A cetaminophen (known as paracetamol, acetyl-para-aminophenol, or APAP) is one of the most widely used pharmaceutical grade antipyretic and analgesic agents available today, in both prescription and nonprescription, over-the-counter (OTC) formulations.

Acetaminophen is available in over 200 products to date, in doses of 325 mg (regular strength), 500 mg (extra strength), or 650 mg (extended release), and in several forms for enteral or parenteral ingestion by both children and adults: tablet, liquid, elixir, suppository, and suspension. Additionally, acetaminophen is available in combination prescription products such as propoxyphene napsylate 100 mg/acetaminophen 650 mg (Darvocet-N 100) and oxycodone/acetaminophen (Percocet), available in several combination strengths. Due to its easy accessibility, low cost, and use in many pharmaceutical preparations, it's one of the most commonly prescribed drugs, a situation that often leads to accidental and intentional overdose or poisoning.1,2 However, the evaluation of possible acetaminophen toxicity is problematic because of the medical, social, and economic costs.

Too toxic

As early as 1995, experts approximated that 30,000 to 40,000 adults and adolescents ingested toxic levels of acetaminophen with the intent of self-harm, requiring an average of 2.7 days of hospitalization. Of these patients, at least 250 died, with an additional 50 needing liver transplants. In 1995, this translated into an annual cost in the United States of $86.9 million.3 As of 2006, the majority of acetaminophen-associated overdoses are recorded as deliberate, self-harm episodes. However, unintentional overdoses due to therapeutic misuse, reportedly contributing 14% to 35% of all acetaminophen-associated hospitalizations, occur at lower doses and are more likely fatal than intentional cases.4-6

Acetaminophen has an excellent safety profile when used at therapeutic dosages, but hepatotoxicity can occur with misuse and overdose. Its wide availability and OTC status perpetuate the belief that acetaminophen is a benign drug-a misconception that accounts for the high incidence of acetaminophen overdose and poisoning.7 In 2003, the American Association of Poison Control Centers reported more than 127,000 exposures involving acetaminophen, of which 65,000 required antidote treatment in a medical facility.8,9 Over 16,000 of these patients received N-acetylcysteine (Mucomyst) to counteract the effects of acetaminophen overdose. During the same time period, 214 analgesic-associated deaths were reported, with acetaminophen overdose toxicity cited as the direct cause of death in 62 cases.8,9

Perhaps more significantly, acetaminophen toxicity is a major cause of fulminant hepatic failure, and is reportedly the primary reason for liver transplantation in Great Britain and the secondary reason in the United States.8,10 Acetaminophen toxicity is also implicated in as many as 39% of all cases at tertiary care hospitals capable of liver transplantation, even if transplantation is not needed.11 This suggests that acetaminophen-induced hepatotoxicity is well recognized; yet, there is an apparent disconnect between identification of the signs and symptoms and diagnosis of possible acetaminophen hepatotoxicity in cases of liver abnormality or acute or chronic liver failure. Unfortunately, there are only nonspecific clinical findings available to identify early stage acetaminophen toxicity, making early recognition and treatment intervention difficult.

Therefore, consider a brief overview of the key identifiers for acetaminophen-induced hepatotoxicity, available treatment options and concerns, help in determining when medical intervention is needed and at what level, and information to optimize patient outcomes and hopefully reduce costs.

