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 .
This topic will discuss the clinical manifestation and evaluation of salicylate overdose and toxicity in children and adults. A rapid overview table to facilitate emergency management is provided (table 1). The management of salicylate poisoning is discussed separately. (See "Salicylate (aspirin) poisoning: Management".)
General management of the poisoned patient and adverse effects of aspirin in therapeutic dosing are discussed separately:
EPIDEMIOLOGY — Approximately 20,000 salicylate exposures and 50 to 70 fatalities are reported annually to United States regional poison control centers [2-5]. Of these, approximately 4000 are children 12 years of age and younger. Pediatric therapeutic salicylate use and toxic exposure has declined since the 1980s once the association with Reye syndrome was recognized . Serious poisoning from unintentional salicylate ingestions in toddlers has also declined with the limitation in dose and number of tablets per bottle of the flavored chewable formulation and the expanded use of child-resistant packaging [6-8]. Deaths from exploratory salicylate overdose in children are rare.
Formulations and sources of salicylates — Sources of salicylate include the following:
●Aspirin – Acetylsalicylic acid (ie, aspirin) is rapidly converted in vivo to salicylic acid. Aspirin is available in chewable tablets, regular tablets and capsules, effervescent tablets, delayed-release formulations, and enteric-coated formulations.
●Methyl salicylate – Used as a flavoring agent and a common ingredient in liniments and ointments for musculoskeletal pain [9,10]. Methyl salicylate can be found in massage oils used within the ethnic Asian community (eg, Red Oil Chinese) . Oil of wintergreen contains 98 to 100% methyl salicylate; one teaspoon (5 mL) is equivalent to approximately 7 g of salicylate or 22 adult aspirin tablets. Ingestion of just 4 mL can be fatal in a child . The methyl salicylate concentration and the bioavailability of salicylate in creams vary by preparation [9,12].
●Bismuth subsalicylate – This is a common ingredient in over-the-counter antidiarrheal agents (eg, Pepto-Bismol, Kaopectate). Bismuth subsalicylate contains 8.7 mg of salicylate per 1 mL, and taking large quantities can cause acute or chronic toxicity, particularly in infants [13,14].
●Magnesium salicylate – This can be found in over-the-counter nonsteroidal antiinflammatory drugs (NSAIDs; eg, Doan's) and some "water pills" (eg, a Diurex formulation). Overdose has been reported to cause salicylate toxicity .
●Salicylic acid – Used as a topical keratolytic agent and wart remover.
Pharmacokinetics and toxicokinetics
●Absorption – In therapeutic dosing, aspirin is rapidly absorbed from the jejunum and, to a lesser extent, from the stomach and duodenum [16,17]. The formulation affects the timing of absorption [18-20]. Peak blood concentrations are usually reached within one hour with regular tablets or capsules but are delayed with enteric-coated or delayed-release formulations .
Absorption is drastically altered following overdose. Peak concentrations are frequently delayed due to pylorospasm or concretion (ie, bezoar) formation. Peak concentrations following ingestion of delayed-release or enteric-coated formulations occur between 4 and 14 hours, and in one extreme case, did not occur until 35 hours following ingestion [18-20,22].
Salicylates are absorbed through the skin but rarely reach toxic concentrations . However, excessive topical application of various salicylates (eg, salicylic acid, methyl salicylate) can rarely result in toxicity.
●Distribution – Toxicity increases when salicylate distributes from the intravascular compartment into vulnerable tissue, such as the central nervous system (CNS). Mortality correlates closely with CNS salicylate concentration, not the serum concentration [24,25]. Protein binding and blood alkalinity limit distribution out of the intravascular compartment.
At therapeutic concentrations, 90 percent of salicylate is protein bound (primarily to albumin) and remains in the intravascular compartment. In overdose, protein binding becomes saturated, and the free-fraction of salicylate that can leave the intravascular compartment increases .
