Acetaminophen overdose is the most common cause of

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2008;6: ORIGINAL ARTICLES LIVER, PANCREAS AND BILIARY TRACT Impact of Liver Disease, Alcohol Abuse, and Unintentional Ingestions on the Outcomes of Acetaminophen Overdose ROBERT P. MYERS,*, ABDEL AZIZ M. SHAHEEN,* BING LI, STAFFORD DEAN, and HUDE QUAN *Liver Unit, Division of Gastroenterology, Department of Medicine, University of Calgary; Health System Analysis Unit, Quality, Safety and Health Information, Calgary Health Region; and Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada See CME exam on page 837. Background & Aims: Acetaminophen overdose is the most common cause of acute liver failure in the U.S. and other Western countries. Unintentional overdoses, alcohol abuse, and underlying liver disease might increase the risk of hepatotoxicity. In this population-based study, we examined outcomes of acetaminophen overdose, with particular attention to these risk factors. Methods: Patients hospitalized for acetaminophen overdose between 1995 and 2004 were identified retrospectively by using administrative data. Comorbid conditions, suicidal intent, and hepatotoxicity were identified by using International Classification of Diseases-Ninth Revision-Clinical Modification and International Statistical Classification of Diseases and Health-Related Problems, 10th revision diagnostic codes. Results: During the 10-year interval, 1543 patients were hospitalized for acetaminophen overdose; 34% were alcohol abusers, 3% had liver disease, and 13% overdosed unintentionally. Seventy patients (4.5%) developed hepatotoxicity. Unintentional overdoses (odds ratio [OR], 5.18; 95% confidence interval [CI], ), alcohol abuse (OR, 2.21; 95% CI, ), underlying liver disease (OR, 3.50; 95% CI, ), and N-acetylcysteine treatment (OR, 6.75; 95% CI, ) were independently associated with hepatotoxicity. Fifteen patients (1.0%) died in-hospital; risk factors included older age, unintentional overdoses, alcohol abuse, comorbidities including liver disease, and hepatotoxicity (14% vs 0.3%; P <.0005). During a median follow-up of 5.2 years (range, 1 day 11.0 years), 79 patients (5.1%) died. Approximately half of these deaths were due to preventable conditions including suicide, substance abuse, and trauma. Conclusions: In this population-based study, acetaminophen overdose had a relatively benign shortterm course but was associated with substantial longterm mortality caused by preventable conditions. Acetaminophen-related hepatotoxicity is more common in patients with unintentional overdoses, alcohol abuse, and underlying liver disease. Acetaminophen overdose is the most common cause of acute liver failure (ALF) in the U.S. and other Western countries. 1,2 Recent data from the U.S. ALF Study Group identified acetaminophen as the etiology in approximately 50% of cases. 1 Acetaminophen overdose typically has a good prognosis, even if hepatic failure has developed. Less than 5% of patients develop acute liver toxicity, 3,4 and survival without transplantation for those who develop encephalopathy ( 65%) exceeds that for most other forms of ALF. 1,2,5 Nevertheless, nearly 30% of those developing encephalopathy will die, and 8% require transplantation. 1,2,5 Many studies have examined risk factors for acetaminophen hepatotoxicity, but most originate in referral centers (eg, liver transplant units) and might be prone to selection and referral bias. 1,6 Unintentional overdoses, often observed in patients using multiple acetaminophen-containing preparations or narcoticcontaining compounds for chronic pain, have emerged as an important risk factor. 1,7 11 Late presentation and delay or failure to receive the antidote, N-acetylcysteine (NAC), likely play a role in such cases Other potential risks include chronic alcohol abuse and preexisting liver disease, although this remains controversial. 1,12,15,16 To clarify these issues, we conducted a population-based study to examine outcomes of acetaminophen overdose in a large Canadian health region by using administrative databases. These databases are increasingly used in studies of outcomes, effectiveness, and health care utilization in a variety of fields 17 including liver disease research. 