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Acetaminophen
Poisoning
in children
Prof. Dr. Saad S Al Ani
Senior Pediatric Consultant
Head of Pediatric Consultant
Khorfakkan Hospital , Sharjah, UAE
saadsalani@aol.com
Acetaminophen
Is a nonsteroidal anti-inflammatory drug with
potent antipyretic and analgesic actions but with
very weak anti-inflammatory activity
1/22/2015
Acetaminophen poisoning
Prof.Dr.Saad S Al Ani Khorfakkan Hospital
2
http://cid.oxfordjournals.org/content/31/Supplement_5/S202.full
dailymed.nlm.nih.gov
Acetaminophen can be:
- Unintentionally ingested by young children
-Taken in an intentional overdose by adolescents
and adults
- Inappropriately dosed in all ages
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Acetaminophen
www.turbosquid.com
Acetaminophen toxicity
Results from the formation of a highly
reactive intermediate metabolite, N-acetyl-
p-benzoquinone imine (NAPQI)
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www.prevention.com
Acetaminophen Metabolism
42% - 67%
26% - 36%
5% - 8%
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1
2
3
acetadote.com
NAPQI
In therapeutic use:
Only a small percentage of a dose (approximately
5%) is metabolized by the hepatic cytochrome P450
enzyme CYP2E1 to NAPQI, which is then
immediately conjugated with glutathione to form a
nontoxic mercapturic acid conjugate.
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drugstudy.weebly.com
In overdose:
Glutathione stores are overwhelmed, and free
NAPQI is able to combine with hepatic
macromolecules to produce hepatocellular
damage
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NAPQI (Cont.)
www.walmart.com
Acute toxic dose of acetaminophen
The single acute toxic dose of acetaminophen is
generally considered to be >200 mg/kg in
children
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www.13wmaz.com
Acute toxic dose of acetaminophen
(Cont.)
Supratherapeutic doses ( >75 mg/kg/day for
consecutive days) can lead to hepatic injury or
failure in some children, especially in the setting
of :
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Fever
Dehydration
Poor
nutrition
Other conditions
↓
↓glutathione stores
Clinical & Laboratory manifestations
Classically, four stages of acetaminophen
toxicity have been described
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fox8.com
Stages of acetaminophen toxicity
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Stage 1
• Within first 0.5 -24 hr
• Clinically:
Anorexia ,Nausea ,Vomiting ,Malaise,
Pallor ,Diaphoresis
• Lab findings :
Normal except acetaminophen level
www.boiseweekly.com
Stages of acetaminophen toxicity (cont.)
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Stage 2
• Within 24-48 hr
• Clinically:
-Resolution of earlier symptoms
-Right upper quadrant abdominal pain and
tenderness
• Lab findings :
-↑Bilirubin , Prothrombin time ,Hepatic
enzymes
- Oliguria
www.sooothe.com
Stages of acetaminophen toxicity (cont.)
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Stage 3
• Within 72-96 hr
• Clinically& Lab findings:
- Peak liver function abnormalities
- Fulminant hepatic failure
- Multisystem organ failure
- Potential death
http://www.3dchem.com/molecules
Stages of acetaminophen toxicity (cont.)
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Stage 4
• Within 4 days – 2 weeks
• Clinically& Lab findings:
- Resolution of liver abnormalities
- Clinical recovery precedes histologic recovery
www.lef.org
Laboratory investigations
If a toxic ingestion is suspected, a serum
acetaminophen level should be measured 4 hr
after the reported time of ingestion.
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For patients who present to medical care >4
hr after ingestion, a stat acetaminophen level
should be obtained.
curriculum.toxicology.wikispaces.net
Laboratory investigations (cont.)
Acetaminophen levels obtained <4 hr after
ingestion are difficult to interpret and cannot be
used to estimate the potential for toxicity.
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Other important baseline labs include :
- Hepatic transaminases
- Renal function tests
- Coagulation parameters www.ganfyd.org
Rumack-Matthew nomogram for
acetaminophen poisoning
This nomogram is only
intended for use in
patients who present
within 24 hr of a single
acute acetaminophen
ingestion with a known
time of ingestion
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Prof.Dr.Saad S Al Ani Khorfakkan Hospital
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www.rxlist.com
Rumack-Matthew nomogram for
acetaminophen poisoning(CONT.)