Blood alkalinity affects distribution into vulnerable tissue. Salicylic acid is a weak acid (pKa = 3.0) that exists in an equilibrium between charged (deprotonated, salicylate, Sal-) and uncharged (protonated, salicylic acid, HSal) forms:
H+ + Sal- <—> HSal
Uncharged, lipid-soluble molecules (eg, HSal), unlike charged molecules (eg, Sal-), easily diffuse across cell membranes such as the blood-brain barrier and the renal tubular epithelium. At the normal extracellular pH of 7.40, the ratio of Sal- to HSal is about 25,000:1; thus, only 0.004 percent of the total extracellular salicylate exists in the protonated form. The plasma and tissue HSal concentrations are in a diffusion equilibrium, but not the ionized Sal- concentration, which poorly crosses membranes.
Metabolic acidosis exacerbates toxicity by driving the above reaction to the right, increasing the plasma concentration of HSal and promoting diffusion into tissues, such as the CNS. More HSal is also reabsorbed into the systemic circulation from the renal collecting system. In patients with salicylate toxicity, an abrupt decrease in blood pH can be fatal .
●Metabolism – Aspirin and methyl salicylate are rapidly hydrolyzed to salicylic acid. In therapeutic dosing, salicylate metabolism follows first-order kinetics with a half-life of two to four hours. Salicylate is metabolized via hepatic glucuronidation, oxidation, and glycine conjugation. The major metabolite, salicyluric acid, is both less toxic and more rapidly excreted than salicylate.
At increasing concentrations, hepatic detoxification enzyme systems become saturated, and metabolism transitions to zero-order kinetics [26,28]. The rate of salicylate metabolism is greatly decreased (may be up to 30 hours), and elimination becomes dependent upon slower renal excretion . In addition, when metabolic enzymes are saturated (eg, chronic daily therapy), a greater-than-expected increase in serum and tissue concentration can occur even with a small change in dose .
●Elimination – The kidneys excrete salicyluric acid and other metabolites. Only a small amount of salicylate is excreted unchanged in the urine. 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. Alkaline urine limits back-diffusion of secreted salicylic acid out of the tubular lumen, thus increasing salicylate excretion . (See "Salicylate (aspirin) poisoning: Management", section on 'Serum and urine alkalinization'.)
Toxic doses — An adult ingesting 10 to 30 g aspirin or a child ingesting as little as 3 g is potentially lethal. The ingested dose, to some extent, determines the clinical manifestations of salicylate toxicity . In general, the aspirin dose ingested produces the following severity of toxicity:
●<150 mg/kg: No symptoms or minimal symptoms
●150 to 300 mg/kg: Mild to moderate toxicity
●301 to 500 mg/kg: Severe toxicity
●>500 mg/kg: Potentially lethal
Mechanism of toxicity — Salicylate causes toxicity via multiple cellular and systemic mechanisms [24,31-33]:
●Interferes with cellular metabolism (eg, inhibition of tricarboxylic acid cycle, uncoupling of oxidative phosphorylation), leading to metabolic acidosis, hyperthermia, and fluid losses. (See "Energy metabolism in muscle", section on 'Anaerobic glycolysis' and "Energy metabolism in muscle", section on 'Oxidative phosphorylation' and "Causes of lactic acidosis", section on 'Pathophysiology'.)
●Depletes glycogen stores and impairs gluconeogenesis, resulting in hypoglycemia and neuroglycopenia.
●Causes a catabolic state, resulting in accumulation of organic acids and ketoacids.
●Activates the respiratory center of the medulla, causing tachypnea, hyperventilation, respiratory alkalosis, increased renal elimination of HCO3, and increased insensible fluid loss.
●Stimulates the chemoreceptor trigger zone in the medulla, causing nausea and vomiting.
●Inhibits cyclooxygenase, thus decreasing synthesis of prostaglandins, prostacyclin, and thromboxanes; contributing to platelet dysfunction and gastric mucosal injury.
●Directly irritates the gastric mucosa, causing gastric ulcers and gastrointestinal hemorrhage.
●Directly effects cochlear hair cells and the eighth nerve afferent fibers, causing tinnitus and hearing changes.
●Completely inactivates CNS cardiorespiratory centers in the setting of severe toxicity.
The mechanism of action of aspirin in therapeutic dosing is discussed separately. (See "Aspirin: Mechanism of action, major toxicities, and use in rheumatic diseases", section on 'Mechanism of action'.)
