Acetaminophen Overdose - Using the Rumack-Matthew Nomogram — Pharmacology clinical case

Pharmacology · Year 2 · from Pharmacology

Case 1: Acetaminophen Overdose - Using the Rumack-Matthew Nomogram

Patient Demographics

Age: 22 years
Sex: Female
Occupation: College student

Chief Complaint

"I took a bunch of pills a few hours ago."

History of Present Illness

A 22-year-old woman is brought to the emergency department by her roommate after admitting she ingested "a handful" of acetaminophen tablets following an argument with her boyfriend approximately 4 hours ago. She reports taking "about 30 pills" of Extra Strength Tylenol (500 mg each) in a single ingestion. She now has mild nausea and abdominal discomfort but otherwise feels okay. She denies co-ingestion of other substances, alcohol, or other medications. She has no suicidal ideation currently and expresses regret. Her roommate found her with an empty bottle that originally contained 50 tablets.

Estimated Ingestion

30 tablets x 500 mg = 15,000 mg (15 g) of acetaminophen
Patient weight: 60 kg
Dose: 250 mg/kg (significantly above toxic threshold of 150 mg/kg)

Past Medical History

Depression (not currently on medications)
No liver disease
No chronic acetaminophen use
No alcohol use disorder

Physical Examination (4 Hours Post-Ingestion)

Vital Signs: BP 118/72 mmHg, HR 82 bpm, RR 16/min, T 37.1C, O2 sat 99% RA
General: Alert, anxious, no acute distress
HEENT: Normal
Cardiovascular: Regular rhythm
Abdomen: Soft, mild RUQ tenderness, no hepatomegaly
Neurologic: Alert, oriented, no asterixis
Skin: No jaundice

Laboratory Workup

Initial Labs (4 hours post-ingestion):

Test	Result	Reference	Interpretation
Acetaminophen level	185 mcg/mL	Therapeutic: 10-20	Toxic
AST	32 U/L	10-40	Normal
ALT	28 U/L	7-56	Normal
Total Bilirubin	0.8 mg/dL	0.1-1.2	Normal
INR	1.0	0.8-1.2	Normal
Creatinine	0.8 mg/dL	0.6-1.2	Normal
pH	7.42	7.35-7.45	Normal
Lactate	1.2 mmol/L	0.5-2.2	Normal
Salicylate level	< 1 mg/dL	-	Negative
Ethanol level	< 10 mg/dL	-	Negative
Urine drug screen	Negative	-	-

Using the Rumack-Matthew Nomogram

The Rumack-Matthew Nomogram:

Used for SINGLE acute acetaminophen ingestions with KNOWN time of ingestion
Plots serum acetaminophen concentration against time post-ingestion
Determines need for N-acetylcysteine (NAC) treatment

Key Treatment Lines:

Line	4-hour level	Risk
Original Rumack-Matthew	200 mcg/mL	"Probable hepatotoxicity"
Treatment Line (US)	150 mcg/mL	Start NAC if above this line
Modified (high-risk)	100 mcg/mL	Used for high-risk patients

This Patient:

Time: 4 hours post-ingestion
Level: 185 mcg/mL
ABOVE the treatment line (150 mcg/mL at 4 hours)
NAC treatment is indicated

Nomogram Interpretation:

            Acetaminophen Concentration (mcg/mL)
                500 |
                    |
    Probable        |___
    Toxicity  200   |   \___ (Rumack-Matthew line)
                    |       \___
    Treatment 150   |___        \___
    Line            |   \___ "Treatment line"
                100 |       \___
                    |           \___
                 50 |               \___
                    |___________________\____
                    0  4  8  12  16  20  24
                       Hours Post-Ingestion

Pathophysiology of Acetaminophen Toxicity

Normal Metabolism:

Acetaminophen predominantly metabolized by glucuronidation (60%) and sulfation (35%)
Small amount (5%) oxidized by CYP2E1 to NAPQI (N-acetyl-p-benzoquinone imine)
NAPQI is highly reactive but immediately conjugated with glutathione to non-toxic metabolite

In Overdose:

Glucuronidation and sulfation pathways become saturated
More acetaminophen shunted to CYP2E1 pathway
Increased NAPQI production
Glutathione stores depleted (when < 30% of normal)
Unconjugated NAPQI binds to hepatocyte proteins
Cellular damage, oxidative stress, and hepatocyte death
Centrilobular necrosis (Zone 3 - highest CYP concentration)

Stages of Acetaminophen Toxicity:

