Salicylate Toxicity

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Background

Salicylates are ubiquitous agents found in hundreds of over-the-counter (OTC) medications and in numerous prescription drugs, making salicylate toxicity an important cause of morbidity and mortality. (See Epidemiology.)

Salicylate is used as an analgesic agent for the treatment of mild to moderate pain. Aspirin is used as an anti-inflammatory agent for the treatment of soft tissue and joint inflammation and vasculitides such as acute rheumatic fever and Kawasaki disease. The product is an antipyretic drug. Low-dose aspirin helps to prevent thrombosis.

Acetylsalicylic acid is colorless or white in crystalline, powder, or granular form. The chemical is odorless and is soluble in water. Salicylate is available for ingestion as tablets, capsules, and liquids. Salicylate is also available for topical application, in creams or lotions.

Salicylate ingestion continues to be a common cause of poisoning in children and adolescents. The prevalence of aspirin-containing analgesic products makes these agents, found in virtually every household, common sources of unintentional and suicidal ingestion. (See Etiology, Epidemiology, and Treatment.)

However, the incidence of salicylate poisoning in children has declined because of reliance on alternative analgesics and the use of child-resistant containers. Repackaging has decreased children's accessibility to lethal amounts, and salicylate's association with Reye syndrome has significantly decreased its use. (See Epidemiology.)

Still, more than 10,000 tons of aspirin are consumed in the United States each year. Aspirin or aspirin-equivalent preparations (in milligrams) include children's aspirin (80-mg tablets with 36 tablets per bottle), adult aspirin (325-mg tablets), methyl salicylate (eg, oil of wintergreen; 98% salicylate), and Pepto-Bismol (236 mg of nonaspirin salicylate per 15 mL).

Ingestion of topical products containing salicylates, such as Ben-Gay, salicylic acid (keratolytic), and oil of wintergreen or methyl salicylate, can cause severe salicylate toxicity. One teaspoon of 98% methyl salicylate contains 7000 mg of salicylate, the equivalent of nearly 90 baby aspirins and more than 4 times the potentially toxic dose for a child who weighs 10 kg. Salicylate toxicity has been reported with the topical use of salicylate-containing teething gels in infants.[1]

A comprehensive review of the existing medical literature on methyl salicylate poisoning has determined that it is a relatively common source of pediatric exposures.[2] In younger children, most of these exposures are accidental. Intentional ingestions are much more common in adolescents.

The prevalence of alternative medicines and the popularity of herbs and traditional medicine formulae are increasing in North America. Many of these medicines may contain salicylate. Therefore, consider salicylate poisoning when topical herbal medicinal oil is involved.

Percy Medicine contains bismuth subsalicylate as the active ingredient and is used as a constipation reliever. A case of neonatal salicylate poisoning due to administration of this medicine as a colic reliever has been reported.[3] It is available OTC, and parents should be educated that salicylate-containing products are not routinely recommended for children aged 1 year or younger.

Phases and symptoms of salicylate toxicity

The acid-base, fluid, and electrolyte abnormalities seen with salicylate toxicity can be grouped into phases. (See Presentation and Workup.)

Phase 1 of the toxicity is characterized by hyperventilation resulting from direct respiratory center stimulation, leading to respiratory alkalosis and compensatory alkaluria. Potassium and sodium bicarbonate are excreted in the urine. This phase may last as long as 12 hours.

In phase 2, paradoxic aciduria in the presence of continued respiratory alkalosis occurs when sufficient potassium has been lost from the kidneys. This phase may begin within hours and may last 12-24 hours.

Phase 3 includes dehydration, hypokalemia, and progressive metabolic acidosis. This phase may begin 4-6 hours after ingestion in a young infant or 24 hours or more after ingestion in an adolescent or adult.

Nausea, vomiting, diaphoresis, and tinnitus are the earliest signs and symptoms of salicylate toxicity. Other early symptoms and signs are vertigo, hyperventilation, tachycardia, and hyperactivity. As toxicity progresses, agitation, delirium, hallucinations, convulsions, lethargy, and stupor may occur. Hyperthermia is an indication of severe toxicity, especially in young children.

Patient education

Advise patients and their families that use or overuse of seemingly benign OTC medications is sometimes dangerous. The ready availability of aspirin and aspirin-containing products does not establish the safety of aspirin.

For patient education information, see the First Aid and Injuries Center, as well as Aspirin Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

Etiology and Pathophysiology

After ingestion, acetylsalicylic acid is rapidly converted to salicylic acid, its active moiety. Salicylic acid is readily absorbed in the stomach and small bowel. At therapeutic doses, salicylic acid is metabolized by the liver and eliminated in 2-3 hours. Salicylate poisoning is manifested clinically by disturbances of several organ systems, including the central nervous system (CNS) and the cardiovascular, pulmonary, hepatic, renal, and metabolic systems. Salicylates directly or indirectly affect most organ systems in the body by uncoupling oxidative phosphorylation, inhibiting Krebs cycle enzymes, and inhibiting amino acid synthesis.

