Journal of The Korean Society of Clinical Toxicology

Original Article

Predicting serum acetaminophen concentrations in acute poisoning for safe termination of N-acetylcysteine in a resource-limited environment: Dahae Kim, Kyungman Cha, Byung Hak So; J Korean Soc Clin Toxicol. 2023;21(2):128-134. Published online December 29, 2023; DOI: https://doi.org/10.22537/jksct.2023.00013

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Abstract PDF: Purpose: The Prescott nomogram has been utilized to forecast hepatotoxicity from acute acetaminophen poisoning. In developing countries, emergency medical centers lack the resources to report acetaminophen concentrations; thus, the commencement and cessation of treatment are based on the reported dose. This study investigated risk factors that can predict acetaminophen detection after 15 hours for safe treatment termination.
Methods
Data were collected from an urban emergency medical center from 2010 to 2020. The study included patients ≥14 years of age with acute acetaminophen poisoning within 15 hours. The correlation between risk factors and detection of acetaminophen 15 hours after ingestion was evaluated using logistic regression, and the area under the curve (AUC) was calculated.
Results
In total, 181 patients were included in the primary analysis; the median dose was 150.9 mg/kg and 35 patients (19.3%) had acetaminophen detected 15 hours after ingestion. The dose per weight and the time to visit were significant predictors for acetaminophen detection after 15 hours (odds ratio, 1.020 and 1.030, respectively). The AUCs were 0.628 for a 135 mg/kg cut-off value and 0.658 for a cut-off 450 minutes, and that of the combined model was 0.714 (sensitivity: 45.7%, specificity: 91.8%).
Conclusion
Where acetaminophen concentrations are not reported during treatment following the UK guidelines, it is safe to start N-acetylcysteine immediately for patients who are ≥14 years old, visit within 15 hours after acute poisoning, and report having ingested ≥135 mg/kg. Additional N-acetylcysteine doses should be considered for patients visiting after 8 hours.

Up-to-date treatment of acetaminophen poisoning: Phil Chung Sung, Moon Jeongmi, Chun Byeongjo; J Korean Soc Clin Toxicol. 2022;20(2):39-44. Published online December 31, 2022; DOI: https://doi.org/10.22537/jksct.2022.20.2.39

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Abstract PDF: N-Acetylcysteine (NAC) is the standard antidote treatment for preventing hepatotoxicity caused by acetaminophen (AAP) poisoning. This review summarizes the recent evidence for the treatment of AAP poisoning. Several alternative intravenous regimens of NAC have been suggested to improve patient safety by reducing adverse drug reactions and medication errors. A two-bag NAC infusion regimen (200 mg/kg over 4 h, followed by 100 mg/kg over 16 h) is reported to have similar efficacy with significantly reduced adverse reactions compared to the traditional 3-bag regimen. Massive AAP poisoning due to high concentrations (more than 300-lines in the nomogram) needs to be managed with an increased maintenance dose of NAC. In addition to NAC, the combination therapy of hemodialysis and fomepizole is advocated for severe AAP poisoning cases. In the case of a patient presenting with an altered mental status, metabolic acidosis, elevated lactate, and an AAP concentration greater than 900 mg/L, hemodialysis is recommended even if NAC is used. Fomepizole decreases the generation of toxic metabolites by inhibiting CYP2E1 and may be considered an off-label use by experienced clinicians. Since the nomogram cannot be applied to sustained-release AAP formulations, all potentially toxic sustained-release AAP overdoses should receive a full course of NAC regimen. In case of ingesting less than the toxic dose, the AAP concentration is tested twice at an interval of 4 h or more; NAC should be administered if either value is above the 150-line of the nomogram.

