Salicylate poisoning in children and adolescents

INTRODUCTION — The clinical manifestations and management of all salicylate intoxications are similar. An overview of salicylate intoxication in children and adolescents will be presented here. General issues relating to the clinical management of drug intoxication are presented separately. (See "Approach to the child with occult toxic exposure" and "Gastrointestinal decontamination of the poisoned patient".)

EPIDEMIOLOGY — The number of pediatric exposures to salicylates reported to the American Association of Poison Control Centers Toxic Exposure Surveillance System (AAPCC TESS) has declined since the 1980s [1]. The use of aspirin (acetylsalicylic acid, ASA) in children has declined since it was associated with Reye syndrome. The incidence of unintentional salicylate intoxication among toddlers also has declined with limitation of the dose of aspirin in chewable, flavored tablets (to 81 mg), restriction of the number of tablets per bottle (to 36), and child-resistant packaging [1-3]. Among children there are approximately 20,000 salicylate exposures reported to United States regional poison control centers annually [4].

Deaths from exploratory salicylate overdose in children are rare. Most pediatric cases of severe salicylate poisoning or death occur among adolescents with intentional ingestion.

FORMULATIONS — Aspirin (acetylsalicylic acid) is available in chewable form, regular tablets, and enteric-coated pills. Other salicylates, such as salicylic acid, bismuth subsalicylate, and methyl salicylate, can cause intoxication when ingested or absorbed through the skin [5,6]. Salicylic acid is a topical keratolytic agent and wart remover. Bismuth salicylate is a common ingredient in over-the-counter antidiarrheal agents (eg, Pepto-Bismol, Kaopectate). Magnesium subsalicylate in combination with caffeine, a combination product known as Diurex, is used as an "antibloat" medicine, but has been reported to cause salicylate toxicity in overdose [7]. Methyl salicylate (oil of wintergreen) is a common ingredient of Chinese herbal medications as well as liniments and ointments used in the management of musculoskeletal pain; it also is used as a flavoring agent [8-10]. One teaspoon (5 mL) of oil of wintergreen contains approximately 7 g of salicylate, the equivalent of 22 adult aspirin tablets; ingestion of just 4 mL can be fatal in a child [9]. The methyl salicylate concentration and the bioavailability of salicylate in methyl salicylate creams vary by preparation [8,11].

PHARMACOKINETICS AND TOXICOKINETICS — After ingestion, salicylate is rapidly absorbed from the gastrointestinal tract, primarily from the jejunum and to a lesser extent, from the stomach and duodenum [12,13]. The type of formulation (eg, liquid, effervescent, extended-release, enteric-coated) affects the degree of absorption [14-16].

With therapeutic dosing of regular aspirin tablets, peak plasma concentrations are usually achieved 15 to 60 minutes after ingestion [17]. Peak concentrations in overdose may be delayed as a result of pylorospasm or bezoar formation. Peak concentrations following ingestion of extended-release or enteric-coated preparations typically occur between 4 and 14 hours after ingestion [14-16].

In therapeutic dosing, 80 to 90 percent of salicylate is protein-bound (primarily to albumin), and remains in the vascular space. However, in overdose, saturation of protein-binding sites leads to an increase in the free fraction of salicylate in the plasma, and increased drug reaching the tissues [18].

Salicylate is metabolized via several routes in the liver. In therapeutic dosing, the metabolism of salicylate, which involves glucuronidation, oxidation, and glycine conjugation, is described by first-order kinetics (where the rate is proportional to the dose) with a half-life of 15 to 20 minutes. At increasing doses, salicylate saturates these enzyme systems, and elimination of the drug undergoes a transition to zero-order kinetics (where a fixed amount of drug is metabolized per unit of time [Michaelis-Menten kinetics]) [18]. Thus, at increased doses, the half-life of salicylate is greatly increased and may be up to 30 hours [1]. In addition, with increasing doses, a greater-than-expected increase in serum and tissue concentration occurs; for children on chronic therapy, even a slight change in dose may result in a great increase in plasma concentration [19].

Salicylic acid (HS) is a weak acid that exists in a charged (deprotonated, sal-) and uncharged (protonated, H+) form:

Uncharged molecules (HS), unlike charged molecules (sal-), can move easily across cellular barriers, including the blood-brain barrier and the epithelium of the renal tubule. Metabolic acidosis drives the above reaction to the right and increases the plasma concentration of HS, thereby promoting diffusion across the blood-brain barrier into the CNS. (See 'Clinical manifestations' below.)

Treatment of salicylate intoxication is directed toward increasing systemic pH via the administration of sodium bicarbonate. By driving the above reaction to the left, salicylate anions are "trapped" in the blood. Alkalinization also "traps" salicylate anions within the renal tubule, preventing back-diffusion across the renal epithelium into the systemic circulation.

An alkaline environment protects the patient from detrimental tissue toxicity, especially in the central nervous system. To appreciate how alkalinization acts, it is important to note that salicylic acid is a weak acid with a pKa of 3.0. Thus, the Henderson-Hasselbalch equation for the reaction above can be expressed as:

At the normal extracellular pH of 7.40, the ratio of deprotonated (charged) salicylic acid to protonated (uncharged) salicylate is about 25,000:1; that is, only 0.004 percent of the total extracellular salicylate exists in protonated form. Salicylic acid is nonpolar, lipid-soluble, and able to cross cell membranes; deprotonated salicylate is polar and crosses membranes poorly. As a result, the plasma and central nervous system (CNS) salicylic acid concentrations are in diffusion equilibrium, but not the ionized salicylate concentrations.

