Forced Diuresis and Manipulation of Urinary pH

Forced diuresis by volume expansion with isotonic sodium-containing solutions, such as 0.9% NaCl or lactated Ringer solution, may increase renal clearance of some molecules. The effect is potentially more important in patients who have had contraction of the extracellular fluid volume as a result of sodium loss. After the extracellular fluid volume is restored, continued infusion of saline increases urine volume proportionally more than the glomerular filtration rate (GFR), which may increase excretion of some small molecules such as urea, but which has marginal efficacy in the case of most poisonings where urine flow is not a significant determinant of excretion. The significant risk of this therapy is extracellular fluid volume overload, manifested by pulmonary and cerebral edema. Administration of diuretics such as furosemide along with saline may diminish the risk of extracellular fluid volume overload, but complicate the therapy, confuse the assessment of extracellular fluid volume, and increase the risk of metabolic alkalosis and hypokalemia. The unproven efficacy of forced diuresis in the management of any overdose has led most experts to abandon its use.

Many xenobiotics are weak acids or bases that are ionized in aqueous solution to an extent that depends on the pKa of the compound and the pH of the solution. Knowing these variables, the Henderson-Hasselbalch equation can be used to determine the relative proportions of the acids, bases, and buffer pairs. Cell membranes are relatively impermeable to ionized, or polar molecules (such as an unprotonated salicylate anion), whereas nonionized, nonpolar forms (such as the protonated, noncharged salicylic acid) can cross more easily. As xenobiotics pass through the kidney, they may be filtered, secreted, and reabsorbed. If the urinary pH is manipulated to favor the formation of the ionized form in the tubular lumen, the drug is trapped in the tubular fluid and not passively reabsorbed into the bloodstream (“ion trapping”). Hence the rate and extent of its elimination can be increased. To make manipulation of urinary pH worthwhile, the renal excretion of the compound must be a major route of elimination.

Acidification of the urine by systemic administration of HCl or NH4Cl to enhance elimination of weak bases, such as phencyclidine or amphetamines, is not useful and is potentially dangerous. The technique has been abandoned because it does not significantly enhance removal of xenobiotics and is complicated by systemic metabolic acidosis.

Alkalinization of the urine to enhance elimination of weak acids has a limited role for xenobiotics such as salicylates, phenobarbital, chlorpropamide, formate, diflunisal, fluoride, methotrexate, and the herbicide 2,4-dichlorophen-oxyacetic acid (2,4-D). These weak acids are ionized at alkaline urine pH and tubular reabsorption is thereby greatly reduced. Alkalinization is achieved by the intravenous administration of sodium bicarbonate, 1-2 mEq/kg body weight every three to four hours. The goal is to increase urinary pH to 7-8.

The risk of extracellular fluid volume overload with sodium bicarbonate administration is the same as with the administration of 0.9% NaCl. Hypernatremia after administration of hypertonic sodium bicarbonate may also ensue. Bicarbonaturia is also associated with urinary potassium losses, so serum potassium concentration should be monitored frequently and KCl given liberally as long as the GFR is not impaired. A further complication of alkalemia is a decrease of ionized calcium, which becomes bound by albumin as protons are titrated off serum proteins; if this occurs, tetany may occur. Increasing urine pH by decreasing proximal tubular bicarbonate reabsorption via administration of carbonic anhydrase inhibitors such as acetazolamide is not recommended.

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