39: Salicylates

Daniel M. Lugassy

HISTORY AND EPIDEMIOLOGY

The Ancient Egyptians recognized the pain-relieving effects of concoctions made from myrtle and

willow leaves. Hippocrates may have been among the first to use willow bark and leaves from

the Salix species to relieve fever, but it was not until 1829 that the glycoside salicin was extracted

from the willow bark and used as an antipyretic. Seven years later, salicylic acid was isolated, and

by the late 1800s, it was being used to treat gout, rheumatic fever, and elevated temperatures. The

less irritating acetylated salicylate compound was first synthesized in 1833, and in 1899

acetylsalicylic acid was commercially introduced as aspirin by Bayer. With that, the modern era of

aspirin therapy and salicylate toxicity began.

The American Association of Poison Control Centers (AAPCC) National Poison Data System

(NPDS) collects and reports annual exposure data in the United States. Analgesics, which include

both aspirin and acetaminophen (APAP), continue to rank first among pharmaceuticals most

frequently reported in human exposures (Chap. 136). Salicylate toxicity and fatalities have long been

a major toxicological “concern.” From the 1950s to 1970s, salicylate was the leading cause of fatal

childhood poisoning. The association with Reye syndrome; safer packaging; and the increased use

of nonsteroidal antiinflammatory drugs (NSAIDs), APAP, and other alternatives to aspirin has

decreased the incidence of unintentional salicylate poisoning. In the last 5 years of data available

(2008–2012), there were 20 to 30 deaths per year reported (Chap. 136). Despite this decline in

reported deaths and general use, it is still imperative that clinicians are adept at early recognition

and swift management of patients with salicylate overdose.

Aspirin and other salicylate containing products continue to be some of the most common

prescription and nonprescription xenobiotics used by the general public. Since landmark trials

demonstrated the inhibition of platelet function by aspirin in the 1970s, its use became the standard

of care for cardiovascular disease prevention and treatment. Subsequent investigations have

demonstrated that aspirin can decrease the incidence of myocardial infarction, colon cancer, and

transient ischemic attack. Its antiinflammatory properties have also continued to make it an active

investigational xenobiotic for cancer.1

Bayer, a company once associated exclusively with aspirin, several years ago turned to making

products containing ibuprofen or APAP. But in a very recent move of re-branding, Bayer is now

marketing a return of aspirin for pain relief with three new products containing aspirin alone; aspirin

with caffeine; and aspirin, caffeine, and APAP. Salicylates continue to be readily available and will

continue to lead to significant morbidity and mortality in overdose.

PHARMACOLOGY

Aspirin and other salicylates have analgesic, antiinflammatory, and antipyretic properties, a

combination of traits shared by all of the NSAIDs (Chap. 37). Most of the beneficial effects of

NSAIDs result from their inhibition of cyclooxygenase (COX). This enzyme enables the synthesis of

prostaglandins, which in turn mediate inflammation and fever.116,136 Contributing to the

antiinflammatory effects and independent of the effects on prostaglandins, salicylates and other

NSAIDs may also directly inhibit neutrophils.9 There are two types of salicylic acid esters, phenolic

esters such as aspirin and carboxylic acid esters, including methyl salicylate, phenyl salicylate, and

glycosalicylate.26 Most of the studies of salicylate metabolism involve aspirin.26 There is an implicit

assumption that all members of the salicylate class have similar properties after being converted to

salicylic acid.

Salicylates and NSAIDs are purportedly most effective in treating the pain accompanying

inflammation and tissue injury. Such pain is elicited by prostaglandins liberated by bradykinin and

other cytokines. Fever is also mediated by cytokines such as interleukin (IL)-1β, IL-6, α and β

interferons, and tumor necrosis factor-α, all of which increase synthesis of prostaglandin E2. In turn,

this inflammatory mediator increases cyclic adenosine monophosphate (cAMP), which triggers the

hypothalamus to elevate the body temperature set point, resulting in increased heat generation and

decreased heat loss.108

Because platelets cannot regenerate COX-1, a daily dose of as little as 30 mg of aspirin inhibits

COX-1 for the 8- to 12-day lifespan of the platelet.108 Adverse effects of aspirin and some NSAIDs

related to alteration of COX include gastrointestinal (GI) ulcerations and bleeding, interference with

platelet adherence,109 and a variety of metabolic and organ-specific effects described later.

To achieve an antiinflammatory effect for patients with chronic conditions such as rheumatoid

arthritis, salicylates are primarily prescribed in doses sufficient to achieve a serum salicylate

concentration between 15 and 30 mg/dL, which is considered the therapeutic range. Concentrations

higher than 30 mg/dL are typically associated with signs and symptoms of toxicity.

PHARMACOKINETICS

Aspirin is rapidly absorbed from the stomach. The pKa of aspirin is 3.5, and the majority is nonionized

(ie, acetylsalicylic acid) in the strongly acidic stomach (pH 1–2).26,56 Although absorption of

acetylsalicylate may be less efficient in the small bowel because of its higher pH, it is substantial and

rapid because of the large surface area and the fact that the increase in pH increases the solubility

of acetylsalicylate.84,85 After ingestion of therapeutic doses of immediate release acetylsalicylate,

significant serum concentrations are achieved in 30 minutes, and maximum concentrations are often

attained in less than 1 hour.26

The plasma half-life of aspirin is about 15 minutes, because it is rapidly hydrolyzed to salicylate. The

apparent half-life for salicylate is about 2 to 3 hours at antiplatelet doses and increases to 12 hours

at antiinflammatory doses demonstrates dose dependent elimination.88 Aspirin undergoes

biotransformation in the liver and is then eliminated by the kidneys. The apparent volume of

distribution (Vd) increases from 0.2 L/kg at low concentrations to 0.3 to 0.5 L/kg at higher

concentrations.73,74,117

TOXICOKINETICS

In overdose, several factors contribute to significantly altered pharmacokinetics that can present very

challenging obstacles to effectively managing patients poisoned with salicylates. The dose obviously

is critical in contributing to the magnitude and duration of toxicity, but other important factors include

the formulation, rate of gastric emptying, bezoar formation, hepatic and renal function, and both the

serum and urine pH.

There is a decrease in protein (albumin) binding from 90% at therapeutic concentrations to less than

75% at toxic concentrations caused by saturation of protein binding sites.2,11,33 Salicylates have

substantially longer apparent half-lives at toxic concentrations than at therapeutic concentrations,

varying from 2 to 4 hours at therapeutic concentrations to as long as 20 hours at toxic

concentrations.28,73 The dosage form of salicylates (eg, effervescent, enteric coated) influences the

absorption rate.107,110,131Therapeutic doses of enteric-coated tablets may not produce peak serum

concentrations until 4 to 6 hours after ingestion, and in overdose the peak may not be reached until

24 hours after ingestion.34,131 Delayed absorption of aspirin may result from salicylate induced

pylorospasm or pharmacobezoar formation.11,107,113

Salicylates are conjugated with glycine and glucuronides in the liver and are eliminated by the

kidneys. Approximately 10% of salicylates are excreted in the urine as free salicylic acid, 75% as

salicyluric acid, 10% as salicylic phenolic glucuronides, 5% as acylglucuronides, and 1% as gentisic

acid108 (Fig. 39–1). As the concentration of salicylates increases, two of the five pathways of

elimination—those for salicyluric acid and the salicylic phenolic glucuronide—become saturated and

exhibit zero-order kinetics. As a result of this saturation, overall salicylate elimination changes from

first-order kinetics to zero-order kinetics73,74 (Chap. 9). In a healthy adult, these altered saturation

kinetics may occur after as little as 1 to 2 g of acute aspirin ingestion.73

FIGURE 39–1.

