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Salicylates


DRUGS INCLUDED IN THIS CATEGORY


Commonly available preparations include
  • aspirin (also in sustained release forms)
  • aspirin in various combinations (with codeine etc.)
  • peptobismol
  • methylsalicylate (oil of wintergreen) (1 tsp = 7000 mg salicylate)

OVERVIEW


Salicylate poisoning is a potentially life threatening condition which is characterised by extreme acid-base disturbances, electrolyte disturbances and decreasing level of consciousness. There is a wide variation in the clinical spectrum of toxicity. There are differences between acute and chronic toxicity and a varying clinical picture which is dependent on the age of the patient and renal function.

MECHANISM OF TOXIC EFFECTS


Metabolic acidosis

The major feature of poisoning is a metabolic acidosis. This is due to "uncoupling of oxidative phosphorylation" which leads to
  • An increase in metabolic rate
  • Increased oxygen consumption
  • Increased CO2 formation
  • Increased heat production
  • Increased glucose utilisation

This may be exacerbated by
  • Accumulation of organic acid metabolites
  • Starvation and dehydration induced ketosis
  • Lactic acidosis

Respiratory alkalosis

Salicylates directly stimulate the respiratory centre leading to hyperventilation and a respiratory alkalosis. This leads to compensatory increased renal excretion of bicarbonate which contributes to the metabolic acidosis which may coexist or develop subsequently.

Glucose metabolism

Hypoglycaemia (intracellular > extracellular) may occur due to
  • increased peripheral glucose demand
  • increased rate of tissue glycolysis
  • impaired rate of glucose synthesis

NB TISSUE GLUCOSE CONCENTRATIONS MAY BE LOWER THAN PLASMA GLUCOSE CONCENTRATIONS.

Hyperglycaemia may occur due to increased glycogenolysis.

Other effects

Potassium depletion occurs in salicylate poisoning because of increased renal excretion as well as intracellular movement of potassium. Hypokalaemic patients or patients with total body potassium depletion are unable to produce an alkaline urine.
Salicylates competitively inhibit vitamin K dependent synthesis of factors II, VII, IX and X reflected in an increased INR.
Salicylates may cause a mild dose dependent hepatitis. The metabolic pathway responsible has not been identified and there is no antidote.

KINETICS IN OVERDOSE


Explanatory note (see also ion trapping). Aspirin is a weak acid (pKa = 3.5).

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Thus, as the pH falls a larger proportion of salicylate is un-ionised and lipid soluble. Therefore the pharmacokinetics of salicylates are pH dependent.

Absorption

Acetylsalicylic acid is a weak acid with a pKA of 3.5 and is rapidly absorbed and hydrolysed to salicylic acid and acetic acid. It is better absorbed from the acid environment of the stomach than from the alkaline small intestine.


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Tablet dissolution may be extremely slow and in overdose pharmacobezoars (large tablet aggregates) may form which may lead to greatly delayed absorption.

Distribution

Salicylates are bound to albumin. The extent of protein binding is concentration dependent (and falls with higher blood concentrations). This, and the effect of acidosis decreasing ionisation, means that the volume of distribution increases markedly in overdose as does CNS penetration and adverse effects.

Metabolism - Elimination

Both the extent of protein binding (50-80%) and the rate of metabolism are concentration dependent. Hepatic clearance has zero order kinetics and thus the therapeutic half-life is 2-4.5 hours but the half-life in overdose is 18-36 hours. In overdose, renal excretion is the most important route of elimination.
Thus, when salicylate concentrations are in the toxic range there is increased tissue distribution and impaired clearance of the drug. Patients with cirrhosis of liver, low protein states or renal impairment are more prone to toxicity. Urinary clearance is greatly increased in an alkaline urine.

Salicylate excretion depends on the following factors
  • Blood and urine pH
  • Potassium concentration
  • Pre-existing liver or renal failure
  • Dose of salicylates
  • Blood and urine pH
  • An alkaline urine (pH >7.5) dramatically increases salicylate clearance by ion trapping.