Acid-base status

The toxic effects of salicylates are complex. Respiratory centers are directly stimulated, causing a primary respiratory alkalosis. Salicylates also cause an inhibition of the citric acid cycle and an uncoupling of oxidative phosphorylation and may produce renal insufficiency that causes accumulation of phosphoric and sulfuric acids. The metabolism of fatty acids is likewise increased in patients with salicylate toxicity, generating ketone body formation. These processes all contribute to the development of an elevated anion-gap metabolic acidosis in patients with salicylate poisoning. This combination of a primary respiratory alkalosis and a primary metabolic acidosis is characteristic of salicylate poisoning, especially in adults, and should make the clinician suspect the diagnosis when it is present.

Catabolism occurs secondary to the inhibition of adenosine triphosphate (ATP) ̶ dependent reactions with the following results:

Adult patients with acute poisoning usually present with a mixed respiratory alkalosis and metabolic acidosis. However, respiratory alkalosis may be transient in children such that metabolic acidosis may occur early in the course. Some patients with mixed acid-base disturbances have been found to have normal anion-gap metabolic acidosis; therefore, normal anion-gap acidosis does not exclude salicylate toxicity.

Respiratory system effects

Salicylates cause direct and indirect stimulation of respiration. A salicylate level of 35 mg/dL or higher causes increases in rate (tachypnea) and depth (hyperpnea) of respiration. Salicylate poisoning may rarely cause noncardiogenic pulmonary edema (NCPE) and acute lung injury in pediatric patients. It is more common in elderly patients with chronic salicylate toxicity. Although the exact etiology is not known, it causes severe hypoxia, necessitating treatment with high concentrations of oxygen. It also makes adequate hydration and sufficient administration of sodium bicarbonate difficult. Pulmonary edema has extremely high mortality in both children and adults; if present, hemodialysis should be considered as soon as possible.

Glucose metabolism

Increased cellular metabolic activity due to uncoupling of oxidative phosphorylation may produce clinical hypoglycemia, although the serum glucose levels may sometimes be within the normal range. As intracellular glucose is depleted, the salicylate may produce discordance between levels of plasma and cerebrospinal fluid (CSF) glucose and symptoms of CNS hypoglycemia (eg, altered mental status) may occur even when blood glucose levels are within the reference range.

Fluid and electrolyte effects

Salicylate poisoning may result in dehydration because of increased gastrointestinal (GI) tract losses (vomiting) and insensible fluid losses (hyperpnea and hyperthermia). All patients with serious poisoning are more than 5-10% dehydrated. Renal clearance of salicylate is decreased by dehydration. Hypokalemia and hypocalcemia can occur as a result of primary respiratory alkalosis.

CNS effects

Salicylates are neurotoxic; this initially manifests as tinnitus. Significant ingestion can lead to hearing loss at serum levels of 30-45 mg/dL or higher. CNS toxicity is related to the amount of drug bound to CNS tissue. It is more common with chronic than acute toxicity. Acidosis worsens CNS toxicity by increasing the amount of salicylate that crosses the blood-brain barrier and increases CNS tissue levels. Other signs and symptoms of CNS toxicity include nausea, vomiting, hyperpnea, and lethargy. Severe toxicity can progress to disorientation, seizures, cerebral edema, hyperthermia, coma, cardiorespiratory depression, and, eventually, death.

GI tract effects

Nausea and vomiting are the most common toxic effects. This can be caused by CNS toxicity or by direct damage to the gastric mucosa. Salicylates can disrupt the mucosal barrier and occasionally cause GI bleeding. Pylorospasm, decreased GI tract motility, and bezoar formation can occur with large doses. These slow elimination and cause greater amounts of salicylates to be absorbed from the GI tract.

Hepatic effects

Hepatitis can occur in children ingesting doses at or above 30.9 mg/dL.[4] Reye syndrome is another form of pediatric salicylate-induced hepatic disease. It is characterized by nausea, vomiting, hypoglycemia, elevated levels of liver enzymes and ammonia, fatty infiltration of the liver, increased intracranial pressure, and coma.

Hematologic effects

Hypoprothrombinemia and platelet dysfunction are the most common effects. Bleeding may also be promoted either by inhibition of vitamin K–dependent enzymes or by the formation of thromboxane A2.

Musculoskeletal effects

Rhabdomyolysis can occur because of dissipation of heat and energy, resulting from oxidative phosphorylation uncoupling.