Salicylic acid metabolism. At excessive doses, the four mechanisms of salicylic acid metabolism are overloaded,

leading to increased tissue binding, decreased protein binding, and increased excretion of unconjugated salicylic

acid. Asterisk indicates Michaelis-Menten kinetics; double asterisk indicates first-order kinetics.

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When administered chronically, a small increase in dosage or a small decrease in metabolism or

elimination may result in substantial increases in serum salicylate concentrations and the risk of

toxicity.65 At very high serum concentrations, salicylate elimination may again resemble first-order

elimination as an increasing fraction undergoes renal clearance.

Free salicylic acid is filtered through the glomerulus and is both passively reabsorbed and actively

secreted from the proximal tubules. More than 30% of an ingested salicylate dose may be eliminated

in alkaline urine and as little as 2% in acidic urine.127 Salicylate conjugates (glycine and glucuronides)

are filtered and secreted by the proximal tubules; salicylate conjugates are not reabsorbed across

renal tubular cells because of limited lipid solubility, and the amount eliminated depends on the

glomerular filtration rate and proximal tubule secretion but not urine pH. Protein-binding

abnormalities, urine and plasma pH variations, and delayed absorption all influence both the

maximum salicylate concentration and the rate of decline.85,107

Other Forms of Salicylate

Topical Salicylate, Methyl Salicylate (Oil of Wintergreen), and Salicylic Acid.

Topical salicylates, which are used as keratolytics (salicylic acid) or as rubefacients (≤30% methyl

salicylate), are rarely responsible for salicylate poisoning when used in their intended manner

because absorption through normal skin is very slow. However, particularly in children, extensive

application of topical preparations containing methyl salicylate may result in poisoning.14,129 After 30

minutes of contact time, only 1.5% to 2.0% of a dose is absorbed, and even after 10 hours of contact

with the methyl salicylate, only 12% to 20% of the salicylate is systemically absorbed.14 Heat,

occlusive dressings, young age, inflammation, and psoriasis all increase topical salicylate

absorption.16,17 In a study of healthy volunteers, a profound effect of transdermal absorption of methyl

salicylate was demonstrated from exercise and heat exposure, with a threefold increase in the

systemic availability of salicylate.25

Ingestion of methyl salicylate may be disastrous because 1 mL of 98% oil of wintergreen contains an

equivalent quantity of salicylate as 1.4 g of aspirin. The minimum toxic salicylate dose of

approximately 150 mg/kg body weight can almost be achieved with 1 mL of oil of wintergreen, which

represents 140 mg/kg of salicylates for a 10-kg child. In Hong Kong, medicated oils containing

methyl salicylate accounted for 48% of acute salicylate poisoning cases treated in one

hospital.16 Methyl salicylate is rapidly absorbed from the GI tract, and much, but not all, of the ester is

rapidly hydrolyzed to free salicylates. Despite rapid and complete absorption, serum concentrations

of salicylates are much less than predicted after ingestion of methyl salicylate containing liniment

compared with oil of wintergreen.129 Vomiting is common, along with abdominal discomfort. The

onset of symptoms usually occurs within 2 hours of ingestion.17 Patients with methyl salicylate

exposure have died in less than 6 hours, emphasizing the need for early determinations of salicylate

concentrations in addition to frequent testing after such exposures.

Bismuth Subsalicylate.

Bismuth subsalicylate, which is available in several nonprescription formulations, releases the

salicylate moiety in the GI tract, where it is subsequently absorbed. Each milliliter of common liquid

preparations of bismuth subsalicylate contains 8.7 mg of salicylic acid.39After a large therapeutic

dose (60 mL), peak salicylate concentrations may reach 4 mg/dL at 1.8 hours after

ingestion.39 Patients with diarrhea and infants with colic using large quantities of bismuth

subsalicylate may develop salicylate toxicity.125 Chronic use should also raise concerns for bismuth

toxicity (Chap. 90).

PATHOPHYSIOLOGY

Because salicylic acid is a weak acid, at physiologic pH, it exists predominantly in a charged

(ionized) state (Chap. 12). But in overdose as the serum pH falls, more salicylate shifts toward a

nonionized (uncharged) salicylic acid form that is highly permeable, allowing swift movement across

lipid bilayers and cell membranes. This is an important effect in that it allows salicylic acid to enter

cells exerting its toxic effects across a wide variety of organs and is discussed later as a target for

management.

Acid–Base and Metabolic Effects

Salicylate interferes with the Krebs cycle, which limits production of adenosine triphosphate

(ATP).63 It also uncouples oxidative phosphorylation, causing accumulation of pyruvic and lactic

acids and releasing energy as heat68 (Chaps. 12 and 13). Salicylate-induced increases in fatty acid

metabolism generates ketone bodies, including β-hydroxybutyric acid, acetoacetic acid, and

acetone. Toxic concentrations of salicylate impair renal hemodynamics, leading to the accumulation

of inorganic acids. The net result of all of these metabolic processes is an anion gap metabolic

acidosis (Chap. 19) in which the unmeasured anions include salicylate and its metabolites, lactate,

ketoacids, and inorganic acids.

The salicylate effect on glucose metabolism is variable and may depend on the severity and phase

of toxicity. Salicylate administration in mice increases glycogenolysis and can result in

hyperglycemia.115 Early adrenergic effects of acute salicylate toxicity may stimulate epinephrine and

glucagon release, enhancing glycogenolysis as well as gluconeogenesis. But salicylate can inhibit

alanine and aspartate aminotransferase, and both enzymes provide key amino acid substrates for

gluconeogenesis. Hypoglycemia may also occur because of the combined effect of increased

energy demands, depletion of glycogen stores, and decreased gluconeogenesis.104

Salicylate poisoned mice had dramatic increases in serum lactate concentration compared with

control mice, likely because of increased glycogenolysis and anaerobic glycolysis to compensate

partly for the energy loss caused by uncoupling of oxidative phosphorylation.53,83 There was also a

marked increase in oxygen consumption in mice even with low salicylate concentrations, highlighting

the importance of salicylate induced uncoupling of oxidative phosphorylation.54 Several investigations

using intact or fragmented mitochondria demonstrate that increasing concentrations of salicylate

result in decreased phosphate uptake and a concomitant decrease in the phosphate/oxygen (P/O)

ratio.83,94 The impaired P/O ratio demonstrates the inefficiency of ATP production by illustrating that

the rate of phosphate incorporation into ATP per molecule falls despite oxygen consumed during

oxidative phosphorylation. Salicylates reduce lipogenesis by blocking the incorporation of acetate

into free fatty acids and increase peripheral fatty acid metabolism as an energy source, resulting in

ketone formation. Salicylate-induced increased fatty acid metabolism generates ketone bodies,

including β-hydroxybutyric acid, acetoacetic acid, and acetone.

NEUROLOGIC EFFECTS

The central nervous system (CNS) effects are the most visible and most consequential clinical

effects in salicylate-poisoned patients. With increasing CNS salicylate concentrations, neuronal

energy depletion likely develops as salicylate uncouples neuronal and glial oxidative

phosphorylation.83 Several other mechanisms also likely contribute to the neurotoxic effects of

salicylates. Salicylate also causes release of apoptosis inducing factor (AIF) or cytochrome C,

triggers p38 mitogen, activated protein kinase, and activates glial caspase-3, which are responsible

for programmed neuronal cell death.105 It is likely that these effects in addition to severe cellular

acidosis lead to neuronal dysfunction and ultimately cerebral edema.

