salicylate intoxication
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Aspirin
It has long been known that aspirin ingestion is associated with an increased risk of significant bleeding.
The mechanism of this effect was clarified when aspirin was shown to inhibit collagen-induced platelet aggregation and the second wave of ADP-induced platelet aggregation, as well as blocking the release of ADP from platelets.
ADP is known to be a potent platelet-aggregating substance.
Aspirin and other non-steroidal anti-inflammatory analgesics have been shown to interfere with platelet prostaglandin synthesis by inhibiting platelet fatty acid cyclo-oxygenase.
This in turn reduces synthesis of labile endoperoxides PGG2 and PGH2 from platelet membrane arachidonic acid, in turn reducing the production of TXA2 (Thromboxane A2), the extremely potent mediator of platelet aggregation.
It is now known that the interference with endoperoxide production inhibits stimulus-induced ADP release, so it is probably the inhibition of cyclo-oxygenase that is the root cause of aspirin-induced platelet dysfunction.
Aspirin acts on cyclo-oxygenase by causing irreversible acetylation of the enzyme, and therefore the effect is irreversible for the life of that platelet (7-10 days). Other non-steroidal anti-inflammatory analgesics have a reversible action on that enzyme, and hence only act until the drug is cleared from the circulation.
Aspirin also inhibits cyclo-oxygenase in the endothelial cells of blood vessels. This action results in inhibition of PGI2 production. PGI2 is the most potent inhibitor of platelet aggregation know. However, endothelial cells can actively synthesise cyclo-oxygenase, so recovery of PGI2 synthesis is possible with intermittent aspirin ingestion.
The use of salicylates dates back 2500 years when Hippocrates recommended the use of willow bark to relieve the pain of childbirth. Salicylic acid is the extract from willow bark that produces the analgesic effect. Today, salicylates are used in many over-the-counter and prescription medications for their analgesic as well as their anti-inflammatory and antipyretic properties. Salicylate ingestion was a common cause of poisoning and death in children in the US prior to the 1970s, when legislation requiring childproof packaging on medications was passed. Despite the reduction of poisonings because of repackaging, salicylate toxicity remains a significant cause of morbidity and mortality today.
In therapeutic doses, aspirin is absorbed rapidly from the stomach and small intestine,
but in overdose, absorption may occur more slowly and the plasma salicylate concentration may continue to rise for up to 24 hours.
The pharmacokinetics of elimination of aspirin are an important determinant in the development of salicylate toxicity.
Metabolic
In salicylate toxicity, as salicylate levels increase, the acid-base disturbance progresses from respiratory alkalosis to mixed respiratory alkalosis and metabolic acidosis.
In children, the progression to metabolic acidosis occurs more rapidly.
Salicylate s directly stimulate respiratory centers in the medulla, causing hyperventilation and, subsequently, respiratory alkalosis.
Salicylates also cause uncoupling of oxidative phosphorylation, which leads to decreased adenosine triphosphate (ATP) production, increased oxygen consumption, increased carbon dioxide production, and increased heat production.
Derangement in the Krebs cycle and carbohydrate metabolism leading to an accumulation of organic acids, including pyruvate, lactate, and acetoacetate, causes metabolic acidosis.
Toxic levels of salicylates also displace large amounts of plasma bicarbonate, further worsening the metabolic acidosis.
The metabolic acidosis in salicylate poisoning is an anion gap acidosis, Na + –(Cl -+HCO 3-) greater than 14 mEq/L.
Other causes of anion gap metabolic acidosis that can be confused with or coexist with salicylate toxicity include
diabetic ketoacidosis,
renal failure,
lactic acidosis,
and volatile alcohol overdose (methanol, ethylene glycol).
Fluid and electrolyte
Increased metabolic rate, pyrexia, tachypnea, and vomiting lead to fluid loss and dehydration.
Compensation for respiratory alkalosis leads to increased renal excretion of bicarbonate and increased excretion of sodium and potassium.
Because of significant water losses, hyponatremia might not be present; however, hypokalemia is prominent.
Central nervous system
Toxic effects in the CNS range from mild confusion to coma.
The exact mechanism that produces CNS toxicity is not known, but the degree of CNS effects, as well as overall mortality, correlates with the concentration of salicylates in brain tissue.
Acidemia increases the nonionized form of salicylates, allowing for movement across the blood-brain barrier and, therefore, increasing CNS toxicity.
Gastrointestinal
Salicylate ingestion can cause nausea, vomiting, and abdominal pain.