Potassium concentration
It is not possible to produce alkaline urine in the presence of hypokalaemia. Sodium that is absorbed in the distal tubule must be exchanged for potassium or hydrogen ions. Hypokalaemia may be noted only when the serum pH is corrected as the acidosis may mask severe potassium depletion (particular common in chronic poisoning).

Pre-existing liver or renal failure
These will reduce clearance of salicylate and at the same time increase free concentrations of salicylate and the volume of distribution because of reduced protein binding.

Dose of salicylates
Salicylates have dose dependent kinetics.

CLINICAL EFFECTS


In children hyperventilation, dehydration and neurological dysfunction are greater in chronic overdoses compared with single acute ingestions.
Symptoms can occur with declining salicylate concentrations because of CNS trapping of ionised salicylate.

Metabolic effects

Acid-base disturbance (respiratory alkalosis, metabolic acidosis)
Respiratory alkalosis is the earliest acid-base disturbance in salicylate poisoning. However, in severe poisoning a profound metabolic acidosis is the major feature of toxicity. Respiratory alkalosis then occurs from direct stimulation and as a response to the acidosis. If respiration is impaired, including by the institution of assisted ventilation, the acidosis and CNS effects become more marked. Respiratory acidosis may be due to one of the following complications:
  • coingestion of respiratory depressants
  • aspiration
  • non cardiogenic pulmonary oedema
  • CNS depression
  • seizures

Electrolyte imbalance
Patients are often significantly dehydrated (chronic > acute). Electrolyte abnormalities are common and include:
  • a large anion gap
  • hyponatraemia
  • hypernatraemia
  • hypokalaemia
  • hypocalcaemia

Hyperglycaemia and hypoglycaemia
Glucose metabolism is altered in a number of ways. It is important to realise that intracellular and CNS glucose concentrations may be low despite a normal blood glucose.

Pyrexia

Mild pyrexia is common and is due to increased metabolic activity.

Gastrointestinal effects

Nausea and vomiting are common. Less common are epigastric pain and haematemesis. Vomiting contributes significantly to electrolyte imbalance and dehydration.

Central nervous system effects

Mild
nausea, vomiting, tinnitus
Moderate
confusion, hyperventilation
Severe
hallucinations, seizures, coma, cerebral oedema

These CNS effects may be caused by electrolyte disturbance or hypoglycaemia as well as direct salicylate toxicity. Seizures and coma may lead to a significant deterioration as they impair respiratory compensation for the metabolic acidosis
Serious toxicity can still occur in the presence of declining serum concentrations of salicylate. This occurs as correction of the acidosis causes trapping of salicylate by ionisation within the central nervous system and persistent high intracellular concentrations.

Haematological effects

A prolonged prothrombin time, usually > 2 x normal, occurs predictably in significant overdoses. Vitamin K will correct the prothrombin time rapidly. As in therapeutic use, aspirin, but not other salicylates, impairs platelet aggregation.

Hepatic effects

Rises in transaminases occur not uncommonly, are usually not clinically significant, and resolve over several days.

Other effects

Non-cardiogenic pulmonary oedema and renal failure occur occasionally and always in association with other signs of significant poisoning.

INVESTIGATIONS


The following investigations should be done in all patients
  • FBC, coagulation profile
  • Electrolytes, calcium, creatinine, glucose
  • Arterial blood gas
  • Urinalysis and urine pH
  • Plasma salicylate concentration

Biochemistry

Patients with moderate or severe poisoning (by any measure) will need 2nd hourly measurement of electrolytes and glucose. CSF glucose concentrations may be low despite normal plasma concentrations.

Blood gases

In adults the acid base disturbance is usually that of a mixed respiratory alkalosis and metabolic acidosis.
However, in children systemic metabolic acidosis predominates because of early failure of compensatory respiratory alkalosis.
Respiratory acidosis is rare and indicates complications such as coingestion of respiratory depressants, aspiration, pulmonary oedema or CNS complications.
Thus, blood gases serve as a guide to the need for further correction of acidosis and may point to the development of respiratory complications.

Blood concentrations

Plasma salicylate should be estimated urgently in any patient who has a potentially serious poisoning, electrolyte or acid-base disturbance.
It is necessary to take repeat concentrations two hours apart until the concentration is falling because of the potential for formation of tablet aggregates (pharmacobezoars), the use of enteric coated tablets and delayed gastric emptying.