Pathophysiology review

For antipyresis or analgesias in adults, acetaminophen is dosed at 325 mg to 650 mg every 4 to 6 hours (or 1,000 mg total), 3 to 4 times per day, for a total of no more than 4 grams/day.12 Many elderly patients can tolerate 1,000 mg orally every 6 hours due to slower metabolism of the drug.13 After oral ingestion, acetaminophen is quickly and completely absorbed from the gastrointestinal (GI) tract. Peak concentrations occur at 30 to 60 minutes postingestion, with a plasma half-life of 1 to 3 hours. Extended release formulations maintain therapeutic levels at 10 mg/mL to 20 mg/mL for 6 to 8 hours, and acetaminophen isn't strongly bound (25%) to plasma proteins.14

Acetaminophen is an active metabolite of phenacetin and phenazopyridine that exhibits significant antipyretic and some analgesic activity plus minimal anti-inflammatory activity as compared to nonsteroidal anti-inflammatory medications (NSAIDs) or aspirin.15 It's rapidly absorbed through the stomach and intestine, and 90% is metabolized by the liver into nontoxic glucuronide and sulfate conjugates, which are readily excreted through the kidneys.2,7 An additional 2% to 4% of acetaminophen is eliminated through the kidneys without alteration. A similar percentage is metabolized by the cytochrome P-450 enzyme and yields a toxic intermediary, N-acetyl-para-benzoquinone-imine (NAPQI), which has an extremely short half-life and readily conjugates with hepatic glutathione, a sulfhydryl donor that converts it to APAP-cysteine and APAP-mercapturate analogs, both of which are readily excreted in the urine.2,7,16 It should be noted that this NAPQI derivative is responsible for hepatic cell death associated with acetaminophen overdosage. It's assumed, therefore, that if normal daily dosing limits are not exceeded, the NAPQI derivative is quickly converted to the nontoxic derivative conjugates of cysteine and mercapturic acid (mercapturate).12 Considering the obvious compatibility of acetaminophen with the human body, it seems counterintuitive that acetaminophen toxicity is becoming problematic.

The answer seems to lie in the cytochrome P-450 metabolic pathway. When an acute overdose occurs-defined as any number of ingestions of 150 mg/kg, or 7 grams to 10 grams in adults (equivalent to oral ingestion of 24 to 30 regular strength tablets or 15 to 20 extra strength tablets/caplets) within a period of up to 8 hours, or when the maximum daily therapeutic range is exceeded for a prolonged period of time-the normal glucuronide and sulfate metabolic pathways become saturated.12,17 This results in increased glutathione conjugation, which rapidly depletes the amount of available glutathione. The remaining unbound NAPQI accumulate and bind to hepatocytes leading to cell necrosis.18 "Chronic" acetaminophen toxicity appears to involve any pattern of multiple ingestions over a period of greater than 24 hours that exceed the recommended maximum adult dosage of 4 grams/day.19,20 The end result, described above, remains the same.

Stages of overdose

Since there are only nonspecific clinical findings available to identify early stage acetaminophen toxicity, early recognition and treatment remains difficult, yet remains essential to preventing morbidity and mortality.21 There are four recognized stages of acetaminophen overdose: Stage I, the first 24 hours postingestion; Stage II, 24 to 48 hours postingestion; Stage III, 72 to 96 hours postingestion; and Stage IV, 4 days to 2 weeks postingestion, also known as the "recovery phase."9,16 Generally, symptomology can persist from 1 to 3 weeks and if left untreated, acetaminophen toxicity can lead to hepatic encephalopathy, liver failure, and untimely death.1,2,13,22

Stage I, the first 24 hours postingestion, is considered most important, and yet is characterized by nonspecific findings: nausea, vomiting, pallor, lethargy, anorexia, and diaphoresis, all of which can be attributed to causes other than acetaminophen toxicity. Adding to the concern is that the patient usually appears normal.9