Emesis is produced by salicylate stimulation of medullary chemoreceptors and by local irritation of the GI tract.
Upper GI ulceration and bleeding can occur.
Gastrointestinal effects are much more prominent in acute ingestion.
Ototoxicity
Salicylate toxicity results in a reversible ototoxicity characterized by tinnitus, deafness, and dizziness.
Pulmonary
Noncardiogenic pulmonary edema is the most common cause of major morbidity and might be related to an increase in permeability of pulmonary vasculature caused by salicylates.
Acute respiratory distress syndrome (ARDS) is more prominent is chronic ingestions than in acute ingestions.
Hematological
Salicylates inhibit vitamin K-dependent synthesis of factors II, VII, IX, and X, leading to a prolonged prothrombin time (PT).
Salicylates prolong bleeding time by inhibiting a prostaglandin-initiated sequence required for platelet aggregation.
Hepatic
Dose-dependent hepatotoxicity can occur with salicylate poisoning.
A small percentage of patients might develop hepatitis, but the majority will have asymptomatic elevation of transaminases.
Renal
Acute renal failure has been reported rarely.
Mortality/Morbidity:
Mortality rates vary with chronicity of exposure. Chronic toxicity carries a higher morbidity and mortality than acute toxicity and is more difficult to treat.
Acute overdose - Mortality rate of less than 2%
Chronic overdose - Mortality rate up to 25%
The biotransformation pathways concerned with the formation of salicyluric acid and salicylphenolic glucuronide are saturable, a fact which has the following clinical consequences:
(i) the time needed to eliminate a given fraction of a dose increases with increasing dose;
(ii) the steady-state plasma concentration of salicylate, particularly that of the pharmacologically active non-protein-bound fraction, increases more than proportionately with increasing dose; and
(iii) as the metabolic pathways of elimination become saturated, renal excretion of salicylate acid becomes increasingly important, a pathway which is extremely sensitive to changes in urinary pH.
Following accidental or intentional exposure, toxic actions of salicylates include:
Stimulation of the CNS respiratory center
Uncoupling of oxidative phosphorylation
Inhibition of Krebs cycle dehydrogenases
Stimulation of gluconeogenesis
Increased lipolysis and lipid metabolism
Inhibition of aminotransferases
Cyclooxygenase inhibition and decreased production of clotting factors
Irritation of the gastric mucosa and stimulation of the CNS chemoreceptor trigger zone.
Respiratory alkalosis accompanied by progressive metabolic acidosis
Hyperpyrexia
Gastrointestinal, renal, pulmonary, and skin losses of body fluids and electrolytes
Initial hyperglycemia followed by hypoglycemia, particularly CNS hypoglycemia
Abnormal hemostasis and coagulation.
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Mechanisms of toxicity
When ingested in overdose, salicylates directly stimulate the respiratory centre to produce both increased depth and rate of respiration,
thereby causing a respiratory alkalosis.
To compensate, bicarbonate, accompanied by sodium, potassium, and water, is excreted in the urine.
Dehydration and hypokalemia result,
but more importantly, the loss of bicarbonate diminishes the buffering capacity of the body and allows an acidosis to develop more easily.
Very high concentration of salicylates in the brain depress the respiratory centre and may further contribute to the development of acidemia.
Simultaneously, a variable degree of metabolic acidosis develops, not only because of the presence of salicylic acid itself, but also because of interference with carbohydrate, lipid, protein, and amino acid metabolism by salicylate ions.
A primary toxic effect of salicylates in overdose is uncoupling of oxidative phosphorylation.
ATP-dependent reactions are inhibited and oxygen utilization and carbon dioxide production increased.
Energy normally used for the conversion of inorganic phosphate to ATP is dissipated to heat.
Hyperpyrexia and sweating results causing further dehydration.
Fluid loss is enhanced because salicylates stimulate the chemoreceptor trigger zone and induce nausea and vomiting and, thereby, diminished oral fluid intake.
Glucose metabolism also suffers as a result of uncoupled oxidative phosphorylation because of increased tissue glycolysis and peripheral demand for glucose.
This is seen principally in skeletal muscle and may cause hypoglycaemia.
The brain appears to be particularly sensitive to this effect and neuroglycopenia can occur in the presence of a normal blood sugar level when the rate of utilization exceeds the rate at which glucose can be supplied from the blood.
