Original Article
`Evaluation of the children with acute acetaminophen overdose
`and intravenous N-acetylcysteine treatment
`Yakup Yesil1, Abdurrahman Avar Ozdemir2
`
`ABSTRACT
`Objective: To evaluate the demographic and clinical features associated with acetaminophen overdose
`and to identify the clinical use of IV (intravenous) N- Acetylcysteine (NAC) treatment in children.
`Methods: This prospective study was conducted in Kanuni Sultan Suleyman Training and Research Hospital
`between August 2016 and August 2017. A total of 59 patients with overdose acetaminophen ingestion were
`
`kg. Rumack-Matthew nomogram was used to evaluate the risk of acute intoxication and to determine the
`decision of using antidote.
`Results: The mean age of the patients was 8.5±6.4 y and 34 of them (58%) were female. The mean time
`from ingestion to admission was 4.3±4.7 h. The mean ingested acetaminophen dose was 142.1±80 mg/kg.
`
`dose, creatinine and INR between antidote and decontamination therapy groups at admission time (p=
`0.00, p= 0.03, p= 0.02, respectively). The complication due to antidote therapy was observed in only 1
`patient.
`Conclusions:
`generally well tolerated in children.
`
`KEY WORDS: Acetaminophen intoxication, N- acetylcysteine, Children.
`
`How to cite this:
`Yesil Y, Ozdemir AA. Evaluation of the children with acute acetaminophen overdose and intravenous N-acetylcysteine treatment. Pak
`J Med Sci. 2018;34(3):590-594. doi: https://doi.org/10.12669/pjms.343.14937
`
`This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0),
`which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
`
`doi: https://doi.org/10.12669/pjms.343.14937
`
`INTRODUCTION
`Acetaminophen is commonly used in children as
`an analgesic and antipyretic. Although its’ safety
`was well established, it is one of the common cause
`of drug poisoning. Repeated supra-therapeutic
`1.
`Yakup Yesil, MD.
`Department of Pediatrics,
`Kanuni Sultan Suleyman Training and Research Hospital,
`Medical Sciences University, Turkey.
`Abdurrahman Avar Ozdemir
`Department of Pediatrics,
`Medicine Hospital, Biruni University, Turkey.
`
`2.
`
`Correspondence:
`
`Yakup Yesil, MD.
`Department of Pediatrics, Kanuni Sultan Suleyman Training
`and Research Hospital, Medical Sciences University, Turkey.
`Atakent Mah. Turgut Ozal Cad. No: 46/1 Kucukcekmece,
`Postal Code: 34303, Istanbul, Turkey.
`E-mail: yakyes@hotmail.com
`
` * Received for Publication:
` * Accepted for Publication:
`
`February 25, 2018
`May 16, 2018
`
`dosing and intentional or unintentional overdose
`usage may result in hepatic failure.1
`Acetaminophen is metabolized by glucuronidation
`and sulfation in liver. However, approximately
`5-10% of the drug is metabolized by Cytochrome
`P450 (CYP450) to a toxic metabolite, N-acetyl-p-
`benzoquinoneimine (NAPQI). When acetaminophen
`is used at the recommended doses, NAPQI is
`eliminated by conjugation with glutathione. If it is
`used overdose, glutathione stores are depleted and the
`clearance of NAPQI is reduced. As a result, this toxic
`metabolite accumulates and causes hepatocellular
`injury.2 Management of acetaminophen overdose
`includes; gastric lavage, using of activated charcoal
`and N-Acetylcysteine (NAC) as an antidote.1-3
`The aim of this study was to evaluate demographic
`and clinical features associated with acetaminophen
`overdose as well as to identify the treatment applied
`in our Pediatric Emergency Unit.
