INTRODUCTION — Aspirin and other salicylates are among the oldest medications remaining in clinical practice. The use of aspirin has declined due to its association with Reye's syndrome in children, and the development of other nonsteroidal antiinflammatory drugs (NSAIDs). However, aspirin remains a common analgesic and a widely prescribed antiplatelet therapy for patients with cardiovascular and cerebrovascular disease, and thus aspirin toxicity remains an important clinical problem . Salicylates are found in a number of medications other than aspirin, including salicylic acid (a topical keratolytic agent and wart remover) and methyl salicylate (Oil of Wintergreen). (See "Aspirin: Mechanism of action, major toxicities, and use in rheumatic diseases" and "Benefits and risks of aspirin in secondary and primary prevention of cardiovascular disease".)
The clinical manifestations and management of all salicylate intoxications are similar. Throughout this section, the terms "aspirin" and "salicylates" will be used interchangeably.
The management of salicylate intoxication will be reviewed here. A summary table to facilitate emergent management is provided (table 1). Aspirin poisoning in children and general issues relating to the clinical management of drug intoxication are presented separately. (See "Salicylate poisoning in children and adolescents" and "General approach to drug poisoning in adults" and "Gastrointestinal decontamination of the poisoned patient".)
MECHANISM OF ACTION — Aspirin has multiple cellular and systemic effects [2-4]:
● Inhibition of cyclooxygenase results in decreased synthesis of prostaglandins, prostacyclin, and thromboxanes. This contributes to platelet dysfunction and gastric mucosal injury.
● Stimulation of the chemoreceptor trigger zone in the medulla causes nausea and vomiting.
● Activation of the respiratory center of the medulla results in hyperventilation and respiratory alkalosis.
● Interference with cellular metabolism (eg, Krebs cycle, oxidative phosphorylation) leads to metabolic acidosis.
ABSORPTION AND METABOLISM — When therapeutic doses of standard formulations of aspirin are ingested, the drug is rapidly absorbed in the stomach, and peak blood concentrations are usually reached within one hour. Absorption and peak concentrations are delayed when enteric-coated or delayed release formulations are ingested.
At therapeutic levels, 90 percent of salicylate is protein bound and therefore limited to the vascular space. Aspirin is metabolized via several different routes in the liver with a half-life of two to four hours. The drug is partially glycinated in the liver to salicyluric acid, which is both less toxic and more rapidly excreted by the kidney than salicylate. Only a small amount of drug is excreted unchanged in the urine.
However, absorption and elimination are drastically altered following overdose. Peak levels are frequently delayed, and may not be reached for six hours or longer after absorption as a result of pylorospasm, bezoar formation, or the use of extended-release, enteric-coated formulations [5-8]. In one extreme case, peak levels did not occur until 35 hours after ingestion .
As aspirin concentrations rise, normal mechanisms that protect against toxicity become overwhelmed . The degree of protein binding falls and hepatic detoxification becomes saturated. Thus, more drug reaches the tissues. As the normal hepatic detoxification is saturated, elimination becomes dependent upon (slow) renal excretion and drug half-life increases from 2 to 4 hours to as long as 30 hours .
FORMULATIONS — Aspirin (acetylsalicylic acid) is rapidly converted to salicylic acid in the body. Other salicylates, such as salicylic acid (a topical keratolytic agent and wart remover) and methyl salicylate (Oil of Wintergreen), can also cause intoxication when ingested or when excessive amounts are applied. Methyl salicylate is a common ingredient in liniments and ointments used in management of musculoskeletal pain. One teaspoon (5 mL) of Oil of Wintergreen contains approximately 7 g of salicylate, the equivalent of 21.7 adult aspirin tablets, and ingestion of just 4 mL can be fatal in a child . Bismuth subsalicylate (eg, found in Pepto-Bismol®) contains 8.7 mg of salicylic acid per mL and can cause acute or chronic toxicity, particularly in infants, if large quantities are used [11,12]. Herbal medications may also contain high levels of salicylates .
CLINICAL FEATURES OF ACUTE OVERDOSE — Early symptoms of acute aspirin toxicity include tinnitus, vertigo, nausea, vomiting, and diarrhea; subsequent symptoms portending a more severe intoxication include altered mental status (ranging from agitation to lethargy), hyperpyrexia, noncardiac pulmonary edema, 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 coingestants. Therefore, neither the diagnosis of aspirin toxicity nor an estimation of overdose severity should be based upon the timing of symptoms and signs.
