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Hong Kong Journal of Emergency Medicine Case report: paracetamol poisoning in a 2-year-old child − from international overview to the role of the Hong Kong Poison Information Centre JYS Sia and YC Chan We report a 2-year-old girl suffering from acute liver failure as a result of paracetamol poisoning. The child successfully recovered after intensive care. We performed literature search for the past decade and found that the pathophysiological response in the child was different from that of the adult. Despite paracetamol poisoning being one of the most common poisonings in the world, there is still no consensus in the treatment protocol. Hence the role of the Hong Kong Poison Information Centre is briefly discussed. (Hong Kong j. emerg.med. 2006;13:225-231) Keywords: Acetaminophen, liver failure, N-acetylcysteine, poisoning Case A 2-year-old girl presented to our department for one minute of generalised tonic-clonic convulsion on 20 November 2002. She enjoyed good past health since birth. Before the convulsion, she suffered from upper respiratory tract infection for two days and received medications prescribed by a private practitioner. The labels of the prescription were hand-written, namely Amoxil (amoxycillin), domperidone, Xylyxanthramic Correspondence to: Sia Yin Shan, Jacky, MBBS, MRCSEd Ruttonjee Hospital, Accident & Emergency Department, 266 Queen’s Road East, Wanchai, Hong Kong Email: [email protected] Hong Kong Poison Information Centre, Hong Kong Chan Yiu Cheung, FRCSEd, FHKCEM, FHKAM(Emergency Medicine) acid, Hydroxyacetamide and others but illegible. The dosages were not labelled. Worse still, Xylysanthramic acid and Hydroxyacetamide are not registered pharmaceuticals in Hong Kong. In the middle of the night, her mother noticed a decrease in conscious level of her child. Further history did not reveal any concurrent use of herbal medication. There was neither travel nor trauma history. Her condition at arrival was fair. The blood pressure was 109/51 mmHg and the pulse rate was 180 beats per minute. The tympanic temperature was 38.9°C and the pulse oximeter showed 98% saturation on room air. The child was sleepy and weak. The pupils were 1 mm in diameter and not reactive to light. The cardiovascular, respiratory and abdominal examinations were unremarkable. The neck was soft and Babinski response was negative bilaterally. The 226 Hong Kong j. emerg. med. Vol. 13(4) Oct 2006 bedside blood sugar level was 1.8 mmol/L. Intravenous dextrose was given in the form of D10 but her clinical response was poor and she remained sleepy after 30 ml of D10. The X-ray chest was normal. The clinical diagnosis was hypoglycaemia and convulsion. Subsequently, the patient was transferred to the paediatric unit in Queen Mary Hospital. and liver enzymes started to decrease after the NAC (Figures 1 & 2). She was able to respond on day 3 after admission and was discharged on day 10 after the intensive management. After admission, her condition deteriorated with respiratory failure that required intubation and mechanical ventilation. She was then transferred to the intensive care unit for further management. Blood tests including complete blood picture, renal function, liver function, prothrombin time, activated partial thromboplastin time, blood culture, and blood gas analysis, were performed. Metabolic workup including organic acid, carnitine, lactate, pyruvate, and amino acid profile were also performed. The results revealed aspartate transaminase >3,000 U/L, alanine transaminase >2,254 U/L, international normalised ratio >3.0. Urgent viral study excluded the possibility of hepatitis B, hepatitis C, human immunodeficiency virus (HIV) antibody and acute cytomegalovirus infection. Computerised tomography of the brain was normal but lumbar puncture was withheld due to the deranged coagulation profile. Urgent electroencephalogram revealed generalised slowing. Toxicology screen showed that the paracetamol level was 556 µmol/L at 8-hour. N-acetylcysteine (NAC) was initiated, starting with 1,800 mg in 200 ml dextrose over 1 hour, then 630 mg in 150 ml dextrose over 4 hours, then 1,200 mg in 250 ml dextrose over 16 hours and finally 1,200 mg in 250 ml dextrose over 24 hours. Besides, urine