Salicylate (aspirin) poisoning: Management

INTRODUCTION — Aspirin and other salicylates are among the oldest medications remaining in clinical practice. Aspirin use has declined as other nonsteroidal antiinflammatory drugs (NSAIDs) were developed and its association with Reye syndrome in children was recognized. Aspirin is still a commonly used analgesic and a widely prescribed antiplatelet therapy for patients with cardiovascular and cerebrovascular disease, and thus, salicylate toxicity (ie, salicylism) remains an important clinical problem [1].

This topic will discuss the management of salicylate overdose and toxicity in children and adults. A rapid overview table to facilitate emergency management is provided (table 1). The clinical manifestations and evaluation of salicylate poisoning are discussed separately. (See "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation".)

General management of the poisoned patient and adverse effects of aspirin in therapeutic dosing are discussed separately:

●(See "General approach to drug poisoning in adults".)

●(See "Approach to the child with occult toxic exposure".)

●(See "Initial management of the critically ill adult with an unknown overdose".)

●(See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions".)

●(See "NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity".)

●(See "Aspirin-exacerbated respiratory disease".)

OVERVIEW OF MANAGEMENT — A rapid overview table for management of salicylate poisoning is provided (table 1). A patient with severe salicylate toxicity can deteriorate rapidly and be challenging to manage. Management principles are listed here and discussed in detail below:

●Rapidly assess and stabilize the airway, breathing, and circulation as needed. Tracheal intubation is potentially dangerous and can result in peri-procedural cardiac arrest but may be unavoidable in a patient having seizures, for administration of sedatives to control agitation if procedures (eg, dialysis line placement) are needed, and to manage respiratory fatigue.

●Assess severity of toxicity based on signs and symptoms, serum salicylate concentration, and acid-base status. Do not rely solely on the serum salicylate concentration as this will commonly underestimate the severity of toxicity.

●Correct fluid and electrolyte imbalance. A large volume of crystalloid is typically required for severe toxicity. Treat hypokalemia aggressively if present.

●Administer supplemental glucose if there are any alterations in mental status, even if peripheral blood glucose is normal.

●Perform gastrointestinal decontamination with activated charcoal (AC), even beyond the typical two-hour timeframe. Administer multiple-dose AC (MDAC) to a patient with moderate or severe salicylate toxicity or any patient who reports a large ingestion (eg, >300 mg/kg of aspirin).

●Frequently measure the serum salicylate concentration, blood gas, serum electrolytes, and urine pH to assess for delayed absorption, tissue distribution, and response to therapy.

●Administer bicarbonate infusion to alkalinize urine, thus increasing urinary salicylate excretion, and to alkalinize serum, thus "trapping" salicylate anions in the blood and preventing diffusion into the central nervous system (CNS).

●Enhance elimination and correct metabolic acidosis with hemodialysis in a patient with severe toxicity.

●Obtain consultation with appropriate services such as toxicology (or a regional poison control center) and nephrology early in a patient's course, even in the immediate absence of hemodialysis indications.

ASSESS SEVERITY OF TOXICITY — Assess the severity of toxicity based on the patient's symptoms, signs, and acid-base status and do not rely solely on the serum salicylate concentration. Interpreting the serum concentration without accounting for the acuity of exposure, the patient's clinical status, the expected time lag in serum salicylate concentration changes, and any laboratory abnormalities (specifically blood pH) will commonly underestimate the severity of toxicity [2-4]. For example, a patient with lethargy and hyperpnea with a serum concentration of 50 mg/dL (3.6 mmol/L) should be considered to have severe toxicity; their concentration in four hours will most likely be >90 mg/dL (>7.2 mmol/L).

Toxicity severity changes with time. Early symptoms typically develop within one to two hours after a single acute ingestion, but various factors can affect symptom onset, such as ingestion of enteric-coated preparations and co-ingestions. As absorption progresses or salicylate distributes into vulnerable tissue, clinical toxicity frequently worsens. (See "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation", section on 'Pharmacokinetics and toxicokinetics'.)

We use the following general principles to determine severity of toxicity (or the course of toxicity) (table 2) [5]:

●Mild (or early) toxicity – Symptoms include tinnitus and nausea; tachypnea may be present. This stage generally correlates with serum salicylate concentrations of 30 to 50 mg/dL (2.2 to 3.6 mmol/L). The blood pH will be normal or increased, and the urine pH will typically be >5.