Fatal aspirin intoxication can occur after the ingestion of 10 to 30 g by adults and as little as 3 g by children. Although toxicity does not correlate completely with serum salicylate concentration and symptoms, most patients exhibit signs of intoxication when the serum level exceeds 40 to 50 mg/dL (2.9 to 3.6 mmol/L); the usual therapeutic range is 10 to 30 mg/dL (0.7 to 2.2 mmol/L) .
Vital signs — Hyperpnea is often observed in salicylate overdose and is an early clinical finding that helps establish the diagnosis. Clinicians should, therefore, pay particular attention not only to the rate, but also to the depth of respiratory effort. Salicylates stimulate the medullary respiratory center, causing tachypnea and hyperventilation. In addition, salicylates uncouple oxidative phosphorylation in the mitochondria; this generates heat and may increase body temperature. However, a lack of hyperthermia should not be used to exclude the diagnosis of salicylate toxicity. Patients may also develop tachycardia due to hypovolemia, agitation, or general distress.
Tinnitus — Salicylates commonly cause tinnitus, even at concentrations within the therapeutic range (20 mg/dL [1.5 mmol/L]). This symptom should be specifically sought in all patients with potential aspirin toxicity. Tinnitus generally resolves along with acute salicylate toxicity and no further work-up is required. Other hearing abnormalities associated with acute aspirin toxicity, including alterations in the perception of sound and transient hearing loss, have been described but are rarely permanent.
Nausea and vomiting — Aspirin can cause nausea and vomiting through multiple mechanisms. These include direct irritation of the gastric mucosa, decreased production of prostaglandins, leading to deterioration of the protective mucosal barrier, and direct stimulation of the chemoreceptor trigger zone in the medulla. Vomiting can be severe and contribute to volume losses. Hemorrhagic gastritis, blood-tinged vomitus, and hematemesis have been described but are far less common.
The authors of a case series of 177 patients treated in intensive care for salicylate intoxication reported that hematemesis was uncommon but noted that nearly half of the 26 patients who died had gastric ulcers noted at autopsy .
Acid-base abnormalities — A variety of acid-base disturbances can occur with salicylate intoxication. Salicylates stimulate the respiratory center directly, resulting in an early fall in the PCO2 and respiratory alkalosis [2,15,16]. An anion-gap metabolic acidosis then follows, due primarily to the accumulation of organic acids, including lactic acid and ketoacids [16,17]. Salicylic acid itself (molecular weight 180) has only a minor effect on serum pH, since a serum level of 50 mg/dL (3.6 mmol/L) represents a concentration that is less than 3 meq/L. The onset of metabolic derangements depends upon the amount and type (eg, standard or enteric coated) of aspirin ingested, whether the ingestion is acute or chronic, the presence of coingestants, and whether pylorospasm or bezoar formation has occurred. (See "Approach to the adult with metabolic acidosis".)
The net effect of these changes is that most adults have either a primary respiratory alkalosis or, more commonly, a mixed primary respiratory alkalosis-primary metabolic acidosis. A pure primary metabolic acidosis is unusual in adults , but may be seen in children who are brought to medical care soon after ingestion . Acute respiratory acidosis is rare in the early stages of aspirin toxicity, but it may occur in later stages of profound poisoning. Respiratory acidosis that occurs early in the course of aspirin poisoning suggests coingestion with a respiratory depressant. Approximately one-third of adults who intentionally overdose on aspirin also ingest one or more other medications, many of which are respiratory depressants . (See "General approach to drug poisoning in adults".)
Salicylic acid is a weak acid that exists in charged (deprotonated) and uncharged (protonated) forms. The uncharged molecule can easily move across cellular barriers, including the blood-brain barrier and the epithelium of the renal tubule. This causes an increase in the salicylate concentration in the central nervous system (which correlates with lethality) and an increase in the amount of salicylate reabsorbed from the renal collecting system. Metabolic acidosis increases the fraction of uncharged (protonated) molecules, which exacerbates toxicity.
Treatment of salicylate intoxication is directed toward decreasing the fraction of uncharged (protonated) molecules, which is accomplished by increasing the systemic pH (ie, lowering the H+ ion concentration). This is referred to as “alkalinization” and is most easily accomplished by administering sodium bicarbonate. Increasing the systemic pH reduces the diffusion of salicylate anions into the central nervous system, as charged molecules do not easily diffuse across the blood-brain barrier. Alkalinization also "traps" salicylate anions within the renal tubule, preventing back-diffusion across the renal epithelium into the systemic circulation. (See 'Alkalinization of serum and urine' below.)