Although rarely a practical, problem, salicylate intoxication may be accompanied by hypoprothombinemia due to a warfarin-like action of salicylates on the physiologically important vitamin K1 epoxide cycle.[see in general]
Clinical features of salicylate poisoning
· Nausea, vomiting, and epigastric discomfort
· Irritability, tremor, tinnitus, deafness, blurring of vision
· Hyperpyrexia, sweating, dehydration
· Tachypnea and hyperpnea
· Non-cardiogenic pulmonary oedema
· Acute renal failure
· Mixed respiratory alkalosis and metabolic acidosis (except in children who usually develop metabolic acidosis alone)
· Hypokalemia, hypernatremia, or hyponatremia
· Hyperglycemia or hypoglycemia
· Hypoprothrominemia (rare)
· Confusion, delirium, stupor, and coma (in severe cases)
Early loss of consciousness does not occur following the ingestion of a salicylate overdose, unless a hypnotic or sedative drug has been taken as well.
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Generally speaking, plasma salicylate levels that lie between
300 and 500mg/L six hours after ingestion of an overdose are associated with only mild toxicity,
levels between 500 and 700 mg/L are associated with moderate toxicity,
and levels in excess of 700 mg/L confirm severe poisoning.
Young children quickly develop a metabolic acidosis following the ingestion of aspirin in overdose but, by the age of 12 years, the usual adult picture of a combined dominant alkalosis and mild metabolic acidosis is seen.
To some extent, the presence of an alkamia protects against serious salicylate toxicity because salicylate remains ionized and unable to penetrate cell membranes easily.
Development of acidaemia allows salicylates to penetrate tissues more readily and leads, in particular, to CNS toxicity characterized by excitement, tremor, delirium, convulsion, stupor, and coma.
Pulmonary oedema is seen occasionally in salicylate poisoning, and although this is often due to fluid overload as a result of treatment, it may be non-cardiac and occur in the presence of hypovolemia.
Gastric erosions and gastrointestinal bleeding are rare following salicylate overdose.
Oliguria is sometimes seen; the common cause is dehydration but, rarely, acute renal failure or inappropriate secretion of antidiuretic hormone may occur.
Lab Studies:
Electrolytes
Hypokalemia
Hypo/hypernatremia
Anion gap acidosis
Hypoglycemia
ABG
Respiratory alkalosis
Metabolic acidosis
Monitor ABG frequently during treatment to assess response to treatment with the goal of maintaining a pH of 7.45-7.55.
BUN and creatinine
Dehydration with increased BUN/creatinine (Cr) ratio
Renal failure (rare)
CBC, PT, partial thromboplastin time, international normalized ratio
Coagulopathy with prolonged PT
Leukocytosis
LFT
Elevated aspartate aminotransferase (AST)
Elevated alanine aminotransferase (ALT)
Salicylate level
Initial level is useful in determining diagnosis.
Six-hour postingestion level (in acute, single ingestion only) can be applied to Done nomogram to assist in predicting level of toxicity. Done nomogram is not valid in situations of chronic overdose (level may be in normal or therapeutic range), ingestion of enteric coated aspirin, salicylates ingested over time period of several hours, salicylates taken in a 24-hour period prior to acute ingestion, or renal failure.
Urine pH: Monitor urine every 2 hours during treatment, with a goal of maintaining alkaline urine with a pH >7.5.
Ferric chloride test/Ames phenestix test: Sensitive but nonspecific tests determine the presence of salicylates in urine.
Imaging Studies:
Chest x-ray might reveal aspiration pneumonitis or noncardiogenic pulmonary edema.
CT scan of head is necessary to rule out structural lesion as a cause of change in mental status if etiology is not clear.
Other Tests:
ECG might reflect hypokalemia (U wave, flattened T wave, QT prolongation) or reveal dysrhythmias (sinus tachycardia, premature ventricular contractions [PVCs], ventricular tachycardia [V tach], ventricular fibrillation [V fib]).
Treatment
Fluid and electrolyte replacement is particularly important. Severe metabolic acidosis requires at least partial correction with bicarbonate
Management of salicylate poisoning
· Gastric lavage or administration of activated charcoal up to 1 hr after ingestion
· Correction of dehydration either orally or parenterally
· Correction of hypokalemia
· Correction of hypoglycemia
· Correction of severe metabolic acidosis with intravenous bicarbonate
· Tepid sponging for hyperpyrexia
· Alkaline diuresis if blood salicylate level > 500 mg/L (particularly if metabolic acidosis is present)
· Consider haemodialysis if neurological features are present and blood salicylate concentration > 700 mg/L and/or if severe acidosis supervenes.
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Supportive care stabilizes the airway, breathing, and circulation and provides respiratory and cardiovascular support, as necessary.