18,19 Their availability and readiness to be analyzed, broad geographic coverage, and relatively complete capture of health care encounters are important advantages over other data sources. The primary objective of our study was to determine rates of acetaminophen-related hepato- Abbreviations used in this paper: AHCIP, Alberta Health Care Insurance Plan; ALF, acute liver failure; CHR, Calgary Health Region; CI, confidence interval; DA, dissemination area; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; ICD- 10, International Statistical Classification of Diseases and Health- Related Problems, 10th revision; LOS, length of hospital stay; MH, Mantel-Haenszel; NAC, N-acetylcysteine; OR, odds ratio; RR, relative risk by the AGA Institute /08/$34.00 doi: /j.cgh

2 August 2008 OUTCOMES OF ACETAMINOPHEN OVERDOSE 919 toxicity and in-hospital mortality and risk factors for these adverse outcomes, specifically preexisting liver disease, alcohol abuse, and unintentional ingestions. Secondary objectives included examining costs, length of hospital stay (LOS), and long-term mortality in patients admitted for acetaminophen overdose. Methods Study Population The study population consisted of hospitalized patients with acetaminophen overdose residing in the Calgary Health Region (CHR) between fiscal years 1995 and The CHR provides virtually all medical and surgical care to approximately 1.2 million residents of Calgary and surrounding communities in southern Alberta, Canada. Acetaminophen overdose cases were identified retrospectively by using CHR hospital discharge administrative data. This database contains 16 diagnosis and 10 procedure coding fields. Cases were identified via a search of the 16 diagnosis fields for code according to the International Classification of Disease, Ninth Revision, Clinical Modification (ICD- 9-CM) 20 in the discharge data and T39.1 according to International Statistical Classification of Diseases and Health-Related Problems, 10th revision (ICD-10) 21 in the discharge data. According to a local validation study (n 181 medical records), 22 the positive predictive value of this coding algorithm for confirmed acetaminophen overdose is 95% (95% confidence interval [CI], 89% 98%). The first admission was assigned as the index admission for patients with repeated hospitalizations for acetaminophen overdose. Definitions of Variables The acetaminophen overdose cases were linked with the Alberta Health Care Insurance Plan (AHCIP) Registry 23 by using a unique personal identifier to obtain demographic information. Because the ACHIP is a government-administered universal plan providing health care for more than 99% of Albertans, this registry includes nearly all Alberta residents. 23 As a proxy for individual income, median household income for each dissemination area (DA) was obtained from 2001 Statistics Canada census data. 24 DAs are composed of 1 or more neighboring blocks with a population of persons; they represent the smallest geographical unit for which census data are reported. To situate individual patients within DAs, the Postal Code Conversion File was used. 25 Median household income has been shown to represent a reasonable proxy for individual income 26 and is able to identify variations in outcomes. 27 Comorbid conditions, including alcohol abuse and preexisting liver disease, were defined by using the list of 30 comorbidities of Elixhauser et al 28 modified by Quan et al 29 for ICD-9-CM and ICD-10 diagnostic codes. This list has been validated for LOS, hospital costs, and in-hospital mortality and has superior control of confounding compared with other indices. 28,30 All comorbid conditions were identified by a diagnosis-type indicator that distinguishes baseline conditions from complications arising during the hospitalization. 31 Because of existing literature suggesting an impact of alcohol abuse and preexisting liver disease on the outcome of acetaminophen overdose, these conditions were considered independently from the remaining 28 comorbidities of Elixhauser et al. Because some of the diagnosis codes for comorbid liver disease overlap with those used to define hepatotoxicity (see below), these codes were excluded from the comorbidity algorithm to limit misclassification of preexisting liver disease as acetaminophen-related hepatotoxicity. In addition to liver disease in general, underlying cirrhosis was identified by using the following diagnostic codes (ICD-9-CM, 571.2, 571.5, 571.6; ICD-10, K70.3, K71.7, K74.3-K74.6, K76.1, P78.8). The circumstance in which the overdose occurred was classified as intentional (ICD-9-CM, E950.0; ICD-10, X60), unintentional (ICD-9-CM, E850.4, E935.4; ICD-10, X40, Y45.5), or other (including homicidal intention and undetermined intent) by using external causes of injury codes (E codes). 