Transcript PowerPoint Presentation - MEDICAL GRANDROUNDS

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
11 hours PTA
(+) nausea, vomiting
(+) abdominal discomfort
5 hours PTA
(+) pallor
(+) anorexia,weakness
consult done at
another hospital
MMC-ER
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
RR: 18 cpm
• Height: 5’2’’
BMI: 21
HR: 72 bpm,reg
Temp: 37.2 C
Weight: 55 kgs
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
Hct
RBC
WBC
Seg
Lym
Mono
PLT
13.7
40.4
4.7
10,270
72
19
9
309,000
Na
K
Cl
Phos
Calc
Glu
BUN
Crea
137
3.6
105
2.9
8.8
105
7
0.8
Laboratory Tests
SGOT
AST
181
(15-37)
SGPT
271
ALT
(30-65)
T.Bili
1.1
Alk Phos 85
Alb
4.2
TP
7.3
Chol
176
Trig
20
PTT
Ctrl
PT
Act
Ctrl
INR
28.8
25.8
15.7
64.1%
11.8
1.3
Single Acute Acetaminophen Overdose Normogram
(Rumack-Matthew)
Therapeutics
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•
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•
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
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•
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N-Acetylcysteine 600mg/tab BID
Lansoprazole 40mg/tab OD
Rebamipide 100mg/tab TID
Motilium 10mg/tab TID
2nd Hospital Day
•Nausea
•Vomiting
1400
1283
1200
1000
•Ab Discomfort
908
800
SGOT
600
SGPT
400
200
271
181
271
0
0
2
Hospital day
• Vitamin K 10mg to BID
•Aminoleban 500cc x 12 hrs
%
70
6 4 .1
60
INR: 1.3
50
4 5 .6
40
INR: 1.7
30
P rotime
20
10
0
0
2
Hospit al Day
3rd Hospital Day
• (-) jaundice
• (-) RUQ pain
• good UO
4500
4180
4000
3500
3000
2500
SGOT
2000
SGPT
1500
1550
1283
908
1000
500
271
181
0
0
2
Hospital day
3
70
64.1
60
INR: 1.3
45.6
50
%
INR: 1.7
40
39.7
INR: 1.9
30
Protime
20
10
0
0
2
Hospital Day
3
• 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
4500
4180
4000
3500
3000
2610
2500
SGOT
SGPT
2000
1500
1550
1283
908
1000
500
433
271
181
0
0
2
3
Hospital day
4
• Vitamin K 10mg to OD
70
67
64.1
60
INR: 1.2
50
%
45.6
39.7
40
INR: 1.9
30
Protime
20
10
0
0
2
3
Hospital day
4
7th Hospital Day
4500
4180
4000
3500
3000
2610
2500
SGOT
2000
1500
1000
500
1744
1550
1283
908
869
433
271
181
0
0
2
SGPT
3
4
Hospital day
126
5
35
7
Protime
100
92
90
1.0
80
%
95.8
70
64.1
60
1.3
67
45.6
50
40
39.7
1.9
30
20
10
0
0
2
3
4
Hospital day
5
7
Take Home Medications
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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
Dose
Biotransformatio
n
Acetaminophen Metabolism
glucoronide
ACETAMINOPHEN
moiety
moiety
C-P450
sulfate
NAPQI
N-acetyl-p-benzoquinonimine
GLUTATHIONE
cysteine and
mercapturic moeity
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
Biotransformation
of APAP
Cytochrome P450
induction
CYP2E1
CYP3A4
Alcohol
ISONIAZID +/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
Anorexia
Nausea
Vomiting
Malaise
Pallor
Sx
Resolution
Reappearance
Renal dysfxn
Resolution
RUQ pain
FULMINANT
OLIGURIC
Oliguria
HEPATIC
FAILURE
renal failure
DEATH
SGOT
LAB
SGPT
10X
BILI
5x
Protime
0h
24h
I
48h
II
72h
96h
III
2w
IV
History of acute APAP overdose
Time since overdose
0 - 4 hours
4 - 8 hours
8 - 24 hours
Activated
Loading dose
Charcoal
NAC
APAP level
Baseline LFT, PT, Bili,
Crea
No further
NAC treatment
Is APAP level above possible toxicity?
NO
YES
Complete
course NAC
Single Acute Acetaminophen Overdose
Normogram
• To determine the risk of
hepatotoxicity
• Guide to recommend nacetylcysteine 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 hepatotoxicity
SGOT/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, 5treatment, 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!