●Moderate (or middle) toxicity – Symptoms and signs include mild hyperthermia, tachycardia, hyperpnea, vomiting, and diaphoresis; mental status is preserved. This stage generally correlates with serum salicylate concentrations of 50 to 90 mg/dL (3.6 to 7.2 mmol/L) but may occur at lower concentrations in the setting of chronic toxicity. The blood pH will be increased (or occasionally in the normal range if metabolic acidosis is overwhelming the primary respiratory acidosis), and the urine pH will typically be <5.

●Severe (or late) toxicity – Symptoms and signs include any alteration in mental status, cerebral or pulmonary edema, clinical deterioration, or other indications for hemodialysis. This generally correlates with serum salicylate concentrations >90 mg/dL (>6.5 mmol/L) in acute toxicity and >60 mg/dL (>4.3 mmol/L) in chronic toxicity. The blood pH is decreased (<7.3), and the urine pH will be <5. (See 'Indications for hemodialysis' below.)

MANAGEMENT IN MOST PATIENTS

ABCs and supportive care — Rapidly assess and stabilize the airway, breathing, and circulation ("ABCs") as needed, and provide general supportive care. Issues specific to salicylate toxicity include the following:

●Airway management – Avoid tracheal intubation of the salicylate-toxic patient, if possible [6]. Reserve tracheal intubation for a patient with hypoventilation, as determined by clinical evaluation or blood gas analysis, or a patient who requires airway protection, such as for seizures or agitation control for procedures. If necessary, plan the intubation and post-intubation management anticipating an exacerbation of the unique pathophysiology of salicylate toxicity. A patient who requires intubation usually also requires hemodialysis.

Tracheally intubating a patient with severe salicylate toxicity is potentially dangerous and can result in peri-procedural cardiovascular collapse and cardiac arrest. In tachypneic patients following a salicylate overdose, prophylactic intubation out of concern that "they may eventually tire" has resulted in death [2,7]. Once a neuromuscular blocking agent (NMBA) terminates the salicylate-induced primary respiratory alkalosis, an acidosis can acutely and substantially worsen, followed by salicylate anions protonating to uncharged salicylic acid, redistributing into vulnerable tissue, and exacerbating toxicity. (See "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation", section on 'Pharmacokinetics and toxicokinetics'.)

•Rapid sequence intubation can exacerbate acidosis — Severe metabolic acidosis is considered a "physiologically difficult airway" because administration of induction agents and NMBAs make the apneic phase of rapid sequence intubation physiologically intolerable. An approach to intubating the physiologically difficult airway is discussed separately and includes the following strategies (see "Approach to the difficult airway in adults for emergency medicine and critical care", section on 'High-risk physiology present'):

-Initiate treatment of the underlying acidosis prior to intubation. In the case of salicylate toxicity, administer a sodium bicarbonate infusion. Some experts will administer intravenous (IV) sodium bicarbonate 7.5 or 8.4% 50 to 100 mL over one to two minutes (ie, one to two ampule pushes) as part of pre-induction medication, but this practice is not uniformly accepted. (See 'Serum and urine alkalinization' below.)

-Perform awake intubation (ie, without NMBA) to avoid an apneic period. Some experts prefer ketamine in this circumstance because it allows the patient to maintain respiratory drive while providing analgesia, amnesia, and sedation. (See "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Conditions precluding use of a paralytic' and "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Ketamine'.)

-If NMBA is administered, the most experienced operator should perform the intubation in order to minimize the apneic time.

•Post-intubation ventilator management must maintain high minute ventilation — Adjust the ventilator settings to mimic the minute ventilation of the patient prior to intubation. Tidal volumes will likely need to exceed the common initial setting of 6 to 8 mL/kg. Compared with spontaneous ventilation, mechanical ventilation often results in relative hypoventilation and respiratory acidosis since it is generally incapable of delivering the high minute ventilation of a spontaneously breathing patient with salicylate toxicity. Unless there is ventilator-patient asynchrony or a comparable problem complicating ventilation, avoid administering long-acting NMBAs or deep sedation since they blunt the patient's ability to breathe over the ventilator [7]. Ventilator asynchrony may actually decrease the patient's ability to maintain appropriate acid-base homeostasis [6]. Auto-positive end-expiratory pressure (PEEP) prevents adequate ventilation and must be recognized and managed quickly if it develops. (See "Mechanical ventilation of adults in the emergency department".)