Clinical course — Early symptoms of acute salicylate toxicity include tinnitus, nausea, and vomiting; subsequent symptoms portending more significant intoxication include tachypnea, hyperpnea, hyperthermia, diaphoresis, altered mental status (ranging from agitation to lethargy), noncardiac pulmonary edema, seizures, and coma. Early symptoms are typically present within one to two hours after a single acute ingestion, but various factors can affect symptom onset, such as multiple aspirin ingestions separated in time, ingestion of enteric-coated preparations, and co-ingestants. Therefore, neither the diagnosis of salicylate toxicity nor an estimation of overdose severity should be based upon the timing of symptoms and signs (table 2). (See "Salicylate (aspirin) poisoning: Management", section on 'Assess severity of toxicity'.)
Hyperthermia, hyperpnea, and tachycardia
●Tachypnea and hyperpnea – Salicylate toxicity characteristically increases the rate and depth of breathing, causing a dramatic rise in minute ventilation. Recognizing this unique respiratory pattern of tachypnea and profound increased tidal volumes raises suspicion for salicylate toxicity and can help establish the diagnosis.
●Hyperthermia – The uncoupling of mitochondrial oxidative phosphorylation generates heat manifested as increased body temperature and diaphoresis. Hypovolemia further limits heat dissipation. However, normothermia does not exclude the diagnosis of salicylate toxicity since hyperthermia is a later finding.
●Tachycardia – The uncoupling of oxidative phosphorylation, fluid losses, agitation, and general distress causes sinus tachycardia.
Tinnitus — This is an early and characteristic symptom that can occur at even therapeutic concentrations (15 to 30 mg/dL [1.1 to 2.2 mmol/L]). Specifically inquire about the presence of tinnitus and any hearing changes since a patient may not equate these with toxicity. Less common auditory toxicity includes alterations in the perception of sound and hearing loss, which are typically transient .
Vomiting and fluid/electrolyte losses
●Nausea and vomiting – These are early and common signs of salicylate toxicity. Vomiting can be severe and result in significant volume loss.
●Other gastrointestinal manifestations – Salicylate causes pylorospasm and delayed gastric emptying . Gastrointestinal bleeding, including hemorrhagic gastritis, blood-tinged vomitus, and frank hematemesis, occurs in 4 percent of patients admitted with salicylate toxicity . Older patients and those with cirrhosis are more likely to have gastrointestinal bleeding. Gastric ulcers are commonly found in autopsies of salicylate poisoning fatalities .
●Fluid losses – Severe salicylate toxicity causes fluid losses of up to 4 to 6 L/m2. In addition to vomiting, insensible losses arise from the elevated metabolic rate (ie, hyperthermia, diaphoresis, uncoupling of oxidative phosphorylation), hyperpnea and associated evaporative losses, and osmotic diuresis (due to organic aciduria and solute excretion) .
●Electrolyte losses – Salicylate toxicity can cause hyponatremia, hypernatremia, hypokalemia, or hypomagnesemia. Sweating contributes to sodium loss. Vomiting contributes to the loss of chloride, potassium, sodium, and bicarbonate. Hypernatremia can occur if free water loss exceeds sodium loss.
During the early stages of salicylate toxicity, the kidneys respond to the respiratory alkalosis by increasing bicarbonate excretion, which is accompanied by increased sodium and potassium excretion. As toxicity progresses and potassium is further depleted, the kidneys attempt to conserve potassium, producing a paradoxically acidic urine .
Acid-base derangements — Salicylate toxicity most commonly causes a respiratory alkalosis or a mixed respiratory alkalosis-metabolic acidosis, but other derangements can also occur. The onset of metabolic derangements depends upon the amount and formulation of ingested salicylate, whether the ingestion is acute or chronic, the presence of co-ingestants, and whether pylorospasm or bezoar formation has occurred. Tools for assessing acid-base disorders are found in the following tables and topics (figure 1 and figure 2). (See "Simple and mixed acid-base disorders" and "Approach to the adult with metabolic acidosis".)
●Respiratory alkalosis – Salicylate directly stimulates the respiratory center, causing hyperventilation and an early decrease in the partial pressure of carbon dioxide (PaCO2) [24,38,39]. The hyperventilation protects against toxicity since alkalosis prevents salicylate distribution into the central nervous system (CNS).
