Critical Care Medicine

TE-acetaminophen

Acetaminophen toxicity

Also known as: Paracetamol. Sold under many brand names (including Tylenol and Panadol) and as a generic product. Also found as a component of many multi-symptom preparations for cough, upper respiratory infections (URI), and headache.

1. Description of the problem

What every clinician needs to know

Acetaminophen toxicity occurs either after acute overdose or after repeated ingestion of supra-therapeutic doses. It can also occur after overdosage of intravenous (IV) acetaminophen or rectal acetaminophen. Some individuals are more susceptible to the development of clinical effects than others. Rare individuals have been described who develop clinical signs of toxicity after doses generally regarded as within the therapeutic range. Individuals with pre-existing hepatic dysfunction or with a history of chronic alcoholism should be considered at increased risk for toxicity.

Clinical features

Initial clinical findings may include nausea (in about half of patients). Vomiting and abdominal pain are less common. Some patients may have no overt clinical findings initially. As toxicity develops, hepatic enzyme elevation (AST and ALT most commonly) is noted. Hepatic synthetic function becomes impaired (as measured by decreased production of hepatic clotting factors, for example), and fulminant hepatic failure may ensue. In severe cases, renal function may also be impaired, and cerebral dysfunction occurs on the basis of hepatic and renal impairment.

Key management points

Obtain serum acetaminophen level at 4 hours after ingestion of a single dose, or as soon as possible thereafter. Levels obtained sooner than 4 hours after ingestion are less predictive of outcome and generally difficult to interpret. If the level exceeds 150mcg/mL at 4 hours after ingestion of a single dose, initiate therapy with n-acetylcysteine either intravenously or orally. If the level is obtained at a different time interval, compare to the Rumack-Matthew nomogram line (Figure 1) that intersects 150mcg/mL at 4 hours; if it is higher than that line, initiate treatment.

Figure 1.

Rumack Matthew nomogram

Therapy initiated within 8 hours after a single acute ingestion has the best prognosis, though most cases make a full recovery if treatment is initiated before the onset of severe toxicity.

After ingestion of multiple supra-therapeutic doses, there is no specific level at which therapy should be initiated or should not be initiated. Consultation with a medical toxicologist or poison center for further guidance is advised.

2. Emergency Management

Acetaminophen toxicity rarely causes sudden decompensation of a previously asymptomatic patient. Other co-ingestants or other causes should be considered prior to ascribing such a suddent deterioration to acetaminophen.

Management points not to be missed

If a potentially toxic dose has been ingested within the previous 2 hours, consider use of activated charcoal in an awake patient with a secure airway. Activated charcoal does bind acetaminophen, but outcome is generally excellent in patients presenting this soon after overdose if laboratory results are obtained in a timely manner and therapy is initiated appropriately.

3. Diagnosis

Diagnostic criteria

The first key to diagnosis is history. If any ingestion is suspected, it is prudent to obtain a serum acetaminophen level. If a clear history of acetaminophen use is obtained in any suspected overdose situation, a 4-hour level (or as soon as possible thereafter) should be obtained and compared to the Rumack-Matthew nomogram (Figure). Any level following a single acute ingestion exceeding the line that intersects 150mcg/mL and 4 hours should be treated with n-acetylcysteine.

The second key to diagnosis is unexplained transaminase elevation in a previously healthy person. Measurement of an acetaminophen serum level may support this diagnosis. However, if the last exposure to acetaminophen occurred more than 24 hours ago, the acetaminophen level may be below the limits of detection even though it may have caused the hepatic findings. If this situation is suspected, empiric administration of n-acetylcysteine should be considered and consultation with a medical toxicologist or poison center should be pursued.

Other diagnostic considerations

The serum acetaminophen level at a known time after ingestion is the key to diagnosis. However, if the exposure occurred at an unknown time, or if there is no history of acetaminophen obtained, diagnosis must be based on clinical judgment. Obtaining assistance from a poison center or medical toxicologist is particularly advised when the diagnosis is uncertain.

Differential diagnosis

Other causes of hepatic dysfunction that produce hepatic enzyme elevation followed by fulminant hepatic dysfunction may mimic acetaminophen toxicity.

Confirmatory tests

There are no specific confirmatory tests to differentiate acetaminophen toxicity from other causes of hepatic dysfunction.

4. Specific Treatment

Administer n-acetylcysteine (NAC). Provide supportive care for clinical effects observed.

NAC is available formulated for IV use under the brand name Acetadote. NAC is also available for oral use as a generic product.

The IV route has long been preferred outside the United States. US data suggests that the IV route produces outcomes that are the same or better than oral NAC, particularly if treatment is initiated within 16 hours after ingestion. The IV regimen reduces average length of hospitalization by a day or longer, but the drug cost is substantially higher than the oral route. Adverse reactions to NAC occur rarely, but more often with the IV route than the oral or nasogastric (NG) route.