In Stage II, 24 to 48 hours postingestion, patients begin developing clinical and laboratory evidence of hepatotoxicity, as evidenced by elevated liver enzymes, although they may actually show improvement in their clinical symptoms.9,16 Patients may also complain of discomfort in the upper right quadrant of the abdomen.15 The Rumack-Matthew treatment nomogram, used to correlate serum aspartate aminotransferase (AST) levels and hepatoxicity, is the primary assessment treatment guide used after acute ingestion of acetaminophen has been confirmed.9,23 This nomogram is used to estimate toxicity severity and represents the serum acetaminophen concentration plotted over time in hours postingestion with the "toxic level" identified as a function of time after ingestion.16 As adapted for use in the United States, the U.S. Food and Drug Administration (FDA) set a 25% lower treatment threshold than that established in Europe. Hence, in the United States, a line connecting 150 mcg/mL at 4 hours and 4.7 mcg/mL at 24 hours, which is considered the "possible toxicity line," is used for the treatment threshold.9,24,25,26 If the acetaminophen level is greater than the toxic level indicated for that time in hours postingestion, possible hepatotoxicity could be present and treatment is warranted. The most accurate acetaminophen level is attained 4 hours postingestion, and the adolescent/ adult ingestion toxicity line is gauged at 7.5 grams acetaminophen.16 It should be noted that the Rumack-Matthew treatment nomogram was validated for, and is only used for, single acetaminophen ingestion episodes.9,16,26 Additionally, the upper line of the nomogram is the "probable line," at which 60% of patients develop actual hepatotoxicity.1

In patients displaying symptoms 24 hours or more postingestion, the treatment line on the Rumack-Matthew nomogram approaches the lower limits of detection at some laboratories. Treatment determination should be based on serum acetaminophen, AST and alanine aminotransferase (ALT) levels, the patient's recollection of the amount of acetaminophen ingested, and risk factors for acetaminophen toxicity. If acetaminophen is detectable at this late point, then the nomogram should be utilized. If acetaminophen isn't detectable and the patient has elevated AST and ALT levels, treatment should be initiated and the patient should be assumed to be within Stage II of acetaminophen toxicity. Since there is a small window of time after 24 hours where acetaminophen levels may be undetectable and AST and ALT levels appear normal, treatment may be withheld in such circumstances with the understanding that acetaminophen induced hepatotoxicity could still manifest itself.9

Stage III is 72 to 96 hours postingestion with greater clinical symptoms evident than at Stage I. Malaise, nausea, and vomiting are common, accompanied by jaundice and central nervous system involvement such as confusion, somnolence, and coma. Evidence of pancreatic, kidney, and heart damage may also be present. Peak abnormalities of AST, ALT, bilirubin, and prothrombin time are often observed, with AST levels elevated to at least 1,000 international units/liter (1,000 units per liter) and with the potential to rise as high as 30,000 international units/liter in severe acetaminophen poisoning. Prothrombin times greater than 2.2 times control and bilirubin levels greater than 4 mg/dL (68 [mu]mol/liter) indicate severe hepatotoxicity.15,27,28

Stage IV, occurring 4 days to 2 weeks postingestion, represents the period of hepatic damage resolution.15 Clinical signs, symptoms, and laboratory values return to near normal or normal and permanent damage occurs infrequently. Of course, this implies that treatment was received at some point during Stage II.

Finally, in looking at Stages I to IV in total, the key diagnostic studies currently employed are: 1) measuring plasma acetaminophen levels at times suggested in Stage II; 2) complete blood cell count panels; 3) renal function testing, such as blood urea nitrogen and creatinine; 4) bilirubin levels (as acetaminophen is known to cause hepatocellular damage); 5) Rumack-Matthew nomogram guidelines for AST and ALT for single overdose or "acute" presentations.22

For nonacute or "chronic" acetaminophen overdosing, the Rumack-Matthew nomogram is not applied, which makes management problematic. Most of these nonacute cases involve individuals at greater risk for acetaminophen induced hepatotoxicity who take supratherapeutic doses of acetaminophen.9,29 In such cases, screening should cover the overall acetaminophen dosage per day, focusing on doses greater than 4 grams/dose and/or equal to or greater than 10 grams/day, as well as the risk factors for hepatotoxicity, such as chronic alcoholism, certain other concomitant drug therapies (such as isoniazid), decreased glutathione stores, febrile illness, toxic and viral hepatitis, vascular insult, and chronic liver disease.9,15 Also, serum levels for acetaminophen, AST, and ALT should be drawn with abnormal levels requiring treatment.9,30,31

