Jaundice in the Emergency Department: Meeting the Challenges of Diagnosis and Treatment

• King's College Criteria for Acetaminophen Toxicity
• Acetaminophen Overdose and N-Acetylcysteine (NAC) Dosing

King's College Criteria for Acetaminophen Toxicity	Acetaminophen Overdose and N-Acetylcysteine (NAC) Dosing
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• Introduction
• Points & Pearls
• Why and When to Use, and Next Steps
• Calculator Review Author
• Critical Actions
• Evidence Appraisal
• Calculator Creator
• References

Introduction

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• The King’s College Criteria (KCC) were developed to determine which patients with fulminant hepatic failure (FHF) should be referred for liver transplant.
• The KCC can be applied to all acetaminophen ingestions (acute or chronic) with signs of severe acute liver injury.
• There are no worldwide standard criteria for transplantation, but the KCC are the most widely applied.
• The KCC indicators predict a poor prognosis, and select the patients most likely to benefit from an immediate liver transplant referral.
• The etiology of the acute liver failure is important in determining indicators of poor prognosis (acetaminophen ingestion vs other causes).
• Metabolic acidosis alone OR a combination of Grade III or IV hepatic encephalopathy (HE), prothrombin time (PT) > 100 sec, and creatinine level > 3.4 mg/dL predicted 77% of total deaths (O'Grady 1989).

Points to keep in mind:

• The KCC are criticized for predicting mortality often when patients are too sick for a transplant.
• The use of prolonged N-acetylcysteine therapy, which was not standard when the KCC were created, has significantly lowered the complication rate and need for transplants.
• PT values are often not comparable across laboratories, due to the use of different reagents.
• Serum lactate (a marker of liver injury) and phosphate (a marker of liver regeneration) have been used as alternative early prognostic indicators or adjuncts to the KCC.
• The KCC is specific but not sensitive; that is, while fulfillment of the criteria carries a poor prognosis, lack of fulfillment may still carry an unfavorable outlook. 

Why and When to Use, and Next Steps 

Calculator Review Author 

Vincent Nguyen, MD

Department of Emergency Medicine

Bronx, New York

Critical Actions

Patients with acute liver failure should be managed in centers with expertise in caring for these patients. This includes patients who do not yet appear to be gravely ill, since it can be hazardous to transfer patients later in the disease course.

Evidence Appraisal

The KCC were derived from a retrospective review of 588 patients with FHF over 13 years (O’Grady 1989). The predictors are slightly different based on the etiology of the FHF (acetaminophen vs other causes). The arterial pH, HE, PT, and creatinine predictors were derived from 310 patients with acetaminophen-induced FHF, and were retrospectively validated on a separate group of 121 patients with acetaminophen-induced FHF (O’Grady 1989).

The criteria are well validated and reflect the degree of multiorgan dysfunction. In addition, the criteria are specific but not sensitive; fulfillment of the criteria suggests a poor prognosis, but patients who do not fulfill the criteria may also still have a poor prognosis.

In the study, patients were transferred to King’s College Hospital at a relatively late stage (median time of 51 hours after acetaminophen ingestion) and were the most severely ill (the majority of patients were admitted with HE stages III or IV). This may have affected the predictive values of the test criteria.

In a systematic review of 14 eligible studies (Bailey 2003), the estimated overall sensitivity and specificity of the KCC for predicting mortality were 58% and 95%, respectively. The search for earlier prognostic indicators with a higher sensitivity for poor prognosis led to investigations of alpha-fetoprotein, coagulation factor V, ketone body ratio, lactate, and phosphate. Lactate and phosphate concentrations were initially found to have improved predictive ability compared to the KCC, but subsequent studies have shown slightly inferior predictive ability. The addition of lactate or phosphate to the KCC may improve sensitivity and negative predictive value. 

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John O'Grady, MD

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References

Original/Primary Reference

• O'Grady JG, Alexander GJ, Hayllar KM, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology.1989;97(2):439-445.

Validation

• Bailey B, Amre DK, Gaudreault P. Fulminant hepatic failure secondary to acetaminophen poisoning: a systematic review and meta-analysis of prognostic criteria determining the need for liver transplantation. Crit Care Med. 2003;31(1):299-305.

Other References

• Bernal W, Donaldson N, Wyncoll D, et al. Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study. Lancet. 2002;359(9306):558-563.
• Schmidt LE, Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity. Hepatology. 2002;36(3):659-665.
• Riordan SM, Williams R. Treatment of hepatic encephalopathy. N Engl J Med. 1997;337(7):473-479.
• Hoffman R, Howland MA, Lewin N, et al. Goldfrank's Toxicologic Emergencies. 10th ed. New York: McGraw-Hill Education/Medical; 2014

Copyright © MDCalc • Reprinted with permission.

