What is the protocol for administering N-acetyl cysteine (NAC) to a patient with suspected acetaminophen overdose, considering potential liver or kidney disease?

N-Acetylcysteine Protocol for Acetaminophen Overdose

Administer N-acetylcysteine (NAC) immediately to any patient with suspected or confirmed acetaminophen overdose when the serum level plots above the "possible toxicity" line on the Rumack-Matthew nomogram, when timing is unknown, or when hepatotoxicity is already present—ideally within 8 hours of ingestion to maximize efficacy. 1, 2

Immediate Actions Upon Presentation

Do not delay NAC administration while awaiting confirmatory acetaminophen levels if there is strong suspicion of significant overdose. 1

• Administer activated charcoal (1 g/kg orally) just prior to starting NAC if the patient presents within 4 hours of ingestion 1, 2, 3
• Draw blood immediately for: acetaminophen level, AST, ALT, INR, bilirubin, creatinine, BUN, electrolytes 2, 3
• Empty the stomach promptly by lavage or induce emesis with syrup of ipecac (15 mL for children, 30 mL for adults) if within 1-2 hours 3
• If activated charcoal was given, perform lavage before NAC administration, as charcoal adsorbs NAC and reduces effectiveness 3

NAC Dosing Regimens

Intravenous Protocol (Preferred Route) 1, 4

The IV route is preferred for acetaminophen overdose, particularly in patients with established hepatotoxicity or those unable to tolerate oral administration. 4

• Loading dose: 150 mg/kg in 5% dextrose over 15 minutes 1, 4, 3
• Second dose: 50 mg/kg over 4 hours 1, 4
• Third dose: 100 mg/kg over 16 hours (total 21-hour protocol) 1, 4

Oral Protocol 1, 4, 3

The 72-hour oral regimen is as effective as the 20-hour IV regimen and may be superior when treatment is delayed beyond 10 hours. 5

• Loading dose: 140 mg/kg orally or via nasogastric tube, diluted to 5% solution in diet cola or diet soft drink 1, 4, 3
• Maintenance dose: 70 mg/kg every 4 hours for 17 additional doses (total 72 hours) 1, 4, 3
• If the patient vomits within 1 hour of any dose, repeat that dose immediately 3
• For persistent vomiting, administer via duodenal intubation 3

Risk Stratification Using Rumack-Matthew Nomogram

Use the nomogram only for single acute ingestions with known time of ingestion when acetaminophen level is drawn 4-24 hours post-ingestion. 2

• Treat if acetaminophen concentration plots at or above the "possible toxicity" line 2
• The nomogram does NOT apply to: repeated supratherapeutic ingestions, extended-release formulations, presentations >24 hours post-ingestion, or unknown time of ingestion 2

Critical Time-Based Treatment Windows

Treatment within 8 hours results in only 2.9% severe hepatotoxicity, compared to 6.1% when treated within 10 hours and 26.4% when treated after 10 hours. 1, 5

• 0-8 hours: Maximal hepatoprotection; NAC provides near-complete protection regardless of acetaminophen level 1, 5
• 8-10 hours: Efficacy begins to diminish; severe hepatotoxicity develops in 6.1% 1, 5
• 10-24 hours: Severe hepatotoxicity develops in 26.4% of at-risk patients 1, 5
• 16-24 hours: Among high-risk patients, hepatotoxicity occurs in 41%—still lower than untreated controls (58%) 1, 5
• >24 hours: NAC still provides benefit and should be administered immediately; nomogram cannot be used 1, 2

Special Clinical Scenarios Requiring Immediate NAC

Established Hepatic Failure 1, 2, 4

Administer IV NAC to all patients with hepatic failure thought to be due to acetaminophen, regardless of time since ingestion. 1, 2

• NAC reduces mortality from 80% to 52% in fulminant hepatic failure 1
• NAC reduces cerebral edema from 68% to 40% and need for inotropic support from 80% to 48% 2
• Early NAC treatment (<10 hours) in fulminant hepatic failure results in 100% survival 2
• Contact liver transplant center immediately; patients require ICU-level care 2, 4

Acute Liver Failure of Unknown Etiology 1, 4

Start NAC in any case of acute liver failure where acetaminophen overdose is suspected or possible, even with inadequate history. 1, 4

• Very high aminotransferases (AST/ALT >3,500 IU/L) are highly correlated with acetaminophen poisoning and should prompt NAC treatment even without confirmatory history 1
• NAC improves transplant-free survival (OR 1.61) and overall survival (OR 2.30) in non-acetaminophen acute liver failure 4

Repeated Supratherapeutic Ingestions 2

Treat with NAC if:

• ≥10 g or 200 mg/kg (whichever is less) during a single 24-hour period 2
• ≥6 g or 150 mg/kg (whichever is less) per 24-hour period for ≥48 hours 2
• Serum acetaminophen ≥10 mg/mL OR AST or ALT >50 IU/L 2