Salicylate poisoning may produce a clinical discordance between serum and cerebrospinal fluid

(CSF) glucose concentrations.104 Despite normal serum glucose concentrations, CSF glucose

concentration decreased 33% in salicylate-poisoned mice compared with control mice.123 In other

words, the rate of CSF glucose use exceeded the rate of supply even in the presence of a normal

serum glucose concentration. This hypoglycorrhachia demonstrates that altered glucose metabolism

and transport may also play a role in the deleterious neurologic effects of salicylate poisoning.

Salicylate-poisoned mice have lower CSF glucose concentrations compared with control mice but

can maintain similar concentrations of ATP by enhanced glycolysis. Administration of dextrose in

these salicylate-poisoned mice suppressed clinical signs of toxicity underlying the importance of

providing supplemental glucose despite normal serum concentrations as discussed later in the

management of toxicity.123

Hepatic Effects

Hepatic injury from either acute or chronic overdose of salicylate is rare. Although the hepatocyte is

the location of its toxic effects on several metabolic pathways such as glycogenolysis and the Krebs

cycle, other concurrent co-ingestants and causes should be considered if there is a clinically

significant elevation of aminotransferases or bilirubin concentration or signs of acute liver failure.134

An unavoidable historical link exists between the hepatic encephalopathy in Reye syndrome and

aspirin. A buildup of fatty acids in the hepatocyte resulting in microvesicular steatosis is

characteristic of Reye syndrome. This may occur through salicylate depletion of intrahepatocyte

coenzyme A (Co-A), where fatty acids entering the hepatocyte cytoplasm cannot be transported into

the mitochondria for β-oxidation. Although there is no mechanism to explain why aspirin has a

causal relationship in Reye syndrome, it is clear from epidemiologic evidence that aspirin is an

essential cofactor among others in the development of this syndrome.46

Otolaryngologic Effects

The molecular mechanism of salicylate ototoxicity is not completely understood but appears to be

multifactorial. Inhibition of cochlear COX by salicylate increases arachidonate, enabling calcium flux

and neural excitatory effects of N-methyl-D-aspartic acid (NMDA) on cochlear spinal ganglion

neurons.100,101,112 Also, the prevention of prostaglandin synthesis interferes with the Na+-K+-adenosine

triphosphatase (ATPase) pump in the stria vascularis, and the vasoconstriction decreases cochlear

blood flow.12,15,37,61 Membrane permeability changes cause a loss of outer hair cell turgor in the organ

of Corti, which may impair otoacoustic emissions.100,102 A more complete description of the

pathophysiology of salicylate-induced ototoxicity and sensorineural alterations as well as

comparisons with the patterns of other ototoxic xenobiotics can be found in Chap. 26.

Pulmonary Effects

Salicylates have very potent stimulatory effects on respiratory drive via several mechanisms. Direct

stimulation of the medullary respiratory neurons produces hyperpnea and tachypnea even at

therapeutic concentrations. In fact, in a human trial, salicylates decreased the number and duration

of apneic events in patients with sleep apnea.96Increased sensitivity to PCO2 and pH further

increases ventilation. Carotid body and peripheral arterial chemoreceptor stimulation also contribute

to salicylate-induced hyperventilation.81

Patients with either acute or chronic salicylism may develop acute respiratory distress syndrome

(ARDS). It is often a sign of severe and advanced toxicity and can be lethal. One study106 that

summarized data from nearly 400 consecutive cases of salicylate toxicity reported in the

literature4,51,122,128 concluded that ARDS occurred in approximately 7% of cases. The development of

ARDS in salicylate poisoning is associated with a history of cigarette smoking, chronic overdose,

metabolic acidosis, and neurologic symptoms at the time of arrival.90

Although the exact etiology of salicylate-induced ARDS is unclear, as with other etiologies ARDS

can result from increased pulmonary capillary permeability and subsequent exudation of high-protein

edema fluid into the interstitial or alveolar spaces.57 Adrenergic excess in salicylate poisoning may

injure the hypothalamus, leading to a shift in blood from the systemic to the pulmonary circulation

because of a loss of left ventricular compliance with left atrial and pulmonary capillary hypertension

(Chap. 17). Additionally, the resulting hypoxia produces pulmonary arterial hypertension and a local

release of vasoactive substances, worsening ARDS.58 Unventilated salicylate-poisoned sheep were

more likely to develop ARDS compared with a mechanically ventilated control group, suggesting that

the mechanical stress of prolonged and severe hyperventilation is a significant contributing factor to

this complication.78

Gastrointestinal Effects

Salicylate disrupts the mucosal barrier that normally protects the gastric lining from the extremely

acidic contents of the stomach. GI injury leading to ulcers or bleeding are among the most common

adverse effects from therapeutic use of aspirin, but in acute overdose, the most common

manifestations result from local gastric irritation presenting with nausea and vomiting. Emesis

appears to be triggered both by local mucosal irritation and central stimulation of the chemoreceptor

trigger zone.10 Hemorrhagic gastritis, decreased gastric motility, and pylorospasm result from the

direct gastric irritant effects of salicylates.110

Renal Effects

The kidneys play a major role in the excretion of salicylate and its metabolites. Although some

believe that salicylates are nephrotoxic, the majority of experimental evidence does not strongly

support this notion.24,35,95 Most of the adverse renal effects historically associated with salicylates

occurred with use of combination products such as aspirin–phenacetin–caffeine (APC) tablets and

appear to have been mostly caused by the phenacetin.35 Renal papillary necrosis and chronic

interstitial nephritis, initially characterized by reduced tubular function and reduced concentrating

ability, rarely occur in adults using salicylates unless they have chronic illnesses that already

compromise renal function.

Volume losses in patients with salicylate toxicity that develop from hyperventilation and hyperthermia

may also cause prerenal acute kidney injury (AKI). Rarely, salicylates may also induce a Fanconilike

syndrome with generalized proximal tubular dysfunction characterized by glucosuria (despite normal

serum glucose), proteinuria, aminoaciduria, and uric acid wasting.124

Hematologic Effects

The hematologic effects of salicylate poisoning include hypoprothrombinemia and platelet

dysfunction.93 The platelet dysfunction, caused by irreversible acetylation of COX-1 and COX-2,

prevents the formation of thromboxane A2, which is normally responsible for platelet aggregation.

Although the platelets are numerically and morphologically intact, they are unresponsive to

thrombogenic stimulation. At supratherapeutic doses, salicylate decreases the plasma concentration

of the γ-carboxyglutamate containing coagulation factors and an accumulation of microsomal

substrates for vitamin K dependent carboxylase in the liver and in the lung.111 The result of this

interruption of vitamin K cycling is similar to that of warfarin,92 leading to hypoprothrombinemia (factor

II) as well as decreases in factors VII, IX, and X (Chap. 60).

CLINICAL MANIFESTATIONS OF SALICYLATE

POISONING

The following sections describe the typical clinical manifestations that follow toxic exposures to

salicylates. The natural course of acute ingestions begins with nonspecific GI symptoms, early

tachypnea caused by direct central respiratory stimulation, development of an anion gap metabolic

acidosis, and several minor neurologic sequelae. As the acidosis worsens, symptoms progress and

will invariably evolve to severe CNS toxicity. Hyperthermia, cerebral edema, coagulopathy, ARDS,

and severe acidemia are the gravest clinical consequences and are often preterminal events.