Salicylate concentrations are used for the following purposes
  • To indicate if GI decontamination has been successful
  • As a guide to severity
  • Indication for ICU admission
  • Indication for haemodialysis
  • To measure the success of elimination enhancement

DIFFERENTIAL DIAGNOSIS


There are a number of poisonings that can present with a metabolic acidosis and impaired concentration or consciousness.

DIFFERENCES IN TOXICITY WITHIN THIS DRUG CLASS


Chronic toxicity is more serious than acute poisonings for a given serum concentration.
Antiplatelet effects will be seen with aspirin but not other salicylates.

DETERMINATION OF SEVERITY


In the initial assessment of the severity of toxicity the four following areas should be considered
  • Dose ingested
  • Salicylate concentration
  • Clinical grading of toxicity
  • Acid-base grading of severity

Ingested Dose
The assessment of ACUTE salicylate intoxication based on dose (Temple, 1981).
Ingested Dose mgs/kg
Estimated Severity
< 150
No toxic reaction expected
150-300
Mild to moderate toxic reaction
300-500
Serious toxic reaction
500
Potentially Lethal
NB Chronic toxicity can develop from doses of 100 mg/kg/day. Patients with cirrhosis, low protein states or renal impairment develop toxicity with lower doses.

Salicylate concentration
Conversion factor
  • mg/L x 0.0072 = mmol/L
  • mmol/L x 138 = mg/L
Salicylate concentrations taken after 6 hours in acute ingestions correlate with clinical severity when plotted on the Done nomogram. This is not the main reason for taking salicylate concentrations.

The concentration may be taken 2 hours following acute ingestion of methyl salicylate (which is absorbed rapidly).

Clinical grading of toxicity

Mild

nausea, vomiting, tinnitus

Moderate

confusion, hyperventilation

Severe

hallucinations, seizures, coma, cerebral or pulmonary oedema.

Acid-base grading of severity
Stage
Blood pH
Urine pH
Comment
I
>7.4
>6
Respiratory alkalosis , Increased urinary excretion of NaHCO3, K+ & Ca++
II
>7.4
<6
Metabolic acidosis with compensating respiratory alkalosis. Intracellular K+ depletion, urine H+ excretion.
III
<7.4
<6
Severe hypokalaemia and metabolic acidosis

TREATMENT


Supportive

Patients should be admitted to ICU if they fulfill any of the following criteria
  • An acute ingestion > 300 mg/kg
  • Moderate or severe clinical severity
  • Stage 2 or 3 acid-base disturbance
  • Salicylate concentration > 4 mmol/L (65 mg%)
There are no specific antidotes.

Close attention should also be paid to the following areas:
  • Hydration
  • Metabolic acidosis
  • Hypokalaemia
  • Hypoglycaemia

Hydration
All patients with clinically significant symptoms are usually dehydrated and should be volume repleted with 4% dextrose in 1/5 normal saline, starting at a rate of at least 10-15 mL/kg/hour.

Fluids should be given to maintain a urine output of 1.5-2 mL/kg/hour. This is adequate for maximal salicylate excretion. Most patients will also require bicarbonate and potassium and the electrolytes should be monitored.

Metabolic acidosis
The acidosis should be treated aggressively as a low serum pH increases central nervous system salicylate concentrations
  • Both the serum pH and the base deficit should be corrected
  • Hypokalaemia will need to be corrected concurrently.
  • The patient should be commenced on 1 mEq/kg/hour of bicarbonate added to the IV fluid. Bolus doses may be required in severe acidosis.
  • Avoid interventions that compromise respiratory drive in unventilated patients
  • Ensure maintenance of airway and ventilation
  • If the patient needs intubation, it is critically important to maintain the high respiratory rates present before intubation as ventilating without maintaining the compensatory respiratory alkalosis can lead to rapid and profound deterioration because of worsening acidosis (see above).