Any patient with a
serum acetaminophen
level in the possible or
probable hepatotoxicity
range per the Rumack-
Matthew nomogram
should be treated with
N-acetylcysteine (NAC)
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Acetaminophen poisoning
Prof.Dr.Saad S Al Ani Khorfakkan Hospital
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Rumack-Matthew nomogram for
acetaminophen poisoning(CONT.)
Patients who have an
initially nontoxic level and
have ingested combination
products or co-ingestants
that can slow GI motility
(e.g., diphenhydramine,
opioids) should have a
second acetaminophen
level drawn 6-8 hr after
ingestion
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Unknown time of ingestion or a history of chronic
supratherapeutic ingestion?
For assessment of such patient,
check :
- Acetaminophen level
- Hepatic transaminases
- Coagulation parameters.
If the acetaminophen level is
>10 μg /mL, even with normal
liver function tests, this patient
is a candidate to be treated
with NAC
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Why?
To catch patients in the
asymptomatic phase of
toxicity,before hepatotoxicity
develops, because a level of
10 g/ mL is potentially toxic
at 20 hr after ingestion
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Remember
Patients who have any signs
of hepatotoxicity (elevated
transaminases and international
normalized ratio [INR]), even
with a low or nondetectable
acetaminophen level, are
also candidates for antidotal
therapy
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Remember (cont.)
Patients who have an
acetaminophen level <10
μg/mL and normal
transaminases are unlikely to
develop significant toxicity.
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Treatment
•Initial treatment :
• Basic life support (ABCs)
• Decontamination with activated
charcoal (within 1-2 hr of
ingestion)
• The antidote for acetaminophen
poisoning is N- acetylcysteine
(NAC) ( which works primarily
via replenishing hepatic
glutathione stores )
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http://www.drclarkstore.eu/images/P/45171-Activated-Charcoal.jpg
www.iherb.com
N- acetylcysteine (NAC)
• Most effective when initiated
within 8 hr of ingestion
• There is no demonstrated benefit
to giving NAC before the 4 hr
post-ingestion mark.
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www.sedico.net
www.shinsheng.com.tw
N- acetylcysteine (NAC) (cont.)
1/22/2015
NAC is available in
oral and intravenous
forms, and both forms
are equally efficacious
Acetaminophen poisoning
Prof.Dr.Saad S Al Ani Khorfakkan Hospital
26
www.drugstore.com
www.indiamart.com
N- acetylcysteine (NAC) (cont.)
•
1/22/2015
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N- Acetylcysteine (Mucomyst)
Dosage: 140 mg /kg loading ,followed by 70 mg / Kg
every 4 hrs. for 17 doses
Route of administration : Oral
Side effects: Nausea ,vomiting
N.B. Most effective if given within 8 hr of ingestion
eshop.chothuoc24h.com
N- acetylcysteine (NAC) (cont.)
1/22/2015
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N- Acetylcysteine (Acetadote)
Dosage: 150 mg /kg over 1 hr ,followed by 50 mg /
Kg over 4 hrs. followed by 100 mg /Kg over 16 hrs.
Route of administration : IV
Side effects: Anaphylactoid reactions
(most commonly with loading dose)
thehealthscience.com www.webmd.com
What is next
A patient who is being on NAC ,the following
lab tests : Transaminases, synthetic function, and
renal function should be followed daily
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Patients who develop hepatic failure in spite of
NAC therapy may be candidates for liver
transplantation
King’s College criteria
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• Are used to determine which patients should
be referred for consideration of liver
transplant.
• These criteria include :
1. Acidosis (pH <7.3) after adequate fluid
resuscitation,
2. Coagulopathy (prothrombin time [PT] >100
sec),
3. Renal dysfunction (creatinine >3.4 mg/dL),
4. Hepatic encephalopathy grade III or IV
References
• Dart RC, Rumack BH: Patient-tailored acetylcysteine administration, Ann Emerg Med
50:280–281, 2007
• Centers for Disease Control and Prevention: Fatal poisoning among young children from
diethylene glycol–contaminated acetaminophen—Nigeria, 2008–2009, MMWR Morb Mortal
Wkly Rep 58:1345–1346, 2009.
• http://www.healthdietmedicine.com/side-effects-of-acetaminophen-paracetamol/
• http://cid.oxfordjournals.org/content/31/Supplement_5/S202.full
• "Paracetamol". University of Oxford Centre for Suicide Research. 25 March 2013.
• "Paracetamol overdose: new guidance on treatment with intravenous acetylcysteine". Drug
Safety Update 6 (2): A1. September 2012.
