I. What every physician needs to know.
Acetaminophen is a common toxic ingestion, resulting in over 400 deaths from fulminant hepatic failure in the United States each year. This ubiquitous over-the counter analgesic has been found to be safe in daily ingestions of less than 4gm daily. However, larger ingestions can be deadly, resulting in hepatic toxicity and fulminant liver failure. Acetaminophen is metabolized in the liver. Approximately 90% is conjugated with glucuronide or sulfate to form non-toxic metabolites whereas 5% is metabolized through the cytochrome p450 mixed-function oxidase enzyme to a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI).
With normal dosing, NAPQI is detoxified by glutathione (GSH) to non-toxic metabolites. However, in acetaminophen overdose, the conjugation pathways are overwhelmed resulting in increased NAPQI and depletion of GSH, which ultimately leads to hepatic injury. Despite the seriousness of acetaminophen overdose and ingestions, an effective antidote exists in acetylcysteine. This should be administered as soon as possible to minimize hepatic damage.
II. Diagnostic Confirmation: Are you sure your patient has acetaminophen overdose?
Acetaminophen toxicity should be high on any differential diagnosis list whenever intentional ingestion is suspected. In the initial phase the patient may be asymptomatic or manifest only non-specific symptoms. The clinician must have a low index of suspicion for this toxic substance in any overdose. Acute ingestions of acetaminophen generally lead to toxicity with doses greater than 7.5-10 grams in adults and 150mg/kg in children. Chronic ingestions of supra-therapeutic doses may also cause hepatic injury in vulnerable populations (most notably chronic alcoholics).
A. History Part I: Pattern Recognition:
Acute acetaminophen poisoning develops in four stages post-ingestion. In the initial 24 hours, patients may be asymptomatic or have non-specific symptoms and findings such as nausea, vomiting, anorexia, abdominal pain, pallor, and lethargy. During the second stage, beginning 24-48 hours after ingestion, patients may develop evidence of hepatic toxicity but are clinically asymptomatic. Most commonly, elevated liver enzymes are seen during the second stage although there are studies that indicate this can occur in the first.
At the third stage, at approximately 72 hours, toxic acetaminophen ingestions may manifest as fulminant hepatic failure, including encephalopathy, coagulopathy and possible progressive multi-organ failure. During the fourth and final stage beginning at 72-96 hours, post-ingestion healing and complete recovery may occur.
B. History Part 2: Prevalence:
Acetaminophen alone or in combination comprises approximately 15% of fatalities associated with ingestions across the United States. Given the prevalence of this ingestion and the ease of initial laboratory testing, all patients with a potential ingestion or unexplained liver failure should be evaluated for acetaminophen toxicity. Patient populations at increased risk for hepatoxicity from acetaminophen include those with induced p450 enzymes leading to increased NAPQI formation or those with reduced GSH stores.
The most commonly encountered inducer of NAPQI formation is ethanol. Therefore chronic alcoholics are at theoretical risk for increased toxicity although the clinical significance has not been established and treatment guidelines remain the same. Similarly, isoniazid and valproic acid may induce NAPQI formation resulting in worse hepatic toxicity. GSH stores are depleted in malnourished patients resulting in increased risk for acetaminophen toxicity in patients with anorexia nervosa, chronic disease leading to poor nutrition and chronic alcoholism. Fasting from a febrile illness and older age are also risk factors for hepatic injury.
C. History Part 3: Competing diagnoses that can mimic acetaminophen overdose
In the initial stage of acute acetaminophen ingestion the diagnosis may remain unclear, as symptoms are non-specific. Once evidence of hepatic toxicity is seen, the leading competing diagnosis is viral hepatitis. In the developing world this is the most common cause of hepatic failure, however, in the United States drug-induced injury predominates.
Acetaminophen toxicity generally presents with a more rapidly progressive clinical course and greater severity of illness than other causes of liver failure. Aminotransferases are markedly elevated and prothrombin time prolongs in acetaminophen toxicity. However, there is increased potential for hepatic regeneration and recovery. Many other drugs have been implicated in liver toxicity but liver failure is exceedingly rare. Alcoholics presenting with aspartate transaminase (AST) levels greater than 1000u/l should prompt evaluation for acetaminophen toxicity as alcoholic hepatitis alone rarely presents with AST levels greater than 300u/l. Checking an acetaminophen level will clarify the diagnosis.
