Although there is no known specific antidote for salicylate toxicity, judicious use of sodium bicarbonate is an essential treatment modality of salicylism. Through its ability to change the concentration gradient of the ionized and nonionized fractions of salicylates, sodium bicarbonate is useful in decreasing tissue (eg, brain) concentrations of salicylates and enhancing urinary elimination of salicylates.74 This therapy may limit the need for more invasive treatment modalities, such as hemodialysis.
Salicylate is a weak acid with a pKa of 3.0. As pH increases, more of the xenobiotic is in the ionized form. Ionized molecules penetrate lipid-soluble membranes less rapidly than do nonionized molecules because of the presence of polar groups on the ionized form. Consequently, when the ionized forms predominate weak acids, such as salicylates, may accumulate in an alkaline milieu, such as an alkaline urine.56,86
Although alkalinizing the urine to increase salicylate elimination is an important intervention in the treatment of patients with salicylate poisoning, increasing the serum pH in patients with severe salicylism may prove even more consequential by protecting the brain from a lethal central nervous system (CNS) salicylate burden. Using sodium bicarbonate to "trap" salicylate in the blood (ie, keeping it out of the brain) may prevent clinical deterioration of salicylate-poisoned patients. Salicylate lethality is directly related to primary CNS dysfunction, which, in turn, corresponds to a "critical brain salicylate level."35 At physiologic pH, at which a very small proportion of the salicylate is in the nonionized form, a small change in pH is associated with a significant change in amount of nonionized molecules (eg, at a pH of 7.4, 0.004% of the salicylate molecules is in the nonionized form; at a pH of 7.2, 0.008% of the salicylate is in the nonionized form). In experimental models, lowering the blood pH produces a shift of salicylate into the tissues.20 Hence, acidemia that is observed in significant salicylate poisonings can be devastating. In salicylate-poisoned rats, increasing the blood pH with sodium bicarbonate produced a shift in salicylate out of the tissues and into the blood.34 This change in salicylate distribution did not result from enhanced urinary excretion because occlusion of the renal pedicles failed to alter these results.
Enhancing the urinary elimination of salicylate by trapping ionized salicylate in the urine also provides great benefit. Salicylate elimination at low therapeutic concentrations consists predominantly of first-order hepatic metabolism. At these low concentrations, without alkalinization, only approximately 10% to 20% of salicylate is eliminated unchanged in the urine. With increasing concentrations, enzyme saturation occurs (Michaelis-Menten kinetics); thus, a larger percentage of elimination occurs as unchanged free salicylate. Under these conditions, in an alkaline urine, urinary excretion of free salicylate becomes even more significant, accounting for 60% to 85% of total elimination.31,75
The exact mechanism of pH-dependent salicylate elimination has generated controversy. The pH-dependent increase in urinary elimination initially was ascribed to "ion trapping," which is the filtering of both ionized and nonionized salicylate while reabsorbing only the nonionized salicylate.82 However, limiting reabsorption of the ionizable fraction of filtered salicylate cannot be the primary mechanism responsible for enhanced elimination produced by sodium bicarbonate.52 Because the quantitative difference between the percentage of molecules trapped in the ionized form at a pH of 5.0 (99% ionized) and a pH of 8.0 (99.999% ionized) is small, decreases in tubular reabsorption cannot fully explain the rapid increase in urinary elimination seen at a pH above 7.0.