Epidemiology

Occurrence in the United States

According to the Toxic Exposures Survey from the American Association of Poison Control Centers' National Poisoning and Exposure Database, more than 20,000 aspirin and nonaspirin salicylate exposures were reported in 2005; 64% required treatment in a health care facility.[5] Of these exposures, 50% were intentional overdoses, and 60 fatal cases were noted.

Age-related demographics

Generally, the degree of the toxicity is more severe in elderly individuals and infants, as well as in persons with coexisting morbidity or chronic intoxication.

Acid-base disturbances vary with age and severity of the intoxication. Infants rarely present with pure respiratory alkalosis. Respiratory alkalosis may not develop in an infant or it may be short-lived. The most common presentation for a child is metabolic acidosis.

Factors contributing to a decline in the incidence of pediatric salicylate intoxication include increased acetaminophen and ibuprofen use and child-resistant packaging.

Prognosis

A 16% morbidity rate and a 1% mortality rate are associated with patients presenting with an acute salicylate overdose. The incidence of morbidity and mortality for a patient with chronic intoxication is 30% and 25%, respectively.

According to the Toxic Exposures Survey from the American Association of Poison Control Centers, 24% of analgesic-related deaths are due to aspirin alone or aspirin in combination with other drugs. Early identification of salicylate poisoning and expeditious institution of appropriate treatment can be lifesaving.

Categories of toxicity

The following 4 categories are helpful for assessing the potential severity and morbidity of an acute, single-event, nonenteric-coated salicylate ingestion:

History

If aspirin usage is suspected, direct questioning is useful. Many patients do not list aspirin or other OTC aspirin-containing products because they may not consider such products as medications. When possible, elicit the following information:

The presence of tinnitus is a clue for salicylate ingestion. Tachypnea, tachycardia, and elevated temperature can be detected by evaluating vital signs. Treatment should not be withheld in symptomatic patients because of pending serum level tests.

The patient who presents with an acute, witnessed, or intentional overdose usually has a history that the physician can directly obtain. Eliciting a history of a chronic overdose in geriatric or psychiatric patients often is harder to accomplish. Thus, diagnosis can be more difficult in these patient populations.

The chronic ingestion of salicylates may produce the appearance of anxiety with its associated tachypnea, diaphoresis, difficulty concentrating, and hallucinations; agitated delirium also may be observed. Elderly individuals may present with deterioration in functional status or with concerns of pneumonia, owing to the presence of tachypnea and fever.

Patients with underlying psychiatric illness may present with symptoms suggestive of an exacerbation of their underlying psychiatric illness (eg, mania, psychosis).

Physical Examination

Pulmonary

Pulmonary symptoms and signs of salicylate poisoning include the following:

Auditory

Auditory symptoms caused by the ototoxicity of salicylate poisoning include the following:

Tinnitus is commonly encountered when serum salicylate concentrations exceed 30 mg/dL. Although the presence of tinnitus is not a very specific or sensitive clinical effect of salicylate poisoning., it can be a very useful early sign of salicylate toxicity given the right clinical setting.

Cardiovascular

Cardiovascular symptoms of salicylate poisoning include the following:

Respiratory depression limits the respiratory alkalosis and causes an increase in the nonionized portion of salicylate. The nonionized salicylate enters cells and crosses the blood-brain barrier much more readily, causing much higher levels of salicylate in brain tissue, leading to severe CNS toxicity.

Neurologic

Neurologic symptoms, signs, and manifestations of salicylate poisoning include the following:

Encephalopathic changes may include irritability, confusion, hyperactivity, and hallucinations. These clinical effects are usually associated with severe cases.

Gastrointestinal

GI symptoms, signs, and manifestations of salicylate poisoning include the following:

Genitourinary

Genitourinary symptoms, signs, and manifestations of salicylate poisoning include the following:

Hematologic

Hematologic effects may include prolongation of the prothrombin and bleeding times and decreased platelet adhesiveness. Disseminated intravascular coagulation (DIC) may be noted with multisystem organ failure in association with chronic salicylate toxicity.

Dermatologic

Contact dermatitis may develop from topical application. Diaphoresis is a common sign in patients with salicylate toxicity.

Electrolytic

Electrolyte-associated symptoms, signs, and manifestations of salicylate poisoning include the following:

Hypokalemia may be a severe iatrogenic complication in patients treated with urinary alkalization, if sufficient potassium supplementation is not provided.

Approach Considerations

Initial and serial salicylate levels are important in the evaluation of salicylate toxicity. The absolute level should not detract from the importance of careful and repeated clinical evaluation. Immediately begin therapy in symptomatic patients. Do not wait for the salicylate levels to return from the laboratory.

