MEDICAL GRANDROUNDS

Acetaminophen Toxicity“how much is too much?”

Ivy Rose C. Nisce, M.D.

September 6, 2007

Paracelsus

“All things are poison, and nothing is without poison. The right dose differentiates a poison

from a remedy”

Objectives

• To present a case of acetaminophen toxicity

• To discuss the pathophysiology, clinical stages, diagnosis, treatment and complications of acetaminophen toxicity

General Data

• 25 year old • Female• Filipino• Married

Chief Complaint

nausea and vomiting

History of Present Illness 18 hours PTA Ingested 20 tab of

Tylenol® 500mg/tab

MMC-ER

11 hours PTA (+) nausea, vomiting (+) abdominal discomfort

5 hours PTA (+) pallor (+) anorexia,weakness

consult done at another hospital

Review of Symptoms

• No headache, dizziness• No fever, weight loss• No cough, colds, difficulty of

breathing• No chest pain, palpitations, PND• No bowel or bladder changes

Past Medical History

• (+) dysmenorrhea – Tylenol 500mg/tab• No hypertension, diabetes, asthma• No previous operations

Family History

• unremarkable

Personal and Social History

• Husband and children reside in the U.S.• Unemployed• Nonsmoker• Not an alcoholic beverage drinker• No illicit drug use• No previous history of overdose

Physical Examination

• Conscious, coherent, ambulatory, not in cardiorespiratory distress

• Vital Signs BP: 120/80mmHg HR: 72 bpm,reg RR: 18 cpm Temp: 37.2 C • Height: 5’2’’ Weight: 55 kgs BMI: 21

Physical Examination

• Warm moist skin, no jaundice, no active dermatosis

• Pink palpebral conjunctiva, anicteric sclerae• Supple neck, no lymphadenopathy• Symmetrical chest expansion, no retractions,

clear breath sounds• Adynamic precordium, regular rate and

rhythm, apex beat at 5th LICS, no murmurs• Flat, soft, normoactive bowel sounds, no

tenderness on palpation, no hepatomegaly• No edema or cyanosis, pulses full and equal

Salient Features

• 25 year old female• Ingested 20 tablets of Acetaminophen

(Tylenol®) • Nausea, vomiting, abdominal discomfort• Pallor, anorexia, body weakness• Stable vital signs• Essentially normal physical examination

Initial Impression

Acetaminophen Toxicity

Nausea, Vomiting, Abdominal Discomfort

CHOLECYSTITIS

• nausea & vomiting

• triad sudden onset of RUQ tenderness, fever, leukocytosis

VIRAL HEPATITIS

• prodromal sx: anorexia, nausea, vomiting, malaise

• jaundice, RUQ pain and discomfort

• serum transaminases peak at 400 - 4000 IU/L

Nausea, Vomiting, Abdominal Discomfort

PEPTIC ULCER

• nausea

• epigastric pain: gnawing or burning discomfort

DRUG-INDUCED

• appropriate temporal sequence from administration of the drug to onset of event

• an appropriate course of the reaction after cessation of the offending drug

• absence of alternative causes

At the emergency room

• Referral to toxicology service

• Referral to psychiatry service– Assessment: adjustment disorder

Laboratory Results

Hgb 13.7Hct 40.4RBC 4.7WBC 10,270Seg 72Lym 19Mono 9PLT 309,000

Na 137K 3.6Cl 105Phos 2.9Calc 8.8Glu 105BUN 7Crea 0.8

Laboratory Tests

SGOT AST

181 (15-37)

SGPTALT

271(30-65)

T.Bili 1.1Alk Phos 85Alb 4.2TP 7.3Chol 176Trig 20

PTT 28.8Ctrl 25.8PT 15.7Act 64.1%Ctrl 11.8INR 1.3

Single Acute Acetaminophen Overdose Normogram(Rumack-Matthew)

Therapeutics

• NPO• D5NSS IL + 30meqs KCL x100cc/hr• Plasil 10mg IV q8• Esomeprazole 40mg IV OD• Vit K 1 amp IV OD

N-acetylcysteine (NAC) Treatment Protocol

Phase I

150 mg/kg IV NAC 20% in 200ml D5W x 1 hr

150mg/kg = 150mg x 55kg = 8250 mg

Phase II

50 mg/kg IV NAC 20% in 500ml D5W x 4 hr

50mg/kg = 50mg x 55mg = 2790 mg

Phase III

100 mg /kg IV NAC 20% in 1000ml D5W x 16hr

100mg/kg = 100mg x 55mg = 5500 mg

1st Hospital Day

• Ultrasound of the upper abdomen– Gallbladder polyp– Cholecystolithiasis– Normal liver, BT, pancreas, spleen, kidneys

