Aspirin Toxicity z4541

• Mild poisoning causes nausea, vomiting, tinnitus, lethargy or dizziness. • More severe poisoning causes dehydration, restlessness, sweating, warm extremities with bounding pulses, increased respiratory rate, hyperventilation and deafness. • A degree of disturbance of acid-base balance is present in most cases. • Hyperglycaemia, normoglycaemia or hypoglycaemia (all with intracellular glucose depletion) may occur. • Uncommon features include haematemesis, hypokalaemia, hyponatraemia/hypernatraemia, hypocalcaemia, thrombocytopenia, abnormal blood coagulation (increased prothrombin ratio/INR), disseminated intravascular coagulation, acute kidney injury and non-cardiac pulmonary oedema. • CNS: confusion, disorientation, coma and convulsions (less common in adults than in children).

Chronic salicylate poisoning • Chronic salicylate poisoning is more common in the elderly and requires lower levels of salicylate ingestion. Chronic salicylate toxicity often goes unrecognised. • The onset of chronic salicylate poisoning may be insidious. An increasing amount of salicylate may be taken over several days to alleviate pain such as t pain. • Chronic salicylate poisoning may cause anxiety, tachypnoea, diffuse sweating, difficulty concentrating, confusion, hallucinations and even agitated delirium. Elderly individuals may present with a deterioration in functional status. • Salicylate poisoning should be considered in the differential diagnosis of an adult patient with acid-base abnormalities of uncertain cause, especially when there are also neurological symptoms. • Delayed diagnosis results in increased morbidity and mortality, particularly in the elderly.

Plasma salicylate concentrations: • The severity of poisoning cannot be assessed from plasma salicylate concentrations alone and the clinical and biochemical features should also be considered. • Should be measured urgently for patients who are thought to have ingested more than 125 mg/kg of aspirin as well as those who have taken methyl salicylate or salicylamide. • The sample should be taken at least two hours (symptomatic patients) or four hours (asymptomatic patients) following ingestion, as it may take several hours for peak plasma concentrations to occur. • A repeat sample should be taken after a further two hours because of the possibility of continuing absorption. Measurements should be repeated every three hours until concentrations are falling.

Plasma salicylate concentrations: • Renal function and electrolytes, FBC, coagulation studies (raised INR/PTR), urinary pH, and blood glucose. • Plasma potassium should be checked every three hours and plasma potassium levels maintained at between 4.0-4.5 mmol/L. • Arterial blood gases (capillary gases or venous blood gases are alternatives in children): some degree of acidbase disturbance is present in most cases: – Adults and older children over the age of 4 years: mixed respiratory alkalosis and metabolic acidosis, with normal or high arterial pH. – Young children: metabolic acidosis is common.

The likelihood of toxicity can be gauged to a degree by: • The ingested dose: – Greater than 125 mg/kg body weight: likely toxicity is mild. – Greater than 250 mg/kg body weight: likely toxicity is moderate. – Greater than 500 mg/kg body weight: likely toxicity is severe, possibly fatal.

• Salicylate concentration: – Severity of poisoning cannot be assessed from plasma salicylate concentrations alone but salicylate intoxication is usually associated with plasma concentrations greater than 350 mg/L (2.5 mmol/L). Most adult deaths occur in patients whose concentrations exceed 700 mg/L (5.1 mmol/L).

• Clinical grading: – Mild (nausea, vomiting, tinnitus). – Moderate (hyperventilation and confusion). – Serious (hallucinations, seizures, coma, cerebral oedema or pulmonary oedema).

• Acid-base staging: – Stage I: blood pH >7.4, urine pH >6.0 - respiratory alkalosis, increased urinary excretion of bicarbonate. – Stage II: blood pH >7.4, urine pH <6.0 - metabolic acidosis with compensating respiratory alkalosis, urinary hydrogen excretion, intracellular potassium depletion. – Stage III: blood pH <7.4, urine pH <6.0 - severe metabolic acidosis and hypokalaemia.

Management Treatment must be in hospital where plasma salicylate, pH and electrolytes can be measured. Absorption of aspirin may be slow and the plasma-salicylate concentration may continue to rise for several hours, requiring repeated measurement of plasma-salicylate concentration. General measures for poisoning. • Consider oral activated charcoal (50 g for an adult, 1 g/kg for a child) if ingested more than 125 mg/kg body weight salicylate less than one hour previously. • A second dose of charcoal may be required in patients whose plasma salicylate level continues to rise or who have taken enteric-coated preparations (absorption may be slower). • Gastric lavage if the patient has ingested more than 500 mg/kg body weight salicylate within one hour. • Aggressive rehydration. • Have a low threshold to give glucose, as intracellular glucose depletion may not be reflected in the blood glucose level.

• Urinary alkalinisation:Elimination of salicylate may be increased by alkalinisation of the urine. The optimum urine pH is 7.5-8.5. • If the salicylate concentration in an adult is above 500 mg/L (3.6 mmol/L): 225 mmol sodium bicarbonate (225 mL of 8.4% over 60 minutes or 1.5 L of 1.26% over two hours). • If the salicylate concentration in a child is above 350 mg/L (2.5 mmol/L): 1 mL/kg 8.4% bicarbonate diluted in 0.5L 5% dextrose or normal saline at 2-3 mL/kg/hour. • The urinary pH should be checked hourly. Further amounts of sodium bicarbonate (8.4%) may be required to maintain the urine pH at 7.5-8.5. • Urinary alkalinisation does not need to be delayed while awaiting haemodialysis but volume overload must be avoided in a patient who is oliguric.