Stage	Time	Clinical Findings	Labs
I	0-24 h	Nausea, vomiting, malaise, or asymptomatic	Normal or mildly elevated AST/ALT
II	24-72 h	RUQ pain, hepatomegaly	Rising AST/ALT, PT prolonged
III	72-96 h	Peak hepatotoxicity, possible hepatic failure	AST/ALT peak (can exceed 10,000), coagulopathy, encephalopathy
IV	4 d - 2 wk	Recovery or death	Resolution or transplant

This patient is in Stage I - she feels relatively well but is at high risk for progression

Treatment

N-ACETYLCYSTEINE (NAC) - The Antidote

Mechanism of NAC:

Replenishes glutathione: NAC is metabolized to cysteine, a glutathione precursor
Direct NAPQI detoxification: Can directly conjugate with NAPQI
Antioxidant effects: Scavenges free radicals, reduces oxidative stress
Hepatoprotective: Improves microcirculation, may support hepatocyte regeneration

Key Timing:

Most effective within 8 hours of ingestion (near 100% protection)
Still beneficial up to 24 hours
Provides benefit even after hepatotoxicity established

NAC Protocols:

IV Protocol (Preferred in most EDs):

Bag	Dose	Duration
Loading	150 mg/kg in 200 mL D5W	1 hour
Bag 2	50 mg/kg in 500 mL D5W	4 hours
Bag 3	100 mg/kg in 1000 mL D5W	16 hours
Total	300 mg/kg	21 hours

Oral Protocol (Alternative):

Loading: 140 mg/kg
Maintenance: 70 mg/kg every 4 hours x 17 doses
Total duration: 72 hours

This Patient's Treatment:

Initiated IV NAC within 4.5 hours of ingestion (excellent timing)
21-hour protocol

Anaphylactoid Reaction to IV NAC:

Occurs in 10-20% of patients
Flushing, pruritus, urticaria, bronchospasm
NOT true IgE-mediated allergy
Usually occurs during loading dose
Management: Slow infusion rate, antihistamines; rarely need to stop

Additional Management

1. GI Decontamination:

Activated charcoal if < 4 hours post-ingestion (she's at 4 hours - borderline)
Dose: 1 g/kg (max 50 g)
Binds acetaminophen, reduces absorption
Administered in this case (just within window)

2. Supportive Care:

IV fluids
Antiemetics for nausea
Monitor for complications

3. Laboratory Monitoring:

Serial AST, ALT, INR, creatinine every 6-12 hours
Monitor for hepatotoxicity development
Peak transaminases expected 48-72 hours if toxicity occurs

4. Psychiatry Consultation:

Required for intentional ingestion
Safety assessment before discharge

Clinical Course

Completed 21-hour IV NAC protocol
Repeat labs at 12 hours: AST 45, ALT 52, INR 1.0 (minimal elevation)
Repeat labs at 24 hours: AST 38, ALT 45, INR 1.0 (normalizing)
No evidence of hepatotoxicity
Psychiatry cleared for discharge with outpatient follow-up
Discharged day 2

When Nomogram Cannot Be Used

Limitations of Rumack-Matthew Nomogram:

Unknown or unreliable time of ingestion
Repeated supratherapeutic ingestions (chronic)
Extended-release acetaminophen (delayed peak)
Co-ingestion slowing GI motility
Presentation > 24 hours post-ingestion

In These Cases:

Start NAC empirically if concern for significant ingestion
Use clinical judgment and serial transaminases
Toxicology consultation recommended

Clinical Pearl

The Rumack-Matthew nomogram is a critical tool for acute single-ingestion acetaminophen overdose but requires accurate timing. NAC is nearly 100% effective in preventing hepatotoxicity when given within 8 hours of ingestion. The mechanism of acetaminophen toxicity involves depletion of glutathione and accumulation of the toxic metabolite NAPQI. NAC works by replenishing glutathione stores and directly conjugating NAPQI. Even patients who present late or develop hepatotoxicity benefit from NAC. Activated charcoal should be given if within 4 hours of ingestion. All intentional overdoses require psychiatric evaluation.

Clinical Image

Liver histopathology demonstrating centrilobular necrosis (Zone 3) characteristic of acetaminophen hepatotoxicity. Zone 3 hepatocytes surrounding the central vein have the highest concentration of CYP450 enzymes that generate the toxic metabolite NAPQI.

Image Source: Wikimedia Commons - "Centrilobular necrosis liver" License: CC BY-SA 3.0 URL: https://commons.wikimedia.org/wiki/File:Centrilobular_necrosis.jpg

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