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`METHODS
`This prospective study was conducted in Kanuni
`Sultan Suleyman Training and Research Hospital
`between August 2016 and August 2017. The
`study protocol was approved by the local ethics
`committee and informed consent was obtained for
`all children from their parents. A total of 59 patients
`who came to Pediatric Emergency Unit with
`overdose acetaminophen ingestion were included
`in this study. The exclusion criteria were refusal
`of treatment or informed consent. Age, gender,
`weight, amount of the ingested acetaminophen, co-
`ingested substances, time elapsed from ingestion,
`method of gastrointestinal decontamination, and
`antidote usage were recorded.
`Amount of ingested acetaminophen was reported
`as milligrams per kilogram and toxic dose for
`
`150 mg/kg.2 Rumack-Matthew nomogram for
`acute acetaminophen intake was used to evaluate
`the risk of acute intoxication and to determine the
`decision of using antidote (NAC).4 Decontamination
`(lavage and activated charcoal) and Intravenous
`(IV) NAC therapy was administered to patients
`who were exposed to toxic dose. Laboratory data
`included serum acetaminophen level, whole blood
`count, aspartate Aminotransferase (AST) level,
`alanine aminotransferase (ALT) level, serum urea
`level, creatinine level, Prothrombin (PT) time,
`activated Partial Thromboplastin Time (aPTT)
`and international normalized ratio (INR). Whole
`blood count was measured on the Cobas 6000 CE
`
`(Roche, Germany) and XN-10 (Sysmex, Japan) was
`used to measure ALT, AST, urea and creatinine.
`Blood samples for acetaminophen levels were
`
`and Neurology Training and Research Hospital by
`a multipoint homogeneous immunoassay on the
`Advia 1800 (Siemens, Japan).
`SPSS Statistics 20 was used for data analysis.
`Descriptive statistics were given as mean, standard
`
`2-test for
`qualitative data and Mann-Whitney U test for
`quantitative data. Correlations between quantitative
`data were analyzed by Spearman’s correlation test.
`RESULTS
`During the study period, 137 patients who
`presented for analgesics/antipyretics overdose in
`our hospital and we found that 59 (43%) of them
`ingested the drugs containing acetaminophen.
`The mean age of the patients was 8.5±6.4 y (min-
`max; 1-17) and 34 of them (58%) were female. The
`patients were divided into 2 groups according
`to age; 34 of them (52%) were in 0-8, 25 (48%) of
`them were in 8-17 years age group. There was male
`dominance (30; 88%) in 0-8 age group, whereas
`there was female dominance (21; 84%) in 8-17 age
`group. The mean weight of the patients was found
`as 32.9±22 kg (min-max; 9-80) (Table-I).
`The mean time from ingestion of the drug to
`admission was found as 4.3±4.7 h (min-max; 0.5-
`20); 50 (85%) of patients came in 8 h and all of them
`
`Table-I: Demographics and clinical characteristics of patients.
`Acetaminophen dose
`(mg/kg) (Mean±SD)
`142±80
`163 ± 89
`112.6 ± 53
`
`8.5±6.4
`34 (58%)
`25 (42%)
`
`n (%)
`
`Age (y) (Mean±SD)
`0-8
`
`Gender n (%)
`Male
`Female
`Weight (kg) (Mean±SD)
`
`>25
`Ingested Substance
`Acetaminophen only
`Acetaminophen and additional drug
`Time from ingestion to admission (Mean±SD)
`
` >8 h
`1Mann-Whitney U Test.
`
`34 (58%)
`25 (42%)
`32.9±22.9
`32 (54%)
`27 (46%)
`
`29 (49%)
`30 (51%)
`4.3±4.7
`49 (83%)
`19 (17%)
`
`164±84
`125±73
`
`165±90
`112±52
`
`174± 89
`109±53
`
`142±81
`138±75
`
`Pak J Med Sci May - June 2018 Vol. 34 No. 3 www.pjms.com.pk 591
`
`p
`
`10.06
`
`10.08
`
`10.05
`
`10.008
`
`10,9
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`Acetaminophen overdose in children
`
`came to hospital in 24 h. When the admission hours
`were analyzed; 25 of them admitted to hospital
`between 18:00-24:00, 17 of them between 12:00-
`18:00 hours, 9 of them between 00:00-06:00 hours
`and 8 of them between 06:00-12:00 o’clock. Twenty
`nine of them (49%) ingested only acetaminophen
`but others (30, 51%) ingested more than one drug.