20,21 Any overdose involving self-inflicted poisoning by another substance in addition to acetaminophen (ICD-9-CM, E950.1 E952.9; ICD-10, X61 X69) was considered intentional. According to the aforementioned validation study, 22 the sensitivity and specificity of these codes for intentional overdoses were 98% (95% CI, 91% 100%) and 93% (95% CI, 81% 99%), respectively. Acetaminophen hepatotoxicity was defined by using the 16 diagnosis fields in the hospital discharge data indicating the development of hepatic necrosis (ICD-9-CM, 570; ICD-10 K71.1), toxic hepatitis (ICD-9-CM, 573.3; ICD-10 K71.2, K71.6, K71.9), or hepatic encephalopathy (ICD-9-CM, 572.2; ICD-10, K72.0, K72.9). According to our local validation study, 22 this algorithm is 93% sensitive (95% CI, 84% 98%) and 85% specific (95% CI, 75% 92%) for hepatotoxicity defined as an ALT 1000 U/L. 6,7,14,32,33 To identify patients who underwent liver transplantation, the University of Alberta Liver Transplant Database was queried. 34 In-hospital deaths were identified by using the hospital discharge data. All-cause mortality was determined via linkage of the study cohort with the AHCIP Registry and Vital Statistics databases. 23 The latter contain death certificate verified data regarding the underlying cause of death for CHR residents dying within Alberta. LOS was calculated as days between hospital admission and discharge. Transfers between hospitals were attributed to the index admission, and cumulative LOS was calculated. Total itemized hospital costs, excluding physician fees, available in fiscal years , were estimated on the basis of expenses accrued from direct and indirect patient care. Direct costs are based on all costs for providing patient care such as nursing staff, drugs, and other supplies. Indirect costs represent the cost of supporting the provision of patient care including administrative infrastructure, fixed facility costs, and health records. Receipt of NAC, available for fiscal years , was ascertained via linkage with the regional pharmacy database. Statistical Methods Descriptive statistical methods were used to describe the characteristics of the cohort. The primary outcome measures were acetaminophen-related hepatotoxicity and all-cause mortality. Between-group comparisons were made with Fisher exact, 2, and Mann-Whitney tests, as appropriate. Independent risk factors for hepatotoxicity were determined with multiple logistic regression. Long-term mortality was examined by using Kaplan-Meier survival analyses with censoring on the day of deregistration from the AHCIP or March 31, 2006, whichever came first. The impact of patient factors on survival was analyzed by using Cox proportional hazards regression with confirmation of the proportional hazards assumption. 35

3 920 MYERS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 8 Table 1. Characteristics of Patients with Acetaminophen Overdose (n 1543) Characteristic Demographics Median age (range), y 26 (0 96) Female gender 68% (1054) Median household income (range), $ a 54,180 (14, ,126) Circumstance of overdose Intentional 85% (1311) Unintentional 13% (205) Other 2% (27) Comorbidities b No./patient 0 17% (265) 1 40% (624) 2 23% (362) 3 19% (292) Depression 55% (842) Alcohol abuse 34% (525) Drug abuse 21% (323) Liver disease 3% (46) Cirrhosis 0.7% (11) NAC treatment c 38% (290) Cost, $ d Median 2123 Range ,182 LOS, days Median 3 Range a Available in 1495/1543 patients (97%). b As defined by Elixhauser et al 28 and modified by Quan et al. 29 c Available in patients hospitalized between 1998 and 2002 (n 771). d Available in 679/694 (98%) patients hospitalized between 2000 and We also examined hospital costs and LOS with logarithmic transformations as a result of the positive skew in their distributions. Factors