If the systemic pH is increased, plasma salicylic acid concentration will fall and cause diffusion of salicylic acid out of the CNS and other tissues into the extracellular fluid down a favorable concentration gradient where it will be trapped as ionized salicylate. The fall in the CNS salicylic acid concentration then causes the first equation to move to the right in the brain cell. This increase in the cellular HS concentration promotes further drug movement out of the CNS.

Increasing the arterial pH from 7.20 to 7.50 will decrease the fractional concentration of HS from 0.006 to 0.003 percent. Although this change appears trivial, it will promote a significant reduction in the tissue salicylate concentration. This will be accompanied by an initial increment in the plasma salicylate concentration, but it is the tissue levels that are dangerous to the patient.

Concurrent alkalinization of the urine is also beneficial by increasing salicylate excretion. Since the salicylate anion is highly protein-bound, it enters the urine primarily via secretion by the organic anion secretory pathway in the proximal tubule, rather than by glomerular filtration. Alkalinization of the urine converts urinary salicylic acid to ionized salicylate thereby minimizing the back-diffusion of secreted salicylic acid out of the tubular lumen [20]. As an example, raising the urine pH from 6.5 to 8.1 by the administration of sodium bicarbonate can increase total salicylate excretion more than fivefold [21,22]. Maintaining a high-urine flow rate with hydration further enhances this process.

MECHANISM OF ACTION — Salicylate has multiple cellular and systemic effects that define its clinical presentation in overdose [1,23,24]:

●Activation of the respiratory center of the medulla results in increased respiratory rate, respiratory alkalosis, increased renal elimination of HCO₃, and increased insensible fluid loss.

●Interference with cellular metabolism (uncoupling of oxidative phosphorylation) leads to metabolic acidosis, hyperpyrexia, fluid loss, and hypoglycemia.

●Inhibition of the tricarboxylic acid cycle leads to metabolic acidosis.

●Inhibition of cyclooxygenase results in decreased synthesis of prostaglandins, prostacyclin, and thromboxanes.

●Stimulation of the chemoreceptor trigger zone in the medulla causes nausea and vomiting.

CLINICAL MANIFESTATIONS — The hallmarks of acute salicylate overdose are hyperpnea, tachypnea, metabolic acidosis, and to a lesser extent, tachycardia. Early symptoms include tinnitus, vertigo, nausea, vomiting, and diarrhea; more severe intoxication can cause fever, altered mental status, coma, noncardiogenic pulmonary edema, and death. Salicylate toxicity is associated with several clinical and laboratory findings (table 1).

Salicylate intoxication, known as salicylism, may be acute, chronic, or acute-on-chronic [25]. Chronic and acute-on-chronic toxicity are uncommon in children, since aspirin is rarely used on a daily basis in children. The discussion below will focus on acute salicylate toxicity. However, it should be noted that chronic or therapeutic (repeated dose) salicylate poisonings in children usually are more serious and involve more severe clinical manifestations than acute ingestions [26,27].

The clinical manifestations of salicylate ingestion are dependent, to some extent, upon the ingested dose [1]. As a general rule, ingestions of less than 300 mg/kg are associated with mild symptoms, ingestions of 300 to 500 mg/kg are associated with moderate toxicity, and ingestions of >500 mg/kg are associated with death. Fatal salicylate intoxication can occur after the ingestion of 10 to 30 g by adults and as little as 3 g by children. Death typically results from severe central nervous system (CNS) toxicity with complete loss of function of the cardiorespiratory centers.

Although there is no absolute correlation between the plasma salicylate concentration and symptoms, most patients show signs of intoxication when the plasma concentration exceeds 30 to 50 mg/dL (300 to 500 mg/L, 2.2 to 3.6 mmol/L); the usual therapeutic range is 10 to 20 mg/dL (100 to 200 mg/L, 0.7 to 1.5 mmol/L) [23].

The clinician should take care in reading and interpreting laboratory reports since some laboratories report salicylate levels as mg/L, rather than mg/dL; such values will be 10-fold higher than those discussed in this topic review. (See 'Evaluation and diagnosis' below.)

Salicylate poisoning leads to a variety of clinical features:

●Vital signs – Salicylate intoxication can lead to increased respiratory rate, temperature, and heart rate.

•Salicylates stimulate the medullary respiratory center, causing tachypnea and hyperventilation. The respiratory rate must be carefully monitored in all patients with suspected salicylate overdose. Salicylate-intoxicated patients have a dramatic increase in minute ventilation. The rate and depth of breathing provide critical clues to salicylate toxicity.

•Salicylates uncouple oxidative phosphorylation in the mitochondria; this generates heat and may increase body temperature. A lack of hyperthermia, however, should not be used to exclude the diagnosis of salicylate toxicity. Hypovolemia further limits the ability to dissipate heat. Children are able to tolerate hyperpyrexia somewhat better than adults, in whom hyperpyrexia suggests a grave prognosis [1].

•Salicylate ingestion can cause tachycardia due to hypovolemia, agitation, or general distress.

●Tinnitus – Salicylates commonly cause tinnitus, and may do so at levels within the therapeutic range (20 mg/dL [1.5 mmol/L]). This specific symptom should be sought in all patients with potential salicylate toxicity. As CNS salicylate concentration increases, diminished auditory acuity may ensue, sometimes leading to deafness [28].