Extended-Release Acetaminophen 1, 2

Extended-release formulations demonstrate prolonged absorption and may show late increases in serum acetaminophen concentration at 14 hours or beyond. 2

• Obtain serial acetaminophen levels 2
• Standard NAC dosing applies, but monitoring and treatment may need extension 1

Unknown Time of Ingestion 1, 2

Administer NAC immediately if detectable acetaminophen levels are present or if hepatotoxicity is evident. 1, 2

High-Risk Populations Requiring Lower Treatment Threshold

Chronic Alcohol Users 1, 2

Treat with NAC even with levels in the "non-toxic" range on nomogram, as severe hepatotoxicity can occur with doses as low as 4 g/day in alcoholics. 2

• Chronic alcohol consumption significantly lowers the threshold for hepatotoxicity 2
• Consider extended NAC treatment duration 2

Other High-Risk Patients 1

Patients at increased risk include those who are fasting, malnourished, or taking enzyme-inducing drugs. 1

• These patients may develop toxicity at lower acetaminophen doses 1
• Treat even if levels are below typical treatment threshold 1

Criteria for Discontinuing NAC

NAC can be discontinued when acetaminophen level is undetectable AND liver function tests remain normal. 2

Laboratory Criteria for Safe Discontinuation 2

• Acetaminophen level undetectable 2
• AST and ALT remain normal (no elevation above baseline) 2
• INR normal 2
• No clinical signs of hepatotoxicity 2

Shortened 12-Hour Protocol (Selected Low-Risk Patients Only) 6

A 12-hour NAC course (250 mg/kg) may be safe in carefully selected low-risk patients with:

• Normal ALT and creatinine on presentation and at 12 hours 6
• Acetaminophen <20 mg/L at 12 hours 6
• Single or staggered overdose (not extended-release) 6

Mandatory Extended Treatment Beyond Standard Protocol 2

Continue NAC beyond the standard protocol for:

• Delayed presentation (>24 hours post-ingestion) 2
• Extended-release acetaminophen 2
• Repeated supratherapeutic ingestions 2
• Unknown time of ingestion with detectable acetaminophen levels 2
• Any elevation in AST or ALT above normal 2
• Rising transaminases 2
• Any coagulopathy 2
• Chronic alcohol use 2

Critical Red Flags Requiring Continuation or Restart of NAC 2

Restart NAC immediately if:

• Any elevation in AST or ALT above normal develops 2
• Transaminases are rising 2
• Any coagulopathy develops 2
• Acetaminophen level becomes detectable 2
• Clinical signs of hepatotoxicity appear 2

If hepatotoxicity develops (AST/ALT >1,000 IU/L), restart NAC immediately and continue until transaminases are declining and INR normalizes. 2

Monitoring During Treatment

Repeat SGOT, SGPT, bilirubin, prothrombin time, creatinine, BUN, blood sugar, and electrolytes daily if acetaminophen plasma level is in the potentially toxic range. 3

• Monitor for complications of acute liver failure: encephalopathy, coagulopathy, renal failure, metabolic derangements 2
• Patients with severe hepatotoxicity (AST >1,000 IU/L) or coagulopathy require ICU-level care 2

Considerations for Patients with Liver or Kidney Disease

Pre-existing liver disease does not contraindicate NAC; in fact, these patients may be at higher risk and should receive NAC promptly. 1, 4

• NAC should be administered regardless of baseline hepatic function 4
• Chronic hepatitis B or other liver disease does not preclude acetaminophen-induced liver failure as the acute cause 4
• Monitor renal function closely, as acetaminophen toxicity can cause acute kidney injury 3
• No dose adjustment is required for renal impairment when treating acetaminophen overdose 4

Adverse Effects and Management

Adverse effects are minimal and should not prevent NAC administration. 4

• Nausea, vomiting, diarrhea, or constipation (most common with oral route) 4, 3
• Transient skin erythema or mild urticaria during IV loading dose (14.3% of patients, usually does not require discontinuation) 7
• Skin rash occurs in <5% of patients 4
• Transient bronchospasm in 1-2% of cases 4
• Generalized urticaria (rare); if severe allergic symptoms occur, discontinue only if not essential and symptoms cannot be controlled 3

Critical Pitfalls to Avoid

• Do not delay NAC while awaiting acetaminophen levels if overdose is strongly suspected 1
• Do not use the nomogram for presentations >24 hours, repeated ingestions, or extended-release formulations 2
• Low or absent acetaminophen levels do NOT rule out acetaminophen poisoning if ingestion was remote or occurred over several days 2
• Do not stop NAC prematurely; ensure all discontinuation criteria are met 2
• Do not withhold NAC in late presentations (>24 hours); it still provides mortality benefit 1, 2
• Activated charcoal adsorbs NAC; if charcoal was given, perform lavage before NAC 3