`The mean ingested acetaminophen dose was found
`as 142.1±80 mg/kg (min-max; 24-300). There were
`
`gender, weight, admission mean time) in terms
`of ingested acetaminophen dose. However, there
`
`acetaminophen and additional drug groups. (p=
`0.008) (Table-I).
`Acetaminophen concentrations were measured
`from the 22 patients (37%) who ingested more
`than 150 mg/kg. Mean serum acetaminophen level
`was found as 14.3±23 µg/mL (min-max; 0.2-107).
`When the laboratory parameters were evaluated,
`the liver enzymes’ elevation was found in 1 patient
`and INR elevation was found in another patient.
`Also, we analyzed correlations between ingested
`acetaminophen dose and time from ingestion to
`admission, serum acetaminophen level, ALT, AST,
`
`correlation (r: 0.00; p= 0.98, r: 0.11; p= 0.6, r: 0.15; p=
`
`0.95, r: 0.076; p= 0.74, r: 0.32; p= 0.12, r: 0.13; p= 0.59,
`r: 0.18; p= 0.53, r:0.17, respectively).
`Twenty four patients (41%) received IV NAC
`therapy as well as decontamination. Patients
`receiving NAC therapy were compared with
`those receiving only decontamination therapy
`
`acetaminophen dose, creatinine and INR between
`groups at admission time (p= 0.00, p= 0.03, p= 0.02,
`respectively) (Table-II). However, there were no
`
`INR between groups at discharged time (p= 0.9, p=
`0.06, respectively). We observed urticarial reaction
`as a complication due to antidote therapy in only 1
`patient.
`Twenty two (37%) of all patients ingested the
`medicines due to suicide attempt. The mean age
`of these were found as 15.8±1 y (range 12-17) and
`17 of them (77%) were female. The number of
`patients received NAC therapy were found as 12
`(55%). Seventeen (77%) of the patients ingested
`multi drugs for suicide. All of patients who attempt
`suicide were referred to psychiatric service for
`consultation. The total number of the ingested
`additional drugs together with acetaminophen
`were 47; 14 (30%) of them were anti-gripal, 9 (19%)
`of them were gastrointestinal drugs, 7 (15%) were
`
`Table-II: Clinical and demographic characteristics of patients according to treatment methods.
`
`Decontamination
`therapy
`(Mean±SD)
`
`Decontamination
`and NAC therapy
`(Mean±SD)
`
`7.2±5.9
`
`Age (y)
`Gender n (%)
`Male
`Female
`Weight (kg)
`Substance ingested n (%)
`Acetaminophen only Additional drug
`Time from ingestion to admission (h)
`Acetaminophen dose (mg/kg)
`Acetaminophen level (µg/mL)
`Hb (gr/dL)
`ALT (UI/L)
`AST (UI/L)
`Urea (mg/dL)
`Creatinine (mg/dL)
`INR
`Total n (%)
`1 Mann-Whitney U test,
`
`15 (43%)
`20 (57%)
`27.5±20
`15 (43%)
`20 (57%)
`4.3±4.7
`106±53
`13±11
`12.5±0,9
`17.5±8.7
`23.5±9.3
`22.9±8.5
`0.43±0.16
`1.0±0.1
`35 (59%)
`2 Chi-Square Test of Independence.