●Nausea and vomiting – Salicylate can cause nausea and vomiting through multiple mechanisms. These include direct stimulation of the chemoreceptor trigger zone in the medulla, delayed gastric emptying, direct irritation of the gastric mucosa, and decreased production of prostaglandins (leading to deterioration of the protective mucosal barrier).

●Pulmonary edema – Salicylate-induced noncardiogenic pulmonary edema is more common among older patients [29] but does occur in children [30]. In one five-year retrospective review of 20 cases of pediatric salicylate poisoning, two children developed pulmonary edema; both children died, while there were no deaths among the 18 without pulmonary edema [30]. Pulmonary edema may occur in the setting of falling or near-therapeutic plasma salicylate concentrations [1]. (See "Noncardiogenic pulmonary edema", section on 'Salicylate toxicity'.)

Hypoxia is the major clinical manifestation [25], although crackles may be present. In addition, arterial blood gas analysis may demonstrate a widened arterial-alveolar gradient [30]. A chest radiograph should be obtained in children with salicylism in whom pulmonary edema is suspected. Radiographic signs of pulmonary edema, which may or may not be present, include pleural effusion, interstitial edema, fluid in the fissures, and septal lymphatic distension.

Salicylate-induced pulmonary edema can complicate volume resuscitation and the administration of sodium bicarbonate, two mainstays of treatment. Thus, pulmonary edema is an absolute indication for hemodialysis (See 'Hemodialysis' below.)

●Central nervous system abnormalities – CNS toxicity, suggestive of severe poisoning, may occur in the setting of falling or near-therapeutic plasma salicylate concentrations [31]. The development of acidemia increases the risk of CNS toxicity since salicylate, a neutral compound at acidic pH, is able to cross the blood-brain barrier and enter the CNS (See 'Pharmacokinetics and toxicokinetics' above.)

CNS toxicity is more common among children younger than five years of age than among older children and adults [27,32]. CNS toxicity manifests as agitation, confusion, restlessness, seizures, and rarely, coma. Seizures are a more common presentation among children with chronic ingestions and severe metabolic acidosis than among children with acute ingestions [27]. The development of CNS toxicity is an indication for hemodialysis, regardless of the plasma salicylate concentration (See 'Hemodialysis' below.)

●Acid-base derangement – A variety of acid-base disturbances can occur with salicylate intoxication. The typical abnormality is a primary respiratory alkalosis with a primary metabolic acidosis. Salicylates stimulate the respiratory center directly, leading to hyperpnea. This results in a decreased PCO2 and respiratory alkalosis [23,32,33]. (See "Simple and mixed acid-base disorders".)

The increase in respiratory rate is critical to survival since alkalosis prevents CNS toxicity, which is the major cause of death. The respiratory alkalosis, which normally promotes lactic acid production to minimize the rise in pH, appears to play a contributory role in the development of metabolic acidosis. In experimental animals, lactate accumulation is minimal if the initial fall in PCO₂ is prevented, but gradually becomes more prominent as hypocapnia is permitted to occur [34]. Salicylic acid itself (mol wt 180) has only a minor effect on serum pH, since a plasma level of 50 mg/dL (3.6 mmol/L) represents a concentration that is less than 3 mEq/L. Thus, the metabolic acidosis following salicylate poisoning is due primarily to the accumulation of organic acids, including lactic acid and ketoacids [33-36]. Inhibition of the tricarboxylic acid cycle by salicylates also contributes to the development of metabolic acidosis [37,38]. (See "Approach to the child with metabolic acidosis".)

Metabolic acidosis increases the concentration of uncharged salicylic acid, thereby promoting diffusion across the blood-brain barrier into the central nervous system. (See 'Pharmacokinetics and toxicokinetics' above.)

The net effect of these changes in most adults is respiratory alkalosis or a mixed respiratory alkalosis-metabolic acidosis. Pure metabolic acidosis is unusual in adults [33], but is more common in children [32]. Children with mild to moderate acute salicylate poisoning lose the respiratory drive and are more likely to present with mixed metabolic and respiratory acidosis [24,32]. (See "Simple and mixed acid-base disorders".)

Acute respiratory acidosis may also occur in adolescents and adults who ingest respiratory depressants at the same time as salicylate [33]. Ingestion of respiratory depressants decreases the respiratory drive, leading to increased PaCO₂ and decreased plasma pH. (See "Simple and mixed acid-base disorders".)

●Fluids, electrolytes, and glucose – Fluid and electrolyte abnormalities are common in salicylate poisoning. Insensible fluid losses from hyperpyrexia, vomiting, diaphoresis, and an elevated metabolic rate can cause hypovolemia. In severe intoxication, free water losses may reach 4 to 6 L/m2 [13,24], resulting in hypernatremia.

During the early stages of salicylate intoxication, when respiratory alkalosis is the primary acid-base disturbance, there is increased loss of HCO₃-, and the kidneys attempt to conserve H+ over K+. As poisoning progresses and potassium is depleted, the kidneys attempt to conserve K+, producing a paradoxically acidic urine [24]. Hypokalemia, if present, must be treated aggressively. (See 'Potassium repletion' below.)

Early in the course, the patient may have hyperglycemia from glycogenolysis, stimulation of gluconeogenesis, and decreased peripheral utilization of glucose. At this stage, urine ketones may be positive [25]. As glucose stores are depleted, hypoglycemia may ensue from impaired gluconeogenesis and increased utilization [5,39,40]. In addition, salicylate intoxication may decrease CNS glucose levels despite a normal peripheral glucose level if CNS glucose utilization exceeds blood supply [41]. (See "Causes of hypoglycemia in infants and children".)