●Oxygenation – Administer supplemental oxygen as needed. A patient with pulmonary edema may ultimately develop high oxygen requirements. For refractory hypoxemia, noninvasive ventilation is a temporizing measure, but tracheal intubation with PEEP is typically required to prevent hypoventilation. (See "Noninvasive ventilation in adults with acute respiratory failure: Practical aspects of initiation" and "Mechanical ventilation of adults in the emergency department" and "Noninvasive ventilation for acute and impending respiratory failure in children" and "Initiating mechanical ventilation in children".)

●Blood pressure support – Fluid resuscitation typically improves hypotension from salicylate toxicity. (See 'Fluid and electrolyte repletion' below.)

In a hypotensive patient who does not respond to crystalloid resuscitation, administer a vasopressor such as phenylephrine or norepinephrine since salicylate toxicity can cause systemic vasodilation. (See "Use of vasopressors and inotropes".)

Gastrointestinal decontamination

●Single-dose activated charcoal (AC) – We recommend that a patient with an acute oral salicylate overdose receive gastrointestinal decontamination with at least one dose of AC (1 g/kg orally; maximum single dose: 50 g) regardless of the time since ingestion. Do not administer AC to a patient with altered mental status who may not be able to protect their airway unless tracheal intubation is performed first. Do not tracheally intubate solely for the purpose of administering AC since maintaining high minute ventilation with spontaneous respiration probably provides greater clinical benefit than AC. Administer AC via orogastric tube to an intubated patient. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Activated charcoal'.)

AC effectively absorbs salicylate [8,9]. A small trial in volunteers who received AC 30 minutes after aspirin ingestion found that peak salicylate concentrations were 50 percent lower compared with controls [10]. Unlike most other ingestions, in which AC is not recommended beyond two hours, patients with a salicylate ingestion likely benefit from a delayed dose of AC since enteric-coated aspirin can form gastric concretions and pylorospasm can cause delayed gastric emptying. A small trial in volunteers who received AC three hours after ingestion of enteric-coated aspirin also showed a significant decrease in absorption [11].

●Decontamination therapies with limited roles – Do not routinely perform whole-bowel irrigation for salicylate toxicity. Studies have not demonstrated a clinical benefit in patients treated with whole-bowel irrigation [12]. Some experts, however, would perform whole-bowel irrigation in the rare circumstance of an alert and cooperative patient after a massive ingestion (eg, entire bottle of tablets) of a delayed-release preparation (but first discuss the risks and benefit with a poison control center or medical toxicologist). (See 'Regional poison control centers' below.)

We recommend not performing gastric emptying by gastric lavage or by syrup of ipecac-induced emesis in a patient who ingests a salicylate [13,14]. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Gastric lavage'.)

Avoid an AC formulation combined with a cathartic (eg, sorbitol) because of adverse effects such as vomiting and dehydration. Administer a combined formulation if a formulation of AC without a cathartic is unavailable, but limit treatment to a single dose in such cases. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Cathartics'.)

Frequent laboratory monitoring — A patient with salicylate toxicity or reported overdose requires frequent laboratory monitoring to assess clinical status, response to therapy, and potential delayed or continuing absorption. Ideally, measure blood gas from an arterial source; venous samples can substitute until an arterial line is placed to avoid multiple painful arterial punctures.

●Measure a serum salicylate concentration and blood gas every two hours until the concentration is decreasing and the acid-base status is stable or improving for at least two consecutive measurements.

●Afterwards, measure salicylate concentrations every four hours until the concentration is <30 mg/dL (<2.2 mmol/L) and the patient is asymptomatic with a normal respiratory rate and effort.

●In a patient receiving alkalinization therapy, measure an hourly blood pH, urine pH, and serum sodium and potassium concentrations. Hypokalemia and hypernatremia (from hypertonic fluids) are common complications.

●In a patient with altered mental status or hypoglycemia, measure a serum glucose concentration or fingerstick glucose measurement every hour until mental status improves or supplemental glucose is not needed. (See 'Supplemental glucose' below.)

Consultation with specialists — Management of a patient with salicylate toxicity can be challenging. We recommend consultation with a medical toxicologist or a regional poison control center to help guide management and to avoid common errors, such as over-reliance on serum concentrations. (See "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation", section on 'Regional poison control centers'.)

Obtain consultation with a nephrologist early in a patient's course, even in the absence of the immediate need for hemodialysis. Alerting the nephrologist early will facilitate hemodialysis in case the patient deteriorates despite aggressive and appropriate supportive care.