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1/22/2015
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www.tvoinews.com

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Acetaminophen poisoning

  • 1. Acetaminophen Poisoning in children Prof. Dr. Saad S Al Ani Senior Pediatric Consultant Head of Pediatric Consultant Khorfakkan Hospital , Sharjah, UAE saadsalani@aol.com
  • 2. Acetaminophen Is a nonsteroidal anti-inflammatory drug with potent antipyretic and analgesic actions but with very weak anti-inflammatory activity 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 2 http://cid.oxfordjournals.org/content/31/Supplement_5/S202.full dailymed.nlm.nih.gov
  • 3. Acetaminophen can be: - Unintentionally ingested by young children -Taken in an intentional overdose by adolescents and adults - Inappropriately dosed in all ages 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3 Acetaminophen www.turbosquid.com
  • 4. Acetaminophen toxicity Results from the formation of a highly reactive intermediate metabolite, N-acetyl- p-benzoquinone imine (NAPQI) 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 4 www.prevention.com
  • 5. Acetaminophen Metabolism 42% - 67% 26% - 36% 5% - 8% 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 5 1 2 3 acetadote.com
  • 6. NAPQI In therapeutic use: Only a small percentage of a dose (approximately 5%) is metabolized by the hepatic cytochrome P450 enzyme CYP2E1 to NAPQI, which is then immediately conjugated with glutathione to form a nontoxic mercapturic acid conjugate. 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 6 drugstudy.weebly.com
  • 7. In overdose: Glutathione stores are overwhelmed, and free NAPQI is able to combine with hepatic macromolecules to produce hepatocellular damage 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 7 NAPQI (Cont.) www.walmart.com
  • 8. Acute toxic dose of acetaminophen The single acute toxic dose of acetaminophen is generally considered to be >200 mg/kg in children 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 8 www.13wmaz.com
  • 9. Acute toxic dose of acetaminophen (Cont.) Supratherapeutic doses ( >75 mg/kg/day for consecutive days) can lead to hepatic injury or failure in some children, especially in the setting of : 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 9 Fever Dehydration Poor nutrition Other conditions ↓ ↓glutathione stores
  • 10. Clinical & Laboratory manifestations Classically, four stages of acetaminophen toxicity have been described 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 10 fox8.com
  • 11. Stages of acetaminophen toxicity 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 11 Stage 1 • Within first 0.5 -24 hr • Clinically: Anorexia ,Nausea ,Vomiting ,Malaise, Pallor ,Diaphoresis • Lab findings : Normal except acetaminophen level www.boiseweekly.com
  • 12. Stages of acetaminophen toxicity (cont.) 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 12 Stage 2 • Within 24-48 hr • Clinically: -Resolution of earlier symptoms -Right upper quadrant abdominal pain and tenderness • Lab findings : -↑Bilirubin , Prothrombin time ,Hepatic enzymes - Oliguria www.sooothe.com
  • 13. Stages of acetaminophen toxicity (cont.) 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 13 Stage 3 • Within 72-96 hr • Clinically& Lab findings: - Peak liver function abnormalities - Fulminant hepatic failure - Multisystem organ failure - Potential death http://www.3dchem.com/molecules
  • 14. Stages of acetaminophen toxicity (cont.) 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 14 Stage 4 • Within 4 days – 2 weeks • Clinically& Lab findings: - Resolution of liver abnormalities - Clinical recovery precedes histologic recovery www.lef.org
  • 15. Laboratory investigations If a toxic ingestion is suspected, a serum acetaminophen level should be measured 4 hr after the reported time of ingestion. 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 15 For patients who present to medical care >4 hr after ingestion, a stat acetaminophen level should be obtained. curriculum.toxicology.wikispaces.net
  • 16. Laboratory investigations (cont.) Acetaminophen levels obtained <4 hr after ingestion are difficult to interpret and cannot be used to estimate the potential for toxicity. 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 16 Other important baseline labs include : - Hepatic transaminases - Renal function tests - Coagulation parameters www.ganfyd.org
  • 17. Rumack-Matthew nomogram for acetaminophen poisoning This nomogram is only intended for use in patients who present within 24 hr of a single acute acetaminophen ingestion with a known time of ingestion 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 17 www.rxlist.com