●Hematologic – Hematologic abnormalities associated with salicylate intoxication include leukocytosis, inhibition of platelet function, and disturbances in vitamin K-dependent and vitamin K-independent clotting factors [42-44]. These abnormalities may manifest with bruising or bleeding.

EVALUATION AND DIAGNOSIS — Salicylism should be suspected in patients with hyperventilation, tachypnea, tachycardia, diaphoresis, tinnitus, and increased anion gap metabolic acidosis. The diagnosis is confirmed by measurement of the plasma salicylate concentration, which should be obtained in patients with these findings, even if a history of salicylate ingestion is lacking. (See 'Plasma salicylate' below.)

History — The evaluation of the child or adolescent with salicylate intoxication should include as much detail about the ingestion as possible.

●How much salicylate was ingested (including the dose per tablet and number of tablets per container)?

●Was the child or adolescent taking salicylate on a regular basis (including over-the-counter antidiarrheal preparations eg, Pepto-Bismol, the United States preparation of Kaopectate, or Diurex)?

●Was the ingestion intentional?

●Does the child or adolescent have any underlying medical problems or take any medication on a regular basis?

●Does the child or adolescent have symptoms (eg, fever, tinnitus, nausea, vomiting, respiratory difficulty, agitation, confusion, restlessness)?

Examination — The physical examination should include a complete set of vital signs and evaluation for diaphoresis, hyperpnea (increase depth of respiration), central nervous system (CNS) disturbance, tinnitus and/or hearing loss. The lungs should be carefully examined for signs of pulmonary edema (eg, hypoxemia, crackles), which may complicate therapy and is an indication for hemodialysis. Vital signs should be frequently remeasured. (See 'Management' below.)

Laboratory — The laboratory evaluation of the child or adolescent with salicylate intoxication should include plasma salicylate concentration and additional tests that help to assess the severity of the ingestion.

Plasma salicylate — Plasma salicylate concentration should be measured in all patients in whom salicylate intoxication is suspected. The result should be interpreted in conjunction with the clinical findings, particularly the plasma pH. Acidosis, by promoting the diffusion of salicylic acid into the CNS, increases the severity of toxicity.

Plasma salicylate concentrations should be repeated several hours after presentation because of the possibility of prolonged or delayed absorption. A decreasing plasma concentration in a patient with progressive clinical manifestations of salicylism may indicate increased tissue and/or CNS distribution. In patients with documented salicylate intoxication, plasma salicylate concentrations should be remeasured frequently (eg, every two to four hours) until there is a consistent decrease in the concentration and clinical improvement in the patient.

The clinician should take care in reading and interpreting laboratory reports since some laboratories report salicylate levels as mg/L, rather than mg/dL; such values will be tenfold higher than those discussed in this topic review. Thus, a laboratory report of "a salicylate level of 110" in an asymptomatic individual should prompt the clinician to check the units of the result in order to avoid confusion.

The usual therapeutic range is 10 to 30 mg/dL (100 to 300 mg/L, 0.7 to 2.2 mmol/L) [23]. Although there is no absolute correlation between plasma salicylate concentration and symptoms, most patients show signs of intoxication when the plasma concentration exceeds 30 to 50 mg/dL (400 to 500 mg/L, 2.9 to 3.6 mmol/L). Plasma salicylate concentrations >100 mg/dL (>1000 mg/L, >7.2 mmol/L) in acute intoxication and >60 mg/dL (>600 mg/L, >4.3 mmol/L) in chronic intoxication are indications for hemodialysis. (See 'Hemodialysis' below.)

Life-threatening complications of salicylate intoxication may occur when plasma concentrations are decreasing or near-therapeutic. Clinicians must continue to follow patients closely, even as salicylate concentrations decline. (See 'Clinical manifestations' above.)

The Done nomogram was developed to correlate plasma salicylate levels with toxicity for acute aspirin ingestions; however, it is no longer in clinical use. The Done nomogram fails to accurately predict toxicity based upon the plasma concentration alone; however, patients with higher levels generally are sicker than those with lower values [45]. Mortality from salicylate poisoning is strongly correlated with CNS salicylate levels, but these are not routinely measured in clinical practice. Ultimately, plasma salicylate concentrations must be interpreted in conjunction with the clinical status of the patient.

Additional tests — The following tests are important in evaluating the severity of salicylate intoxication and/or the need for hemodialysis:

●Arterial or venous blood gas

●Electrolytes and glucose

●Plasma creatinine (to evaluate for renal failure, which is an indication for hemodialysis) (see 'Hemodialysis' below)

●Urinalysis (as poisoning progresses and potassium is depleted). The kidneys attempt to conserve K+, producing a paradoxically acidic urine; urine pH is also followed to monitor success of alkalinization (see 'Urine alkalinization' below)

Depending upon the circumstances of the ingestion and the severity of symptoms, the following additional tests may be indicated:

●Chest radiograph, particularly in patients with hypoxemia or crackles, to evaluate for pulmonary edema

●Rapid toxicology screen, particularly in intentional ingestions

●Plasma acetaminophen concentration (since many over-the-counter preparations contain both aspirin and acetaminophen) (see "Management of acetaminophen (paracetamol) poisoning in children and adolescents")

●Electrocardiogram (particularly in patients with hypokalemia)

●Complete blood count and/or prothrombin time and partial thromboplastin times may be obtained in the initial evaluation of patients with unknown salicylate exposure who manifest fever and shock; although abnormal findings may be present (eg, leukocytosis, impaired clotting), these abnormalities may be seen in both salicylism or sepsis

●Pregnancy test

DIFFERENTIAL DIAGNOSIS — The history of salicylate ingestion may or may not be known. In cases of occult exposure, the differential diagnosis of salicylism includes diabetic ketoacidosis (DKA), sepsis, pneumonia, iron intoxication, ethylene glycol ingestion, and ethanol intoxication [46].