If managing an acute or acute-on-chronic ingestion, repeat the salicylate serum level test every 2 hours until the salicylate level falls. If the levels increase, consider the possibility that a sustained-release preparation was ingested or that a concretion in the GI tract has formed.

The therapeutic range of salicylate is 15-30 mg/dL. Patients are often symptomatic at salicylate concentrations higher than 40-50 mg/dL. Patients with salicylate concentrations approaching or exceeding 100 mg/dL usually have serious or life-threatening toxicity. Patients with chronic poisoning who have levels of 60 mg/dL or greater often have serious toxicity.

One cautionary note is to always confirm the units of measurement with the laboratory. Traditional units are milligrams per deciliter; however, many laboratories report salicylate concentrations in milligrams per liter or micrograms per milliliter, both of which differ by a factor of 10 from the traditional units. For example, a salicylate concentration of 100 mg/dL is seriously toxic, but a concentration of 100 mg/L is subtherapeutic. A concentration of 100 mg/L is equal to a concentration of 10 mg/dL.

Monitoring peak concentration

In overdoses, the peak serum concentration may not occur for 4-6 hours, so concentrations obtained before that time may not reflect peak levels. levels from 15-30 mg/dL are considered to be within the therapeutic range. Signs and symptoms of toxicity begin to appear at levels higher than 30 mg/dL. A 6-hour salicylate level higher than 100 mg/dL is considered potentially lethal and is an indication for hemodialysis. Chronic ingestion can increase the half-life to longer than 20 hours.

In significant ingestions, serum salicylate levels should be monitored at least every 2 hours until a peak has been reached and then every 4-6 hours until the peak falls into the nontoxic range.

Serum electrolytes and renal function studies (BUN and creatinine levels)

Obtain measurements of serum electrolytes, blood urea nitrogen (BUN), creatinine, calcium, magnesium, and glucose. Repeat these tests at least every 12 hours until the salicylate level falls and the acid-base disturbance improves. If hemodialysis is required, testing is needed more frequently.

Monitor serum potassium concentrations; normal levels may be difficult to obtain during alkalization therapy. Electrolyte levels should be obtained every 2-4 hours when the patient is being alkalized, because severe hypokalemia and other electrolyte abnormalities can occur.

Urinalysis

Monitor and maintain an alkaline urine pH every 2 hours during alkalization therapy. Maintain a urine pH of 7.5-8. It is important to monitor the serum pH, as well as the urine pH. Excessive sodium bicarbonate induces severe alkalemia and/or hypernatremia. Consider obtaining a urine specimen for a qualitative toxicology screen.

Imaging studies

A chest radiograph is indicated if evidence of severe intoxication, pulmonary edema, aspiration pneumonitis, or hypoxemia is present.

Consider an abdominal radiograph if an aspirin concretion is suspected. A concretion should be suspected if salicylate levels are rising or fail to decrease despite treatment with gastric lavage and/or activated charcoal.

Other methods of identifying gastric salicylate pharmacobezoars include the following:

Other tests

Other studies to obtain include the following:

Toxicity Versus Serum Level

The toxicity of salicylates does not always correlate well with serum levels, and the levels are often less helpful in patients with long term exposure. Serum salicylate levels may correlate only moderately with clinical manifestations. In acute ingestion, levels may sometimes be high without significant clinical signs, whereas levels in patients with chronic ingestion that are in the high therapeutic range may be associated with significant clinical toxicity. Therefore, levels must always be interpreted and correlated with the history and clinical findings.

Done nomogram

The Done nomogram was formulated in 1960 to assist physicians in predicting the severity of salicylate intoxication based on a serum level and a known time of ingestion. The nomogram was based primarily on previously healthy pediatric patients with acute single-salicylate ingestion. However, clinical application of the nomogram has several limitations. The nomogram is used only to evaluate a single acute ingestion. In contrast to the Rumack-Matthew nomogram,[8] the Done nomogram indicates severity of toxicity based on a 6-hour level of non–enteric-coated aspirin rather than the need for antidotal therapy. Currently, the Done nomogram is regarded as not very useful and is seldom used by clinicians.

Bedside Ferric Chloride Testing

Historically, qualitative determination for the presence of salicylates was rapidly performed in the emergency department by adding a few drops of 10% ferric chloride (FeCl3) to 1 mL of urine. If salicylates are present, the solution changes to a brown/purple color. Positive results with the urine ferric chloride test only indicate that a salicylate is present; however, even very small amounts of a salicylate, such as a single ingested aspirin tablet, can give a positive test result. Most emergency departments no longer perform this test and instead obtain a plasma salicylate level because these results are now rapidly available from almost all hospital laboratories and are much more useful clinically.

