Acetaminophen Toxicity

Question 1

What’s the therapeutics dose of acetaminophen for children and adults?

Answer 1

Children: 10-15mg/kg/dose q4-6h (max 80mg/kg/day) Adults: 325-1000mg q4-6h (max 4g/day)

Question 2

Describe the normal hepatic metabolism of acetaminophen.

Answer 2

90% undergoes conjugation to either a glucuronide or a slight metabolite which are non toxic and are excreted in urine. 5% is excreted unchanged in urine. 5% is metabolized by CYP2e1 to active intermediate metabolite NAPQI which gets inactivated by conjugation w/ glutathione to non toxic metabolites and goes through renal excretion

Question 3

Toxic dose of acetaminophen in acute/chronic doses for children and adults:

Answer 3

Acute: >7.5g (adults), >150mg/kg (children)
Chronic: >4g/day (adults), >90mg/kg/day (children)

Question 4

Describe hepatotoxicity w/ acetaminophen overdose.

Answer 4

The amount of NAPQI produced deletes the glutathione supply (

Question 5

Describe Stage I of acetaminophen toxicity.

Answer 5

Symptoms at 0-24hrs post ingestion.

May be asymptomatic, GI symptoms (anorexia nausea, vomiting), malaise, pallor.

Question 6

Describe Stage II of acetaminophen toxicity.

Answer 6

Symptoms at 24-72hrs post ingestion (onset of hepatic damage).
More specific liver complaints, right upper quadrant pain, increased liver enzymes, bilirubin, coagulation & renal function decline. Maybe disappearance of symptoms from Stage I.

Question 7

Describe Stage III of acetaminophen toxicity.

Answer 7

Symptoms at 72-96 hrs post ingestion (max hepatotoxicity).
More severe form of Stage I/II symptoms. Extreme elevations of liver enzymes, progressive hepatic encephalopathy, coagulation defects, jaundice, renal failure, myocardial necrosis, coma. (GI symptoms may return).

Question 8

Describe Stage IV of acetaminophen toxicity.

Answer 8

Symptoms at 4 days to 2 weeks post ingestion (recovery phase).
Disappearance of clinical symptoms, normalization of lab parameters.

Question 9

What AST level is considered hepatotoxic?

Answer 9

AST > 1000IU/L

Question 10

What is the diagnostic testing for acetaminophen toxicity?

Answer 10

1. Serum acetaminophen via Rumack Matthew Nomogram, level obtained at min of 4h post ingestion.
2. Additional blood work: AST, ALT, ALP, bilirubin, PT/INR, CBC, electrolytes, urea, creatinine, glucose, ABGs.

Question 11

Treat or Do Not Treat: AST > 3x ULN

Answer 11

Treat (regardless of serum acet.)

Question 12

Treat or Do Not Treat: AST normal, serum acet detectable (>10mcg/ml)

Answer 12

Use clinical judgement.

Question 13

Treat or Do Not Treat: AST normal, serum acet. undectable

Answer 13

Do not treat.

Question 14

Treat or Do Not Treat: Patient presents >8h

Answer 14

Treat. Start NAC then re-evaluate after you get blood work.

Question 15

Treat or Do Not Treat: ER Products

Answer 15

Use clinical judgement. Continue approach as normal.

Question 16

Treat or Do Not Treat: acute EtOH + acute acet. overdose

Answer 16

Maybe do not treat. May be protective against acetaminophen toxicity b/c it inhibits CYP2E1 metabolism so less NAPQI formation.

Question 17

Treat or Do Not Treat: chronic EtOH + acute acet. overdose

Answer 17

Treat. Patient at higher risk of toxicity b/c of increased CYP2E1 activity and decreased glutathione stores.

Question 18

Treat or Do Not Treat: chronic EtOH + chronic acet. ingestion

Answer 18

Do not treat if patient not consuming >4g/day on regular basis.

Question 19

What pre-existing conditions cause an increased risk of toxicity w/ repeated excessive doses?

Answer 19

Febrile infants, chronic EtOH consumption, concurrent CYP inducers.

Question 20

What effect do CYP inducers have on acetaminophen toxicity?

Answer 20

Could worsen outcomes and increase toxicity b/c since more acetaminophen is metabolized by the CYP pathway, there’s more NAPQI production.

Question 21

What effect does chronic liver disease in a non-alcohol user have on acetaminophen toxicity?

Answer 21

No increased risk of toxicity b/c though elimination half life go acetaminophen is longer, CYP activity is low so little/low NAPQI production.

Question 22

What are the mechanisms of action of NAC?

Answer 22

1. Augmenting sulfation.
2. Acting as a glutathione precursor.
3. Acting as a glutathione substitute.
4. Modifying the secondary effects of the inflammatory response after the initial direct toxic injury.

Question 23

NAC Oral Dosing:

Answer 23

Loading dose (240mg/kg) diluted to 5%, then 70mg/kg q4h for 17 doses = 72 hours total.

Question 24

NAC IV Dosing:

Answer 24

150 mg/kg in 200ml D5W over 60 min, then 50mg/kg in 500ml over 4 hours, then 100mg/kg in 1000ml over 16 hours = 21 hours total.

Question 25

Advantages of IV NAC Route:

Answer 25

1. Allows for concomitant administration of charcoal & NAC without the risk of NAC adsorption to the charcoal. 2. Decreased risk of vomiting. 3. Administered over a shorter period of time (21h vs 72h) 4. Easier to administer to those w/ altered LOC.

Question 26

Advantages of Oral NAC Route:

Answer 26

1. Doesn't require IV access. 2. No reports of life threatening adverse effects. 3. NAC delivered directly to liver.

Question 27

When is IV NAC route preferred?

Answer 27

Pregnancy, liver failure, severe vomiting, contraindication to oral administration.

Question 28

ADRs for IV NAC:

Answer 28

Anaphylactoid reaction - rash, pruritus, flushing, angioedema, hypotension.

Question 29

ADRs for oral NAC:

Answer 29

GI - nausea, vomiting, reflux, diarrhea.

Question 30

When is hemodialysis appropriate in acetaminophen toxicity?

Answer 30

When massive ingestions w/ very high levels ( >1000mg/L) complicated by coma and/or hypotension.

Question 31

When is liver transplantation considered in acetaminophen toxicity?

Answer 31

1. Arterial pH 3mmol/L after fluid resuscitation. | 2. SCr > 3.3mg/dL, PT > 100sec or INR >6.5, Grade III or IV encephalopathy

Question 32

What is the supportive management in acetaminophen toxicity?

Answer 32

1. Coagulopathy: vitamin K, FFP, prothrombin complex concentrates 2. Cerebral edema: fluid retention, mannitol 3. Nausea/Vomiting: dimenhydrinate 4. Hypoglycemia: dextrose

Question 33

What do you monitor for in acetaminophen toxicity?

Answer 33

1. Bloodwork: LFTs (esp AST), INR, bicarbonate, SCr q12h, daily electrolytes 2. Clinical status: HR, BP, LOC, temp