toxicology tests revealed the presence of benzodiazepine, mefenamic acid, chlorpheniramine, methadone, normethadone and ephedrine. As a result, the medications prescribed by the private practitioner were sent for qualitative and quantitative analysis and was compatible with the urine results. Hence the patient suffered from liver failure due to paracetamol overdose complicated by hypoglycaemia and seizure. Narcotics, anticholinergics and anti-inflammatory drugs might contribute to the clinical presentation of the patient. The child remained sleepy, with episodic hypoglycaemia requiring repeated infusion of dextrose solution. The paracetamol level Paracetamol poisoning is one of the most common drug poisonings in the world. In the United Kingdom, nearly 50% of drug poisoning was due to it. 1 The mortality was about 100 to 200 victims per year. 2-4 Reviewing the database in the Toxic Exposure Sur veillance System ( TESS) of the American Association of Poison Control Centers in 2004, 19,590 cases were under the age of six. 4 The reasons for its highest occurrence are multi-factorial. Firstly, the public believes it is a safe medication. Secondly, it is easily available in the market. Unintentional misuse is the third main reason for paediatric poisoning due to the lack of safety container at home. Finally, dosing error can occur due to mistakes of parents, physicians and even pharmacists.5 Discussion Figure 1. Decreasing trend of paracetamol level after the initiation of N-acetylcysteine. Figure 2. Response of liver enzymes after the initiation of N-acetylcysteine. Sia et al./Paracetamol poisoning in a 2-year-old child The pathophysiological mechanism of paracetamol poisoning is well known. Normally the acetaminophen is mainly metabolised to non-toxic metabolites that are renally excreted. However, in overdose situation, the non-toxic metabolic pathways are saturated and more paracetamol will go through metabolism by the c y t o c h r o m e P 4 5 0 p a t h w a y, r e s u l t i n g i n t h e accumulation of the toxic metabolite N-acetyl-pbenzoquinoneimine (NAPQI). The NAPQI is detoxified by glutathione until the store is depleted. The NAPQI will then bind to cellular proteins causing damage and cell death. The 4-stage clinical manifestation is also well documented although it may be non-specific in paediatric patients. During the first few hours, the patient may present with non-specific symptoms such as vomiting alone. Then the second stage follows during which the patient remains asymptomatic. After two to three days, in the third stage, the patient may deteriorate rapidly with symptoms of acute hepatitis and liver failure. Then finally the symptoms resolved in about 7 to 10 days' time. However, death can result if hepatic failure occurs. 227 Investigations should include complete blood picture, renal function, liver function, coagulation profile and toxicology screening. These are helpful to predict the risk of hepatocellular damage as shown in Table 1. 1,6 In research, scientists found that inflammatory cytokines are elevated in paracetamol poisoning. James et al conducted a study to evaluate the relationship between these cytokines and hepatocellular toxicity. Tumour necrosis factors, interleukin (IL) -alpha, IL-beta, IL-6, IL-8 and IL-10 were measured in adults and children (total 35 patients) who suffered from poisoning. The result showed that only IL-8 >20 ng/ml was associated with peak prothrombin time value, which is one of the predictors in hepatocellular damage. Nevertheless, the authors concluded that further study would be needed before its clinical usage could be developed.7 Measurement of acetaminophen-protein adducts is another area of scientific breakthrough in studying the risk of hepatocellular toxicity.8 It is highly specific for paracetamol induced hepatic injury since it is a biomarker in the centrilobular region of the liver of laboratory animals. It will be present in subjects whose Table 1. Factors predicting risk of hepatotoxicity Sens % Spec % LR+ (1) Clinical finding at presentation (a) Probable toxicity by nomogram 88 72 3.14 (b) Time to treatment >10 hours 88 72 3.14 (c) Emesis at presentation 67 38 1.08 6.25 (2) Laboratory finding (a) PT >14 seconds within 24 hours 75 88 (b) AST or ALT >100 