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Acetaminophen

Acetaminophen
30.May.2017-Expires: 7 days - Do not archive

DESCRIPTION

SUBSTANCE NAME

Acetaminophen (Paracetamol)
 

SUBSTANCE CLASS

Para-Aminophenol Derivative

INTERVENTION CRITERIA

Intervention Level

Acute Exposure

 
Ingestion
 
Aged 6 years or under ingesting
- 200 mg/kg acetaminophen (paracetamol) or more over a period of less than 8 hours
 
For obese children, the weight used should be based on ideal body weight.
 
Aged older than 6 years ingesting
- At least 10 g or 200 mg/kg (which ever is lower) over a period of less than 8 hours
- Exposures with intent to self-harm
 
For obese children, the weight used should be based on ideal body weight.
 
Also investigate if:
- The dose or timing of ingestion is uncertain, or;
- The patient is symptomatic
 

Time of Ingestion Unknown

If the time of ingestion is unknown and the dose is above the acute intervention level or unknown: commence an acetylcysteine infusion and investigate.
 

Supratherapeutic Exposure

 
Ingestion
Aged 6 years or under ingesting
- 200 mg/kg acetaminophen (paracetamol) or more over a single 24-hour period;
- 150 mg/kg or more per 24-hour period for the preceding 48 hours;
- 100 mg/kg or more per 24-hour period for more than 48 hours.
 
For obese children, the weight used should be based on ideal body weight.
 
Aged older than 6 years ingesting
- At least 10 g or 200 mg/kg (whichever is less) over a single 24-hour period;
- At least 6 g or 150 mg/kg (whichever is less) per 24 hour period for the preceding 48 hours;
- More than 4 g per day or 100 mg/kg (whichever is less) per 24-hour period for more than 48 hours in those who also have symptoms indicating possible liver injury (e.g. abdominal pain, nausea or vomiting)
- Exposures with intent to self-harm.
 
For obese children, the weight used should be based on ideal body weight.
 
Also investigate if:
- The dose or timing of ingestion is uncertain
- The patient is symptomatic
 

Investigation and Initial Management

Acute Ingestion

 
 
Decontamination
 
Administer activated charcoal to co-operative adults if within 2 hours of overdose of immediate release solid formulations or within 4 hours for modified release solid formulations.[1]
 
2 to 8 hours post-ingestion
 
Ingestion by children < 6 years of age of liquid acetaminophen (paracetamol)
                                                                                                             
Measure:
Serum acetaminophen (paracetamol) concentration at least 2 hours post-ingestion:[1]
 
- If this concentration is less than 1,000 umol/L (150 mg/L) the child may safely be discharged. Otherwise, repeat the measurement at 4 hours and if above the paracetamol treatment nomogram line administer acetylcysteine.
 
Ingestion of standard release or liquid formulations
 
Measure:
Serum acetaminophen (paracetamol) concentration at least 4 hours and within 8 hours post-ingestion, and plot against the paracetamol treatment nomogram:[1]
 
- If this concentration is below the nomogram line, the patient does not require acetylcysteine;
- If this concentration is above the nomogram line, immediately commence a full course of acetylcysteine;
- If this concentration will not be available within 8 hours of ingestion, immediately commence a full course of acetylcysteine. This treatment can then be halted if the result subsequently returns below the nomogram line.
 
Ingestion of modified release formulations
 
If the ingestion is above the intervention level, immediately commence a full course of acetylcysteine, then:[1]
 
Measure:
Serum acetaminophen (paracetamol) concentration at least 4 hours post-ingestion and a second concentration 4 hours following the first:
 
- If these concentrations are both below the paracetamol treatment nomogram line, and the second concentration less than the first, the acetylcysteine infusion may be halted. Otherwise, the full treatment course must be completed.
 