associated with costs and LOS were examined by using multivariate linear regression models with adjustment for age, sex, and comorbid conditions. The study protocol was approved by the Conjoint Health Research Ethics Board at the University of Calgary. Results Study Population Between fiscal years 1995 and 2004, 1543 patients had 1680 admissions for acetaminophen overdose. The characteristics of the study cohort are outlined in Table 1. The majority (68%) was female, and the median age was 26 years (range, 0 96 years). Depression (55%) and alcohol abuse (34%) were common. In total, 46 patients (3%) had underlying liver disease; 11 (24%) of these patients had cirrhosis (0.7% of the total). The majority of the overdoses (85%) were intentional; 13% were unintentional. The proportion classified as unintentional increased with advancing age ( 30 years, 9% [85/905] vs years, 15% [76/491] vs 50 years, 30% [44/137]; P.0005). Patients with unintentional overdoses had a lower prevalence of depression (18% [38/205] vs 60% [804/1338]; P.0005) but a similar prevalence of alcohol abuse (36% [73/205] vs 33% [452/ 1338]; P.64) and were as likely to receive NAC (42% [34/81] vs 37% [256/690]; P.40). Liver disease was more common in patients with unintentional overdoses (14% [29/205] vs 1.3% [17/1338]; P.0005) and alcohol abuse (7% [35/525] vs 1.1% [11/1018]; P.0005). Acetaminophen Hepatotoxicity According to the diagnostic coding algorithm, 70 patients (4.5%) developed hepatotoxicity. Diagnostic codes for hepatic necrosis, toxic hepatitis, and hepatic encephalopathy were recorded in 43% (n 30), 56% (n 39), and 16% (n 11) of patients, respectively. The majority (87%) had codes recorded for only 1 of these conditions; 11% had 2, and 1.4% had all 3 diagnoses. No patient with hepatotoxicity received a liver transplant, but they were more likely to be admitted to an intensive care unit than patients without hepatotoxicity (16% [11/70] vs 6% [92/1473]; P.005). Clinical factors associated with hepatotoxicity in univariate analysis included older age, unintentional overdoses, underlying liver disease, alcohol abuse, and NAC treatment (Table 2). In a bivariate analysis, alcohol abuse was associated with acetaminophen hepatotoxicity in patients with both unintentional (relative risk [RR], 2.92; 95% CI, ) and intentional overdoses (RR, 2.19; 95% CI, ) (Mantel-Haenszel [MH] 2, P.33). Similarly, hepatotoxicity was more common in patients with preexisting liver disease and both unintentional (RR, 3.31; 95% CI, ) and intentional (RR, 7.06; 95% CI, ) overdoses (MH 2, P.22). Cirrhosis was also a significant predictor of acute liver injury; hepatotoxicity developed in 36% (4/11) of cirrhotics versus only 4% (66/1532) of non-cirrhotics (P.001). In multivariate models including the aforementioned factors, underlying liver disease, alcohol abuse, and unintentional overdoses were independently associated with acetaminophenrelated hepatotoxicity (Table 2). The number of these risk factors in a given patient was highly associated with acute liver injury (P.0005). The proportion developing hepatotoxicity was 1.9% (17/883) in patients with none of these risk factors, 5% (28/565) with one, 19% (14/74) with two, and 52% (11/21) with all three factors. In another multivariate model restricted to fiscal years in which accurate pharmacy data were available (n 771), receipt of NAC was also associated with hepatotoxicity (Table 2). Whereas unintentional overdoses remained associated with hepatotoxicity (odds ratio [OR], 9.63; 95% CI, ), the effects of alcohol abuse (OR, 1.95; 95% CI, ) and liver disease (OR, 1.48; 95% CI, ) were attenuated in this restricted analysis. Length of Stay and Costs The median LOS was 3 days (range, 1 162), and hospital cost was $2,123 (range, $342 $89,182). In univariate analyses, acetaminophen-related hepatotoxicity was associated with prolonged median LOS (8 [range, 1 69] vs 3 [range, 1 162] days; P.0005) and cost ($5,276 [range, $1,328 $73,141] vs $2,010 [range, $342 $89,182]; P.0005). In multivariate models controlling for age, sex, and comorbidities, acetaminophen hepatotoxicity was independently associated with increased LOS (P.01) and hospital costs (P.001). Age and the number of comorbid conditions were also significant in these analyses (P.0005).

