Kidneys perform a number of essential physiologic functions, including water management, electrolyte homeostasis, acid–base balance, and several neurohumoral and hormonal functions. Anesthesiologists are often called upon to (1) assess and manage perioperative oliguria (Table 18–1); (2) provide renal protection; and (3) use renal function to achieve goals not directly related to urine output, such as decreasing brain swelling or decreasing accumulation of fluid in lung alveoli.

This chapter will briefly discuss drugs used to preserve or manipulate renal function. In general, several drugs are effective diuretics but less effective at providing renal protection.

Furosemide was first approved for human use in the United States by the Food and Drug Administration, in July of 1982. It subsequently became a common treatment for congestive heart failure in the late 1980s. Its most common uses are in the treatment of hypertension; mobilization of edema fluid due to renal, hepatic, or cardiac dysfunction; treatment of increased intracranial pressure; and in the differential diagnosis of acute oliguria. Interestingly, furosemide has also long been used in veterinary medicine to prevent thoroughbred racehorses from bleeding through the nose during races.

Mechanism of Action

Furosemide exerts its diuretic effect by inhibiting the reabsorption of sodium and chloride, primarily in the medullary portions of the ascending limb of the loop of Henle. Protein-bound drug is secreted into the renal tubules and specifically acts on the sodium-chloride-potassium cotransporters on the intraluminal side of the loops of Henle (Figure 18–1). The accumulation of ions inside the lumen of renal tubules that occurs after furosemide administration inhibits the passive reabsorption of potassium, calcium, and magnesium. This results in urinary losses of these ions. Furosemide also stimulates renal production of prostaglandins, resulting in renal vasodilation and increased renal blood flow.

Dosing Regimen

Furosemide is effective when administered orally or intravenously. Oral dosing is 0.75 to 3.0 mg/kg and intravenous (IV) dosing is 0.1 to 1.0 mg/kg. If IV furosemide is used to replace oral furosemide, only half of the oral dose is required due to greater bioavailability. IV furosemide is approximately twice as potent and is faster than oral furosemide in inducing diuresis.¹ IV furosemide can be given as a bolus or as a continuous infusion.

Onset and Duration of Action

With oral administration, onset is within 1 hour and the duration is approximately 6 to 8 hours. With IV administration, onset is in 5 minutes and the duration is approximately 2 hours.

Pharmacokinetics

Furosemide is a weak organic acid. It is predominantly cleared by the kidneys (85%). Approximately half is metabolized and half is secreted in an unchanged form by organic acid transporters in the proximal tubules. Greater than 98% of furosemide is protein bound, and only a very small fraction of the drug is filtered through the glomerulus. However, it is the protein-bound drug, secreted into the renal tubules, that facilitates its diuretic effect.² In the setting of hypoalbuminemia, or in the presence of another highly protein-bound drug, tubular secretion of furosemide, and therefore its diuretic effect, is decreased.¹

Plasma clearance of furosemide is prolonged in neonates when compared to adults. The fraction of renal versus nonrenal clearance, and plasma half-life, are higher in neonates. This is attributed to a volume of distribution in infants that is approximately twice that of adults. Administration of furosemide to low-birth-weight neonates and premature infants should be done with caution due to the risk of drug accumulation and potential toxic effects.³

Clinical Applications

Anesthesiologists should have a healthy respect for furosemide. Perioperative oliguria may tempt a provider to administer a potent diuretic; however, the indications for furosemide therapy are more selective than poor urine output. Furosemide is used to treat a variety of pathologic conditions (Table 18–2) but should be administered only under euvolemic or hypervolemic conditions. Furosemide therapy in patients who are oliguric secondary to hypovolemia may cause hypotension and renal ischemic injury.

Furosemide is commonly used in critically ill patients with acute renal failure, but its clinical efficacy remains uncertain. In a recent meta-analysis, loop diuretics were not associated with improved mortality or rate of independence from renal replacement therapy, but loop diuretics were associated with a shorter duration of renal replacement therapy and with increased urine output.⁵ Similarly, despite extensive study, furosemide has not been found to consistently provide a renal protective effect.

Adverse Effects

The most common side effects associated with furosemide therapy are abnormalities of fluid and electrolyte balance. Hypokalemia is the most common imbalance, but hyponatremia, hypocalcemia, and hypomagnesemia are also often seen. Furosemide can deplete myocardial potassium stores, making digitalis toxicity more likely. In addition, renal tissue concentrations of aminoglycosides are increased with furosemide therapy, enhancing the possible nephrotoxic effects of these antibiotics. Acute hypovolemia may result from administration of loop diuretics to hypovolemic patients, which may result in hypotension and ischemic renal injury.

IV furosemide at doses of 1 mg/kg or greater enhances neuromuscular blockade produced by nondepolarizing neuromuscular blocking drugs. This is most likely caused by inhibition of cyclic adenosine monophosphate production, leading to decreased prejunctional acetylcholine.⁶

Ototoxicity, manifested as deafness, is a rare dose-dependent complication of furosemide. Ototoxicity is most likely to occur with prolonged increases in the plasma concentration of furosemide in the presence of other ototoxic drugs (eg, gentamicin, cisplatin, meloxicam), and can be transient or permanent.

Mannitol is a 6-carbon alcohol and was originally isolated from the secretions of the flowering ash tree in southern Europe, called manna after their resemblance to the biblical food. Clinical interest in mannitol began in 1940 when Smith and associates⁷ demonstrated that mannitol clearance closely reflected the glomerular filtration rate in humans, and it was first used as a treatment for intracranial hypertension in 1961.⁸

Mechanism of Action