●Elevated anion gap metabolic acidosis – Accumulation of organic acids, including lactic acid (from uncoupling of oxidative phosphorylation) and ketoacids (from increased catabolism), cause an elevated anion gap metabolic acidosis [39,40]. Inhibition of the tricarboxylic acid cycle also contributes to the development of metabolic acidosis [41,42]. Salicylic acid itself has only a minor impact on serum pH, since a serum concentration of 50 mg/dL (3.6 mmol/L) contributes less than 3 mEq/L of hydrogen ions. A pure metabolic acidosis is unusual in adults  but may be seen in children who are brought to medical care immediately after ingestion .
●Mixed respiratory alkalosis metabolic acidosis – Most adults develop a mixed respiratory alkalosis metabolic acidosis as the net effects of these acid-base derangements.
●Respiratory acidosis – An acute respiratory acidosis is rare in the early stages but may develop in the later stages of profound toxicity. Respiratory acidosis that occurs early in the course of salicylate toxicity suggests co-ingestion of a respiratory depressant. Approximately one-third of adults with intentional aspirin overdoses also ingest one or more other medications, many of which are respiratory depressants . Children are more likely to lose respiratory drive from salicylate toxicity and develop a respiratory acidosis. (See 'Pediatrics' below.)
Altered mental status — CNS toxicity can cause alterations in mental status such as agitation, confusion, restlessness, seizures, and rarely, coma. The presence of CNS toxicity defines severe poisoning and is an indication for hemodialysis, regardless of the serum salicylate concentration. CNS toxicity can occur in the setting of falling or near-therapeutic serum salicylate concentrations .
Salicylate toxicity produces alterations in mental status via three major mechanisms: direct CNS toxicity, neuroglycopenia, and cerebral edema [36,44]. A progressively worsening acidosis exacerbates CNS toxicity by promoting influx of salicylic acid into the CNS. Neuroglycopenia can occur despite normal serum glucose, likely because CNS utilization from increased cerebral glycolysis outpaces the glucose supply available from the blood . Seizures can occur, likely from direct salicylate toxicity or neuroglycopenia, and are typically a preterminal event if not promptly treated.
Pulmonary edema — Noncardiogenic pulmonary edema and acute lung injury are signs of severe poisoning and occur more frequently in older patients with chronic toxicity [46-49]. Pulmonary edema is an indication for hemodialysis because it limits administration of volume and sodium bicarbonate. Hypoxemia and crackles are suggestive clinical findings . The likely mechanism is salicylate-induced increase in fluid and protein permeability in the pulmonary vascular bed . Pulmonary edema can occur in the setting of falling or near-therapeutic serum salicylate concentrations .
●Altered glucose metabolism – Early in the course of toxicity, glycogenolysis, stimulation of gluconeogenesis, and decreased peripheral utilization of glucose cause hyperglycemia. At this stage, urine ketones may be positive . As glucose stores are depleted, impaired gluconeogenesis and increased utilization can cause hypoglycemia [52-54].
●Dysrhythmia – Sinus tachycardia is the most common dysrhythmia. Ventricular dysrhythmias have been described but are typically preterminal events. Fluid and electrolyte shifts (eg, hypokalemia, hypocalcemia, and hypomagnesemia) are the most common cause, although salicylate can directly alter the membrane permeability of cardiac myocytes .
●Hematologic – Leukocytosis, inhibition of platelet function and adhesion, thrombocytopenia, capillary fragility, and disturbances in vitamin K-dependent and vitamin K-independent clotting factors can occur [49,56,57]. The prothrombin time (PT) and international normalized ratio (INR) can be elevated. These abnormalities are usually clinically insignificant, but bruising or large-volume hemorrhage can seldom occur [36,58].
●Vascular – Salicylate toxicity can cause inappropriate systemic vasodilation and distributive shock physiology similar to the systemic inflammatory response syndrome [47,49]. The pathogenesis is unclear but likely due to dysregulated inflammation.
●Hepatic – Acute liver injury, which is typically reversible, and hepatitis have been described in adults . Hepatic effects can contribute to decreased glycogen stores and increased lactate production.