4 August 2008 OUTCOMES OF ACETAMINOPHEN OVERDOSE 921 Table 2. Predictors of Hepatotoxicity (n 70) in Patients With Acetaminophen Overdose Univariate analysis Multivariate analysis Characteristic Proportion developing hepatotoxicity, % (n) P value OR (95% CI) Age (y) 30 (n 905) 2.8 (25) ( ) a (n 491) 6.5 (32) 50 (n 147) 8.9 (13) Gender Male (n 489) 5.3 (26) ( ) b Female (n 1054) 4.2 (44) Household income c $54,180 (n 747) 5.4 (40).18 $54,180 (n 748) 3.9 (29) Unintentional overdose Yes (n 205) 16.6 (34) ( ) No (n 1338) 2.7 (36) Alcohol abuse Yes (n 525) 7.6 (40) ( ) No (n 1018) 3.0 (30) Liver disease Yes (n 46) 32.6 (15) ( ) No (n 1497) 3.7 (55) Cirrhosis Yes (n 11) 36.4 (4) ( ) No (n 1532) 4.3 (56) NAC d Yes (n 290) 9.0 (26) ( ) No (n 481) 1.5 (7) a Per-year increase in age. b Females versus males. c Available in 1495/1543 patients (97%). d Based on a separate model including only patients admitted between 1998 and 2002 in whom drug data are available (n 771). Mortality Fifteen patients (1.0%) died during the index admission. In-hospital death was more common in older and lower income patients, unintentional overdoses, and patients with comorbid conditions (Table 3). Patients with underlying liver disease (including cirrhosis) and those developing acetaminophen-related hepatotoxicity were also more likely to die in hospital. Alcohol abuse, receipt of NAC, and gender were not associated with in-hospital mortality. Among patients with hepatotoxicity, unintentional ingestions (OR, 3.38; 95% CI, ) and liver disease (OR, 5.84; 95% CI, ), particularly cirrhosis (OR, 25.3; 95% CI, ), were associated with in-hospital mortality. Multivariate analyses were not performed because of the small number of events. Seventy-nine patients (5.1%) died during a median follow-up period of 5.2 years (range, 1 day 11.0 years) from the date of admission. The underlying causes of death were available in 73 (92%) of these patients (Table 4). Fifty-four percent (n 43) were female, and the median age at death was 49 years (range, 4 93). The median interval between admission and death was 485 days (range, ). The survival of patients stratified according to acetaminophen-related hepatotoxicity is illustrated in Figure 1 (log-rank, P.0005). Survival at 5 and 10 years was 95.9% (95% CI, 94.6% 96.9%) and 94.1% (95% CI, 92.3% 95.5%) in patients without hepatotoxicity versus 75.5% (95% CI, 62.9% 84.4%) and 72.1%% (95% CI, 57.9% 82.2%) in patients with hepatotoxicity, respectively. Postdischarge survival was significantly lower in patients with unintentional than intentional overdoses (Figure 2; log-rank, P.0005). Survival at 5 and 10 years after discharge was 96.8% (95% CI, 95.5% 97.7%) and 95.5% (95% CI, 93.9% 96.7%) in patients with intentional overdoses versus 89.5% (95% CI, 83.4% 93.4%) and 83.2% (95% CI, 74.1% 89.4%) in patients with unintentional overdoses, respectively. As a proportion of all postdischarge deaths, patients with unintentional overdoses were nonsignificantly less likely than patients with intentional overdoses to die of suicide (5% vs 21%) and trauma (0% vs 9%) but more likely to die of alcohol-related disorders (10% vs 5%), cardiovascular disease (20% vs 12%), and cancer (10% vs 2%). Drug overdoses were the cause in 24% and 23% of these groups, respectively (P.05 for all comparisons). In a multivariate model for long-term survival (excluding overdose intent as a result of its significant associations with several of the following variables), older age, male sex, lower income, number of comorbid conditions, and acetaminophen hepatotoxicity were significant (Table 5). Although alcohol abuse and liver disease were not significant, cirrhosis was an independent predictor of mortality in another model (hazard ratio, 3.52; 95% CI, ). Discussion We examined short-term and long-term outcomes in Canadian patients hospitalized for acetaminophen overdose by using administrative data. This use of population-based data

