Chapter 43. Salicylate Overdose

Salicylates have been used since the 19th century.1 Today, salicylates are used therapeutically throughout the world. The most commonly encountered salicylate is acetylsalicylic acid (aspirin). Other medications include the liniment methyl salicylate (oil of wintergreen) and bismuth subsalicylate, the active ingredient in Pepto-Bismol. Because salicylates are ubiquitous, there is great potential for toxicity, intentional or accidental. In 2008, there were over 19,000 aspirin-alone exposures reported and about 2,000 aspirin coingestions reported to the National Poison Data System.2

At therapeutic concentrations, salicylate ingested is rapidly absorbed into the bloodstream with a peak serum concentration in 1 hour. When gastric contents are present, absorption may be delayed. Eighty to 90% of plasma salicylate is bound to protein, especially albumin. Most salicylate is biotransformed by the hepatic endoplasmic reticulum but about 10% is eliminated unchanged in the urine. Salicylates and its metabolized products are renally eliminated in a pH-dependent manner. The difference between alkaline and acidic urine can cause free excretion to vary from higher than 30% to 2%.3

In overdoses, plasma peak concentrations are often delayed up to 35 hours, especially when ingesting extended-release and/or enteric-coated tablets.4,5 Bezoar may also form, extending the time of absorption and making the time of peak concentration impossible to predict in any given overdose. As salicylate concentration rises above normal, protein binding and hepatic metabolization are saturated. As a result of the saturation, salicylate metabolism changes from first- to zero-order kinetics,6 and a larger portion of the unmetabolized salicylate is excreted in the urine (see Figure 43-1).3

In plasma, salicylates are in equilibrium between the protonated (uncharged) and unprotonated (charged) forms. Salicylic acid is a weak acid (pKa 3.5), which means that a majority of the drug exists in the protonated (uncharged) form. In its uncharged form, it can move easily across membranes and deposit into various tissues, most importantly the CNS. At acidic pH, the equilibrium is shifted farther toward the protonated (uncharged form), increasing the amount of salicylate able to diffuse across the membranes. Conversely, at high serum pH, equilibrium is shifted toward the unprotonated (charged) form. In this charged form, it cannot cross membranes and becomes “trapped” (see Figure 43-2).7

Salicylates affect many organ systems. Gastrointestinal effects are prominent, especially in the acute toxicity. Patients may present with nausea and vomiting from gastric mucosal irritation (from decreased prostaglandin production) and from direct salicylate effects on the medullary chemoreceptor zone. Perforation can occur but is uncommon in acute toxicity.

Salicylates affect the CNS. In the brain, salicylates stimulate the medullary respiratory center causing hyperpnea, tachypnea, and respiratory alkalosis.8 In severe toxicities, cerebral edema, seizures, and coma can occur.

Salicylates disrupt respiration and metabolism. In severe toxicity, acute lung injury may occur. However, the most important effect is on the mitochondria. Salicylates uncouple oxidative phosphorylation, which means the energy generated from the electronic transport chain is dissipated as heat and not available for ATP formation. Heat generation manifests as hyperthermia and lack of ATP for cellular energy leads to increased anaerobic metabolism and production of pyruvate and lactic acid.9 Lipid metabolism is also stimulated, leading to generation of ketones and anion gap acidosis.10 Salicylates also inhibit ATP-dependent reactions resulting in increased oxygen consumption and carbon dioxide production. The increased lipid and glycogen metabolism is especially important in those with poor glycogen storage, for example, infants and chronic alcoholics.

A careful history should be taken to the amount of salicylate the patient ingested and the presence of coingestants. The clinician should identify comorbid conditions that might complicate treatment, such as a history of liver disease, renal failure, or congestive heart failure. The chronicity of ingestion is vital when determining therapy. Acute overdoses are more likely in young patients and intentional overdoses. Ingestions of more than 300 mg/kg is considered serious while greater than 500 mg/kg can be potentially fatal. Chronic toxicity is more likely in the elderly and from unintentional overuse. In contrast with acute ingestion, which is usually easily identified by history, chronic ingestion may not be apparent in the history. In some cases, patients have been hospitalized for days before chronic salicylate poisoning is identified.11–13 The mortality rate for acute overdoses is about 1% compared with 25% for chronic toxicities.