• Introduction
• Points & Pearls
• Why and When to Use, and Next Steps
• Calculator Review Author
• Advice
• Critical Actions
• Evidence Appraisal
• Calculator Creator
• References

Introduction

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• An acetaminophen concentration obtained prior to 4 hours post-ingestion cannot be plotted on the Rumack-Matthew nomogram, and only confirms acetaminophen exposure, not toxicity.
• It is important to get an accurate time of ingestion, as the Rumack-Matthew nomogram is entirely dependent on knowing time of ingestion.
• Start N-acetylcysteine (NAC) treatment within 8 hours post-ingestion to decrease the risk of hepatotoxicity (aspartate transaminase [AST] or alanine transaminase [ALT] > 1000 IU/L).
• For patients presenting 8 to 24 hours post-in-gestion, start NAC while awaiting the acetaminophen concentration; NAC can be continued or discontinued depending on the level when the result is available.

Why and When to Use, and Next Steps 

Calculator Review Author 

Scott Lucyk, MD

Department of Emergency Medicine

University of Calgary, Calgary, Alberta, Canada

Poison and Drug Information Service (PADIS)

Alberta Health Services, Calgary, Alberta, Canada

Critical Actions

Serum acetaminophen concentration should be obtained for all patients who present with an intentional overdose, or those who have used excessive amounts of acetaminophen-containing products. NAC treatment should be initiated within 8 hours post-ingestion to decrease risk of hepatotoxicity.

Advice

• Early administration of NAC (< 8 hours post-ingestion) is vital to decreasing the risk of hepatotoxicity; acetaminophen is a leading cause of drug-induced liver injury.
• Acetaminophen is widely available in prescription and over-the-counter medications, either as a single agent or in combination products (eg, dextromethorphan, opioids, diphenhydramine).
• Maintain a strong index of suspicion for acetaminophen toxicity in all patients with an intentional drug overdose and those with therapeutic misadventures (eg, taking excessive amounts of a single product, or using recommended doses of several different products that contain acetaminophen).

Evidence Appraisal

In 1981, Rumack et al published the results of their nationwide, multiclinic open study, which was started in 1976 at the Rocky Mountain Poison Center in Denver. The study was conducted to assess the effectiveness of oral acetylcysteine in preventing hepatotoxicity in patients with acetaminophen overdose presenting within 24 hours of ingestion. The cohort included 662 consecutive patients with an acetaminophen overdose. Incidence of hepa-totoxicity and time to treatment for patients with acetaminophen concentration in the probable toxic range (a line intersecting 200 μg/mL [1324 μmol/L] at 4 hours and 50 μg/mL [331 μmol/L] at 12 hours) were 7% when treated within 10 hours of ingestion, 29% when treated within 10 to 16 hours of ingestion, and 62% when treated within 16 to 24 hours of ingestion.

Prescott et al (1979) studied 100 patients with acetaminophen poisoning who were treated with intravenous NAC. Serum acetaminophen concentrations above a line intersecting 200 μg/mL (1323 μmol/L) at 4 hours and 30 μg/mL (199 μmol/L) at 15 hours were measured, and the incidence of hepatotoxicity was as follows: 0 of 40 patients treated within 8 hours of ingestion, 1 of 62 patients (1.6%) treated within 10 hours of ingestion, and 20 of 38 patients (53%) treated within 10 to 24 hours of ingestion. A retrospective analysis of 57 patients treated with supportive care alone (no intravenous NAC) showed a 58% incidence of hepatotoxicity (33 of 57 patients).

Another study of 11,195 cases of suspected acetaminophen overdose (Smilkstein 1988) described the outcomes of 2540 patients who were treated with 72-hour oral NAC. Among patients at probable risk for hepatotoxicity (acetaminophen concentration above a line intersecting 200 μg/mL [1323 μmol/L] at 4 hours and 50 μg/mL [331 μmol/L] at 12 hours, and below a line intersecting 300 μg/mL [1985 μmol/L] at 4 hours and 75 μg/mL [496 μmol/L] at 12 hours), 6.1% developed hepatotoxicity when NAC was initiated within 10 hours of ingestion, and 26.4% developed hepatotoxicity when NAC was initiated within 10 to 24 hours of ingestion.

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Barry H. Rumack, MD

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References

Original/Primary Reference

• Rumack BH, Peterson RC, Koch GG, et al. Acetaminophen overdose: 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med. 1981;141(3):380-385.

Validation References

• Prescott LF, Illingworth RN, Critchley JA, et al. Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. BMJ. 1979;2(6198):1097-1100.
• Smilkstein MJ, Knapp GL, Kulig KW, et al. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose: analysis of the national multicenter study. N Engl J Med. 1988;319(24):1557-1562.

Copyright © MDCalc • Reprinted with permission.