Cerebral edema is often seen at autopsy in those who succumb to salicylate toxicity.

The earliest signs and symptoms of salicylate toxicity, which include nausea, vomiting, diaphoresis,

and tinnitus, typically develop within 1 to 2 hours of acute exposure.12,44 But the type of salicylate

containing preparation, comorbidities, co-ingestants, and compromise in renal or hepatic function

may alter the onset of symptoms that can be delayed up to 24 hours after exposure.110 Case reports

of enteric-coated aspirin tablet ingestions have demonstrated delays in symptom onset and time to

initial detectable salicylate concentration, with peak salicylate concentrations reported to occur 2 to 3

days after initial exposure.31,131

Acute Salicylate Toxicity

Salicylates are extremely irritating to the GI lining; early vomiting after ingestion may be a warning

sign of a clinically significant ingestion. Emesis occurs both by direct GI irritation and from salicylate-

induced stimulation of the chemoreceptor trigger zone.10Pylorospasm, delayed gastric emptying, and

decreased GI motility can all be present, complicating toxicity by altering absorption kinetics.

Hemorrhagic gastritis also occurs, likely as a consequence of severe emesis and alteration of

protective GI barriers.

The initial evaluation of a patient suspected of salicylate poisoning must start at the bedside with a

thorough assessment of the respiratory rate and depth. Subtle tachypnea or hyperpnea should not

be overlooked because if missed, delays may occur in the initiation of appropriate laboratory

analysis and management. Direct central stimulation of the respiratory center increases minute

ventilation, determined by the product of respiratory rate and tidal volume. A primary respiratory

alkalosis predominates initially, although an anion gap metabolic acidosis begins to develop early in

the course of salicylate toxicity. By the time a symptomatic adult patient presents to the hospital after

a salicylate overdose, a mixed acid–base disturbance is often prominent.44 This latter finding includes

two primary processes, respiratory alkalosis and metabolic acidosis, and is discernible by arterial

blood gas (ABG) or venous blood gas (VBG) and serum electrolyte analyses. In one study of 66

salicylate-poisoned adults, 22% had respiratory alkalosis, and 56% had mixed respiratory alkalosis

and metabolic acidosis.44

On presentation, salicylate poisoned adults who demonstrate respiratory acidosis should alert the

clinician to the fact that systemic toxicity is severe. This patient may be late in the clinical course of

poisoning and have salicylate induced ARDS, fatigue from hyperventilating for a prolonged period of

time, or CNS depression (from either salicylate itself or co-ingestants). These broad variations of

clinical toxicity can be divided into three general time frames based on rapidly available laboratory

testing. Early, middle, and late salicylate poisoning are demonstrated in Table 39–1.

TABLE 39–1. Acid-Base Stages of Salicylate Toxicity

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Mixed overdoses are common; in one study, one-third of patients with a presumed primary salicylate

overdose had taken other xenobiotics.44 Benzodiazepines, barbiturates, alcohol, and cyclic

antidepressants all blunt the centrally induced hyperventilatory response to salicylates, resulting in

either actual respiratory acidosis (PCO2>40 mm Hg) or metabolic acidosis without some respiratory

compensation (PCO2<40 mm Hg but inappropriately high for the concomitant degree of metabolic

acidosis). In both adults and children, the development of respiratory acidosis may occur as

salicylate poisoning progresses. The combination of metabolic and respiratory acidosis in a

salicylate poisoning results in severe and worsening acidemia that is an exceedingly grave situation

and almost invariably is a preterminal event.98

When clinical and radiographic manifestations of ARDS are observed in the setting of salicylate

toxicity, the following conditions should be considered: aspiration pneumonitis, viral and bacterial

infections, neurogenic ARDS, and salicylate-induced ARDS58,64 (Chap. 29). In 111 consecutive

patients with peak salicylate concentrations above 30 mg/dL, ARDS occurred in 35% of patients

older than 30 years of age and none of the 55 patients younger than 16 years of age. Risk factors for

developing ARDS included cigarette smoking, chronic salicylate ingestion, and the presence of

neurologic symptoms on admission. The average arterial blood pH was 7.37 in the six adult patients

with ARDS and 7.46 in the 30 adults without ARDS. There was no significant difference in salicylate

concentrations, which were approximately 57 mg/dL in both groups.128 In a 2-year review of all

salicylate deaths in Ontario, Canada, 59% of 39 autopsies revealed pulmonary pathology, mostly

“pulmonary edema” (ARDS).80

Although hyperventilation is centrally mediated, patients may develop a spectrum of CNS

abnormalities that includes confusion, agitation, and lethargy and then ultimately seizures and coma.

Human and animal evidence suggests that hypoglycorrhachia despite euglycemia contributes to the

neurotoxic effects. Stupor, coma, and delirium have been acutely reversed by the administration of

dextrose in children and adults with salicylate toxicity and normal serum glucose concentrations. In

one report, a child underwent lumbar puncture, and CSF analysis demonstrated no detectable

glucose.23 The most severe neurologic clinical findings are likely associated with the development of

cerebral edema and portend a poor prognosis. Excluding effects on ventilation, signs of neurologic

toxicity, even if mild, should be of great concern.

Tinnitus, a subjective sensation of ringing or hissing with or without hearing loss, loss of absolute

acoustic sensitivity, and alterations of perceived sounds are the three effects resulting from exposure

to large doses of salicylates.15 The pattern of salicylate-induced auditory sensorineural alterations is

different than that of other ototoxic xenobiotics.15Tinnitus should demonstrate to clinicians that CNS

toxicity has occurred even without alterations in mental status. As CNS salicylate concentrations

increase, tinnitus is rapidly followed by diminished auditory acuity that sometimes leads to

deafness.12 As acute toxicity progresses, other CNS effects may include vertigo, hyperactivity,

agitation, delirium, hallucinations, lethargy, seizures, and stupor. Coma is rare and is generally a late

finding occurring in severe acute poisoning or mixed overdoses.4,133

Paratonia, extreme muscle rigidity, has been observed in severe salicylate poisoning pre- and

postmortem, and in one case, it was even unresponsive to succinylcholine.80,103Decreased ATP

production, impaired glycolysis, increased lactate, and uncoupling of muscular oxidative

phosphorylation likely contribute to this phenomenon. This excess neuromuscular activity may lead

to rhabdomyolysis and most concerning hyperthermia that is typically a preterminal condition.72,83,84

Chronic Salicylate Toxicity

Chronic salicylate poisoning most typically occurs in elderly individuals as a result of unintentional

overdosing on salicylates used to treat chronic conditions such as rheumatoid arthritis and

osteoarthritis5,29,65 (Table 39–2). Presenting signs and symptoms of chronic salicylate poisoning can

be similar to those of acute toxicity and include nausea and vomiting, hearing loss and tinnitus,

dyspnea and hyperventilation, tachycardia, hyperthermia, and neurologic manifestations such as

confusion, delirium, agitation, hyperactivity, slurred speech, hallucinations, seizures, and

coma.4,32,71 Although there is considerable overlap with acute salicylate poisoning, the slow, insidious

onset of chronic poisoning in elderly individuals frequently causes delayed recognition of the true

cause of the patient’s presentation.4,44,70

TABLE 39–2. Differential Characteristics of Acute and Chronic Salicylate Poisoning

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Typically, ill patients who have chronic salicylate poisoning may be misdiagnosed as having delirium,

dementia, or encephalopathy of undetermined origin, or diseases such as sepsis (fever of unknown

origin), alcoholic ketoacidosis, respiratory failure, or cardiopulmonary disease.4,6,20,36 Unfortunately,

many of the signs and symptoms of chronic salicylate toxicity may be mistakenly attributed to the

illness for which the salicylates were administered.20,119 Despite an extensive evaluation during a first

hospitalization for ARDS, chronic salicylism was not diagnosed until a second hospitalization for the

same respiratory symptoms.22 This case highlights the need to include chronic salicylism in the

differential for ARDS with or without neurologic symptoms.