Effects of N-acetylcystein on changes in parvalbumin-positive interneurons in the hippocampus after carbon monoxide poisoning: Seon Tae Kim, Su Jin Yoo; J Korean Soc Clin Toxicol. 2021;19(2):100-109. Published online December 31, 2021; DOI: https://doi.org/10.22537/jksct.2021.19.2.100

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Abstract PDF

Purpose: The purpose of this study was to investigate effect of N-acetylcysteine (NAC) on the injury of putative parvalbumin positive interneurons defined by molecular marker and hippocampal long-term potentiation (LTP), a marker of neural plasticity following acute carbon monoxide (CO) poisoning. Methods: Adult Sprague-Dawley rats were exposed to 1100 ppm CO for 40 minutes followed by 3000 ppm CO for 20 minutes. Animals received daily intraperitoneal injection of NAC (150 mg/kg) for 5 days after CO exposure. Changes in learning and spatial memory were evaluated by Y-maze test 5 days after the poisoning. In vivo LTP in hippocampal CA1 area was evaluated by using extracellular electrophysiological technique. Immunohistochemical staining were adopted to observe expressional damages of parvalbumin (PV) immunoreactive interneurons in the hippocampus following the poisoning. Results: Acute CO intoxication resulted in no changes in memory performance at Y-maze test but a significant reduction of LTP in the in hippocampal CA1 area. There was also a significant reduction of PV (+) interneurons in the hippocampal CA1 area 5 days after CO poisoning. Daily treatment of NAC significantly improved hippocampal LTP impairment and reduced immunoreactivity for PV in the hippocampus following the acute CO poisoning. Conclusion: The results of this study suggest that reduction of hippocampal LTP and PV (+) interneurons in the hippocampus is sensitive indicator for brain injury and daily NAC injections can be the alternative therapeutics for the injury induced by acute CO poisoning.

Citations

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In vitro recording and stimulation performance of multi-electrode arrays passivated with plasma-enhanced atomic layer-deposited metal oxides
Yong Hee Kim, Jaehee Lee, Jung Wook Lim, Kukjoo Kim, Dae Hyun Ahn, Congqi Yang, Seongjun Park, Min Sun Kim, Sang-Don Jung
Nanoscale.2025; 17(14): 8731. CrossRef

Factors of Determining N-acetylcysteine Administration in Patients with Acute Acetaminophen Poisoning: Jeong Hwa Lee, Sangchun Choi, Sang Kyu Yoon, Kyu Cheol Shin; J Korean Soc Clin Toxicol. 2020;18(2):78-84. Published online December 31, 2020; DOI: https://doi.org/10.22537/jksct.2020.18.2.78

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Abstract PDF: Purpose: In acute acetaminophen poisoning, the administration of N-acetylcysteine (NAC) can effectively treat the main complications, such as kidney injury and liver failure. In the current situation, measurements of the acetaminophen concentration are not checked in the usual medical facilities. Therefore, this study examined the factors of determining the administration of NAC in addition to the stated amount of intake. Methods: The medical records of patients who visited Ajou University Hospital emergency center with acetaminophen poisoning from January 2015 to December 2019 were reviewed retrospectively. One hundred and seventy-nine patients were initially included. Among these patients, 82 patients were finally selected according to the inclusion criteria in the study. The inclusion criteria were as follows: patients who were 15 years of age or older; those whose ingested dose, ingested time, and body weight were clearly identified; and patients whose acetaminophen sampling time was within 24 hours. Patients were divided into two groups: NAC administered vs. non-NAC administered. The following variables were compared in these two groups: ingested dose, ingested dose per body weight, hospital arrival time after ingestion, suicide attempt history, psychiatric disease history, classification of toxic/non-toxic groups, duration of hospitalization, and laboratory results. Results: Univariate analysis revealed the ingested dose per body weight, hospital arrival time after ingestion, suicide attempt history, and psychiatric disease history to be the determining factors in administering NAC. Logistic regression analysis confirmed that the ingested dose per body weight was the only significant factor leading to an NAC treatment decision. (Odds ratio=1.039, 95% Confidential interval=1.009-1.070, p=0.009) Conclusion: The ingested dose per body weight was the only determining factor for administering NAC in patients with acute acetaminophen poisoning. On the other hand, additional criteria or indicators for the NAC administration decision will be necessary considering the inaccuracy of the ingested dose per body weight and the efficiency of NAC administration.