8 to 24 hours post-ingestion
 
Immediately commence a acetylcysteine infusion, then
 
Measure:
Serum acetaminophen (paracetamol) concentration
Alanine aminotransferase (ALT)
 
- If the serum acetaminophen (paracetamol) concentration is below the paracetamol treatment nomogram line and the ALT is less than 50 U/L, then the acetylcysteine infusion can be halted and no further medical treatment is necessary.[1]
- If the serum acetaminophen (paracetamol) concentration is above the paracetamol treatment nomogram line or the ALT greater than 50 U/L, then complete a full course of acetylcysteine.[1]
 
If ALT is greater than 50 U/L then also measure:
BUN (Urea)
Creatinine
Electrolytes
Blood sugar
Phosphate
Venous Blood Gas (pH and lactate in particular)
 
24 plus hours post-ingestion, or time of ingestion unknown
 
Immediately commence a acetylcysteine infusion, then
 
Measure:
Serum acetaminophen (paracetamol) concentration
Alanine aminotransferase (ALT)
International Normalized Ratio (INR)
 
- If the serum acetaminophen (paracetamol) concentration is less than 66 umol/L (10 mg/L) and the ALT is less than 50 U/L, then the infusion can be halted and no further medical treatment is necessary.[1]
- If the serum acetaminophen (paracetamol) concentration is greater than 66 umol/L (10 mg/L) or the ALT is greater than 50 U/L, then complete the full course of acetylcysteine.[1]
 
If ALT is greater than 50 U/L then also measure:
BUN (Urea)
Creatinine
Electrolytes
Blood sugar
Phosphate
Venous Blood Gas (pH and lactate in particular)
 

Supratherapeutic Exposure

 
In patients meeting intervention criteria for supratherapeutic ingestion
 
Measure:
Serum acetaminophen (paracetamol) concentration
Alanine aminotransferase (ALT)
 
-If serum acetaminophen (paracetamol) is < 132 umol/L (< 20 mg/L) and ALT < 50 U/L, then no medical treatment is necessary.[1]
-If serum acetaminophen (paracetamol) is > 132 umol/L (> 20 mg/L) or ALT > 50 U/L, then commence an acetylcysteine infusion.[1]
 
After commencement of the infusion measure serum acetaminophen (paracetamol) and ALT concentrations 8 hours after the previous measurement.
-If serum acetaminophen (paracetamol) is < 66 umol/L (< 10 mg/L) and ALT < 50 U/L, then the infusion can be halted and no further medical treatment is necessary.[1]
 
Otherwise continue the infusion and check serum acetaminophen (paracetamol) and ALT at 12 hourly intervals until:
-Serum acetaminophen (paracetamol) is < 66 umol/L (< 10 mg/L) and ALT < 50 U/L, then the infusion can be halted and no further medical treatment is necessary.[1]
 

Observation Period

Observation at Home

No observation is required for those patients with ingested doses or serum acetaminophen (paracetamol) determinations below the intervention levels. However, review is warranted should nausea, vomiting, or abdominal pain occur after discharge, particularly if within 24 to 48 hours after the ingestion.
 

Medical Observation

Medical observation of asymptomatic patients is not required provided serum acetaminophen (paracetamol) investigation is undertaken and the concentration is below the appropriate intervention level.
 

Admission Criteria

Patients requiring intervention for acute acetaminophen (paracetamol) overdose should be appropriately decontaminated and managed in a medical facility able to rapidly determine serum acetaminophen (paracetamol) and provide acetylcysteine.
 
Referral to an intensive care unit and/or liver transplant unit may be required in severe poisoning.
 

TREATMENT

TREATMENT SUMMARY

Decontamination with activated charcoal is recommended in cooperative adults within 2 hours of ingestion of (solid) immediate-release forms, or within 4 hours of ingestion of either modified-release forms or greater than 30 g of acetaminophen (paracetamol).[2][1]
 
Following acute overdose, assessment of serum acetaminophen (paracetamol) concentration between 4 to 8 hours and use of the paracetamol treatment nomogram is necessary to determine requirement for the antidote acetylcysteine. If a result is not available within this timeframe acetylcysteine should be commenced and is considered beneficial at any time post-ingestion.[3] Acetylcysteine administration following supratherapeutic/chronic ingestions is dependent on dose and investigations.
 
In cases of massive acetaminophen (paracetamol) ingestion (greater than 50 g or serum concentrations greater than twice the nomogram line) doubling the final (16 hour) acetylcysteine infusion is recommended.[1] Hemodialysis may be beneficial in severe poisoning with very high blood concentrations and particularly if acetylcysteine is unavailable.[4]
 
Supportive care includes the continued use of acetylcysteine, monitoring of major organ function, and further management as indicated. Use of sedating drugs is not recommended due to their impact on the assessment of mental function/encephalopathy. Acute hepatic and renal failure are well recognized concerns. Most complications are a consequence of hepatic failure and rarely occur in its absence.
 