In a study of 73 consecutive adults hospitalized with salicylate poisoning, 27% were not correctly

diagnosed for as long as 72 hours after admission.4 These patients manifested toxicity with standard

or excessive therapeutic regimens and had significant associated diseases without a history of

previous overdoses. In this group, 60% of the patients had a neurologic consultation before the

diagnosis of salicylism was established. When diagnosis is delayed in elderly individuals, the

morbidity and mortality associated with salicylate poisoning are high. The mortality rate was reported

to be as high as 25% in the 1970s,4 and there are no data to suggest that survival after delayed

diagnosis is substantially better today.

EVALUATION AND DIAGNOSTIC TESTING

The most commonly reported route of salicylate exposure is from the acute ingestion of aspirin,

which, as mentioned earlier, has a very short serum half-life of about 15 minutes during which time it

is rapidly converted to salicylate. The symptoms of toxicity are due to the systemic effects of

salicylate and not the parent compound. Systemic toxicity is concerning after the following

exposures: ingestions of 150 mg/kg or 6.5 g of aspirin, whichever is less; ingestion of greater than a

lick or taste of oil of wintergreen (98% methyl salicylate) by children younger than 6 years of age;

and more than 4 mL of oil of wintergreen by patients 6 years of age and older.21 These patients as

well as those with significant topical exposures and signs of toxicity should be promptly evaluated for

salicylate toxicity.

The initial approach to a patient suspected of salicylate toxicity should obviously include a serum

salicylate concentration. But it is very important to recognize that other laboratory assays such as an

ABG or VBG, electrolytes to determine anion gap, the presence of serum or urine ketones, and a

lactate concentration can be critical in uncovering an unrecognized salicylate poisoning. It also may

be important to evaluate renal and hepatic function because dysfunction in either will exacerbate

toxicokinetic effects in patients with acute or chronic exposures.

As aspirin or other parent compounds are metabolized to salicylate, there should be a drop in serum

bicarbonate, leading to an increase in the anion gap. Elevated anion gaps are caused by increases

in unmeasured anions that are primarily salicylate but also related to increases in lactic acid,

ketoacids, and daily endogenous dietary acids. Volume loss from vomiting and excess metabolic

energy can cause AKI, which will decrease the elimination of dietary acids.

Several studies have suggested that empiric serum salicylate concentrations are not required as part

of a general toxicologic evaluation in patients with acute self-poisoning. Routine salicylate testing is

likely unnecessary without a positive history of salicylate ingestion, an inability to obtain a valid

history (altered mental status), or clinical features of salicylate poisoning.18,48,130 One retrospective

study also suggested that screening for salicylism is not needed in the absence of an elevated anion

gap.114 Although an anion gap metabolic acidosis is likely found in most cases of salicylate toxicity,

severe salicylism may falsely elevate serum chloride, bringing the anion gap closer to a normal

range.59

Although it may be wise to curtail empiric testing, clinicians should likely err on the side of ordering a

salicylate assay if there is any clinical concern because the morbidity and mortality are significantly

increased with delays in recognition and management. Many of the signs and symptoms of salicylate

toxicity are vague and may be mistakenly attributed to another illness with disastrous consequences.

In the review of all salicylate deaths in Ontario, Canada, in 1983 and 1984, the author noted that in

six of the 23 (26%) patients who arrived alert, no salicylate determination appears to have been

made and that probably neither the diagnosis nor the severity of the salicylate poisoning was

recognized.80

Salicylate Analysis

Serum salicylate concentrations are relatively easy to obtain in most hospital laboratories today.

Several methods are available for determining serum salicylate concentrations. The Trinder assay is

the most popular method for the measurement of salicylate in serum by using spectrophotemetric

analysis. Trinder’s reagent contains mercuric chloride and hydrochloric acid used to precipitate

serum proteins. The measured absorbance at 540 nm of a ferric ion–salicylate complex allows for

accurate determination of the serum salicylate concentration. Historically there have been several

bedside urine qualitative tests (ie, mercuric chloride, ferric chloride) used to assess for the presence

of salicylate. They have no clinical utility today because of poor specificity and chemical hazards and

are no longer permissible under the federal Clinical Laboratory Improvement Amendments (CLIA) in

the United States.

Serum salicylate concentrations are commonly reported in mg/dL in the United States, but confusion

can arise because values can also be reported in mg/L and µg/mL. Analyzing and reporting

salicylate concentrations as mg/L when the clinician is accustomed to receiving results as mg/dL or

inadvertently reporting actual mg/L (before internal laboratory conversion) produces erroneous

results.49 These may suggest a toxic salicylate concentration in a patient whose serum salicylate

concentration is actually within the therapeutic range (eg, “165 mg/L” instead of “16.5 mg/dL”). Most

errors can be eliminated before initiation of aggressive therapy, such as hemodialysis (HD), by

determining whether the reported salicylate concentration is consistent with the clinical presentation

and ABG or VBG results and, when time permits, repeating the salicylate determination with

appropriate consideration for methodology and conversion calculations.49 Using the earlier example,

a patient with a serum salicylate concentration of 165 mg/dL would undoubtedly show clinical signs

of salicylate toxicity and have a profound acid–base abnormality, but a patient with a concentration

of 165 mg/L would likely be asymptomatic.

It should also be noted that several clinical scenarios and xenobiotic exposures are recognized to

cause false-positive or falsely elevated true salicylate concentrations. Medications that may interfere

with the assay include thioridazine, promethazine,prochlorperazine, chlorpromazine, acetylcysteine,

and cysteamine.8 Significantly falsely elevated serum salicylate concentrations are well recognized

after diflunisal overdose.30,118 Hyperbilirubinemia can create clinically significant false-positive results

in neonates and adults.8,13 Interestingly, hyperlipidemia can also cause significant interference and

false elevation of serum salicylate concentrations.19 If there is concern for false salicylate

concentrations, clinicians should contact laboratory personnel, who often have information regarding

instrument-specific recognized interferences for each assay as published by the manufacturer.

Several techniques may be used to determine a true salicylate concentration in the setting of a

known interference. One of the most sensitive and specific assays now available is an automated

immunoassay based on specific antisalicylate antiserum with fluorescence polarization

immunoassay (FPIA) detection technology.8

Interpretation of Serum Salicylate Concentrations and Correlation with Toxicity

The recommended therapeutic concentration of salicylate is 10 to 30 mg/dL, but this varies by

indication. Antiinflammatory dosing usually is advised to be on the higher end of this spectrum, but

analgesic effects can be observed as low as 5 to 10 mg/dL. Values above 30 mg/dL are usually not

found unless there is a supratherapeutic, acute, or chronic toxic exposure.