For GI decontamination, administer activated charcoal (1mg/kg) to all patients with suspected toxic ingestions (symptomatic patients or history of ingestion >150 mg/kg). Evidence to support multiple dose-activated charcoal is conflicting. Use additional doses (0.5 mg/kg q4h) if evidence of continued absorption is present, as demonstrated by rising serum salicylate levels. Whole bowel irrigation with polyethylene glycol can be useful in reducing absorption in cases of suspected bezoar formation as well as in cases of enteric-coated aspirin ingestion.
Hydrate and correct electrolyte abnormalities. Patients generally are dehydrated upon presentation; begin correction of fluid deficits with IV crystalloid solution to maintain urine output at 2 cc/kg/h. Treat electrolyte abnormalities aggressively. To correct hypokalemia, add KCl to intravenous fluid (IVF) (20-40 mEq/L) once it is established that the patient is not anuric. Correct hypoglycemia by adding dextrose to IVF or by 50% dextrose in water (D50W) bolus followed by dextrose-containing IVF.
Urinary alkalinization enhances salicylate elimination by promoting the ionization of salicylates. Ionized salicylates cannot be reabsorbed in renal tubules, increasing urinary elimination.
Alkalinization of serum is important in minimizing CNS toxicity. Ionized salicylates are unable to cross the blood-brain barrier, decreasing the concentration in the CNS. Increased CNS salicylate levels have been shown to correlate with CNS toxicity.
Urinary and serum alkalinization is necessary in all symptomatic patients and in patients with acute ingestion who have 6-hour levels greater than 50-60 mg/dL. Alkalinization of urine/serum can be achieved by administration of sodium bicarbonate by boluses of 1-2 mEq/kg, in addition to continuous infusion of 5% dextrose in water (D5W) with 100-150 mEq of sodium bicarbonate at 2 times maintenance rates.
Adequate serum potassium levels are required to maintain alkaline urine. With hypokalemia, potassium will be reabsorbed with sodium instead of hydrogen ions, making it difficult to alkalinize urine. If urinary pH remains acidic despite alkaline serum pH, add additional potassium to IVF.
Do not use carbonic anhydrase inhibitors (acetazolamide) to produce alkaline urine. While they do alkalinize urine, they also produce an acidic serum and have been associated with increased mortality.
Use hemodialysis in cases of severe toxicity to enhance elimination of salicylates and correct fluid and electrolyte abnormalities. Indications for hemodialysis include severe manifestations, such as encephalopathy, coma, seizures, cerebral edema and ARDS, renal failure, deteriorating condition despite adequate alkalinization of urine and supportive care, and deteriorating condition where alkalinization of urine cannot be achieved.
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Sedatives and respiratory depressant drugs should be avoided because they may hasten the development of acidaemia and CNS toxicity.
Mild cases of salicylate poisoning may be managed with either oral or parenteral fluid and electrolyte replacement only.
Patients who exhibit marked symptoms or signs of salicylism and whose blood salicylate concentrations are in excess of 500 mg/L (or lower if acidaemia is present) should receive specific elimination therapy.
An alkaline diuresis is most often used for this purpose.
The pH of the urine during this procedure is of far greater importance than the volume of urine excreted and should be in excess of 7.5.
Occasionally, patients prove refractory to alkaline diuresis and/or this therapy is contraindicated.
Hemodialysis may then prove necessary to remove salicylate from the body
There is conflicting evidence regarding the value of multiple-dose activated charcoal in increasing salicylate elimination.
Hemodialysis is the treatment of choice for severely poisoned patients, particularly those with features of central nervous system toxicity and metabolic acidosis and has the advantage that it enables simultaneous correction of the acid-base and fluid and electrolyte imbalances.
Pulmonary oedema occasionally complicates salicylate toxicity.
Fluid overload should be excluded as far as possible.
Positive and expiratory pressure ventilation appears to be beneficial in this form of pulmonary oedema.
Drug Category: Antidotes - Used to treat poisoning caused by most drugs and chemicals.
Drug Name
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Activated charcoal (Insta-Char, Liqui-Char, Super-Char, Actidose-Aqua)- Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal absorbs 100-1000 mg of drug per g of charcoal. Does not dissolve in water.
For maximum effect, administer within 30 min after ingesting poison.
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Adult Dose
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0.5-1 g/kg PO
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Pediatric Dose
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<1 year: Not recommended
>1 year: Administer as in adults
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Contraindications
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Documented hypersensitivity, poisoning or overdose of mineral acids and alkalies
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Interactions
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Might inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; do not mix charcoal with sherbet, milk, or ice cream (decreases absorptive properties)
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Pregnancy
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C - Safety for use during pregnancy has not been established.