Arterial Blood Gas

Arterial blood gas (ABG) testing should be performed to evaluate for the presence of acid-base disturbances. Primary respiratory alkalosis may occur, followed by concomitant primary metabolic acidosis resulting from production of lactic acid, metabolites, and other organic acids. Therefore, the most common abnormality, especially in adults, is a mixed acid-base disturbance (a primary respiratory alkalosis plus a primary metabolic acidosis). The presence of this finding should raise the suspicion of the possibility of an aspirin overdose.

Repeated blood gases and serum salicylate levels should be done every 2 hours, until the acid-base status is improving, levels are falling, and the patient is clinically improving.

Approach Considerations

Salicylate toxicity continues to be seen in the emergency department as a result of unintentional ingestions or suicide attempts. A high index of suspicion is necessary, with prompt recognition of clinical signs and symptoms of salicylate poisoning, such as tinnitus, hyperventilation, tachycardia, and metabolic acidosis.[9] Early treatment can prevent organ damage and death.

Principles of treatment include stabilizing the ABCs as necessary, limiting absorption, enhancing elimination, correcting metabolic abnormalities, and providing supportive care. No specific antidote is available for salicylates.

Although determination of serial serum salicylate concentrations offers valuable information regarding the effectiveness of the treatment implemented, assessment of these levels alone is not a substitute for clinical evaluation of the patient. When considering treatment options, the final decision should be individualized according to the clinical status of the patient and should not depend only on a particular salicylate level.

Optimal management of a salicylate poisoning depends on whether the exposure is acute or chronic. Gastric lavage and activated charcoal are useful for acute ingestions but not for cases of chronic salicylism. Patients with chronic, rather than acute, ingestions of salicylates are more likely to develop toxicity, especially of the CNS, and require intensive care.

Salicylate poisoning has been shown to cause metabolic derangements with significant inhibition of Krebs cycle enzymes.[10] It also uncouples oxidative phosphorylation. Because of impaired glucose homeostasis, CNS glucose supply is sometimes lowered, which results in hypoglycorrhachia and delirium, even when serum glucose concentration is normal. Glucose boluses in euglycemic patients with salicylate-induced delirium have sometimes caused a prompt improvement in mental status and therefore should be given to any patient with a salicylate overdose who has a change in mental status, despite a serum glucose level within the reference range.

Oral ingestion of a large amount of acetylsalicylate, given for treatment of ear pain, has resulted in severe metabolic derangements and death. Brain histopathology revealed sparse gray matter changes and acute white matter damage.[11]

Onset of chronic salicylism may be insidious; elderly individuals may consume an increasing amount over several days to alleviate arthralgias, subsequently becoming confused because salicylate pharmacokinetics change at higher concentrations. This may lead to a perpetual spiral of increased salicylate consumption and increased confusion. Similar scenarios occur in persons with underlying psychiatric disorders.

Follow-up

Patients with accidental ingestions of less than 150 mg/kg and no signs of toxicity can be discharged 6 hours post ingestion. Arrange a follow-up for these patients in 24 hours.

Consultations

Early consultation with a medical toxicologist is prudent to assist in guiding patient management. Also, consultation with a nephrologist is indicated in serious overdoses to arrange for hemodialysis, if it becomes necessary.

Patients with intentional ingestions should have psychiatric consultation prior to discharge in the emergency department or on the ward.

Triage Care

In one study, authors reviewed US poison center data for 2004 and determined that over 40,000 exposures to salicylate-containing products occurred.[12] They published guidelines on triage care of these patients, discussed below.

Immediate emergency department referral by local poison control centers

Patients who state that an intentional ingestion occurred or in whom a large administration is suspected should immediately be referred to the emergency department. In addition, typical symptoms of salicylate toxicity warrant referral to the emergency department for evaluation.

Further triage care

Determine the dose, time of ingestion, presence of symptoms, history of other medical conditions, and presence of co-ingestants in all patients without evidence of self-harm. Do not induce vomiting for salicylate ingestion. Activated charcoal for acute ingestions of a toxic dose can be given if no contraindications are observed.

Asymptomatic dermal exposures to methyl salicylate or salicylic acid

The skin should be thoroughly washed with soap and water; the patient can be observed at home.

Ocular exposure to methyl salicylate or salicylic acid

The eye or eyes should be irrigated with room-temperature tap water for 15 minutes. If pain, decreased visual acuity, or persistent irritation is reported after irrigation, referral to an ophthalmologist is recommended.

