Correspondence
Acetaminophen Poisoning
N Engl J Med 2008; 359:1962-1965October 30, 2008
- Article
To the Editor:
Heard (July 17 issue)1 reports that acetylcysteine reduces the severity of acetaminophen poisoning–induced liver damage by restoring the hepatic glutathione pool. However, one major concern not mentioned in the article is the possible decrease in the prothrombin index (defined in the legend to Figure 1), a prognostic indicator of hepatotoxicity.
Acetylcysteine may significantly reduce the prothrombin index in the absence of liver or clotting abnormalities.2,3 In an 8-year retrospective analysis, we treated 171 patients who had acetaminophen poisoning with intravenous acetylcysteine according to the recommendations outlined in Heard's article. Among 115 patients without underlying or acute liver injury (alanine aminotransferase concentration <50 IU per liter and prothrombin index >60%), we observed a significant but moderate decrease in the prothrombin index with the use of acetylcysteine (P<0.001), without an alteration in aminotransferase levels (Table 1Table 1
Changes in the Serum Acetaminophen Level, Prothrombin Index, and Aminotransferase Levels during Acetylcysteine Treatment for Acetaminophen Poisoning.). The outcome was uneventful, with normalization of the prothrombin index at discontinuation of acetylcysteine therapy. Thus, a decrease in the prothrombin index with normal aminotransferase levels in patients who are receiving acetylcysteine therapy should not be misinterpreted as being predictive of liver failure. Isolated decreases in the prothrombin index may be attributed to the interaction of acetylcysteine with clotting factors containing disulfide bonds,4 although direct acetaminophen-related inhibition of gamma-carboxylation in the production of vitamin K–dependent factor may result in a functional deficiency of factor VII.5 5 ReferencesBruno Mégarbane, M.D., Ph.D.
Nicolas Deye, M.D.
Frédéric J. Baud, M.D.
Lariboisière Hospital, 75010 Paris, France
bruno-megarbane@wanadoo.fr 1
Heard KJ . Acetylcysteine for acetaminophen poisoning. N Engl J Med 2008;359:285-292
Full Text | Web of Science | Medline2
Schmidt LE ,Knudsen TT ,Dalhoff K ,Bendtsen F . Effect of acetylcysteine on prothrombin index in paracetamol poisoning without hepatocellular injury. Lancet 2002;360:1151-1152
CrossRef | Web of Science | Medline3
Lucena MI ,Lopez-Torres E ,Verge C , et al. The administration of N-acetylcysteine causes a decrease in prothrombin time in patients with paracetamol overdose but without evidence of liver impairment. Eur J Gastroenterol Hepatol 2005;17:59-63
CrossRef | Web of Science | Medline4
Jepsen S ,Hansen AB . The influence of N-acetylcysteine on the measurement of prothrombin time and activated partial thromboplastin time in healthy subjects. Scand J Clin Lab Invest 1994;54:543-547
CrossRef | Web of Science | Medline5
Whyte IM ,Buckley NA ,Reith DM ,Goodhew I ,Seldon M ,Dawson AH . Acetaminophen causes an increased International Normalized Ratio by reducing functional factor VII. Ther Drug Monit 2000;22:742-748
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To the Editor:
We have serious concerns about the risk of noncompliance associated with Heard's final recommendation regarding outpatient oral acetylcysteine therapy. First, the oral regimen is given in doses every 4 hours for 72 hours.1 Most patients find it difficult to be compliant with twice-daily dosing. Asking an asymptomatic patient to awaken during the night in order to self-medicate may be unrealistic. In addition, oral acetylcysteine is a foul-smelling drug that frequently causes vomiting and often deters the most compliant patients from completing therapy without antiemetic drugs.2 Finally, gaps in therapy may have hepatotoxic consequences that render subsequent care less effective.
The concept of outpatient oral acetylcysteine therapy was originally discussed in a report in 1996, and the authors concluded that outpatient therapy was ill-advised because of similar concerns.3 Until data show that this practice is safe and effective, we suggest that all patients who need acetylcysteine therapy be hospitalized.
3 ReferencesBrenna M. Farmer, M.D.
Robert S. Hoffman, M.D.
New York University School of Medicine, New York, NY 100161
Mucomyst (acetylcysteine). Princeton, NJ: Apothecon, 1996 (package insert).