●Children with DKA may present with nausea, vomiting, abdominal pain, lethargy, hypovolemia, hyperglycemia, hyperosmolality, and metabolic acidosis. The diagnosis of uncontrolled diabetes mellitus is usually suspected from the clinical history (eg, polyphagia, polydipsia, polyuria) and on laboratory testing, the presence of hyperglycemia and a high-anion gap metabolic acidosis with ketonuria and ketonemia. In contrast to patients with DKA, patients with salicylism may be hypoglycemic. Plasma salicylate concentrations should be measured in patients in whom the distinction cannot be made clinically. (See "Diabetic ketoacidosis in children: Clinical features and diagnosis".)

●The findings of metabolic acidosis, tachypnea, hypoglycemia, hypovolemia, leukocytosis, and clotting abnormalities may mimic sepsis, pneumonia, or the systemic inflammatory response syndrome, particularly in patients with chronic salicylism or noncardiogenic pulmonary edema [44,47,48]. Salicylate intoxication should be considered when a source of infection is not readily apparent, since survival in both of these disorders is dependent upon prompt recognition and management.

●Similar to acute salicylate intoxication, acute iron intoxication may be associated with metabolic acidosis, vomiting, leukocytosis, hemoconcentration, elevated transaminases, prolonged prothrombin time, and hyperglycemia. Plasma concentrations of iron and salicylate should be measured to make the diagnosis so that appropriate therapy can be instituted. (See "Acute iron poisoning".)

●Ethylene glycol intoxication is associated with neurologic abnormalities, tachypnea, pulmonary edema, and a metabolic acidosis with increased anion gap (oxalate is the unmeasured anion). (See "Methanol and ethylene glycol poisoning: Pharmacology, clinical manifestations, and diagnosis".)

●Similar to salicylate intoxication, ethanol intoxication in children causes metabolic acidosis with increased anion gap, elevated lactate, hypoglycemia, and neurologic symptoms. Ethanol intoxication is diagnosed by measuring a blood alcohol concentration. (See "Causes of hypoglycemia in infants and children", section on 'Ingestions'.)

MANAGEMENT — A rapid overview describes the treatment priorities for salicylate poisoning (table 1). As with all poisoned patients, treatment consists of rapid assessment and stabilization of the airway, breathing, and circulation. This should be followed by gastrointestinal decontamination and the initiation of specific therapy.

The goals of treatment of salicylate intoxication are to correct fluid and electrolyte imbalance and to enhance excretion. Treatment of salicylate intoxication is directed toward increasing systemic pH by the administration of sodium bicarbonate. Alkalinization "traps" salicylate anions in the blood, since charged molecules do not easily diffuse across the blood-brain barrier into the central nervous system (CNS). Alkalinization also "traps" salicylate anions within the renal tubule, preventing back-diffusion across the renal epithelium into the systemic circulation. (See 'Pharmacokinetics and toxicokinetics' above.)

Children and adolescents with significant salicylate toxicity should be managed in consultation with the toxicology service or advice from a regional poison control center (see 'Additional resources' below). In addition, it is advisable to consult with the nephrology service early in a patient's course, even in the absence of indications for acute hemodialysis. (See 'Hemodialysis' below.)

Supportive care — Key aspects of supporting the child or adolescent with salicylate poisoning include maintaining oxygenation, ensuring adequate minute ventilation, providing intravenous glucose, and repletion of fluid and potassium losses.

Airway — Intubation of the salicylate-poisoned patient is dangerous and should be avoided, if possible. Salicylate acts on the respiratory center of the medulla to increase the respiratory rate and can produce a dramatic increase in minute ventilation. As noted above, the resulting respiratory alkalosis "traps" salicylate anions in the blood, preventing them from crossing into the CNS.

When intubation is necessary due to obtundation, hypotension, hypoventilation, or severe metabolic acidosis, care must be taken to ensure appropriately high-minute ventilation and maintain alkalemia with serum pH 7.45 to 7.55. (See 'Urine alkalinization' below.)

Importantly, mechanical ventilation is generally incapable of delivering such high-minute ventilation, and ventilator asynchrony may actually decrease the patient's ability to maintain appropriate acid-base homeostasis [49]. As minute ventilation falls following intubation, increased CO₂ concentrations worsen acidosis. This, in turn, leads to redistribution of salicylate into peripheral tissues and, potentially, worsens toxicity. Patients who require intubation usually also require hemodialysis. (See 'Hemodialysis' below.)

Intubation of tachypneic patients following a salicylate overdose out of concern that "they may eventually tire" has resulted in death [50,51]. Thus, prophylactic intubation should be reserved for those patients with hypoventilation, as determined by clinical evaluation or blood gas analysis. (See "Measures of oxygenation and mechanisms of hypoxemia".)

Breathing — Supplemental oxygen should be administered as needed. The presence of acute lung injury may lead to very high-oxygen requirements.

Pulmonary edema, if present, should be treated initially with oxygen [1]. If necessary, continuous positive airway pressure (CPAP) and/or intubation may be tried. Intubation with positive end-expiratory pressure (PEEP) may be necessary, but should be avoided if possible. (See 'Airway' above.)