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Precautions
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Not very effective in poisonings of ethanol, methanol, and iron salts; induce emesis before administering; after emesis with ipecac, patient might not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns will be black
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Drug Category: Cathartics - Used to accelerate the passage of poisons through the intestinal tract and prevent their absorption.
Drug Name
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Sorbitol- Hyperosmotic laxative that has cathartic actions in the GI tract.
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Adult Dose
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30-150 mL PO of a 70% solution
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Pediatric Dose
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<2 years: Not recommended
2-11 years: 2 mL/kg PO of 70% solution
>12 years: Administer as in adults
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Contraindications
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Documented hypersensitivity, anuria
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Interactions
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Reduces effectiveness of other drugs when administered concomitantly
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Pregnancy
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C - Safety for use during pregnancy has not been established.
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Precautions
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Severe cardiopulmonary or renal impairment and patients unable to metabolize sorbitol
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Drug Name
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Polyethylene glycol (Colovage, Colyte, GoLYTELY)- Laxative with strong electrolyte and osmotic effects that has cathartic actions in GI tract.
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Adult Dose
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240 mL (8 oz) q10min until a total of 4 L are consumed or until rectal effluent is clear
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Pediatric Dose
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Not established; recommended dose is 25-40 mL/kg/h for 4-10 h or until rectal effluent is clear
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Contraindications
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Documented hypersensitivity; colitis, megacolon, bowel perforation, gastric retention, GI obstruction
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Interactions
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Reduces effectiveness and absorption of oral medications
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Pregnancy
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C - Safety for use during pregnancy has not been established.
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Precautions
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Ulcerative colitis, hot loop polypectomy
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Treatment guidelines
SALICYLATE POISONING
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Management
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Comments
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Non-drug treatment
Monitor:
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Admit to high care or intensive care unit if available.
Monitor and maintain within the accepted range for age: Heart rate, respiration, blood pressure, hydration, haematocrit, blood gases, body temperature, electrolytes and minerals.
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Hyperthermia:
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Treat by sponging with tepid water and using a fan.
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Shock:
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Intubate, ventilate and treat if necessary.
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Treatment of shock, see page 240.
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Hypovolaemia /dehydration:
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5% dextrose in 0.45% sodium chloride solution (rehydration solution) IV, 20 mL/kg over 1 hour. Thereafter maintenance volumes according to age.
Monitor fluid balance, urine output, acid–base status, serum electrolytes, blood pressure, urine and serum osmolality.
Monitor blood glucose and maintain within the physiological range.
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Drug treatment
Emesis:
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Induce emesis.
Ipecacuanha syrup, children 6–18 months, 5- 15 mL,
children >18 months, 15- 20 mL.
Repeat after 20 minutes if vomiting has not occurred
OR
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Gastric lavage:
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Perform gastric lavage followed by:
Activated charcoal, < 6 years, 10 g in 50–100 mL water,
> 6 years, 20–50 g in 100–300 mL water.
Repeated doses of 10–50 g every 4 hours may increase clearance of salicylate from the body.
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Since charcoal adsorbs ipecacuanha, it should not be given before the emetic.
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Hypokalaemia:
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Potassium chloride 15%, IV, at a rate not exceeding 0.5 mmol potassium/kg/hour, with ECG monitoring.
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Start potassium replacement before administering bicarbonate (correction of acidosis exacerbates hypokalaemia).
Dilute potassium before use.
Monitor serum potassium levels.
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Urine alkalinisation:
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Alkalinise urine to increase the excretion of salicylates:
Sodium bicarbonate, slow IV bolus, 1 mmol/kg over 1 hour (1 mL/kg of an 8.5% solution), followed by infusion, 2–3 mmol/kg/24hours.
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Urine pH should be maintained at 7.5–8.
Arterial pH should not rise above 7.5.
Dilute 8.5% sodium bicarbonate to 4.2% with sterile water.
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Prolonged prothrombin time:
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Vitamin K, IM, 5 mg (one dose).
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Gastric irritation:
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Antacids to counteract gastric irritation:
Aluminium hydroxide 250 mg / magnesium trisilicate 500 mg/ 5 mL suspension, 5–10 mL as required.
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Severe toxicity:
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Charcoal haemoperfusion or haemodialysis can be considered in severe toxicity not responding to adequate therapy.
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