As expected, salicylate toxicity can present with various clinical findings (see Table 43-1). Patients can report anxiety, difficulty with concentration, hallucinations, lethargy, or even at the end of the spectrum with coma and seizures. On physical examination, patients may be tachycardiac, tachypneic, hyperpneic, and hyperthermic. In acute ingestions, nausea and vomiting may be prominent.

Traditionally, a serum salicylate concentration of up to 30 mg/dL is considered therapeutic. Tinnitus, an early sign of toxicity, occurs at about 35 mg/dL. However, salicylate concentrations should be interpreted in context of the chronicity of ingestion. In acute toxicity, there is a large amount of salicylate in the GI tract and blood and proportionally less in the tissues. In contrast, in chronic salicylate poisoning, in which there is a high tissue burden, patients may exhibit toxicity at lower serum salicylate concentrations. Serum salicylate concentration may not correlate with the CSF salicylate concentration, which is why clinical symptoms are more important than serum concentrations. A toxicity nomogram was once proposed for salicylate poisoning but is not recommended as it does not accurately predict poisoning.14

Salicylate poisoning causes both primary metabolic acidosis and primary respiratory alkalosis. Respiratory alkalosis predominates early in poisoning. As toxicity worsens, a metabolic acidosis develops. Pure metabolic acidosis is unusual in adults unless combined with coingestions of respiratory depressants. Serum pH of 7.4 or less in salicylate poisoning is a marker of severe toxicity.

Electrolyte and fluid abnormalities may occur in salicylate toxicity, as a result of both poisoning and therapy. Emesis and diaphoresis can causes severe hypovolemia. Hypokalemia can result from vomiting and alkalinization, and serum calcium levels may drop from alkalinization. In severe salicylate poisonings, serum glucose concentration can be high from glycogenolysis and gluconeogenesis in the earlier stages and low from impaired gluconeogenesis and increased usage in later stages. However, be mindful that salicylate toxicity can decrease CNS glucose concentration despite a normal peripheral glucose concentration.15

As with most emergency critical care, the clinician should ensure that the airway is stable. However, intubation in a severe salicylate overdose can be dangerous. The presence of hyperpnea and tachypnea should not necessarily be interpreted as “respiratory distress” requiring intubation. Rather, intubation and mechanical ventilation should be reserved for patients who are no longer protecting their airway, are failing to oxygenate, or have serum pH indicating that they are failing to maintain respiratory alkalosis. In severe poisonings, patients are dependent on tachypnea and hyperpnea to breathe off carbon dioxide and maintain near-normal pH. If ventilation is abruptly decreased, a sudden rise in carbon dioxide and drop in serum pH may occur, resulting in passage of more salicylate into the tissues and worsening poisoning. In a case series, mechanical ventilation was associated with worsening of pH in salicylate-poisoned patients.16

If intubation is necessary, an experienced operator should perform the procedure. To minimize hypoventilation, a rapid-onset sedative and paralytic should be used, and patients should be hyperventilated throughout until initiation of laryngoscopy. Once intubated, patients should be hyperventilated to maintain the respiratory alkalosis compensating for the metabolic acidosis. Patients should be sedated to prevent breath-stacking and ventilatory asynchrony. CPAP mode of ventilation should be considered because it will allow the patient to breathe at his or her own rate. As the sedative and paralytic effects dissipate, patient's tachypnea and hyperpnea may return and may cause “breath stacking” and ventilatory asynchrony. Frequent blood gases should be obtained and serum pH should be maintained between 7.5 and 7.6.

