Study setting and design
The data of patients who presented to two emergency medical centers in Seoul and Suwon, the Republic of Korea, between January 1, 2010, and December 31, 2017, were retrieved from the toxicology registers of the centers. The emergency centers were in urban academic hospitals that managed > 60,000 patients annually. The data were recorded by the chief emergency physician on duty using a digitally standardized form on patient presentation.
The inclusion criteria were single acute APAP overdose, emergency department (ED) visitation within 15 h after the overdose, and age ≥ 14 years. The exclusion criteria were staggered ingestion over 1 h, ingestion of extended-release tablets, and unavailability of data on recorded body weight, the ingested dose, or APAP concentration.
The data collected included patient demographics (e.g., age, sex, and weight), the reported ingested dose of APAP and time of ingestion, time of presentation to the ED, intentionality, composition of APAP, co-ingested substances, underlying hepatic disease, alcohol consumption, drug history, treatment methods (e.g., gastric lavage, activated charcoal (AC), and N-acetylcysteine (NAC)), laboratory test results, serum APAP concentration at time, and clinical outcome.
The highest dose of ingested APAP, as estimated from information provided by the patient, his/her guardians, and the emergency services, was used as the ingested dose, and the longest time from ingestion to presentation was also judged as the elapsed time. Staggered ingestion was defined as multiple APAP doses (including supratherapeutic doses) over a > 1 h period, and acute starvation was defined as a state of having suffered a debilitating problem such as receiving treatment for an eating disorder. Co-ingested substances were recorded if they were noted by the patient, identified through the remaining medicines, hospital prescriptions, or by contacting other hospitals. Chronic alcohol consumption was defined as the ingestion of > 14 standard alcohol doses per week, and acute liver injury was defined as alanine aminotransferase (ALT) elevation ≥50% during treatment; hepatotoxicity was defined as ALT elevation > 1000 IU/L. The time for APAP concentration was recorded in minutes from the sampling time in the test result report. If a test was performed before 240 min (4 h) from the overdose onset, assuming the margin of error to be 5%, tests within 12 min were regarded as being performed at 240 min, and tests outside this range were not accepted, and in this case, the next test was regarded as the first test.
Two investigators separately reviewed the registry, and a third investigator independently checked the data and corrected mismatched variables. All three investigators were medical personnel in the ED.
Antidote therapy consisting of intravenous (IV) NAC infusion for 21 h was initiated when the estimated dose of APAP exceeded 200 mg/kg/24 h or ≥ 10 g in total, the ingestion was staggered, or the ingestion time was uncertain. The 21-h IV NAC protocol required IV loading of 150 mg/kg for 15 min, 45 min later, IV infusion of 50 mg/kg for 4 h and 100 mg/kg for 16 h. Blood samples for the first serum APAP concentration were obtained at least 4 h after ingestion, and subsequent tests were performed every 4 h. The participating emergency medical centers lacked laboratory facilities for timely reporting of serum APAP concentrations. Therefore, sample analysis was outsourced to professional clinical laboratory agencies (Seoul Clinical Laboratories, Yongin, Republic of Korea and Samkwang Medical Laboratories, Seoul, Republic of Korea), with the test results confirmed later. The diagnostic systems used by these agencies were the Cobas® 8000 and Cobas® Integra 400 plus (Roche Diagnostics, Mannheim, Germany), respectively.
Continuous variables were reported as means if they followed a normal distribution or medians if they did not. Categorical variables were reported as proportions. The concentration ratio (the first concentration divided by the nomogram concentration at the same time in minutes) was calculated to determine concentrations above the 100-treatment line. The χ2 and Mann–Whitney U tests were used to compare the proportion and distribution of variables between the APAP concentration above-line and under-line groups.
To determine the effect of the ingested dose per weight on APAP serum concentration, a simple linear regression was performed. Using multiple linear regression, variables with variance inflation factor (VIF) greater than 4.0 were excluded from subsequent regression. The correlation between the risk factors used to indicate the need for NAC treatment before the guideline was revised and concentrations above the 100-treatment line were evaluated using univariate and multivariate logistic regression. The odds ratios (OR) and 95% confidence interval (CI) were estimated.
Three subgroups were created based on the reported dose per body weight: the ≤75 mg/kg, 75–200 mg/kg, and > 200 mg/kg ingestion groups, and the occurrence rate of concentration above 100-line and laboratory abnormality of the subgroups were investigated. The area under the receiver operating characteristic curve (AUC) of poisoning dose per body weight for predicting the concentration above the 100-treatment line was calculated. (SPSS version 22.0 software, IBM Corp., Armonk, NY, USA).