Alterations in mental status — Salicylate poisoning produces alterations in mental status via three major mechanisms: direct toxicity of salicylate species in the central nervous system (CNS), neuroglycopenia, and cerebral edema [14,18]. As noted above, progressive acidosis promotes the influx of salicylic acid (HS) into the CNS. Acidemia increases the likelihood of changes in mental status, with the most common findings being agitation, confusion, and restlessness; coma is rare. Lethargy develops as the patient’s metabolic derangements worsen and they start to fatigue.
Seizures may occur and it remains unclear whether they are most often due to direct salicylate toxicity or neuroglycopenia. Salicylates lower the CNS glucose concentration; therefore, neuroglycopenia may occur despite normal serum glucose levels . Mortality from salicylate poisoning correlates closely with CNS salicylate concentration, and altered mental status due to salicylate toxicity is an absolute indication for hemodialysis [2,20]. (See 'Hemodialysis' below.)
Pulmonary edema — Salicylate-induced noncardiogenic pulmonary edema and acute lung injury (ALI) generally occur in older patients with chronic salicylate intoxication [21-24], but they should be considered in all patients presenting with salicylate toxicity. Salicylate-induced ALI and pulmonary edema can complicate volume resuscitation and the administration of sodium bicarbonate, two mainstays of treatment in this setting. Thus, the presence of salicylate-induced pulmonary edema is considered an absolute indication for hemodialysis. (See 'Management' below and "Noncardiogenic pulmonary edema".)
Arrhythmia — Salicylate poisoning most commonly causes sinus tachycardia, but ventricular arrhythmias have been described as a preterminal event. Fluid and electrolyte shifts are the most common cause, although salicylates can directly alter the membrane permeability of cardiac myocytes .
Hypovolemia — Fluid losses associated with salicylate overdose can be significant (up to 4 to 6 L/m2), and are caused by hyperthermia, hyperpnea, lack of food and drink, osmotic diuresis, and vomiting .
Thrombocytopenia — Salicylates can cause thrombocytopenia, capillary fragility, and decreased platelet adhesion. These abnormalities are usually not of clinical significance; frank hemorrhage of any type is rare .
Hepatic effects — Liver injury from salicylate poisoning can lead to decreased glycogen production and increased lactate production, although hepatitis has been described in adults .
Serum salicylate — Therapeutic serum salicylate concentrations fall between 10 to 30 mg/dL (0.7 to 2.2 mmol/L); values above 40 mg/dL (2.9 mmol/L) are associated with toxicity. Although toxicity does not correlate exactly with serum salicylate concentrations and symptoms, most patients exhibit signs of intoxication when the serum concentration exceeds 40 to 50 mg/dL (2.9 to 3.6 mmol/L) . Fatal aspirin intoxication can occur after the ingestion of 10 to 30 g by adults and as little as 3 g by children.
In patients with clinical signs of salicylate poisoning, serum concentrations should be measured every two hours until two consecutive levels show a continuing decrease from the peak measurement, the most recent concentration falls below 40 mg/dL, and the patient is asymptomatic with a normal respiratory rate and effort. Note that concentrations might not begin to rise until five or six hours after ingestion because of pylorospasm, bezoar formation, or the use of enteric-coated tablets, and may rarely peak as late as 35 hours after ingestion .
Monitoring serum salicylate concentrations may help assess the response to therapy and determine the need for more aggressive measures, including hemodialysis. Levels above 100 mg/dL (7.2 mmol/L) are associated with increased morbidity and mortality, and are considered an absolute indication for hemodialysis. (See 'Hemodialysis' below.)
Some laboratories report salicylate concentrations as mg/L; such values are therefore 10-fold higher than those discussed in this topic review. Thus, a laboratory report of "an aspirin level of 110" in an asymptomatic individual should prompt the clinician to check the units of the result in order to avoid confusion.
The Done nomogram is no longer in clinical use. Developed to correlate serum salicylate levels with toxicity, the Done nomogram fails to predict toxicity based upon the serum concentration alone .