`
`10±6.7
`
`10 (42%)
`14 (58%)
`39.2±25
`14 (58%)
`10 (42%)
`4.6±4.9
`191±85
`14.7±26
`12.4±1.7
`21±25.8
`21.5±9.7
`24.7±7.4
`0.55±0.2
`1.1±0.09
`24 (41%)
`
`Total
`
`8.5±6.4
`
`25 (42%)
`34 (58%)
`35.1±23
`29 (49%)
`30 (51%)
`4.4±4.8
`142±80
`14.3±23
`12.5±1.4
`19±18
`22.6±9.4
`23.7±8
`0.49±0.2
`1.1±0.1
`58 (100%)
`
`p
`
`10.07
`
`20.85
`
`10.07
`
`20.4
`
`10.8
`10.00
`10.2
`10.8
`10.9
`10.3
`10.2
`10.03
`10.02
`
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`were antibiotic, 4 (9%) were antidepressant, 2 (4%)
`were steroid, and 5 (10%) were others.
`When the signs and symptoms of the patients
`were evaluated, nausea and abdominal pain were
`determined in 38 (64%) of the patients. Other
`common symptoms were vomiting, headache
`and fatigue. One patient with neurologic disorder
`had convulsion. However, 21 (36%) of them were
`asymptomatic. Total number of patients admitted
`to inpatient service was 18 and 2 of these admitted
`to pediatric intensive care unit due to additional
`drugs. In follow up, clinical course and laboratory
`parameters of all patients were resolved. None of
`patients died.
`
`DISCUSSION
`Analgesics are the most common substance that
`causes poisoning in all ages. When the child age
`group is evaluated, analgesic intoxication is third
`after the cosmetics and cleaning substances for
`younger than 5 years old children according to the
`2014 annual report of the American Association of
`Poison Control Centers. 5 Similarly, acetaminophen
`was reported as the drug most frequently used in
`self-poisoning in UK and Spain.6,7 Unfortunately,
`national data on intoxications in Turkey is limited.
`The number of deaths in 2016 due to intoxications
`were 855; the drugs were the most frequent
`cause for intoxications and acetaminophen was
`leading agent according to the report of National
`Poison Consultation Center (UZEM) and regional
`studies.8-14
`In our study, 684 patients admitted to our
`emergency unit due to intoxication with drugs.
`Similar
`to previous studies, we
`found
`that
`analgesics/antipyretics were the most frequently
`(20%) ingested drugs and acetaminophen was
`
`of the patients was 8.5±6.4 y and it was higher
`than previous studies.10,12,13 This result may be
`associated with distribution of patients’ ages.
`Because, there were no patients between 7.5-13
`years age in our study. The number of patients
`in the 0-8 age group constituted the majority and
`there was a male predominance. However, there
`was a female predominance in 8-17 age group
`and the most frequent reason for intoxication was
`suicide attempt. Similar data were obtained from
`other studies in our country.11-14 These results may
`
`girls experience during adolescence. We found that
`the rate of multidrug ingestion was 51%. When the
`
`multidrug ingestion was evaluated, the anti-gripal
`drugs accounted for 30% of them. In previous
`studies, the ingestion of multidrug was reported as
`5-19%.12,13,15,16 However, those studies included all
`substance exposures.
`ingestion to hospital
`The mean time from
`admission was found as 4.3 h. and the ingested
`
`patients who ingested only acetaminophen. As
`expected, the ingestion of more than one agent
`reduces the proportion of acetaminophen in the
`total dose. No correlations were determined
`between laboratory parameters and ingested dose.
`This result might be related with all of patients
`admitted to hospital due to acute intoxication,
`shortened admission time and early intervention.
`Early studies showed that NAC is an effective
`therapy for acetaminophen toxicity and it initiated
`
`of hepatotoxicity and usually liver failure does
`not develop. It can be given oral or IV route and
`adverse reactions were uncommon.17,2,3 Although,
`there is no consensus on the duration of treatment,
`if it is initiated within 8 h after poisoning, there is no
`difference between 21 h and the longer treatment.3,18
`In our hospital, we used 21 h protocol for I.V NAC
`treatment. In our study, 41% of the patients received
`IV NAC as well as decontamination therapy.