2
Miller MA ,Navarro M ,Bird SB ,Donovan JL . Antiemetic use in acetaminophen poisoning: how does the route of N-acetylcysteine administration affect utilization? J Med Toxicol 2007;3:152-156
CrossRef | Medline3
Dean BS ,Bricker JD ,Krenzelok EP . Outpatient N-acetylcysteine treatment for acetaminophen poisoning: an ethical dilemma or a new financial mandate? Vet Hum Toxicol 1996;38:222-224
Medline
To the Editor:
We wish to comment on aspects of risk assessment associated with acetaminophen poisoning. If it is present, acidosis has prognostic importance,1 and kidney injury may occur independently of hepatic injury.2 Data regarding both conditions are missing from the article, as are normal ranges for alanine aminotransferase. In our clinical experience (>800 cases per year), the risk of liver damage is also increased in acute starvation. Information on nutritional status is also missing from the article.
Hepatic injury impairs acetaminophen clearance.3 The absence of acetaminophen 8 hours after the last ingestion indicates normal acetaminophen clearance. Marginally abnormal biochemical values (the normal range for alanine aminotransferase is not given) are weak evidence of significant hepatic injury. Low acetaminophen concentrations are associated with an increased risk of adverse reactions to the intravenous antidote used extensively in the United States and universally in other countries.4 Therefore, therapy in patients with low or absent levels of acetaminophen may be overly conservative and is potentially harmful.
In discussing acetaminophen poisoning, it is important to emphasize a full risk assessment based on a comprehensive history and comprehensive laboratory data sets. The details presented are insufficient for adequate risk assessment.
4 ReferencesJames W. Dear, Ph.D.
Edinburgh University, Edinburgh EH16 4TJ, United KingdomW. Stephen Waring, Ph.D.
D. Nicholas Bateman, M.D.
Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, United Kingdom
nick.bateman@luht. scot. nhs. uk 1
Mahadevan SB ,McKiernan PJ ,Davies P ,Kelly DA . Paracetamol induced hepatotoxicity. Arch Dis Child 2006;91:598-603
CrossRef | Web of Science | Medline2
Blakely P ,McDonald BR . Acute renal failure due to acetaminophen ingestion: a case report and review of the literature. J Am Soc Nephrol 1995;6:48-53
Web of Science | Medline3
Prescott LF ,Roscoe P ,Wright N ,Brown SS . Plasma-paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage. Lancet 1971;1:519-522
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Waring WS ,Stephen AF ,Robinson OD ,Dow MA ,Pettie JM . Lower incidence of anaphylactoid reactions to N-acetylcysteine in patients with high acetaminophen concentrations after overdose. Clin Toxicol (Phila) 2008;46:496-500
CrossRef | Web of Science | Medline
To the Editor:
Heard's proposed recommendations for the treatment of acetaminophen poisoning with acetylcysteine do not include prolongation of the plasma acetaminophen half-life for more than 4 hours.
In the many cases in which the Rumack–Matthew nomogram is not applicable, a plasma acetaminophen half-life of more than 4 hours is predictive of toxic effects in the liver and is therefore an indication for treatment with acetylcysteine.1-4 An estimation of the plasma acetaminophen half-life can be made in the emergency room by means of two measurements of plasma levels of acetaminophen, carried out 2 hours apart, and made not less than 2 hours after ingestion.
4 ReferencesSantiago Nogué-Xarau, M.D.
Hospital Clínic, 08036 Barcelona, Spain
snogue@clinic.ub. es Bartomeu Castanyer-Puig, Ph.D.
Bernadí Barceló-Martín, Ph.D.
Hospital Son Dureta, 07014 Palma de Mallorca, Spain1
Castanyer-Puig B ,Barcelo-Martin B ,Puiguriguer-Ferrando J ,Rovira-Illamola M ,Soy-Muner D ,Nogue-Xarau S . Clinical value of estimated half-life in paracetamol poisoning as a complement to Rumack's nomogram. Med Clin (Barc) 2007;129:501-503[Erratum, Med Clin (Barc) 2007;129:765.]
CrossRef | Web of Science | Medline2
Prescott LF ,Roscoe P ,Wright N ,Brown SS . Plasma-paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage. Lancet 1971;1:519-522
CrossRef | Web of Science | Medline3
Schiodt FV ,Ott P ,Christensen E ,Bondesen S . The value of plasma acetaminophen half-life in antidote-treated acetaminophen overdosage. Clin Pharmacol Ther 2002;71:221-225
CrossRef | Web of Science | Medline4
Sivilotti ML ,Yarema MC ,Juurlink DN ,Good AM ,Johnson DW . A risk quantification instrument for acute acetaminophen overdose patients treated with N-acetylcysteine. Ann Emerg Med 2005;46:263-271
CrossRef | Web of Science | Medline
To the Editor:
Heard notes that anaphylactoid reactions to acetylcysteine involving angioedema, respiratory symptoms, or hypotension should be treated with diphenhydramine, corticosteroids, and bronchodilators. There is no mention of the use of epinephrine in the treatment of these patients. The updated practice guideline for the diagnosis and management of anaphylaxis,1 which treats the short-term management of anaphylactic and anaphylactoid reactions identically, recommends epinephrine as first-line therapy for such reactions. A delay in the administration of epinephrine is common in cases of death due to anaphylaxis. Antihistamines, corticosteroids, and bronchodilators should be reserved as second-line treatments to be used in conjunction with epinephrine.