THERAPIES IN SELECTED PATIENTS

Moderate or severe toxicity — A patient with moderate salicylate toxicity is treated similarly to severe toxicity but does not require hemodialysis.

Fluid and electrolyte repletion

●Fluid repletion – Salicylate-poisoned patients may exhibit striking hypovolemia. We resuscitate aggressively with crystalloid if the patient is hypovolemic unless cerebral edema or pulmonary edema is present. Fluid repletion is not only important to maintain tissue perfusion, but decreased intravascular volume interferes with efforts at urinary alkalinization, which is a mainstay of therapy. In the severely toxic adult patient, administering more than 6 liters of fluid may be necessary to achieve euvolemia. A reasonable approach is 0.9% sodium chloride at a rate of 10 to 15 mL/kg per hour for the first two to three hours, followed by 1.5 to 2 times maintenance rate titrated to maintain a urine output between 1 to 2 mL/kg per hour [15]. Choice of maintenance fluid and rate in children are discussed separately. (See "Maintenance intravenous fluid therapy in children".)

In a patient who is judged to be hypovolemic, we simultaneously administer normal saline and sodium bicarbonate (for alkalinization therapy). Once the patient is judged to be euvolemic, the alkalinizing fluid can also serve as the maintenance fluid. The composition of alkalinizing fluid is discussed below and separately. (See 'Serum and urine alkalinization' below and "Enhanced elimination of poisons", section on 'Urinary alkalinization'.)

In a euvolemic patient with salicylate toxicity, we cautiously administer any fluids since they are at risk of developing pulmonary and/or cerebral edema. Also, a patient receiving the equivalent of hypertonic sodium bicarbonate (especially if also receiving potassium supplementation) is at risk of developing hypernatremia and needs frequent monitoring of serum sodium. (See 'Frequent laboratory monitoring' above.)

●Potassium/magnesium repletion – Aggressively replete potassium if hypokalemia is present unless the serum potassium is >5.5 mEq/L. Potassium should be repleted to a goal serum concentration >4 mEq/L. Hypokalemia promotes the absorption of potassium in the distal tubule via a K⁺-H⁺ exchange pump (figure 1). The secretion of protons interferes with efforts at urinary alkalinization. We administer enteral or parenteral potassium supplementation to patients with serum potassium concentrations even in the low-normal range, especially those receiving alkalinization therapy, since that will further lower the serum potassium. In most patients, the addition of 20 to 40 mEq/L of potassium chloride to the recommended continuous sodium bicarbonate infusion is sufficient, but some patients may require extra supplemental potassium. (See "Clinical manifestations and treatment of hypokalemia in adults" and "Hypokalemia in children".)

In a patient receiving urinary alkalinization therapy, replete magnesium since magnesium deficiency is frequently associated with and complicates correcting hypokalemia [16]. Some experts will empirically administer magnesium sulfate 2 g intravenously (IV; 25 to 50 mg/kg in children) prior to repleting potassium assuming that the patient is functionally hypomagnesemic if they are also hypokalemic. (See "Hypomagnesemia: Evaluation and treatment".)

Supplemental glucose — In a patient with any neurologic deficit, including altered mental status or seizures, we suggest administering supplemental glucose regardless of the serum glucose. Salicylate toxicity has been shown to decrease cerebral glucose concentrations despite a normal serum glucose [17,18]. (See "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation", section on 'Altered mental status'.)

In a patient with moderate or severe salicylate toxicity, our approach is to maintain the serum glucose in the high normal range (approximately 100 to 140 mg/dL [5.6 to 7.8 mmol/L]). In a patient who is not able to eat, this can be accomplished using IV boluses of dextrose (50 to 100 mL of 50% dextrose) or by adding 50 to 100 g of dextrose to each liter of maintenance fluid. (See "Approach to hypoglycemia in infants and children", section on 'Glucose therapy'.)

Our approach is based on clinical experience as human clinical studies on glucose supplementation in salicylate toxicity do not exist.

Multiple-dose activated charcoal — In a patient with moderate or severe salicylate toxicity or a patient who reports a large ingestion (eg, >300 mg/kg of aspirin), we suggest administering multiple-dose activated charcoal (MDAC). The single-dose AC (described above) is considered the initial dose. (See 'Gastrointestinal decontamination' above.)