`Unfortunately, the results of serum acetaminophen
`level were obtained after 1 day because the blood
`samples sent to another hospital laboratory. The
`previous studies in children showed that the risk
`of hepatotoxicity is lower than adult patient and
`late presentation (>24 h after ingestion) or delayed
`therapy are an important risk factors.19-21 Therefore,
`we decided to initiate NAC therapy based on the
`ingested acetaminophen dose and clinical opinion.
`The studies in Turkey have been conducted in
`the adult age group and are limited in number.
`Duran et al. reported that nausea or vomiting were
`determined in 56.6% of the patients and the mean
`time of therapy initiation was 5.8 h. Hepatotoxicity
`developed in 1 patient and complication due to
`NAC therapy (urticarial reaction) was observed in 1
`patient.22 Karaman et al. reported that hepatotoxicity,
`nephrotoxicity or death were not observed in any
`patients.23 In our study, we found that the most
`
`abdominal pain. The mean time from ingestion to
`initiation of NAC therapy was found as 4.6±4.9 h
`and none of the patients developed hepatotoxicity.
`This short admission period may also explain that
`36% of the patients were asymptomatic. Similarly,
`
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`Acetaminophen overdose in children
`
`urticarial reaction was observed in one patient.
`When the patients who received NAC and only
`decontamination
`therapy were compared, as
`expected we found the ingested acetaminophen
`dose and serum acetaminophen level were higher
`in patients who received antidote. Some previous
`studies reported that INR values were higher in
`patients with acetaminophen poisoning without
`liver damage but these values reduced after NAC
`therapy.23-25 We found that creatinine and INR
`values were slightly high in patients received NAC
`therapy at admission time. However, there were no
`differences in terms of creatinine and INR between
`groups at discharge.
`There are some limitations that should be
`mentioned in our study. The results of serum
`acetaminophen level were obtained after 1 day and
`this delay might have affected treatment choice.
`
`side effects due to IV NAC therapy are uncommon
`and it is generally well tolerated in children.
`Additionally, we found that anti-gripal drugs are in
`
`to avoid the prescription of such drugs containing
`more than one agent because dosing errors can be
`made easily.
`
`REFERENCES
`1. American academy of pediatrics committee on drugs.
`Acetaminophen
`toxicity
`in
`children.
`Pediatrics.
`2001;108:1020. doi: 10.1542/peds.108.4.1020.
`2. Ogilvie JD, Rieder MJ, Lim R. Acetaminophen overdose
`in children. CMAJ. 2012;184(13):1492-1496. doi: 10.1503/
`cmaj.111338.
`
`of acetaminophen (paracetamol) toxicity in pediatrics.
`Available: www.who.int/selection_medicines/.../acetylcys
`teine_rev.pdf (accessed 2017 October 6).
`4. Rumack BH, Matthew H. Acetaminophen poisoning and
`toxicity. Pediatrics. 1975;55:871-876.
`5. Mowry JB, Spyker DA, Brooks DE, Mcmillan N, Schauben
`JL. 2014 Annual Report of the American Association of
`Poison Control Centers’ National Poison Data System
`(NPDS): 32nd Annual Report. Clin Toxicol. 2015;53(10):962-
`1146. doi: 10.3109/15563650.2015.1102927.
`6. Mintegi S, Fernandez A, Alustiza J, Canduela V, Mongil I,
`Caubet I, et al. Emergency visits for childhood poisoning:
`a 2-year prospective multicenter survey in Spain. Pediatr
`Emerg Care. 2006;22(5):334-338.
`Sheen CL, Dillon JF, Bateman DM, Simpson KJ,
`Macdonald TM. Paracetamol toxicity: epidemiology,
`prevention and costs to the health-care system. Q J
`Med. 2002;95:609-619.
`Turkish Statistical Institute. Statistics on child, 2015.
`No:
`21521.
`Avaliable:
`http://www.tuik.gov.tr/
`PreHaberBultenleri.do?id=21521 (accessed 22 April 2016).