D. Physical Examination Findings.
There are no specific physical exam findings that will clarify the diagnosis of acetaminophen toxicity. Initially patients may demonstrate right upper quadrant tenderness. As the disease progresses physical findings will be those of hepatic failure, including encephalopathy with asterixis, jaundice and possible bleeding from coagulopathy.
E. What diagnostic tests should be performed?
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
All patients with suspected acute acetaminophen toxicity should have a 4-hour post-ingestion level drawn and plotted on a Rumack-Matthew treatment nomogram. Serum acetaminophen levels at or above the line connected 200ug/ml at 4 hours and 6.25ug/ml at 24 hours consistently predict hepatotoxicity and are referred to as the probable toxicity line. A level above this line is the indication for acetylcysteine therapy in Europe. In the United States the Food and Drug Administration (FDA) lowered the treatment threshold by 25% and this possible toxicity line is used to determine acetylcysteine therapy, which should be initiated in any patient presenting with acetaminophen levels at or above this line.
Typically the toxic dose corresponds to 150mg/kg or 7.5-10gm ingested in the healthy adult. However, reported ingestions are frequently inaccurate and the nomogram should be used to determine treatment decisions. If Tylenol Extended Relief overdose is suspected the 4-hour level may be inaccurate and a repeat level at 6 hours should be considered. Medications or conditions that slow gastric emptying may have delayed absorption. If the timing is in doubt, an initial level should be drawn followed by a second level 4 hours later. In patients with non-acute overdoses the nomogram is not useful and clinical decision-making should be based on evidence of hepatic toxicity.
In addition to acetaminophen levels, liver function tests (LFTs) and coagulation factors should be drawn to assess for hepatic injury and/or failure. Greater than 24 hours post-ingestion, the acetaminophen level may be lower than the limit of some lab detection methods. If acetaminophen toxicity is suspected, LFTs can be used to guide treatment decisions. If AST and alanine transaminases (ALT) are elevated, it should be assumed that the patient is in the second stage of acetaminophen toxicity and acetylcysteine therapy should be initiated. If LFTs are normal and the acetaminophen level is undetectable, acetylcysteine therapy may be withheld.
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
III. Default Management.
A. Immediate management.
As in all poisoning, gastrointestinal decontamination should be considered. All adult patients presenting within 4 hours of a known acetaminophen ingestion of greater than 7.5gm who are alert and able to protect their airway should receive activated charcoal (1gm/kg) unless there are contraindications. Patients who are intubated may also receive activated charcoal although intubation should not be performed for this purpose. Coingestants are common and patients presenting with an overdose should be evaluated for other toxidromes.
In all acute acetaminophen ingestions in which the level is above the probable hepatic toxicity line, acetylcysteine therapy should be initiated. Most recommend that all ingestions above the possible hepatic toxicity be treated immediately as well. In patients with chronic supra-therapeutic ingestions acetylcysteine should be utilized if there is evidence of hepatic injury.
Those with suspected acetaminophen ingestions of unclear time-course should be treated with acetylcysteine even if acetaminophen is undetectable, if there is evidence of hepatic injury. The efficacy of acetylcysteine has been demonstrated in patients presenting with fulminant hepatic failure regardless of time after ingestion and its use is therefore recommended in patients with acetaminophen-induced elevation of liver enzymes regardless of the timing of ingestion.
There are two FDA approved regimens of acetylcysteine, one that is oral and one that is intravenous (IV). The oral regimen begins with a loading dose of 140mg per kilogram of body weight and continues with a maintenance dose of 70mg per kilogram every 4 hours for 17 doses. The IV regimen consists of a loading dose of 150mg per kilogram of body weight over 15-60 minutes followed by an infusion of 12.5mg per kilogram over 4 hours. This is concluded with a 16-hour infusion of 6.25mg per kilogram.