Poison centers should monitor the onset of symptoms at periodic intervals for approximately 12-24 hours after ingestion. An evidence-based consensus guideline to assist poison center personnel in the appropriate out-of-hospital triage and initial out-of-hospital management of patients with a suspected exposure to salicylates is also available from the Department of Health and Human Services.[12]

Emergency Department Management

Therapeutic objectives include cardiopulmonary stabilization, prevention of absorption, correction of fluid deficits, correction of acid-base abnormalities, and enhancement of excretion and elimination. Large-bore vascular access catheters may be required to facilitate emergent hemodialysis.

Endotracheal intubation may be required for the following reasons:

ABCs

As with all significant overdoses the airway, breathing, and circulation (ABC) should be evaluated and stabilized as necessary. Dehydration and concomitant electrolyte abnormalities must be immediately corrected.

GI tract decontamination

Some authorities recommend performing gastric lavage in all symptomatic patients regardless of time of ingestion. Gastric lavage may be beneficial, unless contraindicated, up to 60 minutes after salicylate ingestion. Warmed (38°C) isotonic sodium chloride solution may be used. Protect the airway before gastric lavage.

Initial treatment should include the use of oral activated charcoal, especially if the patient presents within 1 hour of ingestion. Activated charcoal can limit further gut absorption by binding to the available salicylates. The recommended initial dose of activated charcoal is 1 g/kg of body weight to a maximum of 50 g in children and 1-2 g/kg to a maximum of 100 g in adults. The minimum dose is 30 g.

Use of cathartics is not routinely indicated with activated charcoal; however, many clinicians administer the first dose of activated charcoal with sorbitol. Sorbitol should not be used in young children. Repeat cathartic dosing generally should be avoided because of concern over resultant electrolyte imbalances.

Repeated doses of charcoal may enhance salicylate elimination and may shorten the serum half-life.[13] Although no convincing data support the administration of multidose activated charcoal, some experts strongly recommend this for patients with a very serious ingestion. Repeated doses of charcoal may remove salicylates from the circulation into the GI tract. Repeated doses of activated charcoal may assist in treating bezoars with ongoing absorption of salicylates, which should be suspected when salicylate levels continue to rise or fail to decrease, despite appropriate management. Repeated doses of activated charcoal have also been used to treat overdoses of enteric-coated or sustained-release aspirin; however, whole-bowel irrigation (WBI) with polyethylene glycol is probably more effective in this setting, as noted below.

The passage of stool with charcoal and the resolution of serious clinical manifestations may be the reasonable criteria for discontinuing multiple doses of activated charcoal.

WBI with polyethylene glycol was found to be more effective than single-dose activated charcoal in reducing salicylate absorption. The study was carried out in volunteer subjects 4 hours after they had ingested enteric-coated aspirin.[14] When enteric-coated aspirin has been ingested or when salicylate levels do not decrease despite treatment with charcoal, which may indicate that concretions are present, WBI should probably be used in addition to charcoal therapy.

The use of ipecac syrup is controversial, and many studies indicate that it does not alter the clinical outcome. It is most effective if given within 30 minutes of ingestion; however, it is relatively contraindicated in the presence of severe aspirin ingestion because of the risk of seizures and decreased mental status from aspirin, with the induced vomiting possibly leading to aspiration pneumonitis. In addition, the induced vomiting may cause a delay in administering activated charcoal.

Urinary excretion and alkalization

Provide treatment for correction of fluid deficits and enhancement of excretion and elimination. Administer lactated Ringer or isotonic sodium chloride solution for volume expansion at 10-20 mL/kg/h until a 1- to 1.5-mL/kg/h urine flow is established. Provide maintenance fluids to maintain urinary alkalization. Forced diuresis is not recommended. The greater the urine flow, the more difficult it is to alkalinize the urine. Be cautious of excessive fluid volumes in cases of salicylate-induced pulmonary edema.

Renal excretion of salicylic acid depends on urinary pH. Increasing the urine pH to 7.5 prevents reabsorption of salicylic acid from the urine.[15] Because acidosis facilitates transfer of salicylate into tissues, especially in the brain, it must be aggressively treated by raising blood pH higher than brain pH, thereby shifting the equilibrium from the tissues to the plasma.

Concomitant alkalization of blood and urine keeps salicylates away from brain tissue and in the blood, in addition to enhancing urinary excretion. When the urine pH increases to 8 from 5, renal clearance of salicylate increases 10-20 times. Raising the urinary pH level from 6.1 to 8.1 results in a more than 18-fold increase in renal clearance by preventing nonionic tubular back-diffusion, which decreases the half-life of salicylates from 20-24 hours to less than 8 hours. Because aspirin is a weak acid, it ionizes when exposed to a basic environment, such as alkaline urine. Ions are poorly reabsorbed in the tubules and are excreted more readily. This phenomenon is called ion trapping and also works well for overdoses of other weak acids, such as phenobarbital.