"Diffusion theory" offers a reasonable alternative explanation. Fick's law of diffusion states that the rate of flow of a diffusing substance is proportional to its concentration gradient. A large concentration gradient between the nonionized salicylate in the peritubular fluid (and blood) and the tubular luminal fluid is found in alkaline urine. Because at a higher urinary pH, a greater proportion of secreted nonionized molecules quickly becomes ionized upon entering the alkaline environment, more salicylate (ie, nonionized salicylate) must pass from the peritubular fluid into the urine in an attempt to reach equilibrium with the nonionized fraction. In fact, as long as nonionized molecules are rapidly converted to ionized molecules in the urine, equilibrium in the alkaline milieu will never be achieved. The concentration gradient of peritubular nonionized salicylates to urinary nonionized salicylates continues to increase with increasing urinary pH. Hence, increased tubular diffusion, not decreased reabsorption, probably accounts for most of the increase in salicylate elimination observed in the alkaline urine.52
Controversies regarding the indications for alkalinization in the treatment of patients with salicylism persist. Although urinary alkalinization undoubtedly works to lower serum salicylate concentrations and enhance urinary elimination, the risks associated with alkalinization in the management of salicylism are of concern. Concerns regarding excessive alkalemia, hypernatremia, fluid overload, hypokalemia, and hypocalcemia, as well as the potential delay in achieving alkalinization with sodium bicarbonate (as opposed to more rapid response achieved with hyperventilation), have all been raised.27,48,70,75,82 Early on, patients with pure respiratory alkalosis often have alkaluria, as well as alkalemia, and do not require urinary alkalinization. In the more common scenario in which patients present with a mixed respiratory alkalosis and metabolic acidosis, sodium bicarbonate must be administered cautiously. Young children who rapidly develop metabolic acidosis often require alkalinization but should be at less risk for complications of this therapy.65
Sodium bicarbonate is indicated in the treatment of salicylate poisoning for most patients with evidence of significant systemic toxicity. Although some authors have suggested alkali therapy for asymptomatic patients with concentrations above 30 mg/dL,96 limited data support this approach. For patients with chronic poisoning, concentrations are not as helpful and may be misleading; clinical criteria remain the best indicators for therapy. Patients with contraindications to sodium bicarbonate use, such as renal failure and acute lung injury, should be considered candidates for intubation and subsequent hyperventilation, but extracorporeal removal is often required because of the difficulty and danger of intubation.
Dosing recommendations depend on the acid–base status of the patient. For patients with acidemia, rapid correction is indicated with IV administration of 1 to 2 mEq of sodium bicarbonate per kilogram of body weight.90 After the blood is alkalinized or if the patient has already presented with an alkalemia, continued titration with sodium bicarbonate over 4 to 8 hours is recommended until the urinary pH reaches 7.5 to 8.0.87,90 Alkalinization can be maintained with a continuous sodium bicarbonate infusion of 100 to 150 mEq in 1 L of D5W at 150 to 200 mL/hr (or about twice the maintenance requirements in a child). Obtaining a urinary pH of 8.0 is difficult but is considered to be the goal. Fastidious attention to the patient's changing acid–base status is required. Systemic pH should not go above 7.55 to prevent complications of alkalemia.
Hypokalemia can make urinary alkalinization particularly problematic.48,81 In hypokalemic patients, the kidneys preferentially reabsorb potassium in exchange for hydrogen ions. Urinary alkalinization will be unsuccessful as long as hydrogen ions are excreted into the urine. Thus, appropriate potassium supplementation to achieve normokalemia may be required to alkalinize the urine.99
In the past, proper urinary alkalinization was thought to require forced diuresis to maximize salicylate elimination.23,48 Suggestions included administering enough fluid (2 L/h) to produce a urine output of 500 mL/h. Because forced alkaline diuresis appears unnecessary and is potentially harmful as a result of its unnecessarily large fluid load, the goal is alkalinization at a rate of approximately twice maintenance requirements to achieve a urine output of 3 to 5 mL/kg/h.
Although cardiopulmonary support is the most critical intervention in the treatment of patients with severe phenobarbital overdose, sodium bicarbonate may be a useful adjunct to general supportive care. The utility of sodium bicarbonate is particularly important considering the long plasma half-life (~100 hours) of phenobarbital. Phenobarbital is a weak acid (pKa, 7.24) that undergoes significant renal elimination. As in the case of salicylates, alkalinization of the blood and urine may reduce the severity and duration of toxicity. In a study of mice, the median anesthetic dose for mice receiving phenobarbital increased by 20% with the addition of 1 g/kg of sodium bicarbonate (increasing the blood pH from 7.23 to 7.41), demonstrating decreased tissue concentrations associated with increased pH.93 Extrapolating the animal evidence to humans has suggested that phenobarbital-poisoned patients in deep coma might develop a respiratory acidosis secondary to hypoventilation, with the acidemia enhancing the entrance of phenobarbital into the brain, thus worsening CNS and respiratory depression. Alternatively, increasing the pH with bicarbonate, ventilatory support, or both would enhance the passage of phenobarbital out of the brain, thus lessening toxicity. Given the relatively high pKa of phenobarbital, significant phenobarbital accumulation in the urine is evident only when urinary pH is increased above 7.5.10 As the pH approaches 8.0, a threefold increase in urinary elimination occurs. The urine-to-serum ratio of phenobarbital, although much higher in alkaline urine than in acidic urine, remains less than unity, thereby suggesting less of a role for tubular secretion than in salicylate poisoning.