Subsequent doses are 0.5 g/kg (maximum dose: 50 g) every four hours or 0.25 g/kg (maximum dose: 25 g) every two hours of AC without sorbitol [19]. Withhold the MDAC dose if the patient is vomiting, has signs of poor gastric motility (eg, lack of bowel sounds, high residual in nasogastric/orogastric tube if present), or has a gastrointestinal hemorrhage. Continue MDAC until clinical symptoms have resolved and the serum salicylate concentration is <40 mg/dL (<2.9 mmol/L). (See "Gastrointestinal decontamination of the poisoned patient", section on 'Multidose activated charcoal'.)

MDAC most likely prevents ongoing absorption of retained salicylate concretions or enteric-coated formulations and does not increase elimination by facilitating transluminal diffusion from the body into the bowel lumen (ie, "gut dialysis"). In trials of volunteers who ingested aspirin, MDAC decreased aspirin absorption and salicylate concentrations [20,21]. In a small study with five patients, MDAC seemingly improved salicylate elimination, but this effect was not seen in a small, volunteer trial [22,23]. Animal data support that MDAC does not increase elimination; MDAC did not decrease salicylate concentrations after IV aspirin administration in a porcine model [24].

Serum and urine alkalinization — In a patient with moderate or severe salicylate toxicity, we recommend alkalinizing the serum and urine [25-27]. We administer IV sodium bicarbonate with the goal of a urine pH >7.5 while maintaining a serum pH no higher than 7.55.

Alkalemia from a primary respiratory alkalosis is not a contraindication to alkalinizing serum and urine. Administer sodium bicarbonate even in a patient who presents with an arterial pH between 7.50 and 7.55, which occurs commonly with salicylate toxicity [25]. Frequent monitoring of blood pH ensures that the alkalosis does not become excessive.

●Alkalinizing fluid and rate – A typical initial dose of sodium bicarbonate is 1 to 2 mEq/kg (1 to 2 mL/kg of 8.4% [1 mEq/mL] sodium bicarbonate) given as an IV bolus. This is followed by a sodium bicarbonate continuous infusion at approximately 1.5 to 2 times the maintenance fluid requirement rate. Prepare the continuous infusion fluid by adding 150 mEq of sodium bicarbonate into 1 liter of 5% dextrose in water. In a euvolemic patient, this infusate also serves as the maintenance fluid. (See "Enhanced elimination of poisons", section on 'Urinary alkalinization'.)

Add 20 to 40 mEq/L of potassium chloride to the infusate in a patient with hypokalemia unless the serum potassium >5.5 mEq/L. Hypokalemia and hypomagnesemia must be corrected for urine to be effectively alkalinized, which is discussed further above. (See 'Fluid and electrolyte repletion' above.)

●Titration and monitoring – Titrate the sodium bicarbonate infusion rate to maintain a urine pH ≥7.5. Increases in serum pH up to 7.55 to 7.6 are well-tolerated in patients with normal kidney function, but alkalemia beyond that may be associated with mortality from neurologic and cardiac complications [28]. Measure blood gas analysis and serum sodium and potassium hourly. If hypernatremia develops, it may be necessary to decrease the sodium bicarbonate infusion rate or change the continuous infusion to 50 or 100 mEq/L of sodium bicarbonate in 1 liter of 5% dextrose in water.

Place a Foley catheter to accurately measure urine output and pH. In a patient with severe salicylate toxicity, it is often difficult or impossible to obtain the urine pH goal (≥7.5), particularly in the setting of intravascular volume deficits or whole-body potassium or magnesium depletion.

●Discontinuation – Stop alkalinization therapy when the serum salicylate concentration is <40 mg/dL (<2.9 mmol/L) on two measurements, the acid-base status has normalized, and the patient is asymptomatic with a normal respiratory rate and effort. Continue to measure blood gases and serum salicylate concentrations every two hours and urine pH every hour after discontinuation for four hours to demonstrate resolution of toxicity. If serum and urine pH decrease, serum salicylate concentrations increase, or the patient becomes symptomatic, restart alkalinization therapy.

●Benefits and physiology of alkalinization – Urinary alkalinization significantly enhances salicylate elimination, and serum alkalinization produces an environment that protects the patient from detrimental tissue distribution. The goal of treating salicylate toxicity is to decrease the fraction of uncharged (protonated, HSal) molecules by shifting the equilibrium reaction to the left:

Increasing the systemic pH (ie, lowering the H⁺ ion concentration) decreases the plasma HSal concentration. HSal in the central nervous system (CNS) and other tissues diffuses into the extracellular fluid down a favorable concentration gradient, where it is "trapped" as Sal^-. In order to maintain the equilibrium reaction within brain cells, Sal^- is protonated to HSal, thus promoting further drug movement out of the CNS as long as there is a gradient with the plasma HSal concentration.