1 ReferencesJared B. Goldberg, M.D.
Inova Alexandria Hospital, Alexandria, VA 22304
skijar@aol.com To the Editor:
Heard does not discuss the use of acetaminophen by persons with preexisting liver disorders. Many clinicians caution such patients not to use acetaminophen; their conditions may range from self-limiting hepatitis A to chronic viral and noninfectious hepatitides, with or without cirrhosis. Is there a rationale for recommending that these patients not take full therapeutic doses of acetaminophen (a maximum of 4 g per day in divided doses), especially in light of the potential overall toxicity of over-the-counter alternatives such as nonsteroidal antiinflammatory drugs?
Steven Leiner, N.P.
Mission Neighborhood Health Center, San Francisco, CA 94110
stevenleiner@hotmail.com Author/Editor Response
I agree with Mégarbane et al. that the prothrombin index may be decreased by acetylcysteine. A prolonged prothrombin time without elevation of aminotransferase levels is not evidence of acetaminophen-induced hepatic injury.
Farmer and Hoffman suggest that all patients who require treatment with acetylcysteine should be admitted to the hospital. Although acetylcysteine is administered every 4 hours, the suggested protocol only requires the patient to take two doses on an outpatient basis. Vomiting and noncompliance may occur during treatment for many conditions, and it is therefore important that all patients who are discharged from the emergency department be instructed to return if they cannot tolerate their treatment.
Dear et al. suggest that the case described in my article does not provide sufficient information to make a complete risk assessment. Acidosis and renal dysfunction are markers of life-threatening toxicity. Although rare case reports describe renal injury without hepatic injury, significant acidosis and renal dysfunction are extremely rare while serum aminotransferase levels are minimally abnormal (these conditions may develop as liver injury progresses). Although the unmeasurable acetaminophen concentration is reassuring, this patient already has liver injury (an abnormal alanine aminotransferase level), and therefore, I believe he should be treated until the course of his liver injury is established. Some patients with minimally elevated alanine aminotransferase levels will have progression to life-threatening hepatic injury.1 I agree that patients with malnutrition are probably at increased risk for hepatic injury from acetaminophen poisoning.
Nogué-Xarau et al. describe the use of acetaminophen clearance as a measure of the risk of toxicity. This is a useful tool in patients with acute overdose in whom the acetaminophen concentration can be determined. However, waiting for a second acetaminophen concentration delays the administration of acetylcysteine, which increases the risk of adverse outcomes.2
Goldberg notes that recent guidelines recommend epinephrine for the treatment of anaphylactoid reactions involving respiratory symptoms or hypotension. Although life-threatening reactions to acetylcysteine are rare, and most reactions respond to discontinuation of the infusion and diphenhydramine, I agree that epinephrine is indicated for life-threatening airway or cardiovascular symptoms.
Leiner asks about dose adjustments for acetaminophen in patients with chronic liver disease. Although some clinicians advocate a lower dose (2 g per day), there are no systematic studies suggesting clinical hepatic injury from the maximum therapeutic dose of acetaminophen, even in patients who are at high risk for such injury.3
3 ReferencesKennon J. Heard, M.D.
Rocky Mountain Poison and Drug Center, Denver, CO 80204
kennon.heard@rmpdc. org 1
Daly FF ,O'Malley GF ,Heard K ,Bogdan GM ,Dart RC . Prospective evaluation of repeated supratherapeutic acetaminophen (paracetamol) ingestion. Ann Emerg Med 2004;44:393-398
CrossRef | Web of Science | Medline2
Smilkstein MJ ,Knapp GL ,Kulig KW ,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 1988;319:1557-1562
Full Text | Web of Science | Medline3
Dart RC ,Bailey E . Does therapeutic use of acetaminophen cause acute liver failure? Pharmacotherapy 2007;27:1219-1230
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Carlos Fernández de Larrea, Miguel Lozano, Pedro Castro, Josep Maria Nicolàs. (2009) Respuesta. Medicina Clínica 133:12, 487
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