Although the efficacy of acetylcysteine has been demonstrated, there are no convincing data to support the use of oral or IV therapy preferentially. Decisions regarding the route of administration should be made based on the patient’s ability to take and tolerate oral acetylcysteine as well as the setting, access and drug availability. Those presenting late or with hepatic failure should receive IV therapy. Both forms are relatively inexpensive and accessible in most hospital settings.
Poison control is readily available for additional toxicology information and should be contacted at 1-800-222-1222 in any clinically significant poisoning.
Patients should be assessed for suicidality and personal danger. Those in whom intentional ingestion is suspected should be started on appropriate suicide precautions. Psychiatry consultation should be considered for possible inpatient psychiatric management.
B. Physical Examination Tips to Guide Management.
In the majority of acetaminophen ingestions signs of toxicity are non-specific and physical exam findings are unhelpful. However, patients with hepatic injury should be monitored for signs suggestive of acute liver failure. Classically this would include encephalopathy, jaundice and bleeding to indicate coagulopathy.
Acute liver failure may have additional multi-system effects that should be considered. Tachycardia may be seen due to the systemic inflammatory response and high output state, which can occur. Hypotension may develop as a result of this and impaired glucocorticoid production. Hypoglycemia can complicate the picture due to decreased hepatic gluconeogenesis and the patient’s catabolic state. Pancreatitis, acute respiratory distress syndrome and renal failure may occur. Immediate life threatening complications of acute liver failure include cerebral edema and intracranial hypertension which should prompt intensive care unit (ICU) level care and interventions to prevent herniation.
C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
The course of therapy with acetylcysteine has been standardized to 72 hours for oral dosing and 20 hours for IV dosing. However, the optimal timing for discontinuing acetylcysteine is a source of debate. Some have advocated early termination of oral therapy in patients with normal LFTs and undetectable acetaminophen levels.
Conversely, in patients with elevated LFTs and detectable acetaminophen levels many toxicologists recommend continuing acetylcysteine therapy until significant improvement is noted (i.e., acetaminophen has been metabolized and LFTs are normal or close to normal). Therefore, acetaminophen levels and LFTs should be monitored every 12 hours in patients with evidence of hepatic injury and receiving acetylcysteine therapy to appropriately determine the treatment course.
Patients demonstrating signs of significant hepatic toxicity should be followed closely for signs of fulminant hepatic failure and should have multi-system monitoring. Coagulation parameters should be checked regularly as well as electrolytes, creatinine, glucose and the patient’s acid-base status.
Most patients will have a full recovery; however a small number will require liver transplantation for survival. Efforts have been made to develop prognostic criteria to accurately predict the need for liver transplantation. Although all criteria evaluated have had some limitation, the most widely accepted and well validated are the King’s College criteria (KCC).
According to these, emergency liver transplantation is indicated in patients with acetaminophen poisoning with arterial pH less than 7.3 or all of the following: grade III or IV encephalopathy and prothrombin time greater than 100 seconds and serum creatinine greater than 3.4mg/dl. Patients with these prognostic indicators should be emergently transferred to a tertiary care center to be evaluated for liver transplantation.
D. Long-term management.
In patients that survive the initial insult without requiring transplantation the prognosis is good and full recovery from acetaminophen toxicity is expected in 5-10 days. In accidental overdoses counseling should be given regarding safe acetaminophen dosing. For patients with intentional overdoses, psychiatry consultation and management should be initiated to ensure patient safety.
E. Common Pitfalls and Side-Effects of Management
The main side effect to the oral regimen of acetylcysteine is nausea and vomiting. The oral dose should be repeated if the patient vomits within 1 hour of receiving this antidote. The most commonly reported adverse response to the IV regimen is an anaphylactoid reaction, which has been reported in 15% of patients receiving IV acetylcysteine. This frequently resolves with therapies such as diphenhydramine and occasionally corticosteroids and bronchodilators. However, life-threatening reactions have occurred.
Usually, the IV acetylcysteine may be restarted at a slower rate after the reaction has subsided without any additional difficulty. The most serious adverse effects to IV acetylcysteine have been seen in children in whom cerebral edema and hyponatremia occurred due to inappropriately mixed or dosed acetylcysteine.