Advice should be sought from a specialist liver transplant unit:[1]
If 
The International Normalized Ratio (INR) is greater than 3 at 48 hours or 4.5 at any time after overdose
Or
Oliguria or creatinine is greater than 200 umol/L (2.2 mg/dL)
Or
Persistent acidosis (pH less than 7.3) or arterial lactate greater than 3 mmol/L
Or
Systolic hypotension with a blood pressure less than 80 mmHg, despite resuscitation
Or
Hypoglycemia
Or
Severe thrombocytopenia
Or
Encephalopathy of any degree, or any alteration of consciousness (Glasgow Coma Scale less than 15) not associated with co-ingestion of sedatives
 
Early discussion with a liver transplant unit is essential. Advice may be given and a decision to transport dependent upon results. In general it is considered desirable to transport patients prior to development of grade 2 encephalopathy.
 
Emergency Stabilization
Decontamination
Antidote(s)
Enhanced Elimination
Supportive Care
Hepatic
Renal
Metabolic
Cardiovascular
Hematologic
Respiratory
Gastrointestinal
 

EMERGENCY STABILIZATION

Emergency Stabilization Should Not Be Required

Emergency stabilization of patients following recent ingestion of acetaminophen (paracetamol), solely, is highly unlikely to be necessary. However, massive overdose may lead to early decline in level of consciousness and/or lactic acidosis.[5] Immediate attention should be given to the airways, assessment of blood glucose, and supportive care.[1] Definitive treatment is provided by the antidote acetylcysteine, with hemodialysis possibly indicated.[4] Carefully consider coingestant(s) or non-toxicological causes.
 

DECONTAMINATION

Ingestion

Single Dose Activated Charcoal

Gastrointestinal decontamination is not indicated in any pediatric (< 6 years old) patient following acetaminophen (paracetamol) overdose.[1]
 
Gastrointestinal decontamination with activated charcoal is only indicated:[1]
In co-operative adult patients
If the formulation is a solid (e.g. tablets, capsules)
If at least 10 g or 200 mg/kg (which ever is lower) is ingested
Within 2 hours of the overdose for standard release formulations
Within 4 hours of the overdose for modified release formulations (patients may benefit from activated charcoal beyond 4 hours following large ingestions)
If at least 30 g is ingested
Within 4 hours of the overdose for standard release formulations
 
Further decontamination with activated charcoal may be necessary for co-ingestants.
 
Induction of emesis and gastric lavage are both contra-indicated.
 
Single dose activated charcoal[6]
CHILD
1 to 2 g/kg orally
ADULT
50 to 100 g orally
 

ANTIDOTE(S)

Acetylcysteine

Acetylcysteine is the treatment of choice for acetaminophen (paracetamol) overdose, and its intravenous use considered preferable.[7] When administered within eight hours of acetaminophen (paracetamol) ingestion it is almost completely effective in preventing death.[8] Use beyond this time is also beneficial and recommended.[3]
 
In the case of modified release formulations, acetylcysteine may need to be continued after the initial 21 hour infusion.
 

Indications

Intra-venous acetylcysteine infusion is indicated as outlined in the following links:
 
 
 

Dose and Administration

While acetylcysteine is recommended to be administered intravenously in 5% dextrose in water, 1/2 normal (0.45%) saline may be substituted if necessary.[9] It is recommended that acetylcysteine dose for adults be calculated for actual body weight rounded up to the nearest 10 kg with a ceiling weight of 110 kg.[1]
 
CHILD
 
Children 20 kg or less body weight:[1]
150 mg/kg in 3 mL/kg of 5% dextrose over 60 minutes
Followed by 50 mg/kg in 7 mL/kg of 5% dextrose over 4 hours
Followed by 50 mg/kg in 7 mL/kg of 5% dextrose over 8 hours
Followed by 50 mg/kg in 7 mL/kg of 5% dextrose over 8 hours
 
Children > 20 kg body weight:[1]
150 mg/kg in 100 mL of 5% dextrose over 60 minutes
Followed by 50 mg/kg in 250 mL of 5% dextrose over 4 hours
Followed by 50 mg/kg in 250 mL of 5% dextrose over 8 hours
Followed by 50 mg/kg in 250 mL of 5% dextrose over 8 hours
 
Closely monitor fluid and electrolyte balance.
 