Gastric Decontamination and Actived Charcoal

Gastric lavage should be only considered if a dangerous amount of tablets is still in the stomach. This is usually only within 60 minutes of ingestion, so gastric lavage is rarely used. The risk of aspiration usually outweighs the benefits of possible extraction of tablets still in the stomach. If performed, lavage should be followed by activated charcoal.17

Ipecac should not be used, and was shown to be inferior to activated charcoal in lowering the absorption of salicylates.18

Activated charcoal should be administered in all patients who are not at risk of pulmonary aspiration. It reduces the absorption of therapeutic aspirin doses by 50–80%.19 Adding sorbital to activated charcoal may prevent salicylate absorption.20 It is not clear whether there is increased benefit to multiple-dose activated charcoal.21–24 In theory, multiple-dose activated charcoal will decrease absorption of salicylate still present in the GI tract from bezoar formation or enteric-coated formulations. We recommend charcoal with sorbital on initial presentation followed by charcoal without sorbital at 4-hour intervals until salicylate poisoning has resolved.

Whole bowel irrigation (oral administration of polyethylene glycol electrolyte lavage solution) does not increase the clearance of absorbed salicylate.24,25

Alkalinization

Since an increase in pH shifts the equilibrium of salicylate to the ionized state, alkalinization of blood will limit salicylates from entering other organs (most importantly the brain). This phenomenon has been described as “ion trapping” because ionized salicylate is trapped in the plasma, and thus cannot pass into tissues. Serum alkalinization results in urine alkalinization, which may increase elimination by trapping ionized salicylate in the renal tubules. In support of this concept, it has been shown that elimination of salicylates is dependent on urinary pH.26,27 Excretion increases from 2% in acidic urine to 31% in alkaline urine. As expected, the half-life of salicylate also decreases and total body clearance of salicylate increases under alkaline conditions.27

Alkalinization should be considered in patients with serum salicylate concentration greater than 35 mg/dL and suspected salicylate toxicity until blood pH is available to properly guide treatment. Alkalemia should be achieved with intravenous sodium bicarbonate. The goal should be plasma pH between 7.45 and 7.55 and urinary pH of 7.5–8.0. (We recommend adding 150 mEq of sodium bicarbonate to 1 L of D5W and administering at 150–200 mL/h or twice maintenance rate.) In a critically ill patient receiving bicarbonate therapy, frequent serum and urinary pH should be obtained to determine bicarbonate dosage. Carbonic anhydrase inhibitors, which alkalinize urine, should not be used as they create a metabolic acidosis.

Potassium and calcium are important electrolytes to monitor in salicylate toxicities. Hypokalemia can result from induced alkalemia, urinary potassium loss, diarrhea if cathartic is used, and metabolic alkalosis from vomiting. In the presence of hypokalemia, alkalosis therapy may be hindered. Hypocalcemia can result from bicarbonate therapy and must be repleted quickly.

Extracorporeal Treatment

Extracorporeal treatment is usually reserved for correcting fluid, electrolyte, acid–base, and urea abnormalities along with clearing unwanted solute. In salicylate overdose, extracorporeal treatment is usually reserved for patients with severe toxicity or those who cannot tolerate conventional therapy. It is recommended for patients with CNS toxicity, acute lung injury or pulmonary edema, renal insufficiency, refractory acidosis, or clinical deterioration despite medical therapy. In the absence of these conditions, extracorporeal treatment should be performed for serum salicylate concentration >100 or >60 mg/dL in chronic poisonings (see Table 43-2).28 The serum salicylate concentration indication for extracorporeal treatment in chronic ingestions is set lower, since many cases of fatal cases report lower serum concentrations, some in the 50- to 70-mg/dL range.29 A patient on mechanical ventilation should also be considered, since mechanical ventilation alone may be inadequate to maintain respiratory alkalosis. Finally, hepatic dysfunction may require extracorporeal treatment as salicylates are metabolized by the liver.

Hemodialysis is the extracorporeal technique of choice. Hemoperfusion provides better clearance but hemodialysis has the added benefit of correcting electrolyte imbalances and acid–base disorders. Hemodialysis and hemoperfusion can be done in series but are rarely used in reality.30 In hemodynamically unstable patients who cannot tolerate large fluid shifts caused by hemodialysis, continuous venovenous hemodiafiltration can be used.31 Extracorporeal treatments should be used in conjunction with other therapies and other therapies should not be held while waiting for extracorporeal treatment.