iu/L within 24 hours 50 100 (c) PT >14 seconds within 48 hours 88 84 (d) AST or ALT >100 iu/L within 48 hours 81 100 (a) 24 hours: increase in PT, AST, ALT 81 88 6.75 (b) 48 hours: increase in PT, AST, ALT 100 88 8.33 100 72 3.57 >1000 5.50 >1000 (3) Combination (4) Probable toxicity by nomogram or AST or ALT >100 iu/L within 24 hours Sens: sensitivity; Spec: specificity; LR+: positive likelihood ratio = sensitivity/(1-specificity); PT: prothrombin time; AST: aspartate transaminase ALT: alanine transaminase Hong Kong j. emerg. med. Vol. 13(4) Oct 2006 228 liver transaminase level is greater than 6,000 iu/L. Its clinical usefulness is inconclusive in human. The most common problem nowadays is the absence of treatment consensus in the world − a question that has remained for decades irking scientists. Is there any difference when we give antidote to the child as we do to the adult? If yes, what is the difference? Should we use the Rumack-Matthew nomogram? What should be the value of serum paracetamol level before we initiate NAC? Anatomical and physiological differences It could be disputed that the ratio of liver weight to body weight is relatively larger in a child when compared to that of an adult. This is shown in Table 2. Bond found that the relatively larger liver weight offers protection due to greater glutathione storage. Indeed the toxicity is the interaction of drug, total glutathione store, glutathione synthetic ability and the individual's percentage of cytochrome oxidative metabolism. According to Bond's data, the toxic level of paracetamol should be expressed as milligrams of ingestion per kilogram of liver weight rather than body weight. This implies that a child has to ingest a larger quantity of paracetamol before toxicity occurs, 9 but then what should be the dosage? Anderson et al retrospectively collected data of 1,000 children aged 1 to 5 presenting to the emergency department with accidental paracetamol ingestion from January 1995 to June 1997.10 He compared the timeconcentration relationship of the drug level in children with the database in adult. He showed that clearance of drug was a non-linear function of weight while in Table 2. Relationship between age and liver weight. Age in year Average weight of liver per kilogram of body weight (g/kg) 3 35.8 - 41.0 6 31.7 - 34.3 9 30.0 - 32.0 12 23.8 - 27.0 15 24.0 - 24.4 18 24.8 - 26.6 contrast dose was an expression of linear function of weight. By using sophisticated statistical analysis (PharSight Trial Designer), they calculated the simulation dose in paediatric patients as 300 mg/kg before toxic effect occurs as compared to the 150 mg/ kg in adult patients. The possible toxicity should be at a level of 225 mg/L at 2-hour interval rather than the traditional 150 mg/L in adult. They suggested those who ingested more than 250 mg/kg should have serum paracetamol checked. The 2-hour interval was used because children got faster metabolism and had shorter elimination half-lives. However this guideline is invalid when the child is older than 12 years old as the metabolism will be similar to the adult. Could the scientific calculation be extrapolated to clinical practice? Bond collected database from the American Association of Poison Control Centers and reviewed the data retrospectively.9 All of them ingested less than 200 mg/ kg of paracetamol. He found that 3 out of 866 children aged from 1 to 6 years were reported to have probable risk of liver damage according to the nomogram but none of them suffered. Mohler et al enrolled 1,039 patients who ingested less than 200 mg/kg of paracetamol. About 93% of the patients ingested less than 150 mg/kg while 7% of the patients ingested 150 to 200 mg/kg of paracetamol. They reviewed the data and found that none of them developed hepatocellular damage. They suggested those who ingested less than 200 mg/kg unintentionally could be observed at home. This could reduce hospital cost and parental anxiety.11 However Caravati and his colleagues challenged the validity of Mohler's paper since only a small proportion of the patients were within the probable risk dosage i.e. 150 to 200 mg/kg. Worse still, Mohler's team did not propose their protocol for their own management despite they recommended others to follow their guideline. Caravati criticised this would only give a false sense of safety to the patient, parents and doctors.12 Alander et al studied paracetamol poisoning from another point of view. He retrospectively reviewed the databases from two regional children's hospitals from January 1988 to December 1997. 