The correlation of serum salicylate concentrations and clinical toxicity is often poor and dependent

on several factors. A concurrent arterial or venous blood pH should be determined when a serum

salicylate concentration is obtained because in the presence of acidemia, more salicylic acid leaves

the blood and enters the CSF and other tissues (Fig. 39–2), increasing the toxicity. A decreasing

serum salicylate concentration may be difficult to interpret because it may reflect either an increased

tissue distribution with increasing toxicity or an increased clearance with decreasing toxicity. A

decreasing serum salicylate concentration accompanied by a decreasing or low blood pH should be

presumed to reflect a serious or worsening situation, not a benign or improving one. Patients with

chronic toxicity demonstrate more significant clinical effects at lower concentrations compared with

acute toxicity given the increased distribution over time into tissue compartments and specifically the

CNS.

FIGURE 39–2.

Rationale for alkalinization. Alkalinization of the plasma with respect to the tissues and alkalinization of the urine with

respect to plasma shifts the equilibrium to the plasma and urine and away from the tissues, including the brain. This

equilibrium shift results in “ion trapping.”

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Although impractical clinically, salicylate concentrations in the CSF are likely the most accurate

measure of toxicity, directly correlating with death in a rat model.54 Animals that were lethally

poisoned with salicylate were comatose and died from seizures. The time to death after salicylate

administration varied greatly as did the blood, muscle, and liver salicylate concentrations. However,

regardless of the time of death and the concentrations in blood, muscle, or liver, all animals died with

a consistent range of CSF salicylate concentrations.54 Inhalation of CO2 (lowering serum pH) in a rat

resulted in a precipitous decrease in serum salicylate concentrations, which returned to baseline

rapidly after the discontinuation of CO2.53 This suggests that the salicylate redistributed into tissue

during the period of induced respiratory acidosis and reequilibrated after its correction. After

administration of radiolabeled salicylate to cats, autoradiographs of the brain visually and objectively

documented the profound effect that acidemia has on the distribution of salicylate into the brain.47

Before serum assays were readily available, physicians who prescribed aspirin would advise

patients to take repeated doses until tinnitus occurred and then “back off” a little to maintain this

“steady state.” Tinnitus and the subsequent reversible hearing loss typically occur at serum

salicylate concentrations of 20 to 45 mg/dL.12,15,87 This prompted investigations into whether salicylate-

induced tinnitus could be used as an indicator of serum salicylate concentration and toxicity.

Unfortunately, some patients with therapeutic concentrations of salicylates had tinnitus, and many

with higher or toxic concentrations had no tinnitus. In a study of 94 patients with salicylate

concentrations above 30 mg/dL on one or more occasions, tinnitus only correlated with serum

salicylate concentrations in 30%; 55% had no tinnitus, although audiologic testing results were

usually abnormal regardless of the patient’s perception of presence or absence of tinnitus.50 Thus,

although symptomatic ototoxicity may be a helpful warning sign of salicylate toxicity when present, it

is too nonspecific and too insensitive to serve as an indicator of serum salicylate concentrations.

MANAGEMENT

The management of patients with salicylate toxicity is aimed at supporting vital signs and organ

function, preventing or limiting ongoing exposure from the gut or skin, and enhancing elimination of

salicylate that has already entered the systemic circulation. It is imperative to understand that there

is no true antidote for salicylate toxicity; no xenobiotic can combat the clinical toxicity demonstrated

in consequential exposures. HD, as discussed later, aims to remove salicylate from the tissues but

may not correct severe organ toxicity such as ARDS or cerebral edema and can therefore not

guarantee survival after severe toxicity occurs.40,82 Rather, all therapies are better at preventing tissue

injury than treating it.

It is imperative to understand that the primary toxicity of salicylate is on the CNS, and the amount of

salicylate in the brain is a function of pH with acidemia enhancing CNS penetration of the drug.

Management strategies strive to create concentration gradients and pH conditions that favor exit of

salicylate from the CNS and other tissues and enhanced renal elimination.

Gastrointestinal Decontamination and Use of Activated Charcoal and Catharsis

The use of orogastric lavage and activated charcoal (AC) is discussed in Chap. 8 and Antidotes in

Depth: A1. Their effects on the absorption and elimination of salicylates have been extensively

studied. In vitro studies suggest that each gram of AC can adsorb approximately 550 mg of salicylic

acid.75,89 In humans, AC reduces the absorption of therapeutic doses of aspirin by 50% to 80%,

effectively adsorbing aspirin released from enteric-coated and sustained-release preparations in

addition to immediate-release tablets.75 Presumably, the sooner AC is given after salicylate ingestion,

the more effective it will be in reducing absorption. A 10:1 ratio of AC to ingested salicylate appears

to result in maximal efficacy but is often impractical given the fact that ingestions of salicylate often

reach 20- to 30-g amounts or more. Although peak serum concentrations are markedly decreased

from predicted concentrations, aspirin desorption from the aspirin–AC complex in the alkaline milieu

of the small bowel may diminish the impact of AC on total absorption.42,79,89 The addition of a cathartic

to the initial dose of AC has been questioned and largely abandoned for most xenobiotics, but a

benefit of adding sorbitol to AC in preventing salicylate absorption was demonstrated in one

study.66 A single dose may still therefore be acceptable.

Repetitive or multiple-dose AC (MDAC) is necessary to achieve desired ratios of activated charcoal

to salicylate (and probably limits desorption), which may reduce the concentration of initially

absorbed salicylate to only 15% to 20%.42 MDAC appears to increase the elimination of unabsorbed

salicylates over that achieved by single-dose AC.7,55 Thus, the use of MDAC to decrease GI

absorption of salicylates is warranted, barring contraindications particularly if a pharmacobezoar or

extended-release preparation is suspected (Antidotes in Depth: A1).

The value of MDAC in enhancing salicylate elimination through GI dialysis is controversial and is not

generally warranted.3,60 In one volunteer study of a 2800-mg dose of aspirin followed by 25 g of AC at

4, 6, 8, and 10 hours after ingestion, the total amount of salicylate excreted from the body increased

by 9% to 18% but was not considered statistically significant.67 The efficacy is likely greater in an

overdose situation, when more unbound salicylate is available because of decreased protein

binding. However, in another study of the effects of MDAC on the clearance of high-dose

intravenous (IV) aspirin in a porcine model, MDAC did not enhance the clearance of salicylates

under conditions when the venous bicarbonate was kept at 15 mEq/L or less and urine pH kept at

7.5 or less.60 In contrast to the findings of both of these studies, two children with salicylate

overdoses were successfully treated with MDAC given every 4 hours for 36 hours.126 Overall,

extensive use of MDAC is currently discouraged, but the administration of two to four properly timed

doses is reasonable. The administration of AC or MDAC must be balanced against risks of vomiting

and aspiration, especially in patients with altered mental status and unprotected airways (Chap. 8).

Theoretical support may be found for the use of whole-bowel irrigation (WBI) with polyethylene

glycol electrolyte lavage solution (PEG-ELS) in addition to AC to reduce absorption, particularly for

enteric-coated aspirin preparations.121 However, because the addition of WBI to MDAC does not

increase the clearance of absorbed salicylate in an experimental model,79 it is not routinely

recommended.

Fluid Replacement

There is a need to differentiate between restoration of fluid and electrolyte balance in salicylate-

poisoned patients and increasing the fluid load presented to the kidneys in an attempt to achieve

“forced diuresis.” Fluid losses in patients with salicylate poisoning are prominent, especially in

children, and can be attributed to hyperventilation, vomiting, fever, a hypermetabolic state, cathartic

administration, and perspiration.120 The kidneys also respond to salicylate poisoning by excreting an

increased solute load, including large quantities of bicarbonate, sodium, potassium, and organic

acids.5 For all of these reasons, the patient’s volume status must be adequately assessed and

corrected if necessary along with any glucose and electrolyte abnormalities. As in other cases,

accurate management of volume status in poisoned patients may require invasive or noninvasive

monitoring of central venous pressures, especially in patients with cardiac disease, ARDS, or AKI.