Clinical studies examining the role of alkalinization in phenobarbital poisoning have been inadequately designed. Many are poorly controlled and fail to examine the effects of alkalinization, independent of coadministered diuretic therapy. In one uncontrolled study, a 59% to 67% decrease in the duration of unconsciousness in patients with phenobarbital overdoses occurred in patients administered alkali compared with nonrandomized control subjects.58 In other older studies, treatment with sodium lactate and urea reduced mortality and frequency of tracheotomy to 50% of control subjects, enhanced elimination, and shortened coma.47,61 In a later human volunteer study, urinary alkalinization with sodium bicarbonate was associated with a decrease in phenobarbital elimination half-life from 148 to 47 hours.28 However, this beneficial effect was less than the effect achieved by multiple-dose activated charcoal (MDAC), which reduced the half-life to 19 hours.28 In a nonrandomized study of phenobarbital-poisoned patients comparing urinary alkalinization alone, MDAC alone, and both methods together, both the phenobarbital half-life decreased most rapidly and the clinical course improved most rapidly in the group of patients who received MDAC alone.57 Interesting, the combination approach proved inferior to MDAC alone but was better than alkalinization alone. The authors speculated that when both treatments were used together, the increased ionization of phenobarbital resulting from sodium bicarbonate infusion may have decreased the efficacy of MDAC. These studies suggest that MDAC is more efficacious than urinary alkalinization in the treatment of phenobarbital-poisoned patients, although both approaches are beneficial and indicated.
Sodium bicarbonate therapy does not appear warranted in the treatment of patients with ingestions of other barbiturates, such as pentobarbital and secobarbital, most of which have a pKa above 8.0 or are predominantly eliminated by the liver.
Chlorpropamide is a weak acid (pKa, 4.8) and has a long half-life (30–50 hours). In a human study using therapeutic doses of chlorpropamide, urinary alkalinization with sodium bicarbonate significantly increased renal clearance of the drug.63 This study showed that whereas nonrenal clearance was the more significant route of elimination at a urinary pH of 5 to 6 (only slightly above pKa), at a pH of 8.0, renal clearance was 10 times that of nonrenal clearance. Alkalinization reduced the area under the curve (AUC) almost fourfold and shortened the elimination half-life from 50 to 13 hours. Acidification increased the AUC by 41% and increased the half-life to 69 hours. Although not a study in overdose patients, this report suggests that sodium bicarbonate may be useful in the management of patients with chlorpropamide overdose. The effect of urinary alkalinization on elimination of other sulfonylureas is unnecessary because the benefit presumably is limited as these agents are largely metabolized in the liver.
Alkalinization is indicated in the treatment of patients with poisonings from weed killers that contain chlorophenoxy compounds, such as 2,4-dichlorophenoxyacetic acid (2,4-D) or 2-(4-chloro-2-methylphenoxy) propionic acid (MCPP).73 Poisoning results in muscle weakness, peripheral neuropathy, coma, hyperthermia, and acidemia. These compounds are weak acids (pKa 2.6 and 3.8 for 2,4-D and MCPP, respectively) that are excreted largely unchanged in the urine. In an uncontrolled case series of 41 patients poisoned with a variety of chlorophenoxy herbicides, 19 of whom received sodium bicarbonate, alkaline diuresis significantly reduced the half-life of each by enhancing renal elimination.26 In one patient, resolution of hyperthermia and metabolic acidosis and improvement in mental status were associated with a transient elevation of serum concentration, perhaps reflecting chlorophenoxy compound redistribution from the tissues into the more alkalemic blood. The limited data suggest that the increased ionized fractions of the weak-acid chlorophenoxy compounds produced by alkalinization is trapped in both the blood and the urine (as demonstrated with salicylates and phenobarbital); thus, its use ameliorates toxicity and shortens the duration of effect.