• The plasma salicylate concentration should be repeated 1- to 2-hourly to ensure that treatment has been effective. • Hypokalaemia: – May make alkalinisation of the urine less effective and it is important to recheck the plasma potassium 1- to 2-hourly and to give potassium if the plasma potassium falls below 4.0 mmol/L. – Hypokalaemia should be corrected before giving sodium bicarbonate.

• Forced diuresis: should not be used, as it does not enhance salicylate excretion and may cause pulmonary oedema.

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Haemodialysis is the treatment of choice for severe poisoning and should be seriously considered in patients with: Plasma concentrations greater than 700 mg/L (5.1 mmol/L) Acute kidney injury Congestive cardiac failure Non-cardiogenic pulmonary oedema Coma Convulsions CNS effects not resolved by correction of acidosis Persistently high salicylate concentrations unresponsive to urinary alkalinisation Severe metabolic acidosis (pH below 7.2)

• Patients aged under 10 years or over 70 years have increased risk of salicylate toxicity and may require dialysis at an earlier stage. • Haemofiltration is much less efficient than haemodialysis or haemodiafiltration, but may be an alternative in hospitals without dialysis facilities, especially if transfer is likely to be delayed. • Mechanical ventilation: – Endotracheal intubation may be indicated for deteriorating mental status or acute lung injury and should be considered in those with significant, uncontrollable agitation. – Hyperventilation is not itself an indication for intubation. – Endotracheal intubation and mechanical ventilation can be associated with rapid worsening of clinical salicylate toxicity and increased mortality unless a normal or slightly alkalaemic blood pH is maintained by hyperventilation (causing a low pCO2) and/or intravenous sodium bicarbonate.

Acetaminophen poisoning can cause gastroenteritis within hours and hepatotoxicity 1 to 3 days after ingestion. Severity of hepatotoxicity after a single acute overdose is predicted by serum acetaminophen levels. Treatment is with N -acetylcysteine to prevent or minimize hepatotoxicity.

Acetaminophen Metabolism

Acetaminophen is metabolized through 3 different pathways: •42% to 67% undergoes glucuronidation and is excreted in urine •26% to 36% undergoes sulfation and is excreted in urine •5% to 8% es through the cytochrome P-450 pathway producing a potentially hepatotoxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI) In normal dosing, NAPQI is conjugated with the antioxidant, glutathione, and excreted in urine.

Mechanism of Action Overdose depletes the available glutathione and unbound NAPQI destroys liver cells.2 • IV Acetadote protects liver cells in 2 ways: • It helps replenish glutathione • It binds to and removes NAPQI

When time is liver, timing is critical The critical ingestion-treatment interval for maximum protection against severe hepatic injury is between 0-8 hours.

Prognosis • With appropriate treatment, mortality is uncommon. • Poor prognostic indicators at 24 to 48 h postingestion include all of the following: • pH < 7.3 after adequate resuscitation • INR > 3 • Serum creatinine > 2.6 • Hepatic encephalopathy grade III (confusion and somnolence) or grade IV (stupor and coma) • Hypoglycemia • Thrombocytopenia • Acute acetaminophen toxicity does not predispose patients to cirrhosis.

Treatment

• Oral or IV N -acetylcysteine • Possibly activated charcoal • Activated charcoal may be given if acetaminophen is likely to still remain in the GI tract. • N -Acetylcysteine is an antidote for acetaminophen poisoning. This drug is a glutathione precursor that decreases acetaminophen toxicity by increasing hepatic glutathione stores and possibly via other mechanisms. It helps prevent hepatic toxicity by inactivating the toxic acetaminophen metabolite NAPQI before it can injure liver cells. However, it does not reverse damage to liver cells that has already occurred.

• For acute poisoning, N-acetylcysteine is given if hepatotoxicity is likely based on acetaminophen dose or serum level. The drug is most effective if given within 8 h of acetaminophen ingestion. After 24 h, the benefit of the antidote is questionable, but it should still be given. If degree of toxicity is uncertain, N-acetylcysteine should be given until toxicity is ruled out. • N -Acetylcysteine is equally effective given IV or orally. IV therapy is given as a continuous infusion. A loading dose of 150 mg/kg in 200 mL of 5% D/W given over 15 min is followed by maintenance doses of 50 mg/kg in 500 mL of 5% D/W given over 4 h, then 100 mg/kg in 1000 mL of 5% D/W given over 16 h. For children, dosing may need to be adjusted to decrease the total volume of fluid delivered; consultation with a poison control center is recommended.

• The oral loading dose of N -acetylcysteine is 140 mg/kg. This dose is followed by 17 additional doses of 70 mg/kg q 4 h. Oral acetylcysteine is unpalatable; it is given diluted 1:4 in a carbonated beverage or fruit juice and may still cause vomiting. If vomiting occurs, an antiemetic can be used; if vomiting occurs within 1 h of a dose, the dose is repeated. However, vomiting may be protracted and may limit oral use. Allergic reactions are unusual but have occurred with oral and IV use. • Liver failure is treated ively. Patients with fulminant liver failure may require liver transplantation.

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