1 A total of 322 patients were included and their age ranged from 1 to Sia et al./Paracetamol poisoning in a 2-year-old child 17. The reason for ingestion was categorised as intentional and unintentional. The range of dose reported was from 4 mg/kg to 8,333 mg/kg. The median dose was about 172 mg/kg in the intentional group and 150 mg/kg in the unintentional group. No hepatocellular damage was found under the age of 9. However, Isbister challenged the validity of Alander's study that failure to categorise the age properly was the most paramount confounding variable.13 Caravati conducted a prospective study investigating the relationship between dose ingestion and patient outcome in the Utah Poison Control Center.14 A total of 1,015 patients aged from 1 to 72 months old were recorded. The mean dose was 213±148 mg/kg. Seventy-eight percent of their patients received decontamination if they ingested greater than 140 mg/ kg. Statistical analysis showed that no hepatotoxicity was noted if patients ingested 100-200 mg/kg. None of the patients developed potentially toxic concentrations in the 140 to 200 mg/kg dose range even without gastro-intestinal (GI) decontamination. They recommended for those who ingested within this range should have prompt GI decontamination preferably within one hour and could be safely discharged home. Any dosage greater than 200 mg/kg should have serum concentration checked. Their decontamination guideline is compatible with the recent statement by the American Academy of Clinical Toxicology and the European Association of Poisons Centers and Clinical Toxicologists. GI decontamination and activated charcoal are not required after one hour of ingestion.15 On the contrary, the American Academy of Pediatrics held a different opinion in which they thought activated charcoal could be given even within 6 to 8 hours after the acute ingestion. 16 But then what should be the dosage of NAC to initiate? Indeed, treatment is variable all over the world. The intravenous route is used in Canada and UK while the oral route is the practice in the US.17 Wallace and his team published the only evidence-based flowchart in 2002 and was accepted by the Royal College of Paediatrics and Child Health as a Good Practice Consensus Statement (Figure 3). The dose is 150 mg/kg 229 in 3 ml/kg of 5% dextrose over 15 minutes, followed by 50 mg/kg in 7 ml/kg 5% dextrose over 4 hours followed by 100 mg/kg in 14 ml/kg 5% dextrose over 16 hours. For continuation of NAC as adjuvant therapy for hepatic failure, it should be given at 150 mg/kg per 24 hours.18 Summary This article raises several important points. First of all, a child is not a miniature of adult. We should be aware of the precipitating factors (Table 3) and non-specific toxicological manifestations in this population. Se c o n d l y, t h e re i s s t i l l n o c o n s e n s u s o n t h e management of paracetamol poisoning in the world despite it is the most common poisoning. A standard dosing regimen or treatment protocol for common toxicological problems is absolutely indicated in our locality. Thirdly, the identification of prescription in private practices is important. It was well illustrated in our case since the hand-written prescription was illegible and we had no idea what exactly Xylyxanthramic acid and Hydroxyacetamide contained. The Hong Kong Poison Information Centre (HKPIC), established in 2005, is the pioneer in toxicology management in Hong Kong. Currently it provides consultation service to health care professionals regarding poison information and poisoned patient management. It is worthwhile developing our own protocols for emergency management of common poisonings such as paracetamol in adult and paediatric patients. The report published by Litovitz and his coworkers showed that the number of poisoning deaths reported to the medical examiner alone was 7 times more than that to the regional poison center. 