Overview
Definition:
Acetaminophen (paracetamol) toxicity occurs when the ingested dose exceeds the liver's metabolic capacity, leading to the formation of the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI)
This metabolite depletes hepatic glutathione stores and covalently binds to hepatocytes, causing centrilobular necrosis and acute liver failure
It is a common cause of poisoning in children, often accidental but sometimes intentional.
Epidemiology:
Acetaminophen is one of the most frequently ingested medications in accidental childhood poisonings
While severe toxicity is less common in children compared to adults due to differences in metabolism and often lower doses ingested, it remains a significant concern
The incidence of severe hepatotoxicity is influenced by the amount ingested, time to treatment, and co-ingestion of other substances, particularly those that induce CYP450 enzymes.
Clinical Significance:
Acetaminophen toxicity is a critical pediatric emergency that requires prompt recognition and management
Untreated severe toxicity can lead to fulminant hepatic failure, hepatic encephalopathy, disseminated intravascular coagulation (DIC), multi-organ dysfunction, and death
Early intervention with N-acetylcysteine (NAC) is highly effective in preventing or mitigating liver damage, making accurate assessment of risk and timely administration of antidote paramount for successful outcomes.
Clinical Presentation
Symptoms:
Symptoms often progress in stages: Stage 1 (0-24 hours): Often asymptomatic or with mild, non-specific symptoms like nausea, vomiting, anorexia, and malaise
Pallor may be present
Stage 2 (24-72 hours): Initial symptoms may subside
Right upper quadrant (RUQ) abdominal pain may develop as hepatic injury begins
Transaminases (AST, ALT) start to rise
Stage 3 (72-96 hours): Peak hepatic injury occurs, characterized by jaundice, coagulopathy (prolonged PT/INR), hypoglycemia, hepatic encephalopathy (confusion, lethargy, coma), and potentially acute kidney injury (AKI) or pancreatitis
Stage 4 (>96 hours): Recovery phase in survivors, with gradual improvement in liver function over days to weeks, or progression to death from liver failure.
Signs:
Vital signs may be normal in early stages, or show mild tachycardia and tachypnea due to nausea or pain
Abdominal examination may reveal RUQ tenderness
Later signs include jaundice, asterixis (flapping tremor) indicating hepatic encephalopathy, signs of coagulopathy (bruising, petechiae), and altered mental status (lethargy, coma)
Signs of multi-organ failure may emerge.
Diagnostic Criteria:
Diagnosis is based on a history of acetaminophen ingestion (known or suspected) and clinical signs of toxicity, supported by laboratory findings
The Rumack-Bayer nomogram is a crucial tool for assessing the risk of hepatotoxicity based on serum acetaminophen levels plotted against time since ingestion
Criteria for initiating NAC include: serum acetaminophen level above the treatment line on the nomogram, ingestion of unknown amount/time but with risk factors, elevated transaminases (AST/ALT), or signs of hepatic dysfunction.
Diagnostic Approach
History Taking:
Crucial information includes the exact time of ingestion, the specific acetaminophen product ingested (e.g., plain acetaminophen, combination products), the amount ingested in milligrams per kilogram (mg/kg) of body weight, the child's weight, any co-ingestions (especially alcohol, anticonvulsants, certain antibiotics), and any previous acetaminophen use
Ask about existing liver disease or risk factors for poor metabolism
Enquire about the context of ingestion (accidental vs
intentional).
Physical Examination:
A thorough physical examination is essential, focusing on vital signs, mental status assessment (Glasgow Coma Scale), presence of jaundice, abdominal tenderness (especially RUQ), and assessment for signs of bleeding or coagulopathy
Monitor for signs of hepatic encephalopathy (asterixis) and multi-organ dysfunction.
Investigations:
Serum acetaminophen level (measured 4 hours post-ingestion is ideal for nomogram use, but can be drawn earlier or later depending on clinical suspicion)
Liver function tests (LFTs): AST, ALT, alkaline phosphatase, bilirubin, albumin, prothrombin time (PT)/international normalized ratio (INR)
Monitor these serially (e.g., every 12-24 hours)
Renal function tests: BUN, creatinine
Electrolytes
Glucose
Complete blood count (CBC)
Blood gas analysis if patient is unwell
Consider toxicology screen if co-ingestion is suspected.
Differential Diagnosis:
Other causes of acute liver injury in children, such as viral hepatitis (Hepatitis A, B, E), drug-induced liver injury (e.g., valproic acid, isoniazid), Wilson's disease, autoimmune hepatitis, Reye's syndrome (historically associated with aspirin), and other forms of poisoning (e.g., Amanita phalloides mushroom, carbon tetrachloride).
Management
Initial Management:
If ingestion is recent (within 1 hour) and the dose is potentially toxic, activated charcoal may be administered to reduce absorption
Gastric lavage may be considered in specific circumstances but is less effective beyond 1 hour
Immediate referral to a toxicology center or hospital with pediatric critical care capabilities is crucial
IV fluid resuscitation if dehydrated or in shock.