ADULT
 
Administer:[1]
150 mg/kg in 200 mL diluent IV over 60 minutes
Followed by 50 mg/kg in 500 mL diluent IV over 4 hours
Followed by 100 mg/kg in 1,000 mL diluent over 16 hours
 
 
In the case of massive overdose (those whose acetaminophen (paracetamol) concentration is more than double the nomogram line) it is recommended that the final infusion over 16 hours is doubled to 200 mg/kg.[1]
 

Antidote Endpoint

Acute
Recommended investigations according to time from acetaminophen (paracetamol) ingestion to acetylcysteine treatment[1]
 
Time (hours) from ingestion to start of acetylcysteine
Investigations on admission
Investigations at the completion of acetylcysteine
Less than 8 hours
Serum acetaminophen (paracetamol) concentration
Nil*
8 to 24 hours
Serum acetaminophen (paracetamol) concentration and ALT
ALT, UEC*
Greater than 24 hours
Serum acetaminophen (paracetamol) concentration, ALT and INR
ALT, INR, UEC
Patients with an ALT > 50 U/L
UEC, LFTs, INR, BSL, serum phosphate, blood gas (pH and lactate)
Repeat investigations 12 hourly including: UEC, LFTs, INR, BSL, serum phosphate, VBG
ALT = alanine aminotransferase; BSL = blood sugar level; UEC = BUN (urea), electrolytes, and creatinine; LFTs = liver function tests; VBG = venous blood gases including pH and lactate.
 
* NOTE: If symptoms of hepatotoxicity (e.g. nausea, vomiting, abdominal pain or tenderness) then repeat ALT. Or if initial concentration more than double the nomogram line, then repeat ALT and paracetamol concentration at the completion of acetylcysteine.
 
Patients who have ALT > 50 U/L following completion of initial acetylcysteine require acetylcysteine to be continued at the rate of the last infusion stage (100 mg/kg acetylcysteine over 16 hours or 150 mg/kg/24 hours).[1]
 
Continue acetylcysteine until the patient is clinically improving, ALT is decreasing, INR is improving and < 2, and the acetaminophen (paracetamol) concentration is less than 66 umol/L (10 mg/L).[1][10]
 
Chronic
Following chronic ingestion of acetaminophen (paracetamol) and commencement of acetylcysteine infusion, measure serum acetaminophen (paracetamol) and ALT concentrations 8 hours after the previous measurement.
If serum acetaminophen (paracetamol) is <66 umol/L (<10 mg/L) and ALT is less than 50 U/L, then the infusion can be halted and no further medical treatment is necessary.[1]
 
Otherwise continue the infusion and check serum acetaminophen (paracetamol) and ALT at 12 hourly intervals until:
Serum acetaminophen (paracetamol) is <66 umol/L (<10 mg/L) and ALT is less than 50 U/L, then the infusion can be halted and no further medical treatment is necessary.[1]
 

Precautions

Pregnancy
Acetylcysteine should be administered to pregnant patients following the standard adult regimen. Transplacental transport of acetylcysteine is not thought to be clinically significant,[11] however, delay in initiation of acetylcysteine treatment is associated with increased incidence of spontaneous abortion and fetal death.[12] Acetylcysteine is not considered teratogenic.[13]
 

Adverse Effects

Anaphylactoid Reaction
Six to 23% of patients receiving IV acetylcysteine develop an anaphylactoid reaction.[14][15] These do not represent an immunological (allergic) reaction; rather, they are thought due to a direct dose-dependent effect on histamine release and generally occur within the first two hours of an infusion.
 
History of previous anaphylactoid reaction to acetylcysteine does not contraindicate use. If there is concern of recurrence of the reaction the patient may be pre-treated 15 minutes before commencement of the infusion with an antihistamine.[16]
 
Effects range from mild flushing to urticaria, angioedema, or bronchospasm. Hypotension may occasionally occur. Asthmatics appear more at risk. However, effects are usually easily managed and there is no reason to withhold acetylcysteine from any patient when indicated.[16]
 
Hyponatremia
Hyponatremia has been reported in children if administered acetylcysteine in 5% dextrose following adult protocols for dilution of infused dose.[17]
 

SIGNS AND SYMPTOMS

Initial manifestations of acetaminophen (paracetamol) intoxication may be absent or may only include gastrointestinal effects, malaise, pallor, and diaphoresis.[18][19] Rarely, following massive overdose, there may be an initial metabolic acidosis and coma.[5][20]
 
Hepatic damage is a common feature of acetaminophen (paracetamol) toxicity and further signs and symptoms become apparent if hepatotoxicity develops. As time after overdose increases signs and symptoms associated with acute hepatic failure including right upper quadrant tenderness, hypotension, acidosis, coagulopathy, encephalopathy, and hypoglycemia may develop.[19][21][22] Jaundice is not evident as an early sign but develops as hepatic failure progresses.[19] Additionally, an initial increase in INR can be seen in the first 24 to 48 hours which appears to result from an inhibition of the activation of vitamin K dependent coagulation factors.[23] Later, coagulopathy is typically a result of liver failure.
 