5 922 MYERS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 8 Table 3. Predictors of In-Hospital Mortality in Patients With Acetaminophen Overdose Outcome In-hospital mortality, %(n) RR (95% CI) P value Age a (y) 30 (n 905) 0.4 (4) (n 491) 0.8 (4) 1.84 ( ) (n 147) 4.8 (7) ( ) Gender Male (n 489) 1.4 (7) 1.89 ( ).26 Female (n 1054) 0.8 (8) Household income b $54,180 (n 747) 1.5 (11) 3.67 ( ).03 $54,180 (n 748) 0.4 (3) Unintentional overdose Yes (n 205) 4.9 (10) 13.1 ( ).0005 No (n 1338) 0.4 (5) Alcohol abuse Yes (n 525) 1.7 (9) 2.91 ( ).05 No (n 1018) 0.6 (6) Liver disease Yes (n 46) 15.2 (7) ( ).0005 No (n 1497) 0.5 (8) Cirrhosis Yes (n 11) 54.6 (6) ( ).0005 No (n 1532) 4.8 (73) No. of comorbidities c 2 (n 423) 3.1 (13) 17.2 ( ) (n 1120) 0.2 (2) NAC d Yes (n 290) 1.4 (4) 6.63 ( ).07 No (n 481) 0.2 (1) Acetaminophen hepatotoxicity Yes (n 70) 14.3 (10) 42.1 ( ).0005 No (n 1473) 0.3 (5) a Reference group for RR, 30 y. b Available in 1495/1543 patients (97%). c No. of Elixhauser comorbidities excluding alcohol abuse and liver disease. 28 d Available in patients hospitalized between 1998 and 2002 (n 771). from a large geographic region effectively eliminates the selection and referral bias inherent in studies originating in referral centers. Thus, our data likely provide a more accurate view of the spectrum of acetaminophen overdose in the general population. Reassuringly, acetaminophen-related hepatotoxicity was uncommon (4.5%), despite a low rate of NAC treatment (38%). The latter supports the relatively benign nature of most acetaminophen overdoses, which appear more likely to be hospitalized for psychiatric treatment rather than liver injury. Nevertheless, the clinical impact in patients who developed hepatotoxicity was substantial. These patients were 2.5 times as likely to be admitted to an intensive care unit and more than 40 times more likely to die in hospital than those without liver injury (14% vs 0.3%). Moreover, after adjustment for case-mix, LOS increased over 50% and hospital costs doubled in patients with hepatotoxicity (data not shown). The short-term outcomes observed in our cohort are in keeping with data from 2 recent population-based studies with similar methodology. 3,4 In a Food and Drug Administration analysis of U.S. data from the National Hospital Discharge Survey, Nourjah et al 3 reported hepatotoxicity in 2.1% and in-hospital mortality in less than 1% of 26,256 patients hospitalized between 1990 and In another Canadian analysis, Prior et al 4 reported acute liver injury in 2.2% of patients. In a multicenter Canadian registry with clinical data, Sivilotti et al 36 reported hepatotoxicity (defined as aminotransferases 1000 IU/L) in 7.4% of 1270 hospitalized patients. In the U.S. national multicenter NAC study ( ), 14 death was reported in approximately 0.4% of patients, with similar rates overall and in those who received NAC. These figures compare favorably with the 1% rate of in-hospital mortality observed in our study. Our data shed light on previously disputed risk factors for adverse outcomes in acetaminophen overdose, namely unintentional ingestions, underlying liver disease, and alcohol abuse. All of these factors were significant predictors of hepatotoxicity. With respect to the circumstance of the overdose, patients with unintentional ingestions had a 5-fold risk of hepatotoxicity (17%) and 13-fold risk of in-hospital mortality (5%). Such overdoses, often referred to as therapeutic misadventures, 9,10 occurred in only 13% of our study population but represented 49% of hepatotoxicity cases. These findings are in keeping with data from other series. 7,8 In a study of 71 patients hospitalized in Dallas for acetaminophen overdose, Schiödt et al 7 reported higher rates of liver (and renal) injury, hepatic coma (33% vs 6%), and death (19% vs 2%) in those with accidental versus intentional ingestions. Similarly, Gyamlani and Parikh 8 reported an increased risk of hepatic coma and death and greater Table 4. Underlying Causes of Death in Patients With Acetaminophen Overdose (n 73) a Cause % (n) Drug overdose 23 (17) Undetermined intent 15 (11) Accidental 8 (6) Suicide 14 (10) Intentional drug overdose 8 (6) Hanging, strangulation, or suffocation 6 (4) Cardiovascular disease 12 (9) Trauma 10 (7) Injury 8 (6) Homicide 1 (1) Alcohol-related disorders 8 (6) Malignancy b 4 (3) Chronic obstructive pulmonary disease 4 (3) Gastrointestinal c 4 (3) Endocrine/metabolic d 3 (2) Cerebrovascular disease 3% (2) Other e 15% (11) a Cause of death available in 92% (73/79) of dying patients. b Malignancies included carcinoma of the colon (n 1), breast (n 1), and retroperitoneum (n 1). c Gastrointestinal causes included peptic ulcer disease (n 1), vascular disorder of the intestine (n 1), and esophageal stricture (n 1). d Endocrine/metabolic causes included diabetes mellitus (n 1) and obesity (n 1). e Other causes included seizures (n 2); and dementia, drug abuse, human immunodeficiency virus, urinary tract infection, pulmonary embolism, pleural effusion, varicose veins, unknown postoperative complication, and spina bifida (n 1 each).