Drugs and dosage

IV: Loading dose of 150mg/kg over 30 minutes, then followed by total of 50mg/kg over next 4 hours, then total of 100mg/kg over next 16 hours. If AST, ALT, or INR worsen at end of infusion, consider continuing infusion at last rate and consulting a poison center or medical toxicologist for further guidance.

ORAL: Loading dose of 140mg/kg once, followed by 70mg/kg/dose every 4 hours for 72 hours. Some experts advocate stopping therapy at 48 hours in individuals whose AST and ALT are less than 100 IU/L and whose hepatic function appears otherwise normal. Recheck AST, ALT, international normalized ratio (INR) at end of therapy, and if any are still markedly abnormal, continue therapy further and consult a poison center or medical toxicologist.

NAC has an offensive odor and taste. It is mitigated by the use of a lemon-flavored, lemon-scented solution in which the drug is given.

N-acetylcysteine is supplied either as a 10% or 20% solution. Dilute to 5% before oral or NG administration. To dilute 20% to 5%, add 3 mL of water or lemon-flavored beverage for every mL of drug. To dilute 10% to 5%, add 1 mL of water or lemon-flavored beverage for each mL of drug.

Refractory cases

Some cases display liver enzyme elevation persisting longer than others. The author's approach is to continue NAC therapy until 1) AST and ALT are trending back toward normal and have reached the patient's normal range or an AST and ALT less than 100 IU/L, whichever is greater, and 2) hepatic synthetic function is normal or almost normal.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

Many patients who receive NAC within 8 hours of a single large dose of acetaminophen never display any adverse effects. When adverse effects do occur, the vast majority of patients receiving therapy within 16 hours after a single large dose make a full recovery. Chronic supratherapeutic dosing or therapy first initiated more than 16 hours after a single dose are higher risk settings.

Even in settings of fulminant hepatic failure, many patients will still make a full recovery with intensive support. When considering the management of such a patient and weighing the need for urgent liver transplantation, consultation with a medical toxicologist as well as a transplant specialist is strongly advised.

Despite this data, acetaminophen is still a leading cause of acute hepatic failure in the United States. More than 40 deaths from acetaminophen-induced hepatic failure occur annually in the United States.

Incorrect diagnosis

Development of chronic liver disease speaks against acetaminophen toxicity as the sole cause for illness.

Follow-up

Patients who survive to discharge are expected to make a full recovery if they have not needed a liver transplant. Those requiring liver transplantation follow the usual outcomes for recipients of liver transplants.

Pathophysiology

Acetaminophen is predominantly eliminated by conjugation and glucuronidation at therapeutic levels, with less than 10% eliminated by hepatic cytochrome p450 metabolism or urinary elimination unchanged. Both the glucuronidation pathway and the conjugation pathway display saturation kinetics at supratherapeutic levels, leading to the hepatic p450 metabolic pathway becoming a predominant pathway.

Hepatic metabolism results in the production of N-acetyl-p-quinine imine, a reactive free-radical molecule that causes hepatic injury if insufficient free-radical scavenging compounds (such as glutathione) are immediately available. Therefore, once free radical scavengers are depleted, hepatic injury occurs. N-acetylcysteine serves as a free-radical scavenger, mitigating this injury if it is administered prior to depletion of glutathione and similar endogenous compounds.

Epidemiology

Acetaminophen toxicity is one of the most common causes of pharmaceutical-induced toxicity, because of its widespread availability as a non-prescription pain reliever, a common ingredient in multi-ingredient products intended for cold, allergy, and headache relief, and its inclusion in prescription opioid pain relievers.

Prognosis

Acetaminophen-induced liver dysfunction almost never causes chronic liver disease. Full recovery or complete hepatic failure are the only commonly observed outcomes.

What's the evidence?

Kuehn, B. "FDA focuses on drugs and liver damage: labeling and other changes for acetaminophen". JAMA. vol. 302. 2009. pp. 369-71.

Rumack, BH, Peterson, RC, Koch, GC. "Acetaminophen overdose: 662 cases with oral acetylcysteine therapy". Arch Intern Med. vol. 141. 1981. pp. 380-5.

Smilkstein, M J, Knapp, G L, Kulig, K W, Rumack, BH. "Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985)". N Engl J Med. vol. 319. 1988. pp. 1557-62.

Yarema, MC. "Comparison of the 20-hour intravenous and 72-hour oral acetylcysteine protocols for the treatment of acute acetaminophen poisoning". Ann Emerg Med. vol. 54. 2009. pp. 606-14.

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