Evaluation of Cut-off Values in Acute Acetaminophen Intoxication Following the Revised Guideline of the United Kingdom: Sung Jin Park, Kyungman Cha, Byung Hak So, Hyung Min Kim, Won Jung Jeoung; J Korean Soc Clin Toxicol. 2018;16(2):68-74. Published online December 31, 2018; DOI: https://doi.org/10.22537/jksct.2018.16.2.68

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Abstract PDF: Purpose: In 2012, a revised guideline for acute acetaminophen overdose was proposed in the UK, recommending that the treatment threshold should be lowered to 100 mcg/ml at 4 hours after ingestion without risk stratification of hepatotoxicity. However, the poison centers in some developing countries do not have laboratory resources to provide serum drug levels in time. The primary aim of the study is to evaluate the cut-off value of reported dose per kilogram to determine when N-acetylcysteine treatment is warranted under the revised guideline. Methods: Data were collected retrospectively from the toxicology registry of an urban emergency medical center between 1st January 2010 and 30th June 2017. Inclusion criteria were single acute overdose of more than 75 mg/kg in 15 hours from ingestion and over 14 years of age. Subgroups were created by 25 mg/kg increments of reported dose, then sensitivity, specificity, positive predictive value and negative predictive value were calculated for the cut-off values of 100 mg/kg, 125 mg/kg, 150 mg/kg and 175 mg/kg for toxic serum level over '100-treatment line'. Results: A total of 99 patients were enrolled in the study; 24 patients showed toxic serum levels (24.2%). Zero of 17 patients with an ingestion dose under 100 mg/kg showed toxic level (0%), and 0 of 15 under 125 mg/kg (0%), 2 of 14 under 150 mg/kg (14.3%), and 4 of 12 under 175 mg/kg (33.3%) had toxic levels. The higher the ingested dose per kilogram of weight, the higher the frequency of the toxic serum concentration on the first test (${chi}^2$ test for trend, ${chi}^2=22.66$, p-value<0.001) and the sensitivity of each value was 100%, 100%, 92% and 76%. Conclusion: In acute single acetaminophen intoxication, the ingestion dose of 100 mg/kg of weight will be useful in determining the need for the N-acetylcysteine antidote in the indigent laboratory environment.

Comparison of Silymarin, Penicillin, N-acetylcysteine in Patient with Amatoxin Poisoning: A Systematic Review: Min Woo Choi, Dong Ryul Ko, Taeyoung Kong, Min Hong Choa, Je Sung You, Sung Phil Chung; J Korean Soc Clin Toxicol. 2018;16(1):33-41. Published online June 30, 2018; DOI: https://doi.org/10.22537/jksct.2018.16.1.33

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Abstract PDF: Purpose: This study was conducted to evaluate the clinical efficacy of pharmacologic treatment of amatoxin poisoning patients. Methods: Literature was accessed through PubMed, EMBASE, Cochrane library, KoreaMed, KISS and KMBASE. Studies relevant to human use of pharmacologic therapy including silymarin, penicillin and N-acetylcysteine (NAC) for amanita poisoning were included. Case reports, letters, editorials and papers with insufficient information were excluded. Comparison of clinical outcomes (especially mortality and liver transplantation rate) in each study was analyzed. Results: The final analysis included 13 retrospective studies. None of these studies showed direct comparisons of individual agents. Among 12 studies comparing silymarin vs penicillin, eight showed clinical superiority of silymarin. Among eight studies comparing silymarin with NAC, six showed clinical superiority of silymarin. Among seven studies of NAC vs penicillin, five showed clinical superiority of NAC. Conclusion: This systematic review suggested that clinical superiority of various pharmacological agents used to treat amatoxin poisoning is debatable. Nevertheless, the available evidence suggests it is reasonable to consider combinations of multiple agents for patients with amanita poisoning. Further studies are required to establish a treatment regimen for amanita poisoning.