6 August 2008 OUTCOMES OF ACETAMINOPHEN OVERDOSE 923 Table 5. Predictors of Mortality During Extended Follow-Up (Median 5.2 Years) in Patients With Acetaminophen Overdose a Characteristic Univariate hazard ratio (95% CI) Multivariate hazard ratio (95% CI) Figure 1. Kaplan Meier survival curve of patients hospitalized for acetaminophen overdose, stratified according to the development of hepatotoxicity (log-rank, P.0005). hospital costs associated with accidental overdoses. Several hypotheses have been proposed to explain these findings including the ingestion of larger amounts of acetaminophen during a prolonged period, late presentation to hospital, delayed and/or failed receipt of NAC, and higher rates of alcohol-related disorders. 2,7,8,11,37 Our findings of similar rates of alcohol disorders and NAC treatment in patients with unintentional overdoses argue against the latter hypotheses. Moreover, the impact of overdose intent on hepatotoxicity was independent of NAC treatment in our multivariate analysis. In the absence of detailed clinical data, we cannot address all of these issues by using administrative data. The higher rates of morbidity and mortality that we observed in the setting of unintentional overdoses are important because emerging data suggest that these cases are on the rise. 38 The U.S. ALF Study Group has reported that 50% of ALF cases caused by acetaminophen are unintentional in nature. 1 On the basis of these data, 500 ALF cases and 150 deaths attributable to unintentional overdoses are estimated to occur annually in the U.S. 39 Corresponding data from our health region revealed a 51% decline in hospitalization rates for intentional overdose but a 24% increase in unintentional overdoses between 1995 and These observations are of substantial public health importance, considering the poor outcomes of unintentional cases. Currently more than 100 products containing sometimes Figure 2. Kaplan Meier curve of postdischarge survival in patients hospitalized for acetaminophen overdose, stratified according to the circumstance of the overdose (log-rank, P.0005). Age 1.07 ( ) 1.05 ( ) Male sex 1.95 ( ) 1.65 ( ) Income b 0.67 ( ) 0.75 ( ) Alcohol abuse 1.74 ( ) 0.92 ( ) Liver disease 8.02 ( ) 1.84 ( ) No. of comorbidities c 1.89 ( ) 1.21 ( ) Acetaminophen hepatotoxicity 6.58 ( ) 2.97 ( ) a Mortality analysis includes in-hospital deaths. b Per quartile of median household income. c No. of Elixhauser comorbidities excluding alcohol abuse and liver disease. large amounts of acetaminophen are available over-the-counter, and many patients (and physicians) are unaware of their acetaminophen content. 39 Our data emphasize the necessity of educational initiatives regarding the toxicity of acetaminophen and clear labeling of medications with their acetaminophen content to minimize accidental cases. Despite minimal supportive data, many clinicians recommend reduced acetaminophen dosages in patients with established liver disease. 39 In support of this approach, we observed higher rates of hepatotoxicity and in-hospital mortality in patients with preexisting liver disease, regardless of suicidal intent. However, this finding needs to be interpreted cautiously, considering the high rate of hepatotoxicity (33%) observed in these patients. This finding might relate to our definition of hepatotoxicity, which included diagnostic codes for hepatic necrosis, toxic hepatitis, and hepatic encephalopathy. Although we attempted to minimize misclassification of patients with chronic liver disease as having acute druginduced hepatotoxicity by eliminating diagnostic codes that overlapped between the hepatotoxicity and comorbidity algorithms, we cannot exclude this possibility. Such differential misclassification would tend to exaggerate the association between preexisting liver disease and hepatotoxicity. A related and controversial issue is the association between alcohol abuse and acetaminophen hepatotoxicity. 1,12,15,16 Product labels and most physicians suggest reduced dosages of acetaminophen in alcohol abusers. 33 In our study, alcohol abuse was associated with a doubling of the odds of hepatotoxicity independent of suicidal intent. Reconciling these findings with the literature is difficult. In a prospective trial assessing the safety of acetaminophen in alcoholics, 40 repeated administration of the maximum recommended daily doses to patients entering an alcohol detoxification center was not associated with hepatic injury. In another study of nearly 12,000 acetaminophen overdoses, hepatotoxicity was increased only in alcoholics with acetaminophen levels above the 300 mg/l study line (typically only seen in intentional cases). 41 On the basis of the available data, one expert has concluded that chronic alcoholics are at greater risk than non-heavy drinkers after overdose of acetaminophen, but that there is no change in risk in either group when therapeutic doses are consumed. 33 Our epidemiologic data suggest that this risk extends to both situations.

