Tox: Tylenol

Question 1

Toxic dose(s) of tylenol

Answer 1

Consider toxicity if:
Kids: >150mg/kg over <8hrs
Adults: >7.5g over <8hrs

Acute OD:
>6 yrs: >/10g or 200mg/kg
<6 yrs: >200mg/kg

Repeated supratherapeutic:
>6yrs:
- >/10g/d or 200mg/d over 24 hrs
- >/6g/d or 150mg/kg/d over 48hrs

<6 yrs:
>/200mg/kg over 8-24hrs
>150mg/kg/d for 48 hrs
>100mg/kg/d over 3+days

Question 2

Mechanism of tylenol toxicity

Answer 2

Usually primarily metabolized by the liver with 90% undergoing conjugation with glucuronide or sulfate to non-toxic metabolite.
5% undergoes CYP450 oxidation to toxic metabolite (NAPQI).
Hepatic stores of glutathione then bind NAPQI to form non-toxic metabolite.

In OD: conjugation pathway overwhelmed, increased NAPQI production, overwhelms glutathione stores and and free NAPQI binds cellular proteins causing hepatotoxicity (centrilobular/zone III).

Question 3

Pts at high risk for tylenol OD

Answer 3

Pts with reduced glutathione stores (alcoholics, malnourished).
Pts on CYP450 inducing meds (INH, anticonvulsants)

Question 4

Stages of tylenol toxicity

Answer 4

1) Preclinical, 0-24hrs: n/v, malaise, abdo pain. May be asymptomatic.
2) Hepatotoxicity, 24-72hrs: RUQ pain, transaminitis, +/-increased coags
3) Hepatic failure, encephalopathy, 72-96hrs: LFTs peak, clinical liver failure, acidosis, ARF.
4) Survival or death, >96hrs: multiorgan failure or full resolution of hepatotoxicity

Question 5

When should NAC be empirically started?

Answer 5

1) time of ingestion unknown and APAP level >20mcg/mL or AST/ALT elevated.
2) If suspect has been >/8hrs since ingestion.
3) Time of ingestion not known
4) Massive tylenol overdose

Question 6

What is the 4hr cut off APAP level to start NAC?

Answer 6

150 mcg/mL

Question 7

How should repeat supratherapeutic ingestions be managed?

Answer 7

Do not plot on Rumack Matthew nomogram.
Obtain APAP and ALT/AST level at time of presentation.
If APAP>20mcg/mL or AST/ALT elevated, start NAC

Question 8

Should AC be used with tylenol OD?

Answer 8

Can be considered if presenting within 2hrs and no airway compromise

Question 9

When is NAC most effective?

Answer 9

Given within 8-10hrs (but even late administration beneficial so always give)

Question 10

Compare oral vs IV NAC protocols

Answer 10

Oral (mucomyst): total of 72hrs of tx.
140mg/kg load then 70mg/kg q4h x72hrs.

IV (acetadote): total 21hrs tx. May cause anaphylactoid reaction. 150mg/kg load then 12.5mg/kg/h x4h then 6.25mg/kg/h x16hrs.

Question 11

King’s college criteria for liver transplantation

Answer 11

pH<7.3 after resuscitation OR all 3 of: INR>6.5, Cr>300, grade 3+ encephalopathy

Question 12

Complications of tylenol OD

Answer 12

fulminant hepatic failure, metabolic acidosis, hyperglycemia, hepatorenal syndrome, hepatic encephalopathy, coagulopathy, cerebral edema, infection

Question 13

When can the Rumack Matthew Nomogram NOT be used to make treatment decisions in the setting of tylenol overdose?

Answer 13

1) Ingestion over multiple hours
2) Extended release tablets
3) Tablets mixed with sympatholytic medication or another medication that slows gut motility
4) Unknown time of ingestion
5) Pt has health condition that may exacerbate tylenol toxicity (e.g. ethanol use, liver disease, on CYP450 inductor, malnourished, HIV+, CF)
6) Glutathione deficiency or use of medications that induce hepatic enzymes

Question 14

Clinical end points that must be met after 20 hrs of IV NAC in order to discontinue medication

Answer 14

1) INR <1.3
2) AST or ALT within normal limits
3) Non-detectable acetaminophen level in blood
4) Asymptomatic patient