detailed approach for the treatment of paracetamol toxicity including toxicity dose, pathophysiology, diagnosis, treatment and indications of liver transplant referral

1. PARACETAMOL
TOXICITY
R A K A N A L OTA I B I - M E D I C A L I N T E R N , U M M A L -
Q U R A U N I V E R S I T Y

2. OBJECTIVES
• Introduction
• Toxicity doses
• Pharmacology
• Mechanism of toxicity
• Clinical features with stages
• Investigations
• Treatment
• Antidote therapy
• Liver transplant
• Literature updates

3. INTRODUCTION
• Acetaminophen is the most commonly used analgesic in the United
States
• The most common intoxicated drug
• The most common cause of acute liver failure
• The second most common cause of liver transplantation
• Cause of 56,000 adult ER visits and 30,000 pediatric ER visits annually in
the US
• 44% of adult self-poisoning is resulted from paracetamol toxicity

4. DOSING
• The Normal maximum dose is 4000 mg per 24 hours (1 gram per 6 hours)
• Toxic adult dose: more than 250 mg/kg or 12 grams over 24 hours.
• Toxic pediatric dose: more than 200 mg/kg over 24 hours
• Patients with cirrhosis and alcoholism may require lower doses for toxicity
• The lethal dose is 15 grams

5. PHARMACOLOGY
• Not accurately known, suggested to through inhibition of cyclo-oxygenase 2
resulting in the inhibition of PG-E2 production
• Acetaminophen is absorbed rapidly, with peak plasma concentrations generally
occurring within 1 hour and complete absorption within 4 hours.
• Acetaminophen is normally metabolized in the liver by conjugation with glucuronide
(about 67%), sulfate (20%), and CYP2E1 into a HIGHLY TOXIC metabolite named p-
benzoquinone imine (NAPQI)
• In therapeutic doses, NAPQI is combined with glutathione forming a NON-TOXIC
soluble metabolite and become excreted in the kidney

6. MECHANISM OF TOXICITY
• Ingestion of large amount of acetaminophen will result in excessive production of
NAPQI overwhelming the glutathione stores in the liver.
• NAPQI is highly hepatotoxic resulting in acute liver failure, also acute renal failure

7. CLINICAL FEATURES
• Non-specific: Nausea, Vomiting, Diaphoresis, Malaise, and Anorexia
• Specific: RUQ pain and tenderness, Jaundice, hepatic encephalopathy
• With maximal liver injury, patients develop signs and symptoms consistent with
fulminant liver failure, including metabolic acidosis, coagulopathy, and hepatic
encephalopathy.

8. STAGES OF CLINICAL FEATURES

9. INVESTIGATION
• All patients must undergo serum acetaminophen level ideally 4 hours post-ingestion
or as soon as possible after 4 hours of ingestion.
• If time of ingestion is unknown, serum acetaminophen should be measured
immediately
• Additional labs must include electrolyte, urea, creatinine, bilirubin, PT, PTT, INR, AST,
ALT, amylase, and urinalysis

10. INVESTIGATION
• AST level rises significantly after 8-36 hours reaching a peak after 2-4 days.
• ALT is more specific for liver damage as AST can be elevated in muscle injury and pregnancy.
• Severe toxicity may result in elevations of AST,ALT, and PT within 24 hours.
• Liver enzymes levels return to normal after 5-7 days.
• Serum glucose should obtained to detect hypoglycemia as a result of impaired
gluconeogensis.
• Typically, the levels of AST and ALT will exceed 1000 U/L.

11. SUGGESTIVE LAB FEATURES
• AST and ALT > 1000 U/L
• High bilirubin
• Prolonged coagulation profile (PT, PTT, and INR)
• High Anion gap metabolic acidosis
• Acute kidney injury demonstrated by:
• Increase in serum creatinine by 0.3 mg or more in less than 48 hours
• OR
• Increase in serum creatinine by 50% from baseline
• OR
• Decrease in urine output to less than 0.5 cc/hr for > 6 hours

12. RUMACK-MATTHEW NOMOGRAM
• The Rumack-Matthew nomogram is used to interpret serum acetaminophen
concentrations in relation to time since ingestion, in order to determine wether N-
Acetylcysteine is indicated.
• The nomogram predicts the risk of hepatotoxicity on a single acetaminophen
concentration. It is not a prognostic tool. Therefore, it does not predict fulminant
hepatic failure or death.
• The nomogram predicts the toxicity beginning only at 4 hours till 24 hours after
ingestion (most reliable acetaminophen level is 4-18 hours post-ingestion)
• The measurement of serum acetaminophen prior to 4 hours of post-ingestion can not
reliably exclude toxicity as no sufficient data is supportive and complete absorption
not achieved

