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

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

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.

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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%. 

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

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Acetaminophen Metabolism

Acetaminophen Toxic Dose

• The single acute toxic dose of acetaminophen is generally considered to be >200 mg/kg in children

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• 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

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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 :

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Phases of Acetaminophen Toxicity

• Phase 1 : ( 1^st 24 Hours )
• Clinically:
• Asymptomatic, Anorexia, Malaise, Nausea, pallor, diaphoresis, vomiting
• Lab findings :
• Normal except acetaminophen level

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Phases of Acetaminophen Toxicity

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

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Phases of Acetaminophen Toxicity

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

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Phases of Acetaminophen Toxicity

• Phase 4 : ( 4 Days – 3 Weeks )

Patients who survive critical illness in phase 3

Clinically& Lab findings:

• Resolution of liver abnormalities
• Clinical recovery precedes histologic recovery

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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 .

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The Rumack-Matthew nomogram

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

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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)

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Lab Workup

• Laboratory findings in the phases of acetaminophen hepatotoxicity are as follows:

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• Phase 1: Approximately 12 hours after an acute ingestion, liver function studies show a subclinical rise in serum transaminase concentrations (ALT, AST)

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• Phase 2: Elevated serum ALT and AST, PT, and bilirubin concentration; renal function abnormalities may also be present and indicate nephrotoxicity

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• Phase 3: Severe hepatotoxicity is evident on serum studies; hepatic centrilobular necrosis is diagnosed on liver biopsy .

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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 )

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N- acetylcysteine (NAC)

• Mechanism of action : It works primarily via replenishing (increase) hepatic glutathione stores and conjugate toxic metabolite.
• Used within the 1^st 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

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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 .

N- acetylcysteine (NAC) ORAL

N- acetylcysteine (NAC) IV

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 .

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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

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 .

Thank

You