PERIOPERATIVE ISCHEMIC AND NEPHROTOXIC INJURY

This section will review perioperative agents and events that may disrupt normal renal physiology. If the disruption is severe enough or occurs in susceptible individuals, it may induce ischemic or nephrotoxic renal injury.

Anesthetic Drugs

The choice of an anesthetic technique to preserve renal function during and after surgery is predicated on the preservation of RBF and perfusion pressure; suppression of vasoconstrictor, salt-retaining stress responses to surgical stimulation and postoperative pain; and avoidance or curtailment of nephrotoxic insults. No single anesthetic drug alone meets these criteria.

Regional Anesthesia

Spinal or epidural anesthesia (see Chapter 43 ) that achieves sympathetic blockade of the 4th through 10th thoracic segments is extremely effective in suppressing the sympathoadrenal stress response and release of catecholamines, renin, and AVP. During major surgery, RBF and GFR are preserved as long as adequate renal perfusion pressure is maintained.^{[89] [90] [91]} Maintenance of adequate perfusion pressure implies careful titration of the block, especially in elderly patients with cardiovascular disease, and may necessitate a 25% to 50% increase in intraoperative fluid administration.^[92] However, Gamulin and colleagues^[93] found that the renal sympathetic blockade obtained by epidural anesthesia did not block increases in renal vascular resistance induced by infrarenal aortic cross-clamping, nor did it prevent postoperative decreases in creatinine clearance.

General Anesthesia

The overall effect on renal function of anesthetic drugs in common use (see Chapter 7 , Chapter 10 , and Chapter 11 ) has been well summarized by Priano.^[30] All anesthetic techniques and agents tend to decrease GFR and intraoperative urine flow. Some drugs also decrease RBF, but the FF is usually increased, which implies that angiotensin-induced efferent arteriolar constriction limits the decrease in GFR. However, these effects are much less significant than those caused by surgical stress or aortic cross-clamping, and after emergence from anesthesia they usually resolve promptly. Any anesthetic technique that induces hypotension will result in decreased urine flow because of altered peritubular capillary hydrostatic gradients, even if renal autoregulation is preserved (as it generally is during anesthesia). Permanent injury seldom results unless the kidneys are abnormal to begin with or the hypovolemic insult is prolonged and exacerbated by nephrotoxic injury.

Halothane, enflurane, or isoflurane with nitrous oxide induces mild to moderate reductions in RBF and GFR,

801

Nephrotoxicity of Volatile Anesthetics

The potential nephrotoxicity of volatile anesthetics (see Chapter 8 ) is due to their metabolic breakdown to free fluoride ions, which cause a tubular lesion that results in loss of concentrating ability and polyuric acute renal failure.^[97] Toxicity is exacerbated by aminoglycosides or previous renal dysfunction. Peak fluoride levels less than 50 µm/L seldom induce injury, whereas levels over 150 µm/L are associated with a high incidence of polyuric acute renal failure.^[98] Administration of methoxyflurane at more than one minimum alveolar concentration (MAC) for more than 2 hours is capable of generating a peak fluoride level greater than 100 µm/L, and for this reason methoxyflurane is no longer used. Enflurane is metabolized more rapidly, and most studies indicated that peak fluoride levels seldom rise above 25 µm/L. The antituberculotic agent isoniazid enhances fluoride production, but only isolated reports of fluoride-induced nephrotoxicity from enflurane have ever appeared. Isoflurane produces peak fluoride levels less than 4 m/L, and halothane is not metabolized to fluoride at all.^[99]

The potential nephrotoxicity of sevoflurane remains controversial. Although its metabolism generates more fluoride than enflurane metabolism does, clinically significant fluoride-induced nephrotoxicity has not been detected. Compound A, a vinyl ether formed by the degradation of sevoflurane at low flow through carbon dioxide absorbents, is capable of inducing renal injury in rats. Although acute renal failure has not been reported in humans, Eger and coauthors reported evidence of transient renal injury (albuminuria, tubular enzymuria) in volunteers subjected to 8 hours of 1.25 MAC sevoflurane at a 2-L/min gas flow.^[100] No changes were detected in urinary concentrating ability, serum creatinine, or BUN. Subsequently, Eger and colleagues^[101] described a dose-response relationship between biochemical markers of glomerular and tubular injury (urinary albumin, α-glutathione-S-transferase) and compound A exposure expressed as parts per million per hour. They suggested that the threshold of renal injury is 80 to 168 ppm/hr based on their observation of altered biochemical markers with 1.25 MAC sevoflurane at 2 L/min for 4 hours, which was not seen after 2 hours and not at all with desflurane.

Other laboratories have disputed Eger and associates' findings. Bito and coworkers compared 6-hour patient exposure to low- and high-flow sevoflurane with low-flow isoflurane and found no differences in BUN, creatinine, or tubular enzymes for 3 days postoperatively.^[102] Kharasch and colleagues^[103] had similar results with the use of sevoflurane or isoflurane at 1 L/min in 73 patients undergoing procedures lasting longer than 2 hours, and they concluded that a moderate duration of low-flow sevoflurane anesthesia, even with the formation of compound A, is as safe as low-flow isoflurane anesthesia. Ebert and colleagues^[104] attempted to duplicate the original 8-hour Eger sevoflurane study in volunteers at two sites with blinded laboratory analyses. Biochemical derangements were minimal and transient, and no significant changes were detected in BUN, creatinine, or creatinine clearance. Despite the similarity in experimental design, the mean level of compound A was about 25% lower and mean arterial pressure about 10% higher than in the Eger study, which may have accounted for the difference in results.

In summary, clinically significant renal injury with the use of low-flow sevoflurane anesthesia has not been reported in patients, even with moderate preexisting renal dysfunction. The relationship between compound A formation, biochemical injury, and clinically relevant renal dysfunction remains unclear and unproven. Nonetheless, it appears prudent to follow current FDA guidelines, which recommend a fresh gas flow of at least 2 L/min to inhibit compound A formation and its rebreathing and to enhance its washout.