Alkalinizing urine increases salicylate excretion by trapping salicylate in the charged unprotonated state (Sal^-). In alkaline urine, the equilibrium favors the Sal^- over the HSal state; thus, less HSal is available to diffuse out of the tubular lumen back into the renal epithelium and ultimately the systemic circulation [29]. As an example, raising the urine pH from 6.5 to 8.1 can increase total salicylate excretion more than fivefold [26,27].

In a study of 22 adults with moderate salicylate toxicity, the six patients who received urinary alkalinization had a greater salicylate clearance (mean clearance 24 versus 1.4 mL/minute) and reduced half-life of salicylate (mean half-life 9 versus 29 hours) compared with 16 patients who only received oral fluids [30]. In volunteer studies, urinary alkalinization increased the amount of unchanged salicylate excreted in the urine from 2 to 31 percent and increased clearance from 1 to 100 mL/minute [27,31].

●Options when sodium bicarbonate is unavailable – Sodium acetate has been used to alkalinize urine and treat salicylate toxicity during a sodium bicarbonate shortage. This should not be first-line therapy as evidence is limited to case reports [32]. The infusion consists of 150 mEq of sodium acetate diluted in 1 liter of 5% dextrose in water at twice the maintenance rate. Compared with sodium bicarbonate, the IV bolus administration of sodium acetate, if needed, should be slower (over 15 to 20 minutes), but the dosing is similar (1 mEq per kg).

Indications for hemodialysis — Most indications for hemodialysis are based upon clinical findings irrespective of salicylate concentration; secondary indications for hemodialysis are based upon the salicylate concentration. Any patient who meets a clinical indication for hemodialysis (eg, altered mental status, pulmonary edema) irrespective of serum salicylate concentration deserves immediate hemodialysis. Once a clinical indication for hemodialysis is met, do not delay initiating hemodialysis by repeating a salicylate concentration just to see if it rises above the thresholds [2,8]. Fatal salicylate toxicity despite concentrations below these thresholds has been reported [33-35]. Indications for hemodialysis, which are based on consensus and expert opinion, include the following [36]:

●Any alteration in mental status (eg, delirium, agitation, lethargy, seizure) attributed to salicylism

●Acidosis (blood pH <7.2 or pH <7.3 despite aggressive resuscitation)

●Cerebral or pulmonary edema

●Fluid overload that prevents administration of bicarbonate infusion

●Clinical deterioration (eg, cardiovascular collapse, hypotension, ventricular dysrhythmia, worsening metabolic acidosis or a primary respiratory acidosis) despite aggressive and appropriate supportive care

●Presence of acute kidney injury or chronic kidney disease and serial serum salicylate concentrations are relatively unchanged despite bicarbonate infusion

Additional indications for hemodialysis irrespective of clinical findings include the following salicylate threshold concentrations:

●In acute toxicity with normal kidney function: >100 mg/dL (>7.2 mmol/L)

●In acute toxicity with impaired kidney function (table 3): >90 mg/dL (>6.5 mmol/L)

●In chronic toxicity: >60 mg/dL (>4.3 mmol/L)

Hemodialysis rapidly eliminates salicylate and corrects acid-base, fluid, and electrolyte abnormalities, such as metabolic acidosis or hypokalemia. Salicylate is readily cleared by hemodialysis because it has a low molecular weight (138 Daltons) and volume of distribution (0.21 L/kg) [2]. One study reported a clearance rate of 86 mL/minute [37]. Although salicylate is highly protein bound at therapeutic serum concentrations, the unbound fraction, which is available for clearance by hemodialysis, increases at toxic concentrations [2,38]. In case reports and case series of salicylate toxicity, hemodialysis shortened the duration of toxicity and improved survival despite clinical signs of severe toxicity historically associated with death [38,39].

●Hemodialysis prescription – General principles of the hemodialysis prescription include a blood flow rate of 350 to 400 mL/minute with biocompatible hemodialysis membranes with larger surface areas for at least three to four hours [2]. The dialysate composition should contain a higher potassium and bicarbonate concentration. Multiple hemodialysis treatments may be needed depending on the acid-base status and gastrointestinal burden of salicylate. (See "Acute hemodialysis prescription".)