Increasing fluids beyond restoration of fluid balance to achieve forced diuresis is a practice that was

inappropriately promoted in the past. Although forced diuresis theoretically increases renal tubular

flow and reduces the urine tubular cell diffusion gradient for reabsorption, renal excretion of

salicylate depends much more on urine pH than on flow rate, and use of forced diuresis alone is not

effective regardless of whether diuretics, osmotic agents, or large fluid volumes are used to achieve

the diuresis.97Although renal salicylate clearance varies in direct proportion to flow rate, its relation to

pH is logarithmic.62,70 In summary, although fluid imbalance must be corrected, forced diuresis does

little more than oral fluids to enhance elimination over a 24-hour period97and subjects the patient to

the hazards of fluid overload.

Serum and Urine Alkalinization

The cornerstone of the management of patients with salicylate toxicity is to shift salicylate out of the

brain and tissues into the serum, where elimination through the kidneys can then occur.

Alkalinization of the serum with respect to the tissues and alkalinization of the urine with respect to

the serum accomplishes this goal by facilitating the movement and “ion trapping” of salicylate into

the serum and the urine (Fig. 39–2). Alkalinization of the serum by a substance that does not easily

cross the blood–brain barrier such as intravenously administered sodium bicarbonate reduces the

fraction of salicylate in the nonionized form and increases the pH gradient with the CSF. This both

prevents entry and helps remove salicylate from the CNS.47,52, 53, and 54,119

Alkalinization with IV sodium bicarbonate should be considered for all symptomatic patients whose

serum salicylate concentrations exceed the therapeutic range and for clinically suspected cases of

salicylism until a salicylate concentration and simultaneously obtained blood pH are available to

guide treatment. Patients on therapeutic regimens of salicylates who feel well with salicylate

concentrations of 30 to 40 mg/dL and who do not manifest toxicity do not require intervention.

Alkalinization may be achieved with a bolus of 1 to 2 mEq/kg of sodium bicarbonate IV followed by

an infusion of 3 ampules of sodium bicarbonate (132 mEq) in 1 L of 5% dextrose in water (D5W),

administered at 1.5 to 2.0 times the maintenance fluid range. Urine pH should be maintained at 7.5

to 8.0, and hypokalemia must be corrected (see later discussion) to achieve maximum urinary

alkalinization. Volume load should remain modest while previous losses are repleted (Antidotes in

Depth: A5).

Oral bicarbonate administration should never be substituted for IV bicarbonate to achieve

alkalinization because the oral route may increase salicylate absorption from the GI tract by

enhancing dissolution. Hyperventilation alone should not be relied upon, and intravenous sodium

bicarbonate should be used for alkalinization.

Urine Alkalinization

Because salicylic acid is a weak acid (pKa3.0), it is ionized in an alkaline milieu and theoretically can

be “trapped” there. This occurs because there is no specific uptake mechanism in the kidney for

salicylate ion, and passive reabsorption of a charged molecule is very limited. Thus, alkalinization of

the urine (defined as pH ≥7.5) with sodium bicarbonate results in enhanced excretion of the ionized

salicylate ion.

Alkalinization of the urine should be considered as a first-line treatment for patients with moderately

severe salicylate poisoning who do not meet the criteria for HD.99,123 It should also be administered to

salicylate-poisoned patients who require HD while preparations are being made to perform HD.

Although salicylic acid is almost completely ionized within physiologic pH limits, small changes in pH

obtained by alkalinization may have substantial changes in the relative amount of salicylate in the

charged form.

Regardless of the reason for the change in serum pH, renal excretion of salicylate is very dependent

on urinary pH.62,97,127 Alkalinization increases free salicylate secretion from the proximal tubule but

does not affect renal elimination of salicylate conjugates. Alkalinizing the urine from a pH of 5 to 8

logarithmically increased renal salicylate clearance from 1.3 to 100 mL/min62,86 (Fig. 39–3). Assuming

an overdose Vd of 0.5 L/kg, this increased clearance would decrease salicylate half-life from 310 to

4 hours. However, in reality alkalinizing the urine from a pH of 5 to 8 has a more modest effect on

serum salicylate clearance.97

FIGURE 39–3.

The relationship between urine pH and urine salicylate clearance. This curve was adapted from a logarithmic

relationship determined by Kallen in patients with salicylate poisoning. It illustrates the need to substantially increase

urine pH above 7 to impact elimination.

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Although the administration of acetazolamide, a noncompetitive carbonic anhydrase inhibitor, results

in the formation of bicarbonate-rich alkaline urine, it also causes a metabolic acidosis and

acidemia.41,52,53 This latter effect of acetazolamide is usually self-limited and mild but nevertheless

increases the concentration of freely diffusible nonionized molecules of salicylic acid, thereby

increasing the Vd and most probably enhancing the penetrance of salicylate into the CNS.53,73

Hypokalemia is a common complication of salicylate poisoning and sodium bicarbonatetherapy and

can prevent urinary alkalinization unless corrected. In the presence of hypokalemia, the renal

tubules reabsorb potassium ions in exchange for hydrogen ions, preventing urinary alkalinization. If

urinary alkalinization cannot be achieved easily, hypokalemia, excretion of organic acids, and salt

and water depletion should be considered possible reasons. Calcium concentrations should be

monitored because decreases in both ionized29 and total serum calcium43 are also complications of

bicarbonate therapy.

Glucose Supplementation

As discussed earlier, salicylate poisoning may significantly alter glucose metabolism, transport, and

relative requirements. Clinically, this is relevant in that the presence of a normal serum glucose

concentration may not be reflective of a normal CSF glucose concentration. It is suggested that the

neurotoxicity of salicylism may be partly caused by this hypoglycorrhachia. Dextrose administration

alone has reversed acute delirium associated with salicylate toxicity.23,69 It is therefore wise to liberally

administer dextrose to all patients with altered mental status in salicylate toxicity regardless of their

serum glucose concentration. A bolus of 0.5 to 1 g/kg of dextrose with additional or even continuous

infusion should be considered in patients being treated for severe salicylate toxicity.

Extracorporeal Removal

Extracorporeal measures are indicated if the patient has severe signs or symptoms, a very high

serum salicylate concentration regardless of clinical findings, severe fluid or electrolyte disturbances,

cerebral edema, or ARDS or is unable to eliminate the salicylates because of AKI (Table 39–3). It

should also be considered when a patient cannot tolerate the increased solute load that results from

alkalinization or large-volume infusions necessary. Failure to tolerate such therapy can be

anticipated if the patient has initial symptoms that are consistent with severe salicylate toxicity or has

a history congestive heart failure or chronic kidney disease.

TABLE 39–3. Indications for Hemodialysis in Salicylate Poisoned Patients

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In most instances, HD is the extracorporeal technique of choice, not only to clear the salicylate but

also to rapidly correct fluid, electrolyte, and acid–base disorders that will not be corrected by

hemoperfusion (HP) alone. The combination of HD and HP in series is feasible and theoretically may

be useful for treating patients with severe or mixed overdoses,27 but it is rarely used. A rapid

reduction of serum salicylate concentrations in severely poisoned patients has been described with

the use of continuous renal replacement therapy, a technique that may be valuable for patients who

are too unstable to undergo HD or when HD is unavailable132 (Chap. 10). There is only one published

clinical experience with sustained low-efficiency dialysis (SLED) for salicylate toxicity, which

demonstrated similar clearance rates to other continuous extracorporeal therapies.76 Its role still

requires further investigation.76

While the patient is awaiting HD, alkalinization of serum and urine should be aggressively achieved

with sodium bicarbonate therapy. During HD, it is unnecessary to continue bicarbonate therapy

because it will be provided by HD. It is prudent to reinstitute bicarbonate therapy after HD has been

completed, especially if patients are still symptomatic or serum salicylate concentrations are

pending.