Treatment approach

The goals of treatment are:

* absorption prevention of ingested acetaminophen from the GI tract

* appropriate use of the antidote N-acetylcysteine

* detoxification with supportive care.17

A 2002 study of treatments employed by poison medical directors worldwide found that N-acetylcysteine is the overwhelming treatment of choice for acetaminophen overdose.32 If used early after overdose (usually within the first 8 to 10 hours postingestion), N-acetylcysteine prevents the formation and accumulation of NAPQI by increasing glutathione stores, combining directly with NAPQI as a glutathione substitute, and enhancing sulfate conjugation, assumedly since N-acetylcysteine is a chemical precursor of glutathione.2,13,16,17,23,32 When the conjugation of N-acetylcysteine with NAPQI occurs, the end result is cysteine and mercapturic acid conjugates, which are nontoxic analogs readily excreted in the urine.

Sufficient evidence is available showing that N-acetylcysteine is effective regardless of how late the therapy is initiated or how strongly the patient suffers clinical toxic effects.9 N-acetylcysteine also has anti-inflammatory and antioxidant properties, as well as positive inotropic and vasodilating effects, all of which improve microcirculatory blood flow and oxygen delivery to tissues and seem to contribute to decreasing morbidity and mortality. It should also be noted that even if N-acetylcysteine therapy begins well past the 8 to 10 hour initial period recommended, the therapy is still effective for at least as long as 36 hours postingestion, as shown in the decreased mortality rates among late-presenting patients with fulminant hepatic liver failure with absence of acetaminophen in the serum.2,15 Similarly, if acetaminophen levels are not at the possibly toxic level, N-acetylcysteine therapy is not indicated.

Oral and intravenous (I.V.) forms of N-acetylcysteine are available in the United States. Generally, oral N-acetylcysteine is preferred, although it has a very unpleasant odor and taste, which frequently results in nausea and vomiting.7 The FDA-approved protocol for orally administered N-acetylcysteine is an initial loading dose of 140 mg/kg followed by 17 maintenance doses of 70 mg/kg/every 4 hours, to a total of 1,330 mg/kg.7,9,33 Should vomiting occur within 1 hour of the initial oral dosing, repeat dosing is indicated.

Intravenous N-acetylcysteine therapy is also FDA-approved for use in the United States.9,33 Two I.V. protocols, 1 for 48-hours postingestion and 1 for 20-hours postingestion, are considered safe and effective but aren't widely used. Intravenous therapy is generally favored over oral therapy when intractable vomiting occurs, for obvious reasons, yet there's no firm evidence that I.V. therapy is any more or less effective than oral N-acetylcysteine therapy.9,32,34,35

Other therapies available involve the use of activated charcoal, which absorbs toxic substances on its surface, making it nonabsorbable through the GI tract. Superactivated charcoal is preferred, as it has three times the absorption capacity of standard activated charcoal. Unfortunately, activated charcoal is messy to use and generally unpleasant for the patient. Typical flavorings that are added to nonpalatable pharmaceutical preparations, such as ice cream, milk, chocolate powder, and jelly, are not recommended since they reduce the overall absorptive capacity of the charcoal.7

Sorbitol, a sweetener often used at the retail pharmacy level to enhance palatability of children's drug preparations, may be added without problem. However, sorbitol increases bowel motility, which enhances the removal rate of acetaminophen from the GI tract, but can be inconvenient for the patient. This preparation is available commercially, with weight/volume sorbitol, and is dosed at 1 gram/kg.9

It should be noted that using charcoal is controversial, since it may interfere with and decrease the bioavailability of N-acetylcysteine.12,16,36 Recent studies indicate that patients who are given activated charcoal with N-acetylcysteine were significantly less likely to develop liver injury or hepatotoxicity when compared to those receiving N-acetylcysteine alone in the first 8 hours postingestion.17 Proponents of charcoal therapy suggest increasing the loading dose of N-acetylcysteine, usually 140 mg/kg by 30% to 40% to avoid any interactions with the activated charcoal.

