Paracetamol and tricyclic antidepressant overdose

1. Paracetamol and tricyclic antidepressant overdose

2. Paracetamol dosing : • Paracetamol dose in adults over 50 kg : 1 g up to four times a day,with a minimum of 4 h between each administration (6 h for thosewith renal impairment, i.e. creatinine clearance <30 ml min) • Well tolerated in hepa-tocellular insufficiency and even cirrhosis within the normal recommended dose range, albeit cautiously. • Concomitant intake of enzyme-inducing substances, such as carbamazepine, phenytoin, or barbiturates, as well as chronic alcohol excess, may increase NAPQI production and the risk of paracetamol toxicity

3. How much is too much ? • Hepatotoxicity can occur after ingestion of more than 150mg/kg paracetamol within 24 hours. Rarely, hepatotoxicity can develop after ingestion of doses as low as 75mg/kg within 24 hours. • However, for obese patients, it is important that potentially toxic doses of paracetamol are not underestimated, and when calculating the total amount of paracetamol ingested in mg/kg for a patient who weighs more than 110kg, 110kg should be used, rather than actual body weight. • For pregnant women, calculations should be made using the woman’s pre-pregnancy weight

4. Mechanism of toxicity : • Paracetamol itself is not hepatotoxic. • However, a metabolite of paracetamol, N-acetyl-p-benzoquinone-imine (NAPQI), can cause hepatocyte necrosis. • At therapeutic doses of paracetamol NAPQI is rapidly converted by glutathione to cysteine and mercapturic acid conjugates, both of which are non-toxic. However, when the concentration of NAPQI exceeds that of intracellular glutathione, NAPQI is able to bind to hepatocytes and cause necrosis. • Hepatic necrosis caused by NAPQI can lead to fulminant liver failure (which may require liver transplantation) and death.

5. Antidote -NAC • Acetylcysteine prevents NAPQI-induced hepatic necrosis by increasing synthesis of glutathione • It is considered to be 100 per cent effective in preventing liver damage and death if it is administered within eight hours of overdose, after which the efficacy declines rapidly. • Although it is most effective if treatment is started within eight hours of paracetamol ingestion, acetylcysteine protects the liver if infused up to, and possibly beyond, 24 hours of ingestion.

6. NAC dosing : • The total dose of acetylcysteine recommended for the management of paracetamol toxicity is 300mg/kg; this dose should be divided into three consecutive intravenous infusions, which are given over a total of 21 hours as follows: • - First infusion — 150mg/kg given as an intravenous infusion over one hour • - Second infusion — 50mg/kg given as an intravenous infusion over four hours • - Third infusion — 100mg/kg given as an intravenous infusion over 16 hours

7. Key factors : • Hepatic damage develops over one or two days, and is generally maximal three to four days after overdose. • Because the efficacy of acetylcysteine declines rapidly eight hours after ingestion of paracetamol, acetylcysteine should be administered immediately to patients who present eight to 24 hours after taking an acute overdose of more than 150 mg/kg of paracetamol, even if the plasma-paracetamol concentration is not yet available .

8. Special situations: • A “staggered overdose” involves intentional ingestion of a potentially toxic dose of paracetamol over more than one hour whereas • The inadvertent ingestion of a potentially toxic dose of paracetamol during its clinical use is termed “therapeutic excess • Clinically significant toxicity is unlikely if, 24 hours or longer after the most recent paracetamol ingestion, patients are asymptomatic, plasma-paracetamol concentrations are undetectable, and liver function tests, serum creatinine and INR are normal

9. When to transfer to a liver centre ? • INR >3.0 at 48 hours or >4.5 at any time • Oliguria or creatinine > 2.5 mg/dL • Acidosis with pH < 7.3 after resuscitation • Systolic hypotension with BP < 80mmHg • Hypoglycaemia • Severe thrombocytopenia • Encephalopathy of any degree

10. Liver transplant prediction The King’s College Criteria • pH < 7.3 or • In a 24h period, all 3 of: • INR > 6 (PT > 100s) + • Cr > 300mmol/L + • grade III or IV encephalopathy Modified criteria : Lactate > 3 NOTE : 30% of people who meet KCC in the 12 articles from centres other than King’s College survived without transplant

11. Tricyclic antidepressants • TCA’s exert a number of effects on the central nervous system, which may lead to drowsiness, coma, respiratory depression and seizures. • TCA’s block alpha-adrenergic receptors and have anticholinergic effects. • This may lead to cardiovascular effects including sinus tachycardia, cardiac conduction abnormalities, vasodilatation, arrhythmias, hypotension and asystole • The anticholinergic effects of TCA’s may also lead to dry mouth, blurred vision, dilated pupils, hyperthermia and delayed gastric emptying

12. Airway management • Patients with GCS ≤8 should undergo rapid sequence induction at the earliest opportunity (Grade C). • Some patients with GCS >8 may also need intubation, particularly in the presence of airway compromise, hypoventilation or refractory seizures (Grade C). • Benzodiazepines may be considered to control agitation following TCA overdose (Grade E).

13. Gastric decontamination • Activated charcoal may be considered for use within 1 hour of TCA ingestion but only in patients with an intact or secured airway. • The potential risk of aspiration should be strongly considered before use (Grade D). • Multiple dose activated charcoal should not be considered (Grade D). • Gastric lavage may be considered for potentially life-threatening TCA overdoses only when it can be delivered within 1 hour of ingestion and the airway is protected (Grade D).

14. Risk stratification : ECG & ABG • An ECG should be recorded at presentation to the ED following TCA overdose (Grade B). • Serial ECG recordings should be examined for the presence of QRS prolongation (>100ms), QTc prolongation (>430ms) and R/S ratio >0.7 in lead aVR. it has been shown that prolongation of the QRS duration (>0.16 seconds) is a better predicator of seizures or ventricular arrhythmias than the plasma drug concentration • Blood gas analysis is an important part of the initial assessment and monitoring of patients who have taken a TCA overdose (Grade E

15. Treatment of haemodynamic instability • Fluid bolus should be considered as a first-line therapy to treat hypotension induced by TCA overdose (Grade D). • Sodium bicarbonate is indicated for the treatment of dysrhythmias or hypotension associated with TCA overdose. (Grade C). Sodium bicarbonate may be considered for the treatment of QRS prolongation (>100ms) associated with TCA overdose (Grade E). • The treatment of dysrhythmias or hypotension should include alkalinisation to a serum pH of 7.45 to 7.55. (Grade E). • Inotropes : Epinephrine may be superior to norepinephrine for treating refractory hypotension and preventing arrhythmias.

16. Management of seizures • Phenytoin should be avoided in patients with TCA overdose (Grade D). • Benzodiazepines should be used to control seizures following TCA overdose (Grade E).

17. What about asymptomatic patients ? • Following TCA overdose asymptomatic, stable patients with no significant ECG abnromalities six hours after ingestion may be safely discharged (Grade B).

18. New concepts –Na MORE IMPORTANT THAN BICARBONATE • The administration of hypertonic sodium chloride to rats with desipramine toxicity has been shown to be as effective as sodium bicarbonate in reversing QRS prolongation and hypotension while respiratory alkalosis had little effect • From these experiments it has been suggested that increasing the extracellular sodium concentration is the major mechanism.

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