5 Paracetamol

Question 1

maximum total daily dose of oral paracetamol

Answer 1

500-mg paracetamol:
3000 mg/day

325-mg paracetamol:
3900 mg

children:
max of 75 mg/kg/day
[or five doses of 10-15 mkdose in a 24-hour period)

Question 2

peak serum concentrations of oral paracetamol, when?

Answer 2

therapeutic doses:
30 mins to 2 hours

overdose:
within 2 hours

Question 3

recommended dosing of IV paracetamol

Answer 3

> 50 kg:
650 mg every 4 hours, or
1000 mg every 6 hours
max total daily dose of 4 grams

<50 kg:
12.5 mg/kg every 4 hours, or
15mg/kg every 6 hours
max individual dose of 750 mg
max total daily dose of 75 mg/kg, or 3750 mg, whichever is less

Question 4

peak concentration of IV paracetamol

Answer 4

occur at the end of the 15-min infusion period

Question 5

pathophysiology of acetaminophen toxicity

Answer 5

1. normally, acetaminophen is oxidized by the CYP450 system to NAPQI (N-Acetyl-P-benzoQuinone Imine), which is then detoxified by hepatic glutathione to a nontoxic compound that can be renally eliminated (APAP mercaptate?)
2. however, when glutathione decrease to <30% of normal in the setting of overdose, NAPQI binds to hepatic macromolecules, resulting in CENTRILOBULAR HEPATIC NECROSIS
3. hepatocyte damage progresses with cell lysis on the SECOND DAY, releasing transaminases and NAPQI-hepatic protein adducts in to the circulation where they are detected in the serum
   -this corresponds generally to the development of OVERT CLINICAL TOXICITY

Question 6

Stage 1 of acetaminophen toxicity

Answer 6

first 24 hours
may be asymptomatic or have nonspicific symptoms, such as anorexia, N/V, malaise

Question 7

Stage 2 of acetaminophen toxicity

Answer 7

days 2-3
findings often improve
but clinical signs of hepatotoxicity - RUQ pain and tenderness- may occur
serum transaminases may be elevated

even without treatment, most patients with mild to moderate hepatotoxicity recover without sequelae

Question 8

Stage 3 of acetaminophen toxicity

Answer 8

days 3 to 4
some patients will progress to fulminant hepatic feilure
Abdominal symptoms
Encephalopathy
Coagulopathy
Renal failure
Metabolic acidosis

Question 9

stage 4 of acetaminophen toxicity

Answer 9

patients who survive the complications of fulminant hepatic failure begin to recover over the next 2 weeks (stage 4)

with complete resolution of hepatic dysfunction after 1-3 months

Question 10

this may cause early-onset metabolic acidosis

Answer 10

ingestion of acetaminophen >500 mg/kg, or peak plasma conc’n >750 mcg/mL (or >5000 mmol/L)

with elevated lactate and altered sensorium

likely mechanism include
-depletion of liver glutathione stores
-resulting in generation of 5-oxoproline
-and metabolit-induced inhibition of mitochondrial respiration

Question 11

toxic exposure of acetaminophen

Answer 11

1) >10 g or 200 mg/kg as a single ingestion or over a 24 hour period

2) >6 g or 150mg/kg per 24 hour period over at least 2 consecutive days

children <6 y/o

1) ≥200 mg/kg as a single ingestion or over an 8 hour period

2) 150 mg/kg per 24 hour period for the preceding 48 hours

Question 12

graph for acetaminophen toxicity

Answer 12

Rumack-Matthew nomogram
toxicity line:
150 mcg/mL
1000 mmol/L
window: bet 4 and 24 hours after ingestion

previously:
>200 mcg/mL
>1300 mmol/L
-60% risk of developing hepatotoxicity (ALT >1000 IU/ML
-1% risk of renal failure
-5% risk of mortality

Question 13

this has a 90% risk of developing hepatotoxicity

Answer 13

> 300 mcg/mL
2000 mmol/L

Question 14

“toxicity line” for IV acetaminophen

Answer 14

any single IV acetaminophen dose abve 60 mg/kg
or acetamoinophen conc’n >50 mcg/mL at 4 hours

Question 15

MOA of acetylcysteine

Answer 15

early acetaminophen poisoning (<8 hours after ingestino)
-acetylcysteine prevents the binding of NAPQI to hepatic macromolecules by acting as a glutathione precursor or substitute, or a sulfate precursor, or
-it may directly reduce NAPQI back to acetaminophen

in established acetaminophen toxicity, or >24 hours after ingestion
-it diminishes hepatic necrosis by acting as an to oxidant
»decreasing neutrophil infiltration
» improving microcirculatory blood flow, or
» increasing tissue O2 delivery and extration

Question 16

remarks on acetylcysteine

Answer 16

If acetylcysteine is given within 8 hours of acetaminophen ingestion, it is nearly 100% effective in preventing the development of hepatotoxicity

Question 17

adverse effect of acetylcysteine

Answer 17

anaphylactoid reactions in 4-17% or patients
most during the first 2 hours

mild cases are treated with diphenhydramine

severe cases are treated by temporarily slowing or stopping the infusion

Question 18

regimen of IV acetylcysteine

Answer 18

21 hour protocol:

phase I:
loading dose of 150 mg/kg over 1 hour

phase II:
50 mg /kg over 4 hours

phase III:
100 mg/kg over 16 hours

IV acetylcysteine is commercially available as a 20% solution and requires dilution to a 2% solution for infusion into a peripheral vein
both 5% D5W and half-normal saline can be used as diluents

Question 19

oral acetylcysteine regimen

Answer 19

72-hour oral acetylcysteine protocol:

140 mg/kg loading dose, then

maintenance doses of 70 mg/kg every 4 hours for 17 additional doses

The taste is disagreeable, may cause N/V, so u may give:
Ondansetron 4-8 mg IV/PO every 8 hours
a/e: QT prolongation

Question 20

Indication of ECMO in paracetamol toxicity

Answer 20

“ExtraCorporeal Membrane Oxygenation”

in addition to acetylcystine

ONLY in the setting of encephalopathy,
metabolic acidosis,
elevated lactate, AND
acetaminophen level >900 mg/L

Question 21

when can acetylcysteine be discontinued?

Answer 21

if the serum acetaminophen concentration is
<10 mcg/mL
<66 mmol/L

Question 22

remarks on fulminant hepatic failure

Answer 22

most fatalities occur on days 3 to 5
those who survive generally begin to show evidence of recovery by days 5 to 7
survivors will eventually develop complete hepatic regeneration without any persistence of hepatic impairment

Question 23

criteria for highest risk of mortality from acetaminophen-induced fulminant hepatic failure

Answer 23

King’s College Criteria
metabolic acidosis (arterial pH <7.30) despite fluid and hemodynamic resuscitation

or a cominabtion of
coagulopathy (PT >100s),
renal insuf (crea >3.3 mg/dL, >292 mcmol/L), and
grade III/IV hepatic enceph

Question 24

treatment of fulminant hepatic failure

Answer 24

IV acetylcysteine therapy should be continued past the 21-hour standard regiment [at 6.25 mg/kg/hour] until
-the patient recovers,
-receives a liver transplant,
-or dies

Question 25

massive acetaminophen overdose

Answer 25

> 40 grams or 500mg/kg

options:
-addition of oral acetylcysteine
-increasing the phase III to 200 mg/kg over 16 hours from 100 mg/kg over 16h
-or reloading the standard acetylcysteine regimen at completion of the 21-hour protocol