In animal studies, mortality from salicylate poisoning correlates closely with salicylate concentration in the central nervous system, but these measurements are not routinely available in clinical practice. Ultimately, serum salicylate concentrations must be interpreted in the context of the patient’s clinical status and blood pH. As an example, if a patient has a decreasing salicylate concentration but worsening acidosis and lethargy, this may reflect increased tissue distribution and more severe disease, rather than increased excretion. A small decrease in serum pH will increase the fraction of un-ionized salicylate (HSal), despite a slowly declining total salicylate concentration. (See 'Alkalinization of serum and urine' below.)
Elevated concentrations of serum lipids can interfere with the spectrophotometric determination of the salicylate level . Treatment with a lipemia clearing agent or ultracentrifugation must be performed prior to measuring the salicylate concentration to prevent such interference.
Creatinine — Aspirin is eliminated almost exclusively via the kidneys, so the serum creatinine concentration should be checked in all patients who present with known or suspected salicylate toxicity. Renal failure is an absolute indication for hemodialysis in the salicylate-poisoned patient; mild renal impairment is a relative indication for hemodialysis, and must be interpreted in light of the patient's overall clinical condition.
Potassium — 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 involved in this pump interferes with efforts at urinary alkalinization, which are a mainstay of therapy.
Coagulation studies — Rarely, large salicylate overdoses may cause hepatotoxicity and interfere with vitamin K metabolism leading to a coagulopathy, which manifests as elevations in the prothrombin time (PT) and international normalized ratio (INR). Clinically significant bleeding seldom occurs.
Lactate — Salicylates uncouple oxidative phosphorylation, which results in abnormal cellular energy production and utilization; the cell becomes dependent upon anaerobic metabolism, resulting in accumulation of lactate. Thus, a significant salicylate poisoning will lead to an elevated serum lactate concentration. (See "Energy metabolism in muscle", section on 'Anaerobic glycolysis' and "Energy metabolism in muscle", section on 'Oxidative phosphorylation'.)
Anion gap — The anion gap is generally elevated in the setting of salicylate toxicity (calculator 1). However, there are case reports of patients with a normal anion gap despite severe intoxication, and clinicians should not be dissuaded from making the diagnosis because the anion gap is not elevated .
Imaging studies — In patients with clinical signs of severe salicylate poisoning, important treatment interventions (eg, hemodialysis) should not be delayed in order to obtain imaging studies. The need for imaging with a head CT depends upon the clinical picture, but imaging should be performed in any patient with altered mental status or focal neurological deficits that are not clearly attributable to a noncerebral cause (eg, hypoglycemia). A plain chest radiograph should be obtained if there are clinical signs of pulmonary edema.
DIAGNOSIS — The diagnosis of salicylate intoxication is usually suspected from the history, physical examination, and acid-base findings. Confirmation of the diagnosis requires measurement of the serum salicylate concentration.
CHRONIC SALICYLATE POISONING — Chronic salicylate poisoning is generally seen in young children or the elderly as a result of excessive therapeutic administration of products containing salicylates [31,32]. The diagnosis and management of salicylate poisoning in children is discussed separately. (See "Salicylate poisoning in children and adolescents".)
Chronic salicylate poisoning can be difficult to diagnose in part because there is no clear history of ingestion. Clinical findings in chronic and acute salicylate poisoning overlap, but classic symptoms and signs may be milder or absent with chronic toxicity and are often attributed to other disease processes. As an example, difficulty breathing and pulmonary edema in an elderly patient is often attributed to cardiac or pulmonary illness. Another problem is that many of the signs and symptoms of chronic poisoning may be attributed to the ailment that was being treated with salicylates. The delays in diagnosis caused by these difficulties result in higher overall morbidity and mortality [33,34].
The management of chronic salicylate poisoning does not differ significantly from acute overdose. However, a lower salicylate concentration is generally used as a threshold for treatment with hemodialysis. In fact, some patients with signs of severe chronic toxicity may have a salicylate concentration within the therapeutic range. Hemodialysis is often needed, and should be discussed with a medical toxicologist and nephrologist, for any patient who has a therapeutic or elevated salicylate concentration and any of the following symptoms: CNS dysfunction (eg, delirium, lethargy, seizures), renal failure, pulmonary edema, or severe acid-base (eg, pH <7.3 despite aggressive resuscitation) or electrolyte abnormalities with no alternative explanation .
MANAGEMENT — 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 if indicated and the initiation of specific therapies designed to mitigate the effects of the toxin, which in the case of aspirin consists of alkalinization of the plasma and urine, and in some cases hemodialysis. A summary table to facilitate emergent management of aspirin intoxication is provided (table 1).