13. RUMACK-MATTHEW NOMOGRAM

14. TREATMENT
• The approach is applicable equally as to any toxicity:
• Resuscitation (Airway, Breathing, and Circulation)
• Decontamination
• Enhanced Elimination
• Antidote
• Additional supportive care

15. DECONTAMINATION
• Activated charcoal is the initial treatment in patients presenting up to 2 hours post-
ingestion (ideally one hour), given orally
• Dose: 1 g/kg (max: 50 g)
• Contraindications:
• -Altered mental status (including sedation)
• -Unprotected airway
• -Suspected or proven GI hemorrhage
• -Uncooperative patient

16. ENHANCED ELIMINATION
• Can be achieved only through hemodialysis
• Indications for emergency dialysis:
• High serum acetaminophen (>1000 mg/1 L) at 4 hours post-ingestion
• Serum creatinine >3.5 mg/dl (hepatorenal syndrome)
• Hepatic encephalopathy
• High lactate (> 3.5 mmol/L)

17. ANTIDOTE THERAPY
• N-Acetylcysteine (NAC) is the antidote for paracetamol toxicity
• NAC is proven to reduce the risk of hepatotoxicity virtually 100% if given within 8 hours of ingestion, the efficacy falls
progressively thereafter.
• Mechanism: acts as a precursor for glutathione and a sulfur-containing glutathione substitute, binding to NAPQI
• Best given IV (although PO and IV equally effective) since most patient have nausea and vomiting
• IV route is mandatory if evidence of acute liver failure (eg coagulaopathy, encephalopathy)
• IV NAC reduces mortality in patients with liver failure

18. ANTIDOTE THERAPY
• Ideally, PO route is only indicated if IV can not be given
• Indictions:
• Serum acetaminophen 4 hours or more post-ingestion above the toxicity line in the nomogram
• Suspected or proven ingestion > 150mg/kg (or 7.5 g regardless of weight)
• Unknown ingestion time with serum acetaminophen >10mcg/mL (66 micromol)
• Hx of ingestion with ANY evidence of liver injury (even if presentation>24 hours)
• Approximately 6% of patient on IV NAC develop anaphylactoid reaction (mostly are benign and
transient)
• Mortality reaches zero if NAC started before 8 hours of ingestion (start ASAP)

19. NAC DOSING
• Two methods:
• 20-hour IV protocol (less common): administer
• Step one: 150 mg/kg IV over 15- 60 minutes in 200 ML D5W
• Step two: 50 mg/kg IV over 4 hours in 500 ML D5W
• Step three: 100 mg/kg over 16 hours in 1 L D5W
• 72-hour oral protocol:
• Loading dose of 140 mg/kg , followed by 16 doses of 70 mg/kg Q4H (total
doses: 17)

20. NAC SIDE EFFECTS

21. WHEN TO STOP NAC?
• Must meet all the following:
• - asymptomatic patient
• - no detectable serum acetaminophen
• -decreasing (or normal) LFT
• Otherwise, resume NAC duration protocol

22. LIVER TRANSPLANT
• Indications:
• Arterial pH below 7.30 (irrespective of hepatic encephalopathy grade) OR Grade III
or IV encephalopathy PLUS both of the following:
• -PT time>100 seconds
• -serum creatinine> 3.4 mg/dL
• If positive criteria, then refer for orthotopic liver transplant

23. • Included patients who ingested >40 g, aged>14 among 200 patients
• Median time of presentation: 3.5 hours
• Median ingested dose: 50 g
• 14% of patients (n=28) developed hepatotoxicity
• Those who developed hepatotoxicity had a longer starting treatment time (13 hours)
than those who did not (6 hours), P=<0.0010
• One patient required a liver transplant despite NAC being started 2.5 post-ingestion
• 4 patients had a second serum paracetamol peak 24 h post-ingestion, likely due to
co-ingestion of opioids and anticholinergics impairing the absorption (phenomenon
of double peak)

24. • A total of 48 consecutive patient with proven-liver injury, troponin I was detectable
(>0.05 ng/L) in 13 patients (27.1%) primarily seen in patients with multi-organ failure
• The elevation in troponin in paracetamol toxicity is low (being detectable only) and
sustained presumably an indicative of a diffusely ‘sick myocardium’ and usually
persists long than 2 days unlike ACS.
• This elevation in general is primarily seen in the context of multiorgan failure not to
paracetamol toxicity per se
• Other causes of troponin elevation include renal failure, septic shock, pulmonary
embolism.
• Elevated troponin in the context of acute liver failure due to paracetamol poisoning
was associated with increased death risk and need for tranplant (p=0.0006)

25. • Any questions?