7 924 MYERS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 8 One strength of our study is the examination of all-cause mortality during extended follow-up in patients hospitalized for acetaminophen overdose. As reported in other studies of patients attempting self-harm, we observed a substantial risk of mortality (5% during a median of 5 years) in a very young cohort (median age, 26 years). Of major concern is that approximately half of these deaths were due to preventable conditions including suicide, substance abuse disorders, and trauma. As previously reported, independent risk factors for mortality included male sex, older age, low income, and comorbid conditions (including cirrhosis, but not alcohol abuse) As illustrated in Figure 1, patients with acute hepatotoxicity had significant mortality during the index admission but a survival curve that paralleled that of patients without hepatotoxicity during extended follow-up. These findings highlight the necessity of preventive and intervention strategies initiated during the index hospitalization, in addition to the routine short-term management of acetaminophen overdose. Substance abuse counseling, medical management of comorbid conditions, and maximization of social assistance seem like logical starting points on the basis of the risk factors that we have identified. Our study has several limitations. Most importantly, the accuracy of administrative data for acetaminophen overdose, overdose intent, liver disease, and alcohol abuse must be considered. As previously discussed, our algorithms for acetaminophen overdose, hepatotoxicity, and intentional ingestions were highly accurate in a local validation study. 22 Similar accuracy has been reported for the external causes of injury codes (E codes) used to define suicidal intent in other studies. 45,46 For example, LeMier et al 45 reported 95% agreement between E codes obtained from administrative data and medical record review for defining suicidal intent in a variety of injuries including poisonings, falls, and firearm incidents. For poisonings specifically, agreement was 87%. In another study of adult subscribers to a health maintenance organization in California, medical record reviews confirmed that 86% of hospitalizations assigned intentional E codes were suicide attempts. 46 Although the differences in long-term survival (Figure 2) and causes of death between patients with intentional and unintentional overdoses support our definitions of overdose intent, our results must be validated externally before they can be considered definitive. For example, we suspect that some intentional overdoses were misclassified as unintentional because approximately 12% of the latter patients were assigned psychiatric conditions as their primary diagnosis (vs 40% in the intentional group; data not shown). Administrative data might be even less accurate for identifying liver disease and alcohol abuse. In a validation study of more than 4000 medical records in our region, the specificity for these conditions exceeded 99%, but the sensitivities were only 40% 50% (H. Quan, personal communication, May 2007). Thus, although medical record coders might miss these diagnoses, they are unlikely to record them if they are not present. Inclusion of clinical data would permit validation of these diagnoses and permit us to examine the prognostic significance of clinical variables (eg, amount of acetaminophen ingested, time to NAC treatment, grade of hepatic encephalopathy) and laboratory data (eg, serum creatinine, international normalized ratio, ph) but add substantial time and expense. A detailed review of more than 1500 medical records would cost in excess of $25,000; we obtained this administrative data at no cost. Another limitation of our study is the reliance on discharge data to identify only hospitalized cases. Clearly this strategy will overestimate the clinical severity of acetaminophen overdose because patients with minor overdoses (eg, those not seeking attention or being hospitalized) would not have been captured. 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