Acetaminophen Poisoning in Pediatrics

Pediatric ER Rotation l Security Forces Hospital- Makkah l Thursday 19 / JAN / 2017

Mohammed AlharthiPediatric Resident, R2Taif 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.

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

Acetaminophen Metabolism

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

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 :

Phases of Acetaminophen Toxicity

• Phase 1 : ( 1st 24 Hours ) Clinically:◦ Asymptomatic, Anorexia, Malaise, Nausea, pallor, diaphoresis, vomiting

Lab findings : Normal except acetaminophen level

Phases of Acetaminophen Toxicity

• Phase 2 : ( 24 Hours – 72 Hours ) Clinically:o Resolution of earlier symptomso Right upper quadrant abdominal pain and tendernesso Tachycardia & hypotension

Lab findings :o ↑Bilirubin , Prothrombin time ,Hepaticenzymeso Oliguria

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 jaundiceo Peak liver function abnormalities o Fulminant Hepatic Failureo Acute Renal Faliure o Multisystem Organ Failureo Potential Death

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 abnormalitieso Clinical recovery precedes histologic recovery

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 .

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

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)

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 .

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 )

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

N- acetylcysteine (NAC)• Indications to Start Immediately :

1. Single ingestion of > 200mg /kg ( by history ) 2. Unknown time of ingestion & drug level > 10mcg/L3. 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 .

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