Airway and breathing — Tracheal intubation of the aspirin-poisoned patient is dangerous , and should be reserved for cases of clear respiratory failure. Intubation of tachypneic patients to prevent physical exhaustion following an aspirin overdose has resulted in death .
Aspirin acts on the respiratory center of the medulla to increase the respiratory rate (RR) and tidal volume (Vt). Minute ventilation (MV) is determined by RR and Vt (RR x Vt = MV), so an increase in either can produce a dramatic increase in minute ventilation. As noted above, the resulting respiratory alkalosis "traps" salicylate anions in the blood, preventing them from continuing to cross into the CNS. (See 'Acid-base abnormalities' above.)
Clinicians should be aware of how airway management can exacerbate the condition of patients with salicylate poisoning. The brief period of apnea that occurs with the sedation and paralysis performed in preparation for intubation can cause an acute and substantial worsening of the patient’s respiratory acidosis. During this period, salicylate anions become protonated to uncharged salicylic acid, diffuse across the blood-brain barrier, and increase toxicity. The high respiratory rate and minute ventilation observed in unintubated patients with salicylate poisoning is difficult to replicate with a ventilator. Therefore, orotracheal intubation often causes relative hypoventilation, resulting in a higher PaCO2 than is maintained by spontaneous ventilation, and possibly respiratory acidosis, leading to increased toxicity. In addition, ventilator asynchrony may decrease a patient's ability to maintain appropriate acid-base homeostasis.
In general, intubation should be reserved for those patients with hypoventilation, as determined by clinical evaluation or blood gas analysis. When intubation becomes necessary due to primary respiratory failure, maintaining high tidal volume and a rapid respiratory rate becomes critically important. Ventilator settings should mimic the respiratory rate of the patient prior to intubation and tidal volumes will likely need to exceed the 6 to 8 mL/kg commonly used. Unless there is ventilator-patient asynchrony or a comparable problem making ventilation extremely difficult, long acting neuromuscular blockade and deep sedation, which blunt the patient’s ability to breath over the ventilator, should be avoided as much as possible . In addition, clinicians must remain vigilant for auto-PEEP, which can prevent adequate ventilation. (See "Mechanical ventilation of adults in the emergency department".)
Supplemental oxygen should be administered as needed whether the patient is intubated or not. The presence of acute lung injury may lead to high oxygen requirements. (See 'Pulmonary edema' above.)
Circulation — Aspirin-poisoned patients may be hypotensive due to sensible and insensible fluid losses and inappropriate systemic vasodilation . Aggressive volume resuscitation is warranted in such patients, unless cerebral edema or pulmonary edema is present. Hypotensive patients who do not respond to fluid resuscitation can be treated with a vasopressor (such as phenylephrine or norepinephrine) as appropriate. (See "Definition, classification, etiology, and pathophysiology of shock in adults" and "Use of vasopressors and inotropes".)
Decontamination — Activated charcoal (AC) effectively absorbs aspirin, and at least one initial dose (1 g/kg up to 50 g PO) should be given to all alert and cooperative patients and all intubated patients via orogastric tube who present within two hours of ingestion. AC should be avoided in any patient with altered mental status or increasing somnolence and an unsecured airway. Maintaining high minute ventilation will probably have a greater impact on clinical improvement than AC. Patients who present after two hours may benefit from AC because of delayed absorption due to enteric coated tablets, pylorospasm, or bezoar formation.
Treatment with multiple-dose AC results in lower salicylate levels in volunteers [38,39] and we suggest such treatment, if it is tolerated (eg, does not provoke vomiting), to prevent continued absorption. Dosing is 25 g by mouth every two hours for three doses or 50 g by mouth every four hours for two doses after the initial dose is given . Multiple-dose AC should not be used in patients with poor gastric motility or in those rare patients with salicylate-induced gastrointestinal hemorrhage. (See "Gastrointestinal decontamination of the poisoned patient".)
In general, whole bowel irrigation (WBI) is not routinely used for salicylate toxicity but can be considered for massive ingestions (eg, entire bottle of tablets) of sustained preparation or enteric-coated drugs in an alert and cooperative patient. Animal and human studies have not demonstrated a clinical benefit in patients treated with WBI .
Supplemental glucose — Aspirin intoxication may decrease cerebral glucose concentrations despite a normal serum glucose [19,42]. Thus, supplemental glucose should be given to patients with an altered mental status regardless of the serum glucose concentration.