Circulation — Intravenous fluids should be administered as necessary to replace insensible fluid losses from hyperpyrexia, vomiting, diaphoresis, and elevated metabolic rate. The administered fluid is typically 5 percent dextrose to which sodium bicarbonate and potassium have been added. (See 'Urine alkalinization' below and 'Potassium repletion' below.)

Intravenous fluids should be administered cautiously to avoid pulmonary edema, usually at a rate of 1.5 to 2.0 times maintenance. The rate should be adjusted as necessary to produce 1 to 2 mL/kg of urine per hour [46]. (See "Maintenance intravenous fluid therapy in children".)

Supplemental glucose — Salicylate intoxication may decrease CNS glucose levels despite a normal peripheral glucose level [41]. Supplemental glucose should be given to patients with altered mental status regardless of serum glucose concentration. (See "Approach to hypoglycemia in infants and children", section on 'Glucose therapy'.)

Potassium repletion — Hypokalemia, if present, must be treated aggressively. Hypokalemia promotes the absorption of potassium in the distal tubule; this absorption occurs via a K+-H+ exchange pump (figure 1). The secretion of protons interferes with efforts at urinary alkalinization, which is a mainstay of therapy. Intravenous potassium repletion should be provided based upon the degree of hypokalemia as reflected by 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. (See 'Urine alkalinization' below.)

Gastrointestinal decontamination — We recommend that children and adolescents with an acute salicylate overdose receive gastrointestinal decontamination with activated charcoal (AC, 1 g/kg; maximum single dose: 50 g). AC should be withheld in patients who have altered mental status and may not be able to protect their airway, unless endotracheal intubation is performed first. Because aspirin is known to form gastric concretions in poisoned patients which may delay absorption and peak plasma salicylate levels as long as 60 hours after large ingestions, many experts suggest that AC be given to any patient with clinical signs of salicylate poisoning, even several hours after ingestion.

Evidence for the benefit of AC in salicylate poisoned children is as follows:

●Activated charcoal binds to salicylates [25,52].

●A small trial in healthy adult volunteers who received AC 30 minutes after aspirin ingestion found that peak salicylate levels were 50 percent lower than in untreated controls [53].

●Another small trial in healthy adult volunteers who received AC three hours after ingestion of enteric-coated aspirin also showed a significant decrease in absorption [54].

The recommendation of AC administration following salicylate overdose also derives from indirect evidence of benefit in volunteers, animal studies, and evidence of benefit following ingestions of other medications. Because of adverse effects, such as vomiting and dehydration, the combination of a cathartic (eg, sorbitol) and AC should be used sparingly, if at all, and only a single dose of a cathartic should be given to any patient. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Activated charcoal' and "Gastrointestinal decontamination of the poisoned patient", section on 'Cathartics'.)

We recommend not performing gastric emptying by gastric lavage or by syrup of ipecac-induced emesis in patients who ingest salicylates. This recommendation is based upon randomized controlled trials showing minimal benefit and possible risk to patients who undergo gastric emptying after poisoning. (See "Gastrointestinal decontamination of the poisoned patient".)

Elimination enhancement — Urinary alkalinization and hemodialysis are the primary methods to enhance elimination of salicylates. Multiple dose activated charcoal may also provide some benefit, primarily by preventing ongoing salicylate absorption.

Urine alkalinization — We recommend that children and adolescents with salicylate poisoning and clinical findings of toxicity receive urine alkalinization in addition to administration of activated charcoal and supportive care. The goal of this therapy is to achieve a urine pH >7.5 while maintaining a serum pH no higher than 7.55. Once initial fluid resuscitation has occurred, this therapy is generally started by administering an IV bolus of 1 to 2 mEq/kg (1-2 mL/kg of 8.4 percent [1 mEq/mL] sodium bicarbonate), followed by a continuous infusion of sodium bicarbonate at approximately 1.5 to 2 times maintenance requirements. The fluid for continuous infusion is mixed by placing 150 mEq of sodium bicarbonate into one liter of 5 percent dextrose in water. Patients with hypokalemia should have 20 to 40 mEq/L of potassium chloride added to the infusate. Prior to the initiation of therapy, baseline measurements of electrolytes, blood urea nitrogen, serum creatinine, glucose, systemic pH, urinary pH, and serum drug concentrations should be performed. Placement of a Foley catheter is recommended to accurately measure urine output. (See "Enhanced elimination of poisons", section on 'Technique' and "Enhanced elimination of poisons", section on 'Children'.)

The sodium bicarbonate infusion rate should be titrated to maintain a urine pH ≥7.5. Increases in serum pH up to 7.55 are well-tolerated in patients with normal renal function. Subsequent fluid administration should be based upon urine output and ongoing losses. The sodium bicarbonate infusion should continue until clinical findings of toxicity have resolved and the plasma salicylate concentration is less than 30 mg/dL (300 mg/L). (See "Maintenance intravenous fluid therapy in children".)

Alkalemia from a respiratory alkalosis is not a contraindication to sodium bicarbonate therapy. It is common for salicylate-poisoned patients to present with an arterial pH between 7.50 and 7.55; these patients should be treated with sodium bicarbonate. Blood gas analysis every two hours is indicated for monitoring to prevent severe alkalemia (arterial pH >7.55) which may be associated with high mortality from neurologic and cardiac complications [55].

