on 24-Mar-2021 (Wed)

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.

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.

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.

As aspirin concentrations rise, normal mechanisms that protect against toxicity become overwhelmed [5]. 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 [5].

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 [10]

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) [2].

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.

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.

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

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 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 [16], but may be seen in children who are brought to medical care soon after ingestion [15].

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

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

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].

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

Salicylates lower the CNS glucose concentration; therefore, neuroglycopenia may occur despite normal serum glucose levels [19]. 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]

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

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 [25].

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 [26].

Thrombocytopenia — Salicylates can cause thrombocytopenia, capillary fragility, and decreased platelet adhesion. These abnormalities are usually not of clinical significance; frank hemorrhage may occur but is uncommon [14,27].

Hepatic effects — Liver injury from salicylate poisoning can lead to decreased glycogen production and increased lactate production, although hepatitis has been described in adults [28].

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 [9].

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

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 [29].

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.

Elevated concentrations of serum lipids can interfere with the spectrophotometric determination of the salicylate level [30]. Treatment with a lipemia clearing agent or ultracentrifugation must be performed prior to measuring the salicylate concentration to prevent such interference.

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.

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

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.

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

Chronic salicylate poisoning is generally seen in young children or the elderly as a result of excessive therapeutic administration of products containing salicylates [32,33].

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.

Tracheal intubation of the aspirin-poisoned patient is dangerous [37], 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 [38].

Aspirin acts on the respiratory center of the medulla to increase the respiratory rate (RR) and tidal volume (V_t). Minute ventilation (MV) is determined by RR and V_t (RR x V_t = 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.

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 [38]. In addition, clinicians must remain vigilant for auto-PEEP, which can prevent adequate ventilation.

Aspirin-poisoned patients may be hypotensive due to sensible and insensible fluid losses and inappropriate systemic vasodilation [24]. 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.

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 [39,40] 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 [41]. Multiple-dose AC should not be used in patients with poor gastric motility or in those rare patients with salicylate-induced gastrointestinal hemorrhage.

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 [42].

Aspirin intoxication may decrease cerebral glucose concentrations despite a normal serum glucose [19,43]. 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 with sodium bicarbonate is an essential component of management of the aspirin-poisoned patient [44-46]. 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

Discontinuation of urinary alkalinization can occur when serum salicylate level is <40 mg/dL, serum pH has normalized, metabolic acidosis has resolved, and the patient is asymptomatic with a normal respiratory rate and effort. Arterial blood gases and serum salicylate levels should continue to be checked every one to two hours and urine pH every hour after discontinuation for two to four hours to demonstrate resolution of toxicity. If serum and urine pH decrease, serum salicylate level increases, metabolic acidosis returns, or the patient becomes symptomatic, urinary alkalinization should be restarted.

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 [44]. 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.

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 [47]. 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 [45,46].

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 [26]. 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.

Continuous renal replacement therapy (CRRT) is NOT an appropriate substitute for hemodialysis when treating the salicylate-poisoned patient. Salicylate clearance using modern hemodialysis equipment is several times that of CRRT, and CRRT cannot correct the acid-base or electrolyte abnormalities that often accompany severe salicylate poisoning