There are no clinical studies in humans upon which to base treatment recommendations for supplemental glucose in salicylate poisoning. One reasonable approach is to maintain the patient’s serum glucose in the high normal range (approximately 80 to 120 mg/dL, or 4.4 to 6.6 mmol/L). In patients who are not able to eat, this can be accomplished using IV boluses of dextrose (50 to 100 mL of 50 percent dextrose) or by adding 50 to 100 g of dextrose to each liter of maintenance fluid. In patients with any neurologic deficit, including altered mental status, a serum or fingerstick glucose concentration should be obtained every one to two hours, until the signs of severe toxicity resolve.
Alkalinization of serum and urine — Alkalinization with sodium bicarbonate is an essential component of management of the aspirin-poisoned patient [43-45]. The usual initial dose of sodium bicarbonate is 1 to 2 mEq (or mmol) per kg given as an intravenous bolus. This is followed by a sodium bicarbonate infusion of 100 to 150 mEq (or mmol) in one liter of sterile water with 5 percent dextrose. The rate of the infusion is titrated to a urine pH of 7.5 to 8, but is usually 1.5 to 2 times the maintenance dose for intravenous fluids. Hypokalemia must be corrected or prevented for alkalinization to be effective. Enteral or parenteral potassium supplementation should be initiated even in patients with serum potassium concentrations in the low normal range, as alkalinization will further lower the serum potassium. Close monitoring of the serum potassium (hourly measurements) is required during alkalinization therapy (see "Clinical manifestations and treatment of hypokalemia in adults", section on 'Recommended approach'). Evidence supporting treatment with alkalinization is described separately. (See "Salicylate poisoning in children and adolescents", section on 'Urine alkalinization'.)
To appreciate how alkalinization acts, it is important to note that salicylic acid (HSal) is a weak acid. In the equilibrium reaction
H+ + Sal- <—> HSal,
if the systemic pH is increased, the equation will move to the left. The ensuing fall in the plasma HSal concentration will allow HSal in the CNS and other tissues to diffuse into the extracellular fluid down a favorable concentration gradient where it will be trapped as Sal-. The decrease 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 salicylic acid concentration promotes further drug movement out of the CNS.
Alkalemia from a respiratory alkalosis is NOT a contraindication to sodium bicarbonate therapy. Aspirin-poisoned patients commonly 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 >7.60). A urine pH of 7.5 to 8 is desirable, although this may be difficult to obtain in salicylate-poisoned patients, particularly in the setting of intravascular volume deficits and whole body potassium depletion. (See "Enhanced elimination of poisons", section on 'Urinary alkalinization'.)
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 HSal to Sal-, thereby minimizing the back diffusion of secreted HSal from the tubular lumen back into the renal epithelium and ultimately the systemic circulation . 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 [44,45].
IV fluids are needed to treat dehydration and maintain urine output. Initial fluid resuscitation is performed with isotonic saline, usually at a rate of 10 to 15 mL/kg per hour for the first two to three hours, and is then titrated to maintain a urine output between 1 to 2 mL/kg per hour . We do not suggest the administration of excessive IV fluids beyond the restoration of normal fluid balance (ie, “forced diuresis”) nor do we use diuretics because the excretion of salicylate depends upon pH not on the urinary flow rate. In addition, patients with salicylate poisoning are at risk of pulmonary edema and may not tolerate excessive IV fluids.
Acetazolamide is contraindicated in the standard management of salicylate poisoning. Acetazolamide is a carbonic anhydrase inhibitor that alkalinizes the urine by reducing bicarbonate reabsorption. While this does enhance salicylate excretion, the bicarbonate loss from plasma lowers the arterial pH, which promotes salicylate movement into the brain, potentially worsening salicylate neurotoxicity.
Repeat laboratory testing — Aspirin-poisoned patients require frequent laboratory testing to assess both clinical status and response to therapy. A salicylate concentration and blood gas should be drawn every one to two hours until both the serum salicylate concentration is falling and the acid-base status is stable or improving for two consecutive measurements. Urine pH and serum potassium should be checked hourly. Ideally, blood gas measurements are taken from an arterial source; venous samples can substitute until an arterial line is placed to ensure close monitoring and avoid multiple painful arterial punctures.