Nephrology consultation should be sought early and liberally to anticipate and prevent avoidable

morbidity and mortality. Despite the well-recognized benefit of extracorporeal removal of salicylates

in severe toxicity, delays in initiating HD remain a potentially preventable cause of death despite

repeated calls over many years for prompt HD for patients with salicylate poisoning.40 The initiation of

HD should not be considered definitive treatment because patients may still have a significant GI

burden of salicylate, resulting in continued absorption, and even with early and multiple runs of HD,

patients may still succumb to this poisoning.82

Chemical Sedation, Intubation, and Mechanical Ventilation Risks

Salicylate-poisoned patients have a significantly increased minute ventilation rate brought about by

both tachypnea and hyperpnea, often exceeding 20 to 30 L/min. Any decrease in minute ventilation

increases the PCO2 and decreases the pH. This shifts salicylate into the CNS, exacerbating toxicity.

Thus, extreme caution must be used when considering chemical sedation, intubation, and initiating

mechanical ventilation.

Although induced hyperventilation may effectively increase the blood pH in certain patients,

endotracheal intubation followed by assisted ventilation of a salicylate-poisoned patient poses

particular risks if it is not meticulously performed. Although early endotracheal intubation to maintain

hyperventilation may aid in the management of patients whose respiratory efforts are faltering,

health care providers must maintain appropriate hypocarbia through hyperventilation. Ventilator

settings that result in an increase in the patient’s PCO2 relative to premechanical ventilation will

produce relative respiratory acidosis even if serum pH remains in the alkalemic range.

In a search of a poison center database of patients with salicylate poisoning between 2001 and

2007, seven patients were identified with salicylate concentrations above 50 mg/dL who had both

premechanical ventilation and postmechanical ventilation data. All seven had postmechanical

ventilation pH values below 7.4, and five of the six for whom recorded PCO2 values were available

had postmechanical ventilation PCO2 values above 50 mm Hg, suggesting substantial

underventilation. Two of the seven patients died after intubation, and one sustained neurologic

injury. Inadequate mechanical ventilation of patients with salicylate poisoning was associated with

respiratory acidosis, a decrease in the serum pH, and an abrupt clinical deterioration.116 Even when

achieved, however, respiratory alkalosis sustained by hyperventilation (assisted or unassisted) alone

should never be considered a substitute for use of either sodium bicarbonate (to achieve both

alkalemia and alkalinuria) or HD (when indicated).

If chemical sedation is required, although there is no clear choice of preferred sedative, the goals are

to minimize respiratory depression and use the minimum amount required for desired sedation. If

intubation is deemed necessary, which it often may be in situations of severe toxicity or multidrug

ingestions, the following steps should be taken to optimize before, during, and after intubation

conditions. The goal should be to maintain or exceed minute ventilation rates that were present

before intubation. Before intubation, an attempt should be made to optimize serum alkalinization by

administering a 2-mEq/kg bolus ofsodium bicarbonate. Preparations should be made to minimize the

period of time the patient will spend with apnea or decreased ventilation by considering an awake

intubation. The provider most experienced in intubation should be present as well as any adjunct

materials to increase first-pass success. An intensivist, respiratory technician, or other mechanical

ventilator expert should be consulted to help match preintubation minute ventilation. After

mechanical ventilation has begun, frequent blood gas monitoring should be obtained and ventilator

settings adjusted as needed. An emergent nephrology consult is indicated for HD if not previously

obtained.116 One recent report suggested the use of ketamine for awake intubation, thereby

minimizing the hypoventilation associated with rapid-sequence intubation.38

Serum Salicylate Concentration and pH Monitoring

Careful observation of the patient, correlation of the serum salicylate concentrations with blood pH,

and repeat determinations of serum salicylate concentrations every 2 to 4 hours are essential until

the patient is clinically improving and has a low serum salicylate concentration in the presence of a

normal or high blood pH. In all cases, after a presumed peak serum salicylate concentration has

been reached, at least one additional serum concentration should be obtained several hours later.

Analyses should be obtained more frequently in managing seriously ill patients to assess the efficacy

of treatment and the possible need for HD.

Pediatric Considerations

The predominant primary respiratory alkalosis that initially characterizes salicylate poisoning in

adults may not occur in young children.45,119 This likely results from the limited ventilatory reserve of

small children that prevents the same degree of sustained hyperpnea as occurs in adults. The

typical acidemia noted in seriously poisoned children led some investigators in the past to incorrectly

suggest that pediatric salicylate poisoning produces only metabolic acidosis. Although after a

significant salicylate exposure, some children present with a mixed acid–base disturbance and a

normal or high pH, most present with acidemia,45 suggesting the need for more urgent intervention

because the protective effect of alkalemia on CNS penetration of salicylate is already lost. Although

not routinely recommended, exchange transfusion may effectively remove large quantities of

salicylate in infants too small to undergo emergent HD without extensive delays.77

Pregnancy

Considered a rare event, salicylate poisoning during pregnancy poses a particular hazard to fetuses

because of the acid–base and hematologic characteristics of fetuses and placental circulation.

Salicylates cross the placenta and are present in higher concentrations in a fetus than in the mother.

The respiratory stimulation that occurs in the mother after toxic exposures does not occur in the

fetus, which has a decreased capacity to buffer acid. The ability of a fetus to metabolize and excrete

salicylates is also less than in the mother. In addition to its toxic effects on the mother, including

coagulation abnormalities, acid–base disturbances, tachypnea, and hypoglycemia, repeated

exposure to salicylates late in gestation displaces bilirubin from protein binding sites in the fetus,

causing kernicterus.

A case report described fetal demise in a woman who claimed to ingest 50 aspirin tablets per day for

several weeks during the third trimester of pregnancy. This raises concerns that a fetus is at greater

risk from salicylate exposures than is the mother. Emergent delivery of near-term fetuses of

salicylate-poisoned mothers should be considered on a case-by-case basis91 (Chap. 31).

SUMMARY

The clinical presentation of a patient with a salicylate overdose may be characterized by an

early onset of nausea, vomiting, abdominal pain, tinnitus, and lethargy.

The combination of a primary respiratory alkalosis and a primary metabolic acidosis with net

alkalemia constitutes the classic acid–base abnormality of salicylate poisoning in the adult.

Initial efforts in managing patients with salicylate poisoning include restoration of

intravascular volume, the use of AC to limit absorption, and urinary alkalinization to enhance

renal elimination of salicylate.

HD is indicated in patients with significantly elevated salicylate concentrations, altered mental

status, ARDS, and or AKI.

It is essential to maintain alkalemia to prevent CNS penetration of salicylate. As such,

sedation and mechanical ventilation can be rapidly lethal, if they impair minute ventilation,

causing rises in PCO2 and a fall in pH.

Acknowledgment

Neal E. Flomenbaum, MD, Eddy A. Bresnitz, MD, Donald Feinfeld, MD (deceased), and Lorraine

Hartnett, MD, contributed to this chapter in previous editions.

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