19 Protocols, management plans and expert advice could be faxed to the medical officer asking for consultation. Whether we should set up a compulsory reporting system is debatable, but a simple notification sheet, similar to the notification of infectious diseases developed by the Department of Health, should be highly advocated. The corollary is the accumulation of our updated database for analysis in future and continuous quality improvement could be conducted. 230 Hong Kong j. emerg. med. Vol. 13(4) Oct 2006 Figure 3. Flow chart to guide management in paracetamol poisoning. (Reproduced with permission from the BMJ Publishing Group. In: Wallace CI, Dargan PI, Jones AL. Paracetamol overdose: an evidence based flowchart to guide management. Emerg Med J 2002;19(3):202-5. The reference numbers quoted in the chart correspond to references cited in that article only.) Sia et al./Paracetamol poisoning in a 2-year-old child Table 3. Precipitating factors in paracetamol poisoning Risk factors16 Childhood obesity Chronic liver problem Chronic medical illness Concomitant viral infection Diabetes mellitus Malnutrition Prolonged fasting Repetitive small doses Co-ingestion of anti-histamine Enzyme inducers (1) Human: isoniazid, rifampicin, phenobarbital, carbamazepine, ethanol (2) Animal: dexamethasone, doxorubicin, prolonged fasting 231 Reasons Depletion of glutathione store Slower metabolism Non-specific clinical manifestation causing delay in medical consultation Slow down gastric emptying Induction of cytochrome P450 References 9. 1. 10. 2. 3. 4. 5. 6. 7. 8. Alander SW, Dowd MD, Bratton SL, Kearns GL. Pediatric acetaminophen overdose: risk factors associated with hepatocellular injury. Arch Pediatr Adolesc Med 2000;154 (4):346-50. Litovitz TL, Klein-Schwartz W, Dyer KS, Shannon M, Lee S, Powers M. 1997 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1998;16(5):443-97. Schiodt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital. N Engl J Med 1997;337(16):1112-7. Watson WA, Litovitz TL, Rodgers GC, Klein SW, Reid N, Jessica Y, et al. 2004 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. [cited 2006 June 15]. Available from: http://www.aapcc.org/Annual%20Reports/04report/ 04Sect.htm. Joseph DL. Acetaminophen dose accuracy and pediatric emergency care. Pediatr Emerg Care 2004;20(5):285-8. James LP, Wells E, Beard RH, Farrar HC. Predictors of outcome after acetaminophen poisoning in children and adolescents. J Pediatr 2002;140(5):522-6. James LP, Farrar HC, Darville TL, Sullivan JE, Givens TG, Kearns GL, et al. Elevation of serum interleukin 8 levels in acetaminophen overdose in children and adolescents. Clin Pharmacol Ther 2001;70(3):280-6. James LP, Farrar HC, Sullivan JE, Givens TG, Kearns GL, Wasserman GS, et al. Measurement of acetaminophenprotein adducts in children and adolescents with acetaminophen overdoses. J Clin Pharmacol 2001;41(8): 846-51. 11. 12. 13. 14. 15. 16. 17. 18. 19. Bond GR. Reduced toxicity of acetaminophen in children: it's the liver. J Toxicol Clin Toxicol 2004;42 (2):149-52. Anderson BJ, Holford NH, Armishaw JC, Aicken R. Predicting concentrations in children presenting with acetaminophen overdose. J Pediatr 1999;135(3):290-5. Mohler CR, Nordt SP, Williams SR, Manoguerra AS, Clark RF. Prospective evaluation of mild to moderate pediatric acetaminophen exposures. Ann Emerg Med 2000;35(3): 239-44. Caravati EM. Safety of childhood acetaminophen overdose. Ann Emerg Med 2001;37(1):114-6. Isbister G, Whyte I, Dawson A. Pediatric acetaminophen poisoning. Arch Pediatr Adolesc Med 2001;155(3):417-9. Caravati EM. Unintentional acetaminophen ingestion in children and the potential for hepatotoxicity. J Toxicol Clin Toxicol 2000;38(3):291-6. Krenzelok E, Vale A. Position statements: gut decontamination. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol 1997;35(7): 695-786. American Academy of Pediatrics. Committee on Drugs. Acetaminophen toxicity in children. Pediatrics 2001;108 (4):1020-4. Kozer E, Koren G. Management of paracetamol overdose: current controversies. Drug Saf 2001;24(7):503-12. Wallace CI, Dargan PI, Jones AL. Paracetamol overdose: an evidence based flowchart to guide management. Emerg Med J 2002;19(3):202-5. Litovitz TL, Felberg L, White S, Klein-Schwartz W. 1995 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1996;14(5):487-537.