IV. Management with Co-Morbidities
A. Renal Insufficiency.
No change in standard management. Dose adjustment to acetylcysteine is not required.
B. Liver Insufficiency.
There are no data to suggest that patients with chronic liver insufficiency are more susceptible to acetaminophen toxicity and in general those with pre-existing liver disease are not more likely to experience drug-induced liver toxicity.
C. Systolic and Diastolic Heart Failure
No change in standard management.
D. Coronary Artery Disease or Peripheral Vascular Disease
No change in standard management.
E. Diabetes or other Endocrine issues
No change in standard management.
No change in standard management.
G. Immunosuppression (HIV, chronic steroids, etc).
No change in standard management.
H. Primary Lung Disease (COPD, Asthma, ILD)
No change in standard management.
I. Gastrointestinal or Nutrition Issues
Patients with malnutrition are at higher risk for acetaminophen toxicity. However, no change in standard management is recommended.
J. Hematologic or Coagulation Issues
No change in standard management.
K. Dementia or Psychiatric Illness/Treatment
In patients with underlying depression or previous suicide attempts the index of suspicion for intentional acetaminophen ingestion should be lowered. Suicide precautions should be initiated and psychiatry consultation considered. At discharge, efforts must be made to create a patient safety plan. Otherwise, there are no changes in standard medical management.
V. Transitions of Care
A. Sign-out considerations While Hospitalized.
The timing of acetaminophen ingestion, most recent acetaminophen levels and LFTs should be readily available on sign-outs for patients with acetaminophen toxicity. Any evidence of hepatic injury and suspected complications should be clearly delineated. If the patient meets any of the KCC for liver transplantation this must be indicated, with appropriate plans for liver transplantation evaluation described. Additionally, the course of acetylcysteine therapy with parameters for discontinuation should be clear. Any active suicidal ideations should also be included.
B. Anticipated Length of Stay.
The length of stay for acetaminophen toxicity is variable depending on the severity of ingestion and liver toxicity. In patients with normal LFTs receiving IV acetylcysteine, a full course of therapy may be as short as 20 hours. The majority of patients will not have significant hepatic injury and hospital stays may typically be 2-3 days. In those with hepatic failure, recovery generally occurs within 5-10 days. However, those requiring transplantation will have significantly longer hospital stays.
C. When is the Patient Ready for Discharge.
Patients may safely be discharged when acetylcysteine therapy is no longer indicated and suicide is not felt to be a risk. For patients in whom LFTs are normal, with undetectable acetaminophen levels, this may occur prior to the completion of the full 72-hour oral course of acetylcysteine therapy. In patients with evidence of hepatic injury this may take several days beyond the standardized regimen.
D. Arranging for Clinic Follow-up
1. When should clinic follow up be arranged and with whom.
Follow-up should be arranged with a general medicine clinic in 1-2 weeks. Those with significant hepatic injury should see gastroenterology as an outpatient. Additional appointments should be directed at the underlying cause for the toxic ingestion. Pain management referral may be indicated in patients with unintentional acetaminophen poisoning. Patients presenting with intentional acetaminophen ingestions should be followed up closely with psychiatry and may require inpatient care. Community support resources and counselors should be identified to help prevent future suicide attempts.
2. What tests should be conducted prior to discharge to enable best clinic first visit.
3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.
None for the majority of patients. Those in whom LFTs were still mildly elevated at discharge should have follow-up laboratory evaluation to ensure normalization of any abnormalities.
E. Placement Considerations.
The most common placement consideration in acetaminophen ingestion involves inpatient psychiatry transfer. Patients with intentional ingestions may require inpatient psychiatry therapy after completing the course of acetylcysteine.
F. Prognosis and Patient Counseling.
In patients receiving early acetylcysteine therapy, hepatic injury is rare and the majority of patients experience no long-term effects. In those presenting later or with larger ingestions (over 12gms) hepatic toxicity is more common and longer courses of therapy may be needed. However, fulminant hepatic failure occurs in less than 1% of adults with acetaminophen toxicity. In patients who experience hepatic failure due to acetaminophen, the prognosis is better for full recovery than in those with hepatic failure from other causes. Nevertheless, liver transplantation is sometimes needed for survival and fatalities do occur.