• Endoscopy– Gastritis– GERD A– Duodenitis

Therapeutics

• General liquids

• N-Acetylcysteine 600mg/tab BID• Lansoprazole 40mg/tab OD• Rebamipide 100mg/tab TID• Motilium 10mg/tab TID

2nd Hospital Day

271 181

908

271

1283

0

200

400

600

800

1000

1200

1400

0 2

Hospital day

SGOT

SGPT

•Nausea

•Vomiting

•Ab Discomfort

Vitamin K 10mg to BID•Aminoleban 500cc x 12 hrs

64.1

45.6

0

10

20

30

40

50

60

70

%

0 2

Hospital Day

Protime

INR: 1.3

INR: 1.7

3rd Hospital Day

181

908

1550

271

1283

4180

0

500

1000

1500

2000

2500

3000

3500

4000

4500

0 2 3

Hospital day

SGOT

SGPT

• (-) jaundice

• (-) RUQ pain

• good UO

64.1

45.639.7

0

10

20

30

40

50

60

70

%

0 2 3

Hospital Day

Protime

INR: 1.3

INR: 1.7

INR: 1.9

• Serum APAP level <10 ug/ml (10-30)• T Bili 1.4 Direct 0.5 Indirect 0.9

• Referral to toxicology service– Acetaminophen Ingestion,non-accidental– NAC tablet discontinued

Phase III

5500 mg IV NAC 20% in 1000ml D5W x 16hr

4th Hospital Day

181

908

1550

433271

1283

4180

2610

0

500

1000

1500

2000

2500

3000

3500

4000

4500

0 2 3 4

Hospital day

SGOT

SGPT

64.1

45.639.7

67

0

10

20

30

40

50

60

70

%

0 2 3 4

Hospital day

ProtimeINR: 1.9

INR: 1.2

Vitamin K 10mg to OD

7th Hospital Day

181

908

1550

433126 35

271

1283

4180

2610

1744

869

0

500

1000

1500

2000

2500

3000

3500

4000

4500

0 2 3 4 5 7

Hospital day

SGOT

SGPT

Protime

64.1

45.639.7

67

9295.8

0

10

20

30

40

50

60

70

80

90

100

%

0 2 3 4 5 7

Hospital day

1.3

1.9

1.0

Take Home Medications

• Lansoprazole 30mg/tab OD• Rebamipide 100mg/tab TID• Domperidone 10mg/tab TID• Lactulose 20cc OD HS

Final Diagnosis

•Acetaminophen Toxicity, non-accidental, resolved

•Gastritis, GERD A, Duodenitis s/p EGD

•Adjustment disorder

Discussion

Acetaminophen

• Most widely used analgesic and antipyretic in the world today

• One of the most frequent causes of poisoning due to a pharmaceutical agent worldwide

Clinical Management Poisoning and Drug Overdose 3rd edition

Leading Causes of Toxicity

1.Pesticide

2.Sodium Hydrochloride

3.Acetaminophen

4.Ferrous Sulfate

5.Isoniazid

***UP National Poison Management and Control Center

Epidemiology

• Majority of APAP-related injury have resulted from large single overdoses

• Suicide attempts• Adolescents or young adults• 60% female

Pharmacokinetics

• Absorption is rapid and usually complete by 1 hour after a therapeutic dose

• Half life: 2.5 to 4 hours• Protein binding: 10%

Acetaminophen Toxicity

Glutathione

Stores

NAPQI

Dose

Biotransformation

sulfate

moiety

Acetaminophen Metabolism

glucoronide

moiety

ACETAMINOPHEN

NAPQIN-acetyl-p-benzoquinonimine

cysteine and

mercapturic moeity

GLUTATHIONE

C-P450

Glutathione

Stores

Hepatic necrosis occurs when doses deplete >70% of the

hepatic GSH

GSH levels are depleted

Malnutrition

Fasting

Alcohol

Histopathology

• Zone 3 hemorrhagic hepatic necrosis

• Centrilobular hepatic necrosis with periportal

sparing

Factors Affecting Toxicity of a Single Large Overdose

DOSE Formation of NAPQI

Saturation of conjugation pathway

Factors Affecting Toxicity of a Single Large Overdose

Cytochrome P450 induction

Biotransformation

of APAP

CYP3A4

CYP2E1

AlcoholISONIAZID +/rifampicin Phenytoin

Carbamazepine

FASTING

How much is too much?