DIFFERENTIAL DIAGNOSIS — Because salicylism can mimic several other disorders, a key step in the differential diagnosis is to measure a serum salicylate concentration in any patient with a metabolic acidosis without a clear etiology, even with a normal anion gap . Salicylate toxicity classically increases the anion gap (calculator 1), but there are case reports of patients with an artifactually normal anion gap due to interference on some analyzers reporting a falsely elevated chloride concentration .
●Diabetic ketoacidosis (DKA) presents with nausea, vomiting, lethargy, hypovolemia, hyperglycemia, and metabolic acidosis. The clinical history (eg, polydipsia, polyuria) combined with hyperglycemia, ketonuria, ketonemia, and a high anion gap metabolic acidosis is highly suggestive of DKA. Salicylism does not cause significant hyperglycemia and is more likely to cause hypoglycemia. Euglycemic DKA (plasma glucose <250 mg/dL [<13.8 mmol/L]), such as described with sodium-glucose co-transporter 2 inhibitors (eg, canagliflozin), could be easily confused with salicylism. Measure a serum salicylate concentration when the distinction cannot be made clinically. (See "Diabetic ketoacidosis in children: Clinical features and diagnosis" and "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis" and "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Diabetic ketoacidosis'.)
●Sepsis, pneumonia, or the systemic inflammatory response syndrome can cause hyperthermia, metabolic acidosis, tachypnea, hypoglycemia, hypovolemia, leukocytosis, and clotting abnormalities [47,49,62]. Salicylate-induced noncardiogenic pulmonary edema can be confused with a pulmonary infection. Measure a serum salicylate concentration in a patient who clinically appears septic with an acidosis, but a source of infection is not readily apparent. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis" and "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis" and "Noncardiogenic pulmonary edema".)
●Acute iron intoxication can cause metabolic acidosis, vomiting, leukocytosis, hemoconcentration, elevated transaminases, prolonged prothrombin time (PT), and hyperglycemia. Compared with salicylism, iron intoxication is more likely to cause bloody vomiting and delayed (ie, 6 to 24 hours) development of acidosis and can be differentiated by measuring a serum iron concentration. (See "Acute iron poisoning".)
●Other causes of metabolic acidosis (eg, ethylene glycol poisoning) can mimic salicylism and are presented in the tables (table 3 and table 4). These can often be differentiated by history, serum salicylate concentration, and serum osmolality (eg, toxic alcohol poisoning). (See "Approach to the adult with metabolic acidosis" and "Approach to the child with metabolic acidosis" and "Methanol and ethylene glycol poisoning: Pharmacology, clinical manifestations, and diagnosis".)
●In children, ethanol intoxication can cause metabolic acidosis with increased anion gap, elevated lactate, hypoglycemia, and neurologic symptoms. Measuring a serum ethanol concentration confirms or excludes ethanol intoxication. (See "Causes of hypoglycemia in infants and children", section on 'Ingestions'.)
EVALUATION AND DIAGNOSTIC TESTING
History and examination — In a patient with possible salicylate toxicity, inquire regarding the details of the ingestion or salicylate use, such as the following:
●How much aspirin was ingested (including the dose per tablet and number of tablets per container)? Was the ingestion intentional or accidental?
●Was the patient taking aspirin on a regular basis?
●If the patient was not taking aspirin, could they have been taking another source of salicylate such as Pepto-Bismol, Kaopectate, Doan's, or oil of wintergreen? (See 'Formulations and sources of salicylates' above.)
●Does the patient have symptoms attributable to salicylate toxicity (eg, hyperthermia, tinnitus, hearing loss, nausea, vomiting, trouble breathing, agitation, confusion, restlessness)? (See 'Clinical manifestations' above.)
The physical examination provides an early clue regarding the diagnosis and severity of toxicity. Assess respirations, focusing on the respiratory rate, depth of respirations, and signs of pulmonary edema (eg, hypoxemia, crackles). Examine the skin for diaphoresis and signs of hypovolemia (eg, decreased turgor, cool extremities). Thoroughly evaluate mental status since agitation and restlessness can be early signs of severe toxicity. Frequently reassess vital signs and mental status.