  • 18. Rumack-Matthew nomogram for acetaminophen poisoning(CONT.) Any patient with a serum acetaminophen level in the possible or probable hepatotoxicity range per the Rumack- Matthew nomogram should be treated with N-acetylcysteine (NAC) 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 18
  • 19. Rumack-Matthew nomogram for acetaminophen poisoning(CONT.) Patients who have an initially nontoxic level and have ingested combination products or co-ingestants that can slow GI motility (e.g., diphenhydramine, opioids) should have a second acetaminophen level drawn 6-8 hr after ingestion 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 19
  • 20. Unknown time of ingestion or a history of chronic supratherapeutic ingestion? For assessment of such patient, check : - Acetaminophen level - Hepatic transaminases - Coagulation parameters. If the acetaminophen level is >10 μg /mL, even with normal liver function tests, this patient is a candidate to be treated with NAC 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 20
  • 21. Why? To catch patients in the asymptomatic phase of toxicity,before hepatotoxicity develops, because a level of 10 g/ mL is potentially toxic at 20 hr after ingestion 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 21
  • 22. Remember Patients who have any signs of hepatotoxicity (elevated transaminases and international normalized ratio [INR]), even with a low or nondetectable acetaminophen level, are also candidates for antidotal therapy 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 22
  • 23. Remember (cont.) Patients who have an acetaminophen level <10 μg/mL and normal transaminases are unlikely to develop significant toxicity. 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 23
  • 24. Treatment •Initial treatment : • Basic life support (ABCs) • Decontamination with activated charcoal (within 1-2 hr of ingestion) • The antidote for acetaminophen poisoning is N- acetylcysteine (NAC) ( which works primarily via replenishing hepatic glutathione stores ) 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 24 http://www.drclarkstore.eu/images/P/45171-Activated-Charcoal.jpg www.iherb.com
  • 25. N- acetylcysteine (NAC) • Most effective when initiated within 8 hr of ingestion • There is no demonstrated benefit to giving NAC before the 4 hr post-ingestion mark. 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 25 www.sedico.net www.shinsheng.com.tw
  • 26. N- acetylcysteine (NAC) (cont.) 1/22/2015 NAC is available in oral and intravenous forms, and both forms are equally efficacious Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 26 www.drugstore.com www.indiamart.com
  • 27. N- acetylcysteine (NAC) (cont.) • 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 27 N- Acetylcysteine (Mucomyst) Dosage: 140 mg /kg loading ,followed by 70 mg / Kg every 4 hrs. for 17 doses Route of administration : Oral Side effects: Nausea ,vomiting N.B. Most effective if given within 8 hr of ingestion eshop.chothuoc24h.com
  • 28. N- acetylcysteine (NAC) (cont.) 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 28 N- Acetylcysteine (Acetadote) Dosage: 150 mg /kg over 1 hr ,followed by 50 mg / Kg over 4 hrs. followed by 100 mg /Kg over 16 hrs. Route of administration : IV Side effects: Anaphylactoid reactions (most commonly with loading dose) thehealthscience.com www.webmd.com
  • 29. What is next A patient who is being on NAC ,the following lab tests : Transaminases, synthetic function, and renal function should be followed daily 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 29 Patients who develop hepatic failure in spite of NAC therapy may be candidates for liver transplantation
  • 30. King’s College criteria 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 30 • Are used to determine which patients should be referred for consideration of liver transplant. • These criteria include : 1. Acidosis (pH <7.3) after adequate fluid resuscitation, 2. Coagulopathy (prothrombin time [PT] >100 sec), 3. Renal dysfunction (creatinine >3.4 mg/dL), 4. Hepatic encephalopathy grade III or IV
  • 31. References • Dart RC, Rumack BH: Patient-tailored acetylcysteine administration, Ann Emerg Med 50:280–281, 2007 • Centers for Disease Control and Prevention: Fatal poisoning among young children from diethylene glycol–contaminated acetaminophen—Nigeria, 2008–2009, MMWR Morb Mortal Wkly Rep 58:1345–1346, 2009. • http://www.healthdietmedicine.com/side-effects-of-acetaminophen-paracetamol/ • http://cid.oxfordjournals.org/content/31/Supplement_5/S202.full • "Paracetamol". University of Oxford Centre for Suicide Research. 25 March 2013. • "Paracetamol overdose: new guidance on treatment with intravenous acetylcysteine". Drug Safety Update 6 (2): A1. September 2012. 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 31
  • 32. 1/22/2015 Acetaminophen poisoning Prof.Dr.Saad S Al Ani Khorfakkan Hospital 32 www.tvoinews.com