1. Acetaminophen
Poisoning in Pediatrics
Pediatric ER Rotation l Security Forces Hospital- Makkah l Thursday 19 / JAN / 2017
Mohammed Alharthi
Pediatric Resident, R2
Taif Children’s Hospital

2. Main Points
• Introduction .
• Acetaminophen Metabolism and toxicity .
• Epidemiology & Prognosis .
• Toxic Dose .
• Signs & Symptoms .
• Stages of Acetaminophen toxicity .
• Lab workup
• Approach of Management
• Antidote (N-Acetylcysteine )
• Prevention

3. Introduction
• Acetaminophen is a nonsteroidal anti-inflammatory drug with potent antipyretic and analgesic actions but
with very weak anti-inflammatory activity .
• Acetaminophen is the most widely used over-the-counter analgesic agent in the world.
• Acetaminophen is one of the most commonly used oral analgesics and antipyretics.
• It has an excellent safety profile when administered in proper therapeutic doses.
• It is involved in a large proportion of accidental pediatric exposures and deliberate self-poisoning cases
and is the leading pharmaceutical agent responsible for calls to Toxicology Centers .
• Acetaminophen is also the single most commonly taken drug in overdoses that lead to hospital
presentation and admission.
• Hepatic failure and death are uncommon outcomes, although paracetamol remains the most important
single cause of acute fulminant hepatic failure in Western countries.
• Acetaminophen metabolism occurs primarily in the liver.

4. Epidemiology & Prognosis
• The Annual Report of the American Association of Poison Control Centers' National Poison Data
System reported 50,396 single exposures to acetaminophen alone in 2014 .
• Acetaminophen exposure alone resulted in 65 deaths.
• Acetaminophen toxicity is the most common cause of hepatic failure requiring liver
transplantation in Great Britain.
• In the United States, acetaminophen toxicity has replaced viral hepatitis as the most common
cause of acute hepatic failure and is the second most common cause of liver failure requiring
transplantation.
• With aggressive supportive care and antidotal therapy, the mortality rate associated with
acetaminophen hepatotoxicity is less than 2%.

5. Acetaminophen Toxicity
• Results from the formation of a highly reactive intermediate metabolite, N-
acetyl-p-benzoquinone imine (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.
• In overdose:
 Glutathione stores are overwhelmed, and free NAPQI is able to combine
with hepatic macromolecules to produce hepatocellular damage

6. Acetaminophen Metabolism

7. Acetaminophen Toxic Dose
• The single acute toxic dose of acetaminophen is generally
considered to be >200 mg/kg in children
• The Repeated supratherapeutic Toxic doses:
 > 200 mg/kg (or 10g) ingested over a 24 hour period
 > 150 mg/kg/day (or 6 g) ingested over a 48 hour period
 > 100 mg/kg/day ingested over a 72 hour period

8. Sign and Symptoms
• Most patients who overdose on acetaminophen will initially be
asymptomatic, as clinical symptoms of end-organ toxicity do not
manifest until 24-48 hours after an acute ingestion.
• Therefore, to identify a patient who may be at risk of hepatoxicity, the
clinician should determine the time(s) of ingestion, the quantity, the
dose, co- ingestion and the formulation of acetaminophen ingested.
• The clinical course of acetaminophen toxicity generally is divided into
four phases :

9. Phases of Acetaminophen Toxicity
• Phase 1 : ( 1st 24 Hours )
 Clinically:
◦ Asymptomatic, Anorexia, Malaise, Nausea, pallor, diaphoresis,
vomiting
Lab findings :
Normal except acetaminophen level

10. Phases of Acetaminophen Toxicity
• Phase 2 : ( 24 Hours – 72 Hours )
 Clinically:
o Resolution of earlier symptoms
o Right upper quadrant abdominal pain and tenderness
o Tachycardia & hypotension
 Lab findings :
o ↑Bilirubin , Prothrombin time ,Hepaticenzymes
o Oliguria

