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.
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.97 Although 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 period97 and 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.
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
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.
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 bicarbonate therapy 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.
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 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 ||Download (.pdf) TABLE 39–3. Indications for Hemodialysis in Salicylate Poisoned Patients
Congestive heart failure (relative)
Acute Respiratory Distress Syndrome
Persistent Central Nervous System disturbances
Progressive deterioration in vital signs
Severe acid–base or electrolyte imbalance despite appropriate treatment
Hepatic compromise with coagulopathy
Salicylate concentration (acute) >90 mg/dL (in the absence of the above)
Hemodialysis for patients with chronic poisoning is indicated for those with concerning symptoms regardless of salicylate concentrations
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 of sodium 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.
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
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).