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!