Nursing considerations

In cases of possible acetaminophen overdose, nurses must assess the time of ingestion and the reason acetaminophen was originally administered.7 Time of ingestion is critical in deciding upon the proper management and initiating treatment. In addition to assessing the acetaminophen overdosage, nurses should obtain complete drug histories to ascertain whether any other medications were administered simultaneously and if those drugs contained additional acetaminophen.

Additionally, assess patients for malnutrition and alcohol use, since these conditions can contribute to an increased risk of hepatotoxicity in acetaminophen overdoses.13,22,37 Patients with hepatic dysfunction and/or histories of alcohol abuse should be cautioned about proper dosing, as any increase in acetaminophen dosing can increase the existing risk for hepatotoxicity.13,38

Patient education

Patients must be instructed on how to read medication labels, cautioned to follow recommended dosages of medications, and made to understand the correct dose of medication prescribed. As stated earlier, the recommended acetaminophen dosage is 325 to 650 mg every 4 to 6 hours orally, not to exceed a maximum dose of 4 grams/day for adults/adolescents.13 Additionally, it is important to teach patients how to read medication labels so they can avoid the additive effects of taking multiple prescribed and OTC acetaminophen-containing medications without knowing. Patients need to recognize the common names of acetaminophen, such as APAP, paracetamol, and acetyl-para-aminophenol.39

Healthcare providers should instruct patients not to mix pain medications, as some routinely ordered prescription pain medications contain acetaminophen, such as propoxyphene napsylate/acetaminophen, oxycodone/ acetaminophen, and hydrocodone/ acetaminophen (Vicodin). Patients should also know the signs and symptoms of overdose and proper emergency procedures to take.

Further, patients need to be cautioned against using other NSAID therapy concomitantly with acetaminophen to avoid an increased risk of renal toxicity developing.13,22

Finally, patients exhibiting a history of alcohol abuse should discuss this with their clinician before using acetaminophen since consuming more than 24 ounces of alcohol per day creates a greater potential for hepatotoxicity.40

Priorities in care

Priorities in nursing care should include assessment of the patient, appropriate antidotal therapy, and facilitation of a cognitive psychological evaluation, if warranted. Attaining a thorough patient history focusing on the dosage of acetaminophen taken, risk factors present, and following the Rumack-Matthews nomograph for acute single dose assessment will help clinicians determine when and if antidotal therapy is warranted (usually with N-acetylcysteine). Patients also need to be assessed throughout stages I through IV of acetaminophen toxicity to watch for potential adverse effects developing and to gauge appropriate responses to treatment. Understanding the process surrounding the development of acetaminophen toxicity undoubtedly reduces the likelihood that hepatotoxicity will result when patients overingest the medication.

How much is too much?

The maximum recommended dosage of acetaminophen is 4 grams/day for short-term use in adults. (Patients with liver problems shouldn't take acetaminophen or other over-the-counter analgesics without first consulting their primary care provider.)

American Association of Poison Control Centers guidelines indicate that the acute toxic dose of acetaminophen for patients over age 6 is 10 grams or 200 mg/kg/day, whichever is lower.8 This is equal to 31 regular-strength or 20 extra-strength tablets over 8 hours or less.1,2

The Florida Poison Information Center uses the 10 grams or 200 mg/kg/ day for children under age 18, but considers 7.5 grams an acute toxic dose in adults. This equals 24 regular-strength or 15 extra-strength tablets over 8 hours or less.1,2

Rumack-Matthew nomogram

The lines on the nomogram indicate the risk of hepatic toxicity based on the patient's serum acetaminophen level between 4 and 24 hours after acute ingestion.

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