●Bicarbonate therapy in a patient receiving hemodialysis – We stop the bicarbonate infusion during the hemodialysis session so as not cause a severe metabolic alkalosis. We restart the bicarbonate infusion after the hemodialysis session until the next session or the serum salicylate concentration is <40 mg/dL (<2.9 mmol/L) on two measurements, the acid-base status has normalized, and the patient is asymptomatic with a normal respiratory rate and effort.

●Cessation of hemodialysis session – We stop a hemodialysis session if the serum salicylate concentration obtained four to six hours into the session is <19 mg/dL (<1.4 mmol/) or after a four- to six-hour session if obtaining the concentration is not feasible [36].

We continue to measure a serum salicylate concentration and blood gas every two hours after a dialysis session to assess for tissue redistribution and continued absorption. A gastric concretion (ie, bezoar) from a massive ingestion can lead to rebound toxicity. (See 'Frequent laboratory monitoring' above.)

●Role of continuous renal replacement therapy (CRRT) – If hemodialysis is available, do not use CRRT for the management of salicylate toxicity. CRRT can be used to marginally increase salicylate clearance in the rare circumstance when CRRT but not hemodialysis is available or when hemodialysis is absolutely contraindicated. Compared with modern hemodialysis equipment, CRRT does not clear salicylate nearly as well and cannot correct the acid-base or electrolyte abnormalities that often accompany severe salicylate toxicity.

Mild toxicity — Mild toxicity often resolves with just observation, but close monitoring is necessary to ensure that absorption is not ongoing or more severe toxicity is developing. If there was a reported ingestion (as opposed to supratherapeutic misadventure), we still administer a dose of AC to prevent further absorption in case salicylate is still present in the gastrointestinal tract. (See 'Gastrointestinal decontamination' above.)

We measure serial salicylate concentrations until there are two downtrending concentrations <30 mg/dL (2.2 mmol/L) and signs and symptoms have resolved. (See 'Frequent laboratory monitoring' above.)

IV fluids, electrolyte repletion, and MDAC are typically not necessary unless serial salicylate concentrations increase or the patient develops worsening toxicity. We suggest consulting with a poison control center or medical toxicologist since a common error is not sufficiently monitoring a patient who is early in the course of more severe toxicity. (See "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation", section on 'Regional poison control centers'.)

INEFFECTIVE THERAPIES — Do not perform forced diuresis (ie, administration of excessive intravenous [IV] fluids beyond the restoration of normal fluid balance). It is less effective than urinary alkalinization for enhancing salicylate elimination and provides no added benefit when combined with alkalinization [30,31]. Attempts at forced diuresis can cause fluid overload, increasing the risk of pulmonary or cerebral edema and complicating urinary alkalinization. Avoid administering diuretics since salicylate excretion depends upon urine pH and not the flow rate.

Acetazolamide is contraindicated in the management of salicylate poisoning. Acetazolamide is a carbonic anhydrase inhibitor that alkalinizes the urine by reducing bicarbonate reabsorption, thus increasing renal elimination of bicarbonate. While this does enhance salicylate excretion, the plasma bicarbonate loss decreases the blood pH, which promotes salicylate distribution into tissue and worsens toxicity.

DISPOSITION — A patient with salicylate toxicity whose symptoms have resolved, has normal vital signs and examination, and has two downtrending salicylate concentrations <30 mg/dL (2.2 mmol/L) can be discharged home or referred for mental health evaluation as clinically indicated. All other patients should be managed in an intensive care unit since frequent monitoring is required.

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment" and "Society guideline links: Treatment of acute poisoning caused by specific agents other than drugs of abuse".)

SUMMARY AND RECOMMENDATIONS

●Assess severity of toxicity – Assess the severity of toxicity based on the patient's symptoms, signs, and acid-base status (table 2). Do not rely solely on the serum salicylate concentration since that will commonly underestimate the severity of toxicity. (See 'Assess severity of toxicity' above.)

●Avoid tracheal intubation, if possible – Reserve tracheal intubation for a patient with hypoventilation, as determined by clinical evaluation or blood gas analysis, or a patient who requires airway protection, such as for seizures or agitation control for procedures. If intubation becomes necessary, initiate treatment of the underlying acidosis prior to intubation, minimize the apneic phase of rapid sequence intubation, and ensure appropriately high minute ventilation after intubation. (See 'ABCs and supportive care' above.)