Hemodialysis — The efficiency of salicylate removal can be enhanced by hemodialysis . Indications for hemodialysis include the following:
●Altered mental status
●Pulmonary or cerebral edema
●Renal insufficiency that interferes with salicylate excretion
●Fluid overload that prevents the administration of sodium bicarbonate
●A serum salicylate concentration >100 mg/dL (7.2 mmol/L) in acute overdose
●Clinical deterioration despite aggressive and appropriate supportive care
Consultation with the nephrology service should occur early in a patient's course, even in the absence of the immediate need for acute hemodialysis. Alerting the nephrologist early in the patient's course will facilitate hemodialysis in the event that the patient deteriorates despite aggressive and appropriate supportive care.
Treatment and continued diagnostic testing is no longer necessary when the patient has clinically improved, their acid-base status has normalized, and the blood salicylate level is no longer in the toxic range.
ADDITIONAL RESOURCES — Regional poison control centers in the United States are available at all times for consultation on patients who are critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222 FREE). In addition, some hospitals have clinical and/or medical toxicologists available for bedside consultation and/or inpatient care. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. The World Health Organization provides a listing of international poison centers at its website: www.who.int/gho/phe/chemical_safety/poisons_centres/en/index.html
SUMMARY AND RECOMMENDATIONS
●Salicylate poisoning remains a significant clinical problem. Fatal aspirin intoxication can occur after the ingestion of 10 to 30 g by adults and as little as 3 g by children. (See 'Introduction' above and 'Mechanism of action' above.)
●Early recognition is the key to successful management. The diagnosis must be considered in any patient with a suspected drug overdose and in those with an unexplained increase in the anion gap. The diagnosis is made on the basis of the history, physical examination, and acid-base findings. Confirmation of the diagnosis requires measurement of serum salicylate concentration. A summary table to facilitate emergent management is provided (table 1).
●Prominent early clinical features of acute salicylate poisoning include: tinnitus, vertigo, vomiting and diarrhea; more severe intoxication can cause altered mental status, hyperpyrexia, coma, noncardiac pulmonary edema, and death. (See 'Clinical features of acute overdose' above.)
●A variety of acid-base disturbances can occur with salicylate poisoning. Most adults have either a primary respiratory alkalosis or a mixed primary respiratory alkalosis-primary metabolic acidosis. (See 'Acid-base abnormalities' above.)
●Therapeutic serum salicylate concentrations are 10 to 30 mg/dL (0.7 to 2.2 mmol/L); values above 40 mg/dL (2.9 mmol/L) may be associated with toxicity. In patients with clinical signs of salicylate poisoning, serum concentrations should be measured every two hours until two consecutive levels show a continuing decrease from the peak measurement, the most recent concentration falls below 40 mg/dL, and the patient is asymptomatic with a normal respiratory rate and effort. (See 'Diagnostic testing' above.)
●Chronic salicylate intoxication is often misdiagnosed and a high index of suspicion is needed, especially in high risk patients such as the elderly. Treatment is the same as for acute toxicity, with the important exception that a lower salicylate concentration is used as the threshold for hemodialysis. (See 'Chronic salicylate poisoning' above.)
●Intubation of the aspirin-poisoned patient is dangerous and should be AVOIDED if at all possible. When intubation is necessary due to primary respiratory failure, care must be taken to ensure appropriately high minute ventilation and maintain alkalemia with serum pH 7.50 to 7.59. (See 'Airway and breathing' above.)
●We suggest that adults with salicylate poisoning and clinical signs of toxicity be treated with alkalinization of the serum and urine (Grade 1B). Alkalinization is the mainstay of therapy. We use intravenous sodium bicarbonate for this treatment; details are provided in the text. Early nephrology consultation should be obtained and hemodialysis considered for all patients with clinical evidence of severe intoxication. Specific indications for hemodialysis are provided in the text. (See 'Alkalinization of serum and urine' above and 'Hemodialysis' above.)
●Aspirin-poisoned patients may be hypotensive. Aggressive volume resuscitation is warranted, unless cerebral edema or pulmonary edema is present. Hypotensive patients who do not respond to fluid resuscitation can be treated with a vasopressor (eg, norepinephrine). (See 'Circulation' above.)
●Aspirin intoxication may decrease cerebral glucose concentrations despite a normal serum glucose. Therefore, we suggest that adults with salicylate poisoning who are hypoglycemic or manifest alterations in mental status, regardless of their serum glucose concentration, be treated with supplemental glucose (Grade 2C). (See 'Supplemental glucose' above.)