lactation). June 6, 2016. http://online.lexi.com.online.uchc.edu/lco/action/doc/retrieve/doc id/1090/5711016. The information presented in this course is intended solely for the use of healthcare professionals taking this course, for credit, from NurseCe4Less.com. The information is designed to assist healthcare professionals, including nurses, in addressing issues associated with healthcare. The information provided in this course is general in nature, and is not designed to address any specific situation. This publication in no way absolves facilities of their responsibility for the appropriate orientation of healthcare professionals. Hospitals or other organizations using this publication as a part of their own orientation processes should review the contents of this publication to ensure accuracy and compliance before using this publication. 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