`9. Ozcan N, Ikinciogullari D. Ulusal Zehir Danisma Merkezi
`2008 Yili Calisma Raporu Ozeti. Turk Hij Den Biyol Derg.
`2009;66(ER3):29-58.
`
`7.
`
`8.
`
`10. Aygin D, Acil H. The study of the intoxiation cases of the
`patients (0-18 years) admitting to pediatric emergency unit.
`Med Bull Sisli Etfal Hosp. 2014;48(1):27-33. doi: 10.5350/
`SEMB2014480105.
`11. Bicer S, Sezer S, Cetindag F, Kesikminare M, Tombulca
`N, Aydogan G, et al. Evaluation of acute intoxications in
`pediatric emergency clinic in 2005. Marmara Medical J.
`2007;20(1):12-20.
`
`applied to the pediatrics emergency unit. Turk Arch Ped.
`2011;46:234-240. doi: 10.4274/tpa.46.80.
`13. Akin Y, Agzikuru T, Comert S, Atilkan P, Erdag GC, Telatar
`B. Hospitalizations for pediatric intoxication: a study from
`Istanbul. The Turk J Pediatr. 2011;53:369-374.
`14. Ozenir M, Selcuk Duru N, Elevli M, Karakus A, Civilibal
`M. The Familial Factors and Demographic Characteristics
`of Children with Drug Poisoning. Med Bull Haseki.
`2013;51:157-161. doi: 10.4274/Haseki.1165.
`
`Oyman G, et al. An evaluation of the admissions to a tertiary
`hospital pediatric emergency department with intoxication.
`Smyrna Tip Dergisi 2012;41-44.
`16. Turkmenoglu Y, Gumusoglu Aksahin B, Saritas U, Yilmaz
`B, Arat C, Safak E, et al. Update Glance on Childhood
`
`10.5222/otd.2015.082.
`17. Bebarta VS, Kao L, Froberg B, Clark RF, Lavonas E, Qi M, et
`al. A Multi-center Comparison of the Safety of Oral versus
`Intravenous Acetylcysteine for Treatment of Acetaminophen
`Overdose. Clin Toxicol (Phila). 2010;48(5):424-430. doi:
`10.3109/15563650.2010.486381.
`18. Williamson K, Wahl MS, Mycyk MB. Direct comparison of
`20-hour IV, 36-hour oral, and 72-hour oral acetylcysteine for
`treatment of acute acetaminophen poisoning. Am J Ther.
`2013;20(1):37-40. doi: 10.1097/MJT.0b013e318250f829.
`19. Rumack BH. Acetaminophen overdose in young children:
`treatment and effects of alcohol and other ingestants in 417
`cases. AJDC. 1984;138:428-433.
`20. Rivera-Penera T, Gugig R, Davis J, McDiarmid S, Vargas J,
`Rosenthal P, et al. Outcome of acetaminophen overdose in
`pediatric patients and factors contributing to hepatotoxicity.
`J Pediatr. 1997;130:300-304.
`21. Alander SW, Dowd D, Bratton SL, Kearns GL. Pediatric
`acetaminophen overdose risk factors associated with
`hepatocellular
`injury. Arch Pediatr Adolesc Med.
`2000;154:346:350.
`
`Y. Use of Intravenous N-Acetyl Systein in Paracetamol
`Intoxication. JAEM. 2011;10:145-147.
`23. Karaman K, Avcil M, Kantekin B, Ozluer YE, Yasar HE, Avcil
`S, et al. Evaluation of Patients with Paracetamol Intoxication
`Who Admitted to Emergency Service. Meandros Med Dent
`J. 2016;17:11-16. doi:10.4274/meandros.2533.
`24 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(6):742-748.
`25. Wasserman GS, Garg U. Intravenous Administration of
`N-Acetylcysteine: Interference with Coagulopathy Testing.
`Ann Emerg Med 2004;44:546-547.
`Authors’ Contribution:
`YY: Designed and did statistical analysis, writing &
`editing of manuscript.
`AAO: Did data collection and manuscript writing.
`
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