Renal failure associated with acetaminophen (paracetamol) overdose may rarely appear acutely, or more usually over a period of days and in association with hepatotoxicity/failure.[24] Cardiovascular concerns are rarely an acute consequence of poisoning, but hypotension and myocardial injury may appear in patients with fulminant hepatic failure as part of multisystem organ failure.[25]
 

Onset/Duration of Symptoms

Acetaminophen (paracetamol) in the form of liquid formulations and oro-dispersable tablets are more quickly absorbed than standard tablets,[26] so may alter the onset of symptoms. Modified release tablets may additionally alter the time course of toxicity.
 
Four phases of acute acetaminophen (paracetamol) toxicity have been described.[18]
 
Phase 1 (0.5 to 24 hours after overdose): During the first 24 hours following acute overdose a patient may have few if any signs or symptoms. However, they may demonstrate malaise, anorexia, nausea, vomiting, pallor, and diaphoresis.[18][19]Rarely, following massive overdoses, metabolic acidosis and coma may occur in this phase as a direct toxic effect.[5][20]
 
Phase 2 (24 to 72 hours after overdose): Previous symptoms subside. Right upper quadrant pain may appear indicating hepatic damage with associated raised hepatic transaminases. International Normalized Ratio (INR) increases. Renal function may begin to deteriorate, however blood urea may remain low due to decreased hepatic urea formation.[18][19]
 
Phase 3 (72 to 96 hours after overdose): Continuing hepatic centrilobular necrosis with associated coagulation defects, hypoglycemia, metabolic acidosis, and jaundice. Renal failure and cardiac complications frequently occur. Hepatic encephalopathy and death may ensue.[18][19]
 
Phase 4 (4 days to 2 weeks after overdose): If phase 3 is survived complete resolution of hepatic and renal function is usual.[18][27]
 

Severity of Poisoning

Mild Acetaminophen (Paracetamol) ToxicityModerate Acetaminophen (Paracetamol) ToxicitySevere Acetaminophen (Paracetamol) Toxicity
Malaise
Nausea
Vomiting
Pallor
Diaphoresis
Upper right quadrant pain
Increased INR
Metabolic acidosis
Hypoglycemia
Jaundice
Renal failure
Fulminant hepatic failure
Hepatic encephalopathy
Coma
 

CHRONIC EFFECTS

Symptoms in chronic situations are broadly similar to acute ones. Heptotoxicity and its complications are the major concern.[28][29]
 