Is it Adequate to Determine Acetaminophen Toxicity Solely on Patients' History? An Analysis on Clinical Manifestation of Intoxication Patients with Positive Serum Acetaminophen Concentrations: Jee Hyun Kim, Won-joon Jeong, Seung Ryu, Yong Chul Cho, Jang Hyuck Moon, Hyun Soo Choi, Song Hee Yang, Hee Sun Chung; J Korean Soc Clin Toxicol. 2017;15(2):94-100. Published online December 31, 2017; DOI: https://doi.org/10.22537/jksct.2017.15.2.94

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Abstract PDF: Purpose: Acute acetaminophen intoxication is a common occurrence that can cause lethal complications. In most domestic emergency departments, clinicians tend to treat acetaminophen intoxication based on patients' history alone, simply due to the lack of a rapid acetaminophen laboratory test. We performed a 20-month study of intoxication patients to determine the correlation between the history of patients and serum laboratory tests for acetaminophen. Methods: We took blood samples from 280 intoxication patients to evaluate whether laboratory findings detected traces of acetaminophen in the sample. Patients were then treated according to their history. Laboratory results came out after patients' discharge. Agreement between patients' history and laboratory results were analyzed. Results: Among the 280 intoxicated patients enrolled, 38 patients had positive serum acetaminophen concentrations; 18 out of 38 patients did not represent a history suggesting acetaminophen intoxication. One patient without the history showed toxic serum acetaminophen concentration. Among the patients with the history, two patients with toxic serum acetaminophen concentration did not receive N-acetylcysteine (NAC) treatment due to their low reported doses, while other 2 patients without significant serum acetaminophen concentration did receive NAC treatment due to their high reported doses. Conclusion: This study showed a good overall agreement between history and laboratory test results. However, some cases showed inconsistencies between their history and laboratory test results. Therefore, in treating intoxication patients, a laboratory test of acetaminophen with rapid results should be available in most domestic emergency departments.

Low-dose Intravenous N-acetylcysteine for the Prevention of Contrast-Induced Nephropathy in Emergency Patients Undergoing Computed Tomography: Tae Wan Lee, Ji-Hoon Kim, Seung Pil Choi; J Korean Soc Clin Toxicol. 2017;15(2):122-130. Published online December 31, 2017; DOI: https://doi.org/10.22537/jksct.2017.15.2.122

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Abstract PDF: Purpose: To evaluate the effects of low-dose intravenous N-acetylcysteine on the prevention of contrast-induced nephropathy (CIN) in patients undergoing computed tomography (CT). Methods: All patients presenting to our emergency department and undergoing CT with intravenous contrast media between August 2014 and April 2016 were retrospectively enrolled. We included hospitalized patients with renal dysfunction [estimated glomerular filtration rate (GFR) between 30 and $89mL/min/1.73m^2$]. A 600-mg injection of N-acetylcysteine was given to patients once before and once immediately after CT, depending on the preference of physician. The primary outcome was CIN defined as an increase in creatinine level of ${geq}25%$ or ${geq}0.5mg/dL$ from the baseline within 48 to 72 hours after CT. A trained person blindly reviewed all medical records. Results: Of the 1903 admitted patients, CIN occurred in 9.8% of patients who received 1200 mg intravenous N-acetylcysteine (24/244) and 6.8% of patients who did not (113/1659, p=0.090). In a multivariable regression analysis, N-acetylcystine was not relevant to the prevention of CIN (odds ratio=1.42 [95% CI, 0.90-2.26]). Even in the stratified analysis using the propensity score matching, N-acetylcysteine was irrelevant (GFR 30-59: odds ratio=1.06 [95% CI, 0.43-2.60]; GFR 60-89: odds ratio=1.76 [95% CI, 0.75-4.14]). After adjustment, crystalloids were significantly associated with the reduction in CIN compared with dextrose water (odds ratio=0.60 [95% CI, 0.37-0.97]). Conclusion: No effect was found when low-dose intravenous N-acetylcysteine was used to prevent CIN. However, there seems to be an association between crystalloids and reduction in CIN.