Medical Management:
The cornerstone of treatment is N-acetylcysteine (NAC)
It acts as a glutathione precursor, replenishing hepatic stores and detoxifying NAPQI
The standard NAC protocol involves an initial loading dose followed by maintenance infusions
The recommended pediatric dosing for intravenous NAC is: Loading dose: 150 mg/kg IV over 1 hour
Second dose: 150 mg/kg IV over 1 hour (administered 1 hour after the first dose, if AST/ALT are elevated or level is above treatment line)
Maintenance dose: 50 mg/kg IV over 16 hours (infuse the remainder of the 16-hour dose)
For oral NAC: Loading dose: 140 mg/kg PO, followed by 17 doses of 70 mg/kg PO every 4 hours
NAC is most effective when started within 8-10 hours of ingestion but can still be beneficial even when initiated later, especially if LFTs are elevated
Monitor LFTs, PT/INR, glucose, renal function, and electrolytes closely
Continue NAC until serum acetaminophen levels are undetectable and LFTs are normal or improving.
Surgical Management:
Liver transplantation is reserved for patients who develop fulminant hepatic failure with severe coagulopathy (INR > 4-5 despite vitamin K therapy), encephalopathy (grade III-IV), rising creatinine, and hemodynamic instability, and who are not showing signs of recovery
This is a last resort in cases of irreversible liver damage.
Supportive Care:
Aggressive supportive care is vital
This includes fluid and electrolyte management, glucose monitoring and supplementation (to prevent hypoglycemia), correction of coagulopathy with fresh frozen plasma or vitamin K if indicated, management of hepatic encephalopathy (e.g., lactulose, rifaximin if appropriate, but often managed with supportive care and NAC), and respiratory support if intubation is required
Continuous monitoring in an intensive care setting is often necessary.
Complications
Early Complications:
Acute liver injury (hepatotoxicity), acute kidney injury (AKI), pancreatitis, hypoglycemia, metabolic acidosis, coagulopathy (elevated PT/INR), hepatic encephalopathy, cardiac arrhythmias (particularly with rapid IV infusion of NAC if not properly diluted or if patient has hypersensitivity).
Late Complications:
Chronic liver disease, post-necrotic cirrhosis (rare with timely NAC), neurological deficits from severe encephalopathy, or death from multi-organ failure if treatment is delayed or ineffective.
Prevention Strategies:
Educate parents about safe storage of medications, keeping them out of reach of children
Emphasize correct dosing instructions and using the measuring device provided with the medication
Advise against giving multiple products containing acetaminophen simultaneously
Promptly seek medical attention if an overdose is suspected
Regular monitoring of serum acetaminophen levels and timely administration of NAC are key to preventing severe outcomes.
Prognosis
Factors Affecting Prognosis:
The most critical factor is the time to initiation of NAC therapy
treatment within 8-10 hours of ingestion significantly improves the prognosis
The magnitude of acetaminophen level and the rate of its decline also predict outcome
Presence of risk factors such as chronic alcohol use, malnutrition, or concurrent use of enzyme-inducing drugs can worsen prognosis
Severity of LFT abnormalities and coagulopathy at presentation are important indicators.
Outcomes:
With prompt and appropriate NAC administration, the prognosis for acetaminophen toxicity is generally excellent, with minimal or no long-term sequelae
Most children recover fully
However, in cases of delayed treatment or massive overdose, severe hepatotoxicity can lead to irreversible liver damage, requiring transplantation or resulting in mortality
Fulminant hepatic failure carries a high mortality rate without transplantation.
Follow Up:
Children treated for acetaminophen toxicity should have follow-up LFTs to ensure complete recovery
For severe cases or those who developed significant liver dysfunction, periodic liver function monitoring may be recommended for several months
Patients experiencing severe encephalopathy or multi-organ dysfunction require thorough assessment for residual deficits
Patients with intentional ingestions should undergo psychiatric evaluation and counseling.
Key Points
Exam Focus:
The Rumack-Bayer nomogram is a critical visual aid
know its axes (serum acetaminophen level vs
time post-ingestion) and the treatment line
Remember the loading and maintenance doses for IV and oral NAC
Understand the stages of acetaminophen toxicity
Be aware of co-ingestions that can alter metabolism (e.g., enzyme inducers).
Clinical Pearls:
Always obtain a serum acetaminophen level 4 hours post-ingestion if the time of ingestion is known and dose is potentially toxic
If the time of ingestion is unknown or >24 hours, still measure the level and assess for clinical signs and LFTs
Never hesitate to administer NAC if there is any doubt about significant ingestion or risk of hepatotoxicity, especially if LFTs are elevated
Serial LFTs are crucial for monitoring progress and determining duration of NAC therapy.
Common Mistakes:
Delaying NAC administration due to waiting for LFTs to rise (hepatotoxicity occurs before LFTs become significantly abnormal)
Incorrectly calculating NAC doses, especially for IV infusions which require dilution
Not considering combination products containing acetaminophen
Dismissing symptoms in early stages of toxicity
Failing to assess for co-ingestions which can significantly impact management and prognosis.