●Serum salicylate concentration
●Serum electrolytes, magnesium, and glucose
●Serum creatinine and blood urea nitrogen
●Arterial or venous blood gas
●Urinalysis and urine pH
●Complete blood count
●Coagulation studies (prothrombin time [PT] and partial thromboplastin time [PTT])
●Pregnancy test in females of childbearing age
Serum salicylate concentration — Measure a serum salicylate concentration in any patient with suspected salicylate toxicity (eg, reported ingestion, characteristic signs and symptoms, metabolic acidosis). Interpret the result in conjunction with the signs, symptoms, and acid-base status since the severity of clinical toxicity does not correlate exactly with serum salicylate concentration [24,63,64]. (See "Salicylate (aspirin) poisoning: Management", section on 'Assess severity of toxicity'.)
●Toxic concentration – Most patients exhibit signs of toxicity when the serum salicylate concentration exceeds 30 to 50 mg/dL (2.2 to 3.6 mmol/L). Therapeutic anti-inflammatory serum salicylate concentrations are 15 to 30 mg/dL (1.1 to 2.2 mmol/L) .
●Role of measuring serial concentrations – Measure a repeat serum salicylate concentration every two to four hours (depending on the patient's clinical status) to evaluate for possible prolonged or delayed absorption, to account for tissue distribution, to help assess the response to therapy, and to determine the need for more aggressive measures. Timing of laboratory monitoring is discussed below. (See "Salicylate (aspirin) poisoning: Management", section on 'Frequent laboratory monitoring'.)
The serum concentration often lags behind any change in the patient's clinical status by hours, which results from a change in the tissue concentration. The serum concentration will not accurately reflect clinical status until it has time to equilibrate with the tissue concentration.
Life-threatening complications of salicylate toxicity can occur with decreasing or near-therapeutic serum concentrations. A decreasing concentration in a patient with progressively worsening clinical manifestations of salicylism (eg, worsening acidosis or lethargy) indicates increased tissue distribution and more severe disease rather than increased elimination.
The serum concentration might not begin to rise until five or six hours after ingestion. (See 'Pharmacokinetics and toxicokinetics' above.)
●Asymptomatic patient with a very elevated concentration – Laboratory issues are often responsible for a surprisingly elevated (eg, >100 mg/dL [>7.2 mmol/L]) salicylate concentration in a patient without signs or symptoms attributable to salicylate toxicity. Some laboratories report salicylate concentrations using mg/L units; such values are therefore tenfold higher than those discussed in this topic. Thus, a laboratory report of "an aspirin level of 110" in an asymptomatic individual should prompt the clinician to check the reported units. Also, hyperlipidemia can interfere with the spectrophotometric measurement and spuriously elevate the salicylate concentration . In the presence of lipemia, most laboratories will use a lipemia clearing agent or ultracentrifugation prior to measuring the concentration of salicylate as well as many other analytes. Erroneous salicylate concentration measurements can also occur in patients taking structurally related medications such as diflunisal.
●Done nomogram – This nomogram is no longer used clinically. The Done nomogram was developed to predict the severity of toxicity based on the serum salicylate concentration and time elapsed after ingestion . However, subsequent studies found it has inadequate accuracy, likely because of delayed absorption kinetics of enteric-coated aspirin .
Role of imaging studies and other tests — Obtain the following studies based upon the patient's clinical status, but do not delay important treatment interventions (eg, hemodialysis) to obtain further studies:
●Obtain an electrocardiogram in any potentially critically ill patient or when there is concern for electrolyte abnormalities, which is common in salicylate toxicity.
●Perform a plain chest radiograph if there are clinical signs of pulmonary edema (eg, hypoxemia, rales).
●Perform a computed tomography scan of the brain in a patient with altered mental status or focal neurological deficits that are not clearly attributable to a noncerebral cause (eg, hypoglycemia).
DIAGNOSIS — The diagnosis of salicylate toxicity is suspected from a history of an ingestion or characteristic signs, symptoms, and acid-base findings (eg, vomiting, tinnitus, hyperpnea, tachypnea, respiratory alkalosis, elevated anion gap metabolic acidosis). The diagnosis is confirmed by a supratherapeutic serum salicylate concentration (ie, >30 mg/dL [>2.2 mmol/L]). (See 'Clinical manifestations' above.)