Most experts alkalinize the urine by giving an initial intravenous bolus of 1 mEq/kg of sodium bicarbonate and then start a sodium bicarbonate intravenous infusion. The continuous intravenous infusion is made by adding 3 ampules of sodium bicarbonate (each ampule containing 44 mEq of sodium bicarbonate) to a liter of D5W. The infusion is initially run at 2 times the maintenance rate and then titrated to keep the urinary pH greater than 7.5. Once the patient is putting out good amounts of urine, and it has been established that the patient is not in renal failure and is not hypokalemic, then 40 mEq of potassium can be added to each liter of this solution. A simple regimen for the use of bicarbonate in pediatric salicylate poisoning has been described by Ong.[16]

Hypokalemia and dehydration limit the effectiveness of urine alkalization. Hypokalemia prevents excretion of alkaline urine by promoting distal tubular potassium reabsorption in exchange for hydrogen ions. Symptomatic patients typically have low or borderline-low serum potassium concentration. Treatment with sodium bicarbonate alone may produce further intracellular shift of potassium ions, which further impairs the ability to excrete alkaline urine. Repletion of potassium is often necessary, even when serum potassium levels are in the low reference range (eg, < 4.5 mEq/L).

Urinary alkalization should be continued at least until serum salicylate levels decrease into the therapeutic range (< 30 mg/dL). Although acetazolamide results in the formation of a bicarbonate-rich alkaline urine, it unfortunately also causes metabolic acidosis that can worsen toxicity and, therefore, should not be used.

Hemodialysis

Indications for hemodialysis include a serum level greater than 120 mg/dL (acutely) or greater than 100 mg/dL (6 h postingestion), refractory acidosis, coma or seizures, noncardiogenic pulmonary edema, volume overload, and renal failure.

In chronic overdose, hemodialysis may be required for a symptomatic patient with a serum salicylate level greater than 60 mg/dL.

Although charcoal hemoperfusion has a slightly higher rate of drug clearance than does hemodialysis, dialysis is recommended because of its ability to correct for fluid and electrolyte disorders and to remove salicylates.

Peritoneal dialysis is only 10-25% as efficient as hemoperfusion or hemodialysis and is not even as efficient as renal excretion.

Inpatient Care

Admit patients with major signs and symptoms (eg, neurologic, cardiopulmonary, metabolic) to an intensive care unit under the care of a medical toxicologist, if available. Consult psychiatric service personnel for patients with intentional overdose.

Admit patients with minor signs and symptoms (eg, tinnitus, nausea) to an extended care observational unit or medical floor.

Admit the following patients, regardless of salicylate levels:

A patient may be discharged following adequate GI tract decontamination with activated charcoal if toxicity is mild, clinical improvement is progressive, acid-base disturbance is not significant, and serial decrease in serum salicylate levels towards the therapeutic range is documented. If any doubt is noted, the patient should be admitted to an appropriate facility.

Medication Summary

No specific antidote for salicylate poisoning is available. Therapy is focused on immediate resuscitation, correction of volume depletion and metabolic derangement, GI tract decontamination, and reduction of the body's salicylate burden. Early consultation with a medical toxicologist is prudent.

As previously mentioned, initial treatment should include the use of oral activated charcoal, especially if the patient presents within 1 hour of ingestion.

In a study, whole bowel irrigation (WBI) with polyethylene glycol was found to be more effective than single-dose activated charcoal in reducing salicylate absorption.[14] When enteric-coated aspirin has been ingested or when salicylate levels do not decrease despite treatment with charcoal, WBI should probably be used in addition to charcoal therapy.

Activated charcoal (Actidose-Aqua, Char-Caps, Kerr Insta-Char)

Clinical Context:  Activated charcoal can limit further gut absorption by binding to available salicylate. This is effective for the regular and sustained-release preparation. No convincing data support the use of repeated doses of activated charcoal in salicylate toxicity. Some authorities recommend repeated doses of activated charcoal to enhance elimination.

Class Summary

Consider activated charcoal decontamination in any patient who presents within 4 hours of ingestion. Activated charcoal is used for drug absorption and may be all that is required in mild to moderate toxicity. Activated charcoal is not absorbed and is excreted entirely through the GI tract.

Polyethylene glycol (Miralax, Dulcolax Balance)

Clinical Context:  Polyethylene glycol is a laxative with strong electrolyte and osmotic effects that has cathartic actions in the GI tract. Consider WBI when sustained-release products are involved. Remember that this agent does not adsorb anything but instead merely pushes things through the GI tract at a faster rate.

Class Summary

Laxatives with strong osmotic effects that cause cathartic actions to empty the bowel may be useful in this setting.