The Experiences of the Emergency Antidote Stock and Delivery Service by the Korean Poison Information Center: So Young Park, Bum Jin Oh, Chang Hwan Sohn, Ru Bi Jeong, Kyoung Soo Lim, Won Kim, Seung Mok Ryoo; J Korean Soc Clin Toxicol. 2013;11(1):9-18. Published online June 30, 2013

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Abstract PDF: Purpose: Antidotes for toxicological emergencies can be life-saving. However, there is no nationwide stocking and delivery system for emergency antidotes in Korea. We report on a two-year experience of a nationwide stocking and delivery trial for emergency antidotes at emergency departments in Korea. Methods: An expert panel of clinical toxicologists reviewed and made a list of 15 stocked antidote. These antidotes were purchased or imported from other countries and delivered from 14 antidote stocking hospitals nationwide 24 hours per day, seven days per week. Results: From August 1, 2011 to April 30, 2013, 177 patients with acute poisoning, with a median age of 48.5 years, were administered emergency antidotes. The causes of poisoning were intentional in 52.0% and 88.0% were intentional as a suicide attempt. Regarding clinical severity, using the poisoning severity score, 40.7% of patients had severe to fatal poisoning and 39.0% had moderate poisoning according to clinical severity. The most frequent presenting symptom was neurologic deficit, such as altered mentality (62.7%). alerted mentality (62.7%). Emergency antidotes were administered as follows: methylene blue (49 cases), flumazenil (31), N-acetylcysteine (25), glucagon (17), 100% ethanol (15), cyanide antidote kit (12), anti-venin immunoglobulin (5), pyridoxine (4), hydroxocobalamine (2), and deferoxamine (1). The median time interval from antidote request to delivery at the patient's bedside was 95 minutes (interquartile range 58.8-125.8). Conclusion: Findings of this study demonstrated the possibility of successful operation of the nationwide system of emergency antidotes stocking and delivery in Korea.

Oral vs. Intravenous Administration of N-acetylcysteine in the Acetaminophen Poisoning: Hyo Ju Chae, Nu Ga Rhee, Hyun Jong Kim, Je Sung You, Sung Phil Chung, Hahn Shick Lee; J Korean Soc Clin Toxicol. 2012;10(2):97-102. Published online December 31, 2012

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Abstract PDF: Purpose: Serious acetaminophen (AAP) poisoning causes hepatotoxicity. N-acetylcysteine (NAC) is the most effective therapy for AAP poisoning and can be administered orally and intravenously (IV). Several studies have compared the efficacy of these two routes of administration and the results have been controversial. The purpose of this study was to compare the efficacy of oral and IV NAC for the prevention of hepatic toxicity in Korean patients whose serum AAP levels were higher than normal. Methods: A retrospective before/after study was performed, in which the patients presented to the emergency department with an AAP overdose from February 1995 to March 2012. A 3-day oral NAC regimen was used in the beginning, and a 20-hr intravenous regimen was then used from 2007. This study assessed the complications of an AAP overdose, such as hepatotoxicity, hepatic failure and renal failure as well as the side effects of the treatment regimen. Results: A total of 41patients was enrolled in this study. The median ALT and AST were 63 (IU/L) and 57 (IU/L) for the oral NAC treated patients, and 14 (IU/L) and 20 (IU/L) for the IV NAC treated patients (p=0.004 and p=0.001, respectively). The incidence of complications was similar in the treatment groups (p=0.399). Among the patients, 7 patients developed hepatotoxicity and were treated successfully with oral or IV NAC. Conclusion: This study suggests that IV NAC and oral NAC can prevent and successfully treat hepatic toxicity in patients whose serum AAP levels are higher than normal.

Acetaminophen Poisoning: Sung-Pil Chung, Seung-Ho Kim, Hahn-Shick Lee; J Korean Soc Clin Toxicol. 2008;6(1):1-8. Published online June 30, 2008

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Abstract PDF: Acetaminophen (AAP) overdose can result in potentially serious hepatotoxicity. The ingested dose and time from ingestion to presentation are important prognostic factors. Toxic dose in adult is thought to be at least 10 g or 200 mg/kg. However, early management of acute overdose should be guided by the plasma AAP concentration. The antidote for AAP poisoning is N-acetylcysteine (NAC). It provides complete protection against hepatotoxicity if given within 8 h of acute overdose. If the concentration is above the possible toxicity line as predicted by the Rumack-Matthew nomogram, either the 72-hr oral or the 20-hr intravenous NAC regimen should be administered. NAC is also effective if started late in patients with established hepatic failure. This article summarizes the current consensus of clinical assessment and management for acute AAP overdose.