11. Phases of Acetaminophen Toxicity
•Phase 3 : ( 72 Hours – 96 Hours )
 Clinically & Lab findings :
o continued nausea and vomiting, abdominal pain,
and a tender hepatic edge jaundice
o Peak liver function abnormalities
o Fulminant Hepatic Failure
o Acute Renal Faliure
o Multisystem Organ Failure
o Potential Death

12. Phases of Acetaminophen Toxicity
• Phase 4 : ( 4 Days – 3 Weeks )
Patients who survive critical illness in phase 3
Clinically& Lab findings:
o Resolution of liver abnormalities
o Clinical recovery precedes histologic recovery

13. Lab Workup
• Serum Acetaminophen Concentration
 The basis for diagnosis and treatment.
 If a toxic ingestion is suspected, a serum acetaminophen level should be measured 4 hr after
the reported time of ingestion.
 For patients who present to medical care >4 hr after ingestion, a stat acetaminophen level
should be obtained.
 It is helpful, even in the absence of clinical symptoms, because clinical symptoms are delayed.
 The Rumack-Matthew nomogram interprets the acetaminophen concentration (in micrograms
per mL) in relation to time (in hours) after ingestion, and is predictive of possible
hepatotoxicity after single, acute ingestions of acetaminophen.
 At 4 hrs , 8hrs & 12 hrs .

14. The Rumack-Matthew nomogram

15. The Rumack-Matthew nomogram
• 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
• 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)
• 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

16. Lab Workup
• Recommended serum studies are follows:
 Liver function tests : [ALT], [AST]), bilirubin [total and fractionated], [ALP] .
 Prothrombin time (PT) with international normalized ratio (INR)
 Glucose
 Renal function studies (electrolytes, BUN, creatinine)
 Lipase and amylase (in patients with abdominal pain)
 Salicylate level (in patients with concern of co-ingestants)
 Arterial blood gas and ammonia (in clinically compromised patients)
• Additional recommended studies are as follows:
 Urinalysis (to check for hematuria and proteinuria)
 ECG (to detect additional clues for co-ingestants)

17. Lab Workup
• Laboratory findings in the phases of acetaminophen hepatotoxicity are as follows:
 Phase 1: Approximately 12 hours after an acute ingestion, liver function studies
show a subclinical rise in serum transaminase concentrations (ALT, AST)
 Phase 2: Elevated serum ALT and AST, PT, and bilirubin concentration; renal function
abnormalities may also be present and indicate nephrotoxicity
 Phase 3: Severe hepatotoxicity is evident on serum studies; hepatic centrilobular
necrosis is diagnosed on liver biopsy .

20. Approach of Management
• Initial treatment :
 Basic life support (ABCs)
 Call Toxicology Center
 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 )

21. N- acetylcysteine (NAC)
• Mechanism of action : It works primarily via replenishing (increase)
hepatic glutathione stores and conjugate toxic metabolite.
• Used within the 1st 24 hrs post ingestion
• Most effective when initiated within 8 hr of ingestion
• There is no demonstrated benefit to giving NAC before the 4 hr
post-ingestion mark.
• NAC is available in oral and intravenous forms, and both forms are
equally efficacious

22. N- acetylcysteine (NAC)
• Indications to Start Immediately :
1. Single ingestion of > 200mg /kg ( by history )
2. Unknown time of ingestion & drug level > 10mcg/L
3. Sever clinical symptoms
4. Abnormal liver enzymes
5. Possible hepatic toxicity on normogram .
6. High risk group child .

23. N- acetylcysteine (NAC) ORAL

24. N- acetylcysteine (NAC) IV

25. What is Next ?
• A patient who is being on NAC ,the following lab tests :
Transaminases, synthetic function, and renal function
should be followed daily .
• Patients who develop hepatic failure in spite of NAC
therapy may be candidates for liver transplantation .

26. King’s College criteria
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

27. Prevention
• Inform parents and caregivers that acetaminophen, although safe when dosed properly, can
cause significant harm if misused.
• Educate parents in the proper dosing for children and the danger associated with misusing
various acetaminophen preparations of different concentration
• Parents should always be given clear dose and formulation instructions based on the age and
weight of the child.
• Parents and caregivers must ensure proper storage of medications within the home.
• Supply parents and caregivers with contact information for their local Toxicology center .