●Changes in serum salicylate concentration lag behind clinical signs – Since the elevation in serum salicylate concentration can lag behind the development of clinical signs by hours, do not exclude the diagnosis in a patient with clinical salicylism (eg, history of ingestion with classic signs). Instead, start treatment based on clinical signs and acid-base status with the expectation that the serum concentration will increase on serial laboratory measurements. (See "Salicylate (aspirin) poisoning: Management", section on 'Assess severity of toxicity'.)
●Acute versus chronic toxicity – Once salicylate toxicity has been diagnosed, determine whether it is acute toxicity (ie, single overdose) or chronic toxicity (ie, daily supratherapeutic dosing). The management of chronic salicylate toxicity does not differ significantly from acute overdose, but the threshold concentration for dialysis is lower . Chronic toxicity generally occurs in young children (<6 years old) or older adults from excessive therapeutic use of products containing a salicylate [69,70].
Chronic salicylate toxicity can be difficult to diagnose in the absence of a clear history of ingestion or use. Clinical findings in chronic and acute salicylate toxicity overlap. However, as compared with acute toxicity, symptoms in chronic toxicity can be milder, often go unrecognized or attributed to another condition, and occur at lower serum salicylate concentrations. Many of the signs and symptoms of salicylate toxicity are often attributed to the ailment that was being treated with the salicylate. Some patients with chronic toxicity may even have a salicylate concentration within the therapeutic range.
The general pharmacokinetic principle of chronic toxicity is a steady state of saturated tissue burden during which any extra salicylate distributes into vulnerable tissue. Conversely, in acute or early toxicity, the tissue burden is low and extra salicylate can distribute into less vulnerable tissue compartments .
●Impact of diagnostic delay – Mortality increases with diagnostic delay, which is more likely to occur in older adults, young children (<6 years old), patients without a previous history of drug overdose, and patients who accidentally develop toxicity from therapeutic salicylate use [72,73].
●Assess severity of toxicity – In addition to diagnosing salicylate toxicity, it is important to assess the severity of toxicity, which can change over time, since that determines treatment (table 2). (See "Salicylate (aspirin) poisoning: Management", section on 'Assess severity of toxicity'.)
Pediatrics — Chronic toxicity is uncommon in children, since therapeutic pediatric aspirin use declined once the association with Reye syndrome was recognized. In general, children and adults with salicylate toxicity are managed similarly. However, in a neonate or very young child, salicylate can be eliminated with an exchange transfusion if dialysis is not available or feasible.
The clinical manifestations and evaluation of salicylate toxicity in children and adults vary slightly:
●Compared with adults, recognizing the clinical picture of salicylate toxicity can be more challenging in children because tachypnea and irritability are common and often normal for age. A child with elevated temperature, tachypnea, tachycardia, and vomiting can easily be misdiagnosed as having a viral syndrome.
●Compared with acute pediatric ingestions, chronic salicylate toxicity in children is usually more serious and presents with more severe clinical manifestations at the equivalent salicylate concentration [69,74].
●Salicylate-induced noncardiogenic pulmonary edema is less common in children compared with adults but is an ominous finding when it does occur [46,75]. In a study of 20 cases of pediatric salicylate toxicity, the two children who developed pulmonary edema died, while there were no deaths among the 18 without pulmonary edema .
●Children with salicylate toxicity are more likely to lose their respiratory drive and more likely to present with mixed metabolic and respiratory acidosis [31,38]. Children are also more likely to develop a pure metabolic acidosis as compared with adults .
●Central nervous system (CNS) toxicity is more common among children younger than five years of age compared with older children and adults [38,69]. Seizures are more common among children with chronic ingestions and severe metabolic acidosis than among children with acute ingestions .
●Children are better able to tolerate hyperthermia compared with adults .
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
●Pharmacology – Aspirin (acetylsalicylic acid) is rapidly converted in vivo to salicylic acid. Overdose drastically alters absorption, and peak concentrations are frequently delayed due to pylorospasm or concretion (ie, bezoar) formation. Acidosis exacerbates toxicity by increasing salicylate diffusion into vulnerable tissue and decreasing renal elimination. Mortality correlates closely with central nervous system (CNS) salicylate concentration, not the serum concentration. (See 'Pharmacology' above.)