REFERENCES

 
[1] Chiew AL, Fountain JS, Graudins A, Isbister GK, Reith D, Buckley NA. Summary statement: new guidelines for the management of paracetamol poisoning in Australia and New Zealand. Med J Aust 2015 Sep 7; 203 (5): 215-8.
[2] Buckley NA, Whyte IM, O'Connell DL, Dawson AH. Activated charcoal reduces the need for N-acetylcysteine treatment after acetaminophen (paracetamol) overdose. J Toxicol Clin Toxicol 1999; 37 (6): 753-7.
[3] Keays R, Harrison PM, Wendon JA, Forbes A, Gove C, Alexander GJ, Williams R. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ 1991 Oct 26; 303 (6809): 1026-9.
[4] Gosselin S, Juurlink DN, Kielstein JT, Ghannoum M, Lavergne V, Nolin TD, Hoffman RS. Extracorporeal treatment for acetaminophen poisoning: recommendations from the EXTRIP workgroup. Clin Toxicol (Phila) 2014 Sep-Oct; 52 (8): 856-67.
[5] Zezulka A, Wright N. Severe metabolic acidosis early in paracetamol poisoning. Br Med J (Clin Res Ed) 1982 Sep 25; 285 (6345): 851-2.
[6] Fountain JS, Beasley DM. Activated charcoal supercedes ipecac as gastric decontaminant. N Z Med J 1998 Oct 23; 111 (1076): 402-4.
[7] Buckley NA, Whyte IM, O'Connell DL, Dawson AH. Oral or intravenous N-acetylcysteine: which is the treatment of choice for acetaminophen (paracetamol) poisoning? J Toxicol Clin Toxicol 1999; 37 (6): 759-67.
[8] Prescott LF, Illingworth RN, Critchley JA, Proudfoot AT. Intravenous N-acetylcysteine: still the treatment of choice for paracetamol poisoning. [Letter] Br Med J 1980 Jan 5; 280 (6206): 46-7.
[9] Cumberland-Pharmaceuticals. Acetadote (Acetylcsyteine) Injection - Package Insert. Nashville TN: Cumberland Pharmaceuticals Inc, 2011: [Cited 27 Jan 2012]. URL: http://www.acetadote.net
[10] ACMT Position Statement: Duration of Intravenous Acetylcysteine Therapy Following Acetaminophen Overdose. J Med Toxicol 2017 Mar; 13 (1): 126-127.
[11] Selden BS, Curry SC, Clark RF, Johnson BC, Meinhart R, Pizziconi VB. Transplacental transport of N-acetylcysteine in an ovine model. Ann Emerg Med 1991 Oct; 20 (10): 1069-72.
[12] Riggs BS, Bronstein AC, Kulig K, Archer PG, Rumack BH. Acute acetaminophen overdose during pregnancy. Obstet Gynecol 1989 Aug; 74 (2): 247-53.
[13] Janes J, Routledge PA. Recent developments in the management of paracetamol (acetaminophen) poisoning. Drug Saf 1992 May-Jun; 7 (3): 170-7.
[14] Mant TG, Tempowski JH, Volans GN, Talbot JC. Adverse reactions to acetylcysteine and effects of overdose. Br Med J (Clin Res Ed) 1984 Jul 28; 289 (6439): 217-9.
[15] Bailey B, McGuigan MA. Management of anaphylactoid reactions to intravenous N-acetylcysteine. Ann Emerg Med 1998 Jun; 31 (6): 710-5.
[16] Schmidt LE, Dalhoff K. Risk factors in the development of adverse reactions to N-acetylcysteine in patients with paracetamol poisoning. Br J Clin Pharmacol 2001 Jan; 51 (1): 87-91.
[17] Sung L, Simons JA, Dayneka NL. Dilution of intravenous N-acetylcysteine as a cause of hyponatremia. Pediatrics 1997 Sep; 100 (3 Pt 1): 389-91.
[18] Linden CH, Rumack BH. Acetaminophen overdose. Emerg Med Clin North Am 1984 Feb; 2 (1): 103-19.
[19] Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975 Jun; 55 (6): 871-6.
[20] Roth B, Woo O, Blanc P. Early metabolic acidosis and coma after acetaminophen ingestion. Ann Emerg Med 1999 Apr; 33 (4): 452-6.
[21] Dargan PI, Jones AL. Acetaminophen poisoning: an update for the intensivist. Crit Care 2002 Apr; 6 (2): 108-10.
[22] Bernal W, Auzinger G, Dhawan A, Wendon J. Acute liver failure. Lancet 2010 Jul 17; 376 (9736): 190-201.
[23] 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 Dec; 22 (6): 742-8.
[24] Jones AL, Prescott LF. Unusual complications of paracetamol poisoning. QJM 1997 Mar; 90 (3): 161-8.
[25] Lip GY, Vale JA. Does acetaminophen damage the heart? J Toxicol Clin Toxicol 1996; 34 (2): 145-7.
[26] Ceschi A, Hofer KE, Rauber-Lüthy C, Kupferschmidt H. Paracetamol orodispersible tablets: a risk for severe poisoning in children? Eur J Clin Pharmacol 2011 Jan; 67 (1): 97-9.
[27] Hamlyn AN, Douglas AP, James OF, Lesna M, Watson AJ. Liver function and structure in survivors of acetaminophen poisoning. A follow-up study of serum bile acids and liver histology. Am J Dig Dis 1977 Jul; 22 (7): 605-10.
[28] Barker JD Jr, de Carle DJ, Anuras S. Chronic excessive acetaminophen use and liver damage. Ann Intern Med 1977 Sep; 87 (3): 299-301.
[29] Ebenezer K, Agarwal I, Fleming D. Acute hepatic failure in an infant caused by acetaminophen (paracetamol) toxicity. Ann Trop Paediatr 2008 Dec; 28 (4): 301-3.

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