Sodium bicarbonate

Clinical Context:  Constant infusion of sodium bicarbonate produces urinary alkalization if the serum potassium is adequate (typically, >4.5 mEq/L). Urinary alkalization promotes the excretion of salicylate.

If the serum potassium level is low or in the lower end of the reference range (eg, < 4.5 mEq/L), hydrogen ions, instead of potassium ions, follow bicarbonate ions into the urine. Hence, the urine may remain acidic during bicarbonate infusion without potassium repletion.

Class Summary

Sodium bicarbonate is used as a gastric, systemic, and urinary alkalinizer and has been administered in the treatment of acidosis resulting from metabolic and respiratory causes. It also increases renal clearance of acidic drugs. Alkalization of the urine enhances elimination of salicylates through ion trapping in the renal tubules.

Author

Muhammad Waseem, MD, MS, Associate Professor of Emergency Medicine in Clinical Pediatrics, Weill Medical College of Cornell University; Consulting Staff, Department of Emergency Medicine, Lincoln Medical and Mental Health Center

Disclosure: Nothing to disclose.

Coauthor(s)

Joel R Gernsheimer, MD, FACEP, Visiting Associate Professor, Department of Emergency Medicine, Attending Physician and Director of Geriatric Emergency Medicine, State University of New York Downstate Medical Center

Disclosure: Nothing to disclose.

Muhammad Aslam, MD, Assistant Professor of Pediatrics, Harvard Medical School; Staff Physician, Division of Newborn Medicine, Department of Pediatrics, Massachusetts General Hospital

Disclosure: Nothing to disclose.

Chief Editor

Timothy E Corden, MD, Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin

Disclosure: Nothing to disclose.

Additional Contributors

Fred Harchelroad, MD, FACMT, FAAEM, FACEP Chair, Department of Emergency Medicine, Director of Medical Toxicology, Allegheny General Hospital; Associate Professor, Department of Emergency Medicine, Drexel University College of Medicine

Disclosure: Nothing to disclose.

Lance W Kreplick, MD, FAAEM, MMM Medical Director of Hyperbaric Medicine, Fawcett Wound Management and Hyperbaric Medicine; Consulting Staff in Occupational Health and Rehabilitation, Company Care Occupational Health Services; President and Chief Executive Officer, QED Medical Solutions, LLC

Lance W Kreplick, MD, FAAEM, MMM, is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physician Executives

Disclosure: Nothing to disclose.

Michael E Mullins, MD Assistant Professor, Division of Emergency Medicine, Washington University in St Louis School of Medicine; Attending Physician, Emergency Department, Barnes-Jewish Hospital

Michael E Mullins, MD is a member of the following medical societies: American Academy of Clinical Toxicology and American College of Emergency Physicians

Disclosure: Johnson & Johnson stock ownership None; Savient Pharmaceuticals stock ownership None

Mark S Slabinski, MD, FACEP, FAAEM Vice President, EMP Medical Group

Mark S Slabinski, MD, FACEP, FAAEM is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, and Ohio State Medical Association

Disclosure: Nothing to disclose.

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Jeffrey R Tucker, MD Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut School of Medicine, Connecticut Children's Medical Center

Disclosure: Merck Salary Employment

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Additional Contributors

Fred Harchelroad, MD, FACMT, FAAEM, FACEP Chair, Department of Emergency Medicine, Director of Medical Toxicology, Allegheny General Hospital; Associate Professor, Department of Emergency Medicine, Drexel University College of Medicine

Disclosure: Nothing to disclose.

Lance W Kreplick, MD, FAAEM, MMM Medical Director of Hyperbaric Medicine, Fawcett Wound Management and Hyperbaric Medicine; Consulting Staff in Occupational Health and Rehabilitation, Company Care Occupational Health Services; President and Chief Executive Officer, QED Medical Solutions, LLC

Lance W Kreplick, MD, FAAEM, MMM, is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physician Executives

Disclosure: Nothing to disclose.

Michael E Mullins, MD Assistant Professor, Division of Emergency Medicine, Washington University in St Louis School of Medicine; Attending Physician, Emergency Department, Barnes-Jewish Hospital

Michael E Mullins, MD is a member of the following medical societies: American Academy of Clinical Toxicology and American College of Emergency Physicians

Disclosure: Johnson & Johnson stock ownership None; Savient Pharmaceuticals stock ownership None

Mark S Slabinski, MD, FACEP, FAAEM Vice President, EMP Medical Group

Mark S Slabinski, MD, FACEP, FAAEM is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, and Ohio State Medical Association

Disclosure: Nothing to disclose.

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Jeffrey R Tucker, MD Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut School of Medicine, Connecticut Children's Medical Center

Disclosure: Merck Salary Employment

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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