●Clinical manifestations – Early clinical features of salicylate toxicity include tinnitus, vomiting, tachypnea, and hyperpnea. As toxicity progresses, manifestations include tachycardia, hyperthermia, diaphoresis, significant fluid and electrolyte losses, acid-base disturbances, altered mental status (eg, agitation, confusion, restlessness, seizures, coma), noncardiac pulmonary edema, cerebral edema, and death. Hypoglycemia can occur, and neuroglycopenia may occur despite a normal serum glucose. (See 'Clinical manifestations' above.)
●Acid-base derangements – Most adults have either a respiratory alkalosis or a mixed respiratory alkalosis-metabolic acidosis. Accumulation of organic acids and inhibition of the tricarboxylic acid cycle causes an elevated anion gap metabolic acidosis. An acute respiratory acidosis may develop in the later stages of profound toxicity or from co-ingestion of a respiratory depressant. (See 'Acid-base derangements' above.)
●Differential diagnosis – In cases of occult exposure or chronic salicylate toxicity, when the history of salicylate ingestion is unknown, salicylism can mimic conditions such as diabetic ketoacidosis, sepsis, iron intoxication, pediatric ethanol intoxication, and other etiologies of metabolic acidosis (eg, ethylene glycol ingestion) (table 3 and table 4). Chronic salicylate toxicity is often misdiagnosed since many of the signs and symptoms may be attributed to the ailment that was being treated with the salicylate. (See 'Differential diagnosis' above.)
●Evaluation and diagnostic testing – A rapid overview table for the evaluation of salicylate toxicity is provided (table 1). Enquire regarding the details of the ingestion or salicylate use. The physical examination provides an early clue regarding the diagnosis and severity of toxicity. (See 'History and examination' above.)
Measure a serum salicylate concentration when salicylate toxicity is suspected and in any patient with a metabolic acidosis without a clear etiology.
Obtain the following additional tests: serum electrolytes, magnesium, glucose, creatinine, blood urea nitrogen, lactate, and acetaminophen concentration; arterial or venous blood gas; urinalysis and urine pH; complete blood count; coagulation studies; liver enzymes; pregnancy test in females of childbearing age; and an electrocardiogram. Obtain a plain chest radiograph if there are signs of pulmonary edema and a computed tomography scan of the brain if there is altered mental status or focal neurological deficits that are not clearly attributable to a noncerebral cause (eg, hypoglycemia). (See 'Laboratory studies' above and 'Role of imaging studies and other tests' above.)
●Serum salicylate concentration – The serum concentration does not exactly correlate with the severity of toxicity. Therapeutic anti-inflammatory serum salicylate concentrations are between 15 and 30 mg/dL (1.1 to 2.2 mmol/L). Most patients exhibit signs of toxicity when the serum concentration exceeds 30 to 50 mg/dL (2.2 to 3.6 mmol/L). Remeasure the concentration every two to four hours in a patient with confirmed salicylate toxicity. (See 'Serum salicylate concentration' above.)
●Diagnosis – The diagnosis of salicylate toxicity is suspected from a history of ingestion and characteristic signs, symptoms, and acid-base findings (eg, vomiting, tinnitus, hyperpnea, tachypnea, respiratory alkalosis, elevated anion gap metabolic acidosis). The diagnosis is confirmed by measuring a supratherapeutic serum salicylate concentration (ie, >30 mg/dL [2.2 mmol/L]). (See 'Diagnosis' above.)
Since the elevation in serum salicylate concentration can lag behind the development of clinical symptoms by hours, do not exclude the diagnosis in a patient with clinical salicylism but a nontoxic serum concentration. Determine whether the patient has acute toxicity (ie, single overdose) or chronic toxicity (ie, daily supratherapeutic dosing), especially since hemodialysis is recommended at a lower salicylate concentration threshold in chronic toxicity. It is also important to assess the severity of toxicity, which helps determines treatment (table 2).
●Pediatric considerations – In general, children with salicylate toxicity are managed similarly to adults. In a neonate or very young child, salicylate can be eliminated with an exchange transfusion if dialysis is not available or feasible. Compared with adults, children are more likely to mask salicylate toxicity because tachypnea and irritability are common and often normal for age. Children are more likely to lose respiratory drive from salicylate toxicity and develop a respiratory acidosis. (See 'Pediatrics' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Stephen J Traub, MD, former section editor of the toxicology program, for 20 years of dedicated service.
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