Hypokalaemia
Hypokalaemia should be corrected providing there is a urine output. In adults the acid-base grading of severity can be used as a guide to initial therapy.
  • Stage 1: 10-20 mEq KCL per liter
  • Stage 2: 20-40 mEq KCL per liter
  • Stage 3: 40-60 mEq KCL per liter

Hypoglycaemia
All patients with CNS depression or seizures should receive an intravenous bolus of 50% glucose regardless of their blood sugar.

GI Decontamination

Oral activated charcoal should be given to all patients ingesting more than 150 mg/kg of salicylate who present within 4-6 hours.
Gastric lavage should be considered for larger ingestions if the patient
  • presents within 1-2 hours
  • is unconscious
Repeated doses of activated charcoal should be considered.

Whole bowel irrigation should be considered in enteric coated salicylate ingestions.

Treatment of specific complications

Pulmonary oedema
Initial treatment is with ventilation with PEEP and supplemental oxygen. This is also an indication for haemodialysis.

Seizures
Seizures indicate a serious prognosis and are an indication for haemodialysis. Seizures should be initially treated with an IV bolus of 50% glucose and followed by diazepam 0.1-0.2 mg/kg/dose. Refractory seizures require special treatment.

Patients should be assessed for evidence of METABOLIC CAUSES contributing to seizures, such as hyponatraemia, hypoglycaemia and hypocalcaemia as well as cerebral oedema. If seizures do not respond then patients should be given calcium without waiting for laboratory confirmation.

Prolonged prothrombin time
This will correct with vitamin K.

Hyperthermia
Treatment is by external cooling (wet towels, fans, cooling blankets, etc.).

Elimination enhancement

The clearance of salicylate can be increased by any of the following

Urine alkalinisation

Renal excretion (in overdose) is the major route of elimination.

Salicylate excretion depends on the following factors
  • Blood and urine pH
An alkaline urine pH (> 7.5) dramatically increases salicylate clearance by ion trapping.
  • Potassium concentration
Potassium depletion occurs because of increased renal excretion and intracellular movement of potassium. Hypokalaemic patients are unable to produce an alkaline urine.

  • Initially give the patient 1 mEq/Kg of sodium bicarbonate in 5% dextrose over one hour
  • then start an infusion of 0.25- 0.5 mEq/Kg per hour of sodium bicarbonate in 5% dextrose

Moderate to severe intoxications require additional boluses of 50-100 mEq of sodium bicarbonate over 1-2 hours with close monitoring of blood pH to correct systemic acidosis.
If the urine pH does not rise to above 7.5 (paradoxical aciduria) in spite of correction of systemic acidosis and the production of a systemic alkalosis this usually indicates the patient is potassium depleted.

Alkaline diuresis should not be attempted in patients who have evidence of pulmonary oedema or those with renal failure. These patients should undergo haemodialysis. Oral bicarbonate is contraindicated as it enhances salicylate absorption.

Haemodialysis & haemoperfusion

Both of these methods will enhance clearance of salicylate substantially but haemodialysis is generally preferred over haemoperfusion as it also corrects acidosis and electrolyte imbalances.

Indications
  • Pre-existing CARDIAC or RENAL FAILURE
  • Pulmonary oedema
  • INTRACTABLE ACIDOSIS or severe electrolyte imbalance
  • SALICYLATE concentrations
  • >9.4 mmol/L in ACUTE ingestions (when the concentration has been taken within 6 hours of ingestion)
  • >4.5 mmol/L in CHRONIC intoxication
  • CLINICALLY SERIOUS TOXICITY (regardless of concentration)

LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP


Long term sequelae (neuropsychiatric) are a significant risk in severe poisonings due to the potential for damage from acidosis, hypoglycaemia and hypoxia.

Risk factors for neuropsychiatric sequelae or death include
  • Old age
  • Seizures
  • Coma on admission
  • Low pH
  • Low pO2
  • Low K
  • Chronic toxicity

REFERENCES


Notarianni L. A reassessment of the treatment of salicylate poisoning. Drug Safety. 1992;7(4):292-303.
Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med 1981;141:366.
Done AK. Aspirin overdose: Incidence, diagnosis and management. Pediatrics 1978;62(suppl):895.

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