Wednesday, 9 December 2015

PARACETAMOL TOXICITY

 Paracetamol Toxicity





PACETAMOL *              GENERIC-**ACETAMINOPHEN

OVERVIEW
  • Most common OD in the west
  • Hepatic metabolism
  • Following overdose glucuronidation and sulphation pathways are rapidly saturated -> increased metabolism to NAPQI (N-acetyl-P-benzoquineimine)
  • Glutathione is required to inactivate NAPQI and when levels depleted -> hepatocellular death takes place
CLINICAL FEATURES
  • overdose of > 10g or > 200mg/kg
  • doses of > 250mg/kg associated with massive hepatic necrosis and liver faillure
  • be aware of the late presenters (> 8 hours since OD and start NAC empirically)
Stage 1 (0-24hrs)
  • asymptomatic or GI upset only
Stage 2 (24-48 hrs)
  • resolution or nausea and vomiting
  • RUQ pain and tenderness
  • progressive elevation of transaminases, bilirubin, PT
Stage 3 (48-96 hrs)
  • hepatic failure (jaundice, coagulopathy, encephalopathy)
Stage 4
  • death from hepatic failure
  • normalisation of LFT’s and complete resolution of hepatic architecture by 3 months
RISK FACTORS FOR TOXICITY
Underlying hepatic impairment
  • viral hepatitis
  • alcoholic liver disease
Microsomal enzyme induction
  • phenobarbitone
  • carbamazepine
  • phenytoin
  • rifampicin
  • OCP
  • chronic alcohol ingestion
  • starvation
Acute glutathione depletion states
  • acute illness with decreased nutrient intake
  • anorexia/bulimia/malnutrition
  • chronic alcoholism
  • HIV
INVESTIGATIONS
  • paracetamol (APAP) levels:
    -> compare to Australasian nomogram (modified version of Rumack-Matthews nomogram)
    -> no role in chronic toxicity
    -> treat if above threshold @ 4 hrs
    -> a level of > 153mg/L is above treatment threshold regardless of time of ingestion
    -> NAC must be given within 8 hours of OD (if level going to take longer than 8 hours start NAC empirically)
  • transaminases: peak @ 72 hrs
  • PT: if >180 seconds on day 4 will need transplantation
  • renal failure
  • metabolic acidosis = poor prognostic marker
MANAGEMENT
Resuscitation
A: may require intubation and intubation if polypharmacy overdose and unrousable
B: lung protective ventilation
C: volume resuscitation
D: dextrose for hypoglycaemia
Evaluation
History
  • Timing
  • Quantity
  • Dose
  • Other meds
  • Psychiatric history
Examination
  • Fuliminant hepatic failure signs
  • Signs of other drug toxicity
Investigations
  • LFTs
  • paractamol level
  • urine tox
  • coag’s
  • ECG
  • lactate
  • amylase
  • blood alcohol
  • pregnancy test
  • ECG
Treatment
Specific
  • decrease absorption: activated charcoal if presented within 4 hours (controversial as if NAC given then this is a benign OD)
  • N-acetyl cystine in D5W (based on 4 hour level or empirically if > 8 hours since OD):
    -> 150mg/kg LD
    -> 50mg/kg over 4 hours
    -> 100mg/kg over 16 hours
  • can be administered at any time of presentation (up to 72 hours post ingestion with some improvement in outcome)
  • can be administered orally but efficacy reduced by 40% if given with activated charcoal
  • provides a substrate of glutathione and acts as an alternative substrate for NAPQI metabolism via the cytochrome P450 pathway
  • watch for adverse effects: rash, bronchospasm, hypotension, angioedema (antihistamines helpful and also slowing of infusion)
Liver failure management
  • don’t correct coagulopathy unless bleeding (vitamin K IV, blood products)
  • arterial ammonia (aids in prognostication: absolute level and failure to fall)
  • glucose monitoring
  • avoid hypothermia
  • reverse jugular venous saturation monitoring
  • ICP monitoring (controversial)
  • avoid hyponatraemia
  • ventilate to normocapnia
  • thiopentone and indomethacin infusions (consult with liver unit)
  • renal failure management
  • MARS therapy: some benefit shown in paracetamol OD as a bridge to transplantation
General
  • don’t give FFP until discussed with transplant unit as indicated or liver function (unless bleeding)
  • metabolic acidosis from hepatic and renal failure -> supportive care
  • withhold any renal or hepatotoxic medications
  • intubation and ventilation if indicated
  • GI prophylaxis
  • attention to pressure areas
  • feed
  • airway toilet
Disposition
  • discuss early with transplantation team (develop liver failure within 48 hours)
  • admit to medical/gastro unless requires ICU
  • will require psychiatric assessment if was an intentional overdose
Prognostication — can use the O’Grady criteria:
  • acidaemia (pH < 7.3)
  • renal impairment (creatinine > 300micromoles/L)
  • hepatic encephalopathy (grade III or IV)
  • PT > 100 seconds (INR > 6.5)
  • factor V level < 10%

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