VI. Patient Safety and Quality Measures
A. Core Indicator Standards and Documentation.
B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.
For this admission standard deep vein thrombosis (DVT) prophylaxis is indicated unless the patient becomes severely coagulopathic due to hepatic failure. Suicide precautions should be initiated in all suspected intentional ingestions. Fall precautions may be indicated in patients with altered mental status due to coingestants or hepatic encephalopathy. Education must be provided on appropriate acetaminophen dosing and psychiatric intervention is indicated for intentional ingestions.
VII. What's the evidence?
Bronstein, AC, Spyker, DA, Cantilena, LR, Green, JL, Rumack, BH, Giffin, SL. “2009 annual report of the American association of poison control centers' national poison data system (NPDS): 27th annual report”. Clin Toxicol. vol. 48. 2010. pp. 979-1178.
Singer, AJ, Carracio, TR, Mofenson, HC. “The temporal profile of increased transaminase levels in patients with acetaminophen-induced liver dysfunction”. Ann Emerg Med. vol. 26. 1995. pp. 49-53.
Rowden, A, Norvell, J, Eldridge, D, Kirk, MA. “Updates on acetaminophen toxicity”. Med Clin North Am. vol. 89. 2005. pp. 1145-59.
Kurtovic, J, Riordan, SM. “Paracetamol-induced hepatotoxicity at recommended dosage”. J Intern Med. vol. 253. 2003. pp. 240-3.
Bernal, W, Auzinger, G, Dhawan, A, Wendon, J. “Acute liver failure”. The Lancet. vol. 376. 2010. pp. 190-201.
Tolman, KG. “Hepatotoxicity of non-narcotic analgesics:”. Am J Med. vol. 105. 1998. pp. 13S-9S.
Rumack, BH. “Acetaminophen hepatotoxicity: The first 35 years”. J Toxicol Clin Toxicol. vol. 40. 2002. pp. 3-20.
Rowden, AK, Norvell, J, Eldridge, DL, Kirk, MA. “Updates on acetaminophen toxicity”. Med Clin North Am. vol. 89. 2005. pp. 1145-59.
Heard, KJ. “Acetylcysteine for acetaminophen poisoning”. N Engl J Med. vol. 359. 2008. pp. 285-91.
Larsen, L, Fuller, SH. “Management of acetaminophen toxicity”. Am Fam Physician. vol. 53. 1996. pp. 185-90.
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- I. What every physician needs to know.
- II. Diagnostic Confirmation: Are you sure your patient has acetaminophen overdose?
- A. History Part I: Pattern Recognition:
- B. History Part 2: Prevalence:
- C. History Part 3: Competing diagnoses that can mimic acetaminophen overdose
- D. Physical Examination Findings.
- E. What diagnostic tests should be performed?
- 1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- 2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
- III. Default Management.
- A. Immediate management.
- B. Physical Examination Tips to Guide Management.
- C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
- D. Long-term management.
- E. Common Pitfalls and Side-Effects of Management
- IV. Management with Co-Morbidities
- A. Renal Insufficiency.
- B. Liver Insufficiency.
- C. Systolic and Diastolic Heart Failure
- D. Coronary Artery Disease or Peripheral Vascular Disease
- E. Diabetes or other Endocrine issues
- F. Malignancy
- G. Immunosuppression (HIV, chronic steroids, etc).
- H. Primary Lung Disease (COPD, Asthma, ILD)
- I. Gastrointestinal or Nutrition Issues
- J. Hematologic or Coagulation Issues
- K. Dementia or Psychiatric Illness/Treatment
- V. Transitions of Care
- A. Sign-out considerations While Hospitalized.
- B. Anticipated Length of Stay.
- C. When is the Patient Ready for Discharge.
- D. Arranging for Clinic Follow-up
- 1. When should clinic follow up be arranged and with whom.
- 2. What tests should be conducted prior to discharge to enable best clinic first visit.
- 3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.
- E. Placement Considerations.
- F. Prognosis and Patient Counseling.
- VI. Patient Safety and Quality Measures
- A. Core Indicator Standards and Documentation.
- B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.
- VII. What's the evidence?