●Gastrointestinal decontamination – In a patient with an acute oral salicylate overdose, we recommend administering at least one dose of activated charcoal (AC; 1 g/kg orally; maximum single dose: 50 g) regardless of the time since ingestion (Grade 2C). AC effectively absorbs salicylate, and even a delayed dose provides benefit since enteric-coated aspirin can form gastric concretions and pylorospasm can cause delayed gastric emptying. (See 'Gastrointestinal decontamination' above.)

In a patient with moderate or severe salicylate toxicity or a patient who reports a large ingestion (eg, >300 mg/kg of aspirin), we suggest administering multiple-dose AC (MDAC) (Grade 2C). Subsequent doses of AC are 0.5 g/kg (maximum dose: 50 g) every four hours or 0.25 g/kg (maximum dose: 25 g) every two hours of AC without sorbitol. (See 'Multiple-dose activated charcoal' above.)

●Frequent laboratory monitoring – In a patient with salicylate toxicity or reported overdose, we measure a salicylate concentration and blood gas every two to four hours. In a patient receiving alkalinization therapy, we obtain an hourly blood pH, urine pH, and serum sodium and potassium concentrations. (See 'Frequent laboratory monitoring' above.)

●Consultations with specialists – We recommend consultation with a medical toxicologist or a regional poison control center and consultation with the nephrologist early in a patient's course, even in the absence of the immediate need for hemodialysis. (See 'Consultation with specialists' above and 'Regional poison control centers' above.)

●Patient with moderate or severe toxicity – A patient with moderate salicylate toxicity is treated similarly to severe toxicity but does not require hemodialysis. (See 'Moderate or severe toxicity' above.)

•Fluid and electrolyte repletion – Resuscitate aggressively with crystalloid if the patient is hypovolemic unless cerebral edema or pulmonary edema is present. Aggressively replete potassium and magnesium since deficiencies interfere with efforts at urinary alkalinization. (See 'Fluid and electrolyte repletion' above.)

•Provide supplemental glucose if neurologic signs present – In a patient with altered mental status, seizures, or neurologic deficit, we suggest administering supplemental glucose regardless of the serum glucose concentration (Grade 1C). We maintain the serum glucose in the high normal range (approximately 100 to 140 mg/dL [5.6 to 7.8 mmol/L]). (See 'Supplemental glucose' above.)

•Serum and urine alkalinization – In a patient with moderate or severe salicylate toxicity, we recommend alkalinizing the serum and urine (Grade 1B). We administer intravenous (IV) sodium bicarbonate titrated to a urine pH >7.5 while maintaining a serum pH no higher than 7.55. Alkalemia from a primary respiratory alkalosis is not a contraindication to administering sodium bicarbonate. (See 'Serum and urine alkalinization' above.)

•Indications for hemodialysis – In a patient with any of the following, we recommend hemodialysis (Grade 1B), which rapidly eliminates salicylate and corrects acid-base, fluid, and electrolyte abnormalities (see 'Indications for hemodialysis' above):

-Any alteration in mental status attributed to salicylism

-Acidosis (blood pH <7.2 or pH <7.3 despite aggressive resuscitation)

-Cerebral or pulmonary edema

-Fluid overload that prevents administration of bicarbonate infusion

-Clinical deterioration despite aggressive and appropriate supportive care

-Presence of acute kidney injury or chronic kidney disease and serial serum salicylate concentrations are relatively unchanged despite bicarbonate infusion

We also suggest hemodialysis in patients who do not meet the above criteria but have any of the following (Grade 2C):

-In acute toxicity with normal kidney function: serum salicylate concentration >100 mg/dL (>7.2 mmol/L)

-In acute toxicity with impaired kidney function (table 3): serum salicylate concentration >90 mg/dL (>6.5 mmol/L)

-In chronic toxicity: serum salicylate concentration >60 mg/dL (>4.3 mmol/L)

Once a clinical indication for hemodialysis is met, do not delay initiating hemodialysis by repeating a salicylate concentration just to see if it rises above the concentration thresholds. 

●Patient with mild toxicity – Mild toxicity will often resolve with just observation, but close monitoring is necessary to ensure that absorption is not ongoing or more severe toxicity is developing. (See 'Mild toxicity' above.)

●Disposition – A patient with salicylate toxicity whose signs and symptoms have resolved, has normal acid-base status, and has two downtrending salicylate concentrations <30 mg/dL (<2.2 mmol/L) can be discharged home or referred for mental health evaluation as clinically indicated. All other patients should be managed in an intensive care unit since frequent monitoring is required. (See 'Disposition' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Stephen J Traub, MD, former section editor of the toxicology program, for 20 years of dedicated service.