Is N-acetylcysteine Treatment Based on Ingestion Amount Valid in Acute Acetaminophen Overdose Patients?: Tae-Geun Kim, Min-Joung Kim, Jin-Hee Lee, Sung-Pil Chung, Hahn-Shick Lee, Yoo-Seok Park; J Korean Soc Clin Toxicol. 2006;4(2):107-112. Published online December 31, 2006

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Abstract PDF: Purpose: In many Korean hospitals, serum acetaminophen concentrations in cases of overdose cannot be measured initially because of inadequate laboratory facilities. Under these circumstances, physicians base the administration of the antidote, N-acetylcysteine, on ingestion amounts as determined by initial history taking. We therefore examined the correlated between ingested amounts and serum acetaminophen concentrations. Methods: Medical records were reviewed retrospectively for patients who presented to the ED with acetaminophen overdose between January 2002 and March 2006. Fifty-nine patients were recruited and sixteen patients were excluded. The forty-three remaining patients were placed into either the high-risk or low-risk group based on their ingested amount (140 mg/kg), and were separately categorized into the toxic or non-toxic group based on their serum acetaminophen concentrations, according to the Rurnack-Matthew nomogram. Results: Ten patients (83.3%) among twelve in the high-risk group were found to have non-toxic serum concentrations, and just one patient (3.2%) among thirty-one in the low-risk group fell into the toxic group based on their serum concentrations. The sensitivity and specificity of risk stratification of the ingested amount as a predictor of intoxication requiring antidote therapy were 66.7% and 75.0%, respectively. Conclusion: This study suggests that the therapeutic decision for acetaminophen overdose should not be based solely on ingested amount only, but requires assessment of acetaminophen concentration.

A Fatal Case of Methylene Blue Threatment Failure in Methemoglobinemia: Ji-Yae Shim, Yun-Seok Seo, Jong-Oh Yang, Eun-Young Lee, Sae-Yong Hong, Hyo-Wook Gil; J Korean Soc Clin Toxicol. 2006;4(2):151-154. Published online December 31, 2006

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Abstract PDF: Acute toxic methemoglobinemia is an infrequent complication of the use of various drugs. Severe methemoglobinemia is very often fatal. Methylene blue is an effective drug in the treatment of methemoglobinemia patients. However, failure to respond to methylene blue has been described in patients with sulfhemoglobinemia, chlorate poisoning, and glucose-6-phosphate dehydrogenase deficiency. It is even possible that hemolysis may occur due to methylene blue treatment itself. We encountered a case of a 71-year-old woman who developed methemoglobinemia caused by alprazolam intoxication. She presented with hemolytic anemia and did not respond to methylene blue. In spite of concerted N-acetylcysteine therapy, the hemolytic anemia became aggravated and the patient died eleven days after intoxication.

A Case of Acute Dapsone Poisoning Complicated with Methylene Blue-induced Hemolytic Anemia: Mi-Jin Lee, Kyu-Nam Park; J Korean Soc Clin Toxicol. 2006;4(2):170-174. Published online December 31, 2006

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Abstract PDF: Methylene blue is a basic thiazine dye frequently used for histologic staining. In clinical toxicology settings, it is also used to treat clinically significant methemoglobinemia. It has dose-dependent oxidation or reduction properties, acting as a reducing agent at lower doses and as an oxidizing agent at higher doses. Hemolytic anemia and hyperbilirubinemia are known toxic effects of methylene blue treatment that have been reported clinically. A 42-year-old woman developed significant methemoglobinemia after acute dapsone overdose; she was treated appropriately with intravenous methylene blue in the therapeutic range. The patient's methemoglobin levels returned to normal. However, 2-4 days later she was noted to have rebound methemoglobinemia, hemolytic anemia, and hyperbilirubinemia. A repeat of Coomb's test and other anemia workups were negative. For management of methylene blue-induced hemolytic anemia, she was administered steroid therapy, N-acetylcysteine, and a blood transfusion. She ultimately recovered, and there were no long-term sequelae from the methylene blue poisoning.

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