Recommended daily dose

– 4 grams per day (adults)

Toxic dose

– 7.5 to 10 grams as single dose (adults)

– 140mg/kg(7700mg)

Clinical Stages of Acetaminophen Toxicity

0h 24h 48h 72h 96h 2w I II III IV

Sx

AnorexiaNauseaVomitingMalaisePallor

RUQ pain

Oliguria

Resolution Reappearance

FULMINANT

HEPATIC FAILURE

Renal dysfxn Resolution

OLIGURIC

renal failure

DEATH

LAB

SGOT

SGPT

BILI

10X

Protime

5x

8 - 24 hours0 - 4 hours 4 - 8 hours

APAP level

Baseline LFT, PT, Bili, Crea

History of acute APAP overdose

Time since overdose

Activated

Charcoal

Loading dose

NAC

Is APAP level above possible toxicity?

NO YES

No further

NAC treatment

Complete course NAC

Single Acute Acetaminophen Overdose Normogram

• To determine the risk of hepatotoxicity

• Guide to recommend n-acetylcysteine therapy

NAC

• NAC is virtually 100% effective when administered within the first 8 to 10 hrs

• Benefits may be seen for up to 24 hrs after ingestion

Adult Toxicology in Critical Care. CHEST 2003; 123:897-922

Antidotal Therapy: NAC

synthesis and availability of glutathione

enhances sufate conjugation

scavenges free radicals and accumulation or neutrophils in the injured liver

nitric oxide production and local oxygen

delivery to peripheral tissue

NAC Treatment Protocol

– 150 mg/kg NAC in 200ml D5W x 1hour– 50 mg/kg NAC in 500ml D5W x 4hours– 100 mg/kg NAC in 1000ml x 16hours

Complications

• In the US, acetaminophen-induced hepatic failure is one of the most common reasons for liver transplant

Severe hepatotoxicitySGOT/SGPT > 1000 IU/L

Fulminant hepatic failure

Liver

Transplatation Death

Liver Transplantation Criteria at

King’s College Hospital London

Arterial pH< 7.3 (at any time after FHF develops)

OR

In patient’s with normal arterial pH, all 3 of the ff:

INR > 6.5

Creatinine level > 3.4 mg/dL

Grade III or IV hepatic encephalopathy

Aminotransferase Elevations in Healthy Adults Receiving 4 Grams of Acetaminophen Daily

• To characterize the incidence and magnitude of ALT elevations in healthy participants receiving 4 g of acetaminophen daily, either alone or in combination with selected opioids, as compared with participants treated with placebo

• A randomized, single-blind, placebo-controlled, 5-treatment, parallel-group, inpatient study of 145 healthy adults in 2 US inpatient clinical pharmacology units

Watkins et al; JAMA. July 5, 2006;296:87-93.

• None of the 39 participants assigned to placebo had a maximum ALT >3X ULN

• The incidence of maximum ALT >3x ULN was 31% to 44% in the 4 treatment groups receiving acetaminophen

• Compared with placebo, treatment with acetaminophen was associated with a markedly higher median maximum ALT

• Trough acetaminophen concentrations did not exceed therapeutic limits in any participant and, after active treatment was discontinued, often decreased to undetectable levels before ALT elevations resolved

Comparison of oral and i.v. acetylcysteine in the treatment of acetaminophen poisoning

• Oral and i.v. acetylcysteine are equally effective when given within 8-10hrs of acetaminophen overdose and when the oral route is tolerated

• I.V. NAC should be administered when patients are treated >10 hours post-ingestion of acetaminophen

AM J Health-Syst Pharm - Vol 63 Oct 1, 2006

Adverse effects

• 3-6% anaphylactoid reactions to i.v NAC

• Symptoms– Pruritus - Bronchospasm– Rash - Tachycardia– Angioedema - Nausea & vomiting

• Occur 30 mins after infusion of the loading dose

• All patients had good outcomes

Summary

• Acetaminophen although safe when when taken at therapeutic doses, is hepatotoxic when taken as an acute single overdose or in continual excess

• Toxicity is a result if its metabolite NAPQI

• The Rumack nomogram is a reliable guide for determining which patients require antidote therapy after an acute overdose

• Treatment with NAC is beneficial for all patients with a massive single overdose but is most effective if started within 8 hours and effectiveness declines for each hour after 8 hours

Thank you!