This recommendation for urine alkalinization derives from the following evidence:

●Among 22 adults with moderate salicylate poisoning, the 6 patients who received urinary alkalinization had a significantly greater clearance of salicylates than the 16 patients who only received oral fluids (mean clearance 24 versus 1.4 mL/min, respectively). Patients who received alkalinization also had a significantly reduced half life of elimination for salicylates when compared to controls (mean half-life 9 versus 29 hours) [21].

●In human volunteers, urinary alkalinization increases the amount of salicylic acid excreted in the urine unchanged from 2 to 31 percent and increases its clearance from 1 to 100 mL/minute [22,56]

●In a report describing two separate episodes of severe salicylate poisoning (seizures with salicylate level >69 mg/dL [690 mg/L, 5 mmol/L]) in the same patient, urinary alkalinization alone was given for one episode and hemodialysis alone was performed for the other [57]. When compared to hemodialysis alone, urinary alkalinization was more rapidly performed and resulted in a faster reduction in plasma salicylate concentration during the first four hours of care. Similar salicylate levels were achieved at 24 hours after overdose with both methods of elimination enhancement.

●An abrupt fall in blood pH in patients with salicylate poisoning has resulted in exacerbation of toxicity and death [50]. The mechanism of this sudden deterioration is thought to be related to increased salicylic acid uptake by the tissues, especially the central nervous system, as a result of the increased blood salicylic acid level. (See 'Pharmacokinetics and toxicokinetics' above.)

Thus, urinary alkalinization enhances the excretion and significantly shortens the half-life of salicylates in poisoned patients. This therapy also produces an alkaline environment in the blood which mitigates tissue toxicity. (See 'Pharmacokinetics and toxicokinetics' above.)

Treatments to avoid — Forced diuresis should not be performed. It is less effective than urinary alkalinization in enhancing salicylate elimination and provides no added benefit when used in conjunction with alkalinization [21,56]. In addition, attempts at forced diuresis can cause fluid overload, increasing the risk of pulmonary or cerebral edema, and may make it more difficult to alkalinize the urine [21,56].

Acetazolamide also should not be administered since it produces alkaline urine by causing renal elimination of bicarbonate and a systemic metabolic acidosis that is harmful in patients with salicylate poisoning. (See 'Pharmacokinetics and toxicokinetics' above.)

Hemodialysis — The efficiency of salicylate removal can be enhanced by hemodialysis. It is advisable to consult with the nephrology service early in the patient's course, even in the absence of specific indications for acute hemodialysis. This is because the clinical condition in children with salicylate poisoning can deteriorate rapidly, even if the plasma salicylate concentration is decreasing or near-therapeutic [51].

We recommend hemodialysis in addition to urine alkalinization and multiple dose activated charcoal for patients with salicylate poisoning and any one of the following clinical findings:

●Persistent CNS disturbance (eg, coma, seizures) or persistent focal neurologic signs

●Pulmonary or cerebral edema

●Renal insufficiency that interferes with salicylate excretion

●Intractable acidosis

●Clinical deterioration despite aggressive and appropriate supportive care (eg, worsening metabolic acidosis or the development of respiratory acidosis)

●Plasma salicylate concentration >100 mg/dL (1000 mg/L, 7.2 mmol/L) in the setting of acute ingestion or plasma salicylate concentration >60 mg/dL (600 mg/L, 4.3 mmol/L) in the setting of chronic salicylate poisoning

A common error is for clinicians to not dialyze patients who meet one or more clinical criteria because the plasma salicylate concentration is not available or does not exceed the threshold values listed above [25,51]. However, fatal poisoning despite plasma salicylate levels below these thresholds has been reported. Thus, emergency clinicians and nephrologists managing patients with severe clinical manifestations of salicylate poisoning should not delay hemodialysis if indicated by physical findings.

Salicylates are readily removed by hemodialysis because it has a low-molecular weight and volume of distribution (0.17 L/kg). Although salicylates are highly protein bound at low-plasma levels, at high-plasma levels protein binding falls [51,58]. Clearances up to 86 mL/min can be achieved [59]. Hemodialysis also corrects acid-base and fluid and electrolyte abnormalities, such as metabolic acidosis or hypokalemia typically associated with severe salicylate poisoning.

Case reports and case series document that hemodialysis has resulted in survival despite clinical signs of severe salicylate historically associated with death and also shortens the course of salicylate poisoning [58,60].

Multiple dose activated charcoal — We suggest that children and adolescents with signs of salicylate poisoning (eg, tachypnea, anion gap acidosis, altered mental status) or asymptomatic patients who have ingested a large number of aspirin receive multiple dose activated charcoal (MDAC). The initial dose is 1 g/kg (maximum dose 50 g) with sorbitol followed by 0.5 g/kg (maximum dose 50 g) every four hours without sorbitol until clinical symptoms have resolved and the plasma salicylate concentration is <40 mg/dL. Only the first dose of activated charcoal should be given with sorbitol; multiple doses of sorbitol may produce profound dehydration and life-threatening hypernatremia, especially in infants and young children. (See "Enhanced elimination of poisons", section on 'Multiple-dose activated charcoal'.)

The potential benefit of MDAC for patients with salicylate poisoning derives primarily from its potential ability to prevent ongoing absorption of retained aspirin concretions or enteric coated tablets.

MDAC also has been shown to enhance the elimination of salicylates in two small randomized crossover adult volunteer studies and in one observational study of poisoned adults [61-63]. However, the effect of MDAC in all studies was modest and deemed not clinically significant in one study [63]. Another randomized crossover study of nine poisoned adults found that MDAC did not enhance salicylate clearance when compared to controls [64].

MDAC was shown not to decrease salicylate levels after intravenous aspirin administration in a porcine model [65]. Thus, intestinal dialysis does not appear to play a role in its elimination enhancement of salicylates.

Laboratory monitoring — Salicylate-poisoned patients require frequent laboratory monitoring to assess both clinical status and response to therapy. A salicylate level and blood gas should be drawn every two hours until both the plasma salicylate level is falling and the acid-base status is stable or improving for at least two consecutive readings. Patients receiving urinary alkalinization warrant hourly measurements of blood pH, urine pH, and serum potassium.

Mental health referral — Once they are medically stable, patients who have ingested salicylate intentionally should be referred to a mental health professional. (See "Suicidal behavior in children and adolescents: Epidemiology and risk factors".)

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

●A rapid overview provides key information regarding the diagnosis and treatment of salicylate poisoning (table 1). Children and adolescents with significant salicylate toxicity should be managed in consultation with a medical toxicologist or advice from a regional Poison Control Center (1-800-222-1222) (see 'Additional resources' above). In addition, it is advisable to consult with the nephrology service early in a patient's course, even in the absence of indications for acute hemodialysis.

●Salicylate poisoning in children and adolescents presents with tachypnea, hyperpnea, tinnitus, and unexplained increase in the anion gap and typically follows an acute ingestion. It may also occur as a chronic intoxication or acute on chronic overdose in children who are on aspirin therapy (eg, those with Kawasaki disease). (See 'Clinical manifestations' above.)

●Plasma salicylate concentrations should be measured in all patients in whom salicylate intoxication is suspected, and remeasured every two hours in patients in whom salicylate intoxication is documented. The units of the reported value should be checked carefully since some laboratories report salicylate levels as mg/L, rather than mg/dL. (See 'Plasma salicylate' above.)

●There is no absolute correlation between the plasma salicylate concentration and symptoms; life-threatening complications of salicylate intoxication may occur when plasma concentrations are decreasing or near-therapeutic. Thus, plasma salicylate concentrations must be interpreted in conjunction with the clinical status of the patient. Nonetheless, plasma salicylate concentrations >100 mg/dL (7.2 mmol/L) in acute intoxication and >60 mg/dL (4.3 mmol/L) in chronic intoxication are indications for hemodialysis. (See 'Plasma salicylate' above and 'Hemodialysis' above.)

●Intubation of the salicylate-poisoned patient is dangerous and should be avoided if possible. However, oxygen should be administered as necessary. (See 'Airway' above.)

●Intravenous fluids should be administered as needed to replace insensible fluid losses. The fluid should contain dextrose, since salicylate intoxication may decrease central nervous system (CNS) glucose levels despite a normal peripheral glucose level. Intravenous repletion of renal potassium losses should be provided based upon serum potassium measurements. (See 'Circulation' above and 'Supplemental glucose' above.)

●We recommend that children and adolescents with an acute salicylate overdose receive gastrointestinal decontamination with activated charcoal (AC, 1 g/kg; maximum single dose: 50 g) (Grade 1B). AC should be withheld in patients who have altered mental status and may not be able to protect their airway, unless endotracheal intubation is performed first. (See 'Gastrointestinal decontamination' above.)

●We recommend not performing gastric emptying by gastric lavage or by syrup of ipecac-induced emesis in patients who ingest salicylates (Grade 1B). (See 'Gastrointestinal decontamination' above.)

●We recommend that children and adolescents with salicylate poisoning and clinical findings of toxicity receive urine alkalinization in addition to activated charcoal and supportive care (Grade 1B). The goal of this therapy is to achieve a urine pH of >7.5 while maintaining a serum pH no higher than 7.55. Sodium bicarbonate infusion should continue until the plasma salicylate concentration is <30 to 40 mg/dL (300 to 400 mg/L, 2.2 to 2.9 mmol/L) and symptoms have resolved. (See 'Urine alkalinization' above.)

●Alkalemia from a respiratory alkalosis is not a contraindication to sodium bicarbonate therapy. However, arterial blood gas measurements should be obtained every two hours (along with the plasma salicylate concentration) to prevent severe alkalemia (arterial pH >7.55). In addition, worsening metabolic acidosis or respiratory acidosis despite appropriate therapy are indications for hemodialysis. (See 'Urine alkalinization' above.)

●We suggest that children and adolescents with signs of salicylate poisoning (eg, tachypnea, anion gap acidosis, altered mental status) or who have ingested a large number of aspirin receive multiple dose activated charcoal (MDAC) (Grade 2C). Multiple-dose activated charcoal should be continued until the plasma salicylate concentration is <30 to 40 mg/dL (300 to 400 mg/L, 2.2 to 2.9 mmol/L) and symptoms have resolved. (See 'Multiple dose activated charcoal' above.)

●We recommend hemodialysis in addition to urine alkalinization and multiple dose activated charcoal for patients with salicylate poisoning and any one of the following clinical findings (Grade 1B) (see 'Hemodialysis' above):

•Persistent CNS disturbance (eg, coma, seizures) or persistent focal neurologic signs

•Pulmonary or cerebral edema

•Renal insufficiency that interferes with salicylate excretion

•Intractable acidosis

•Clinical deterioration despite aggressive and appropriate supportive care (eg, worsening metabolic acidosis or the development of respiratory acidosis)

•Plasma salicylate concentration >100 mg/dL (1000 mg/L, 7.2 mmol/L) in the setting of acute ingestion or plasma salicylate concentration >60 mg/dL (600 mg/L, 4.3 mmol/L) in the setting of chronic salicylate poisoning