The advent of sevoflurane changed all that. Sevoflurane - a non-irritating volatile anesthetic agent with rapid onset and offset of action, has already achieved considerable popularity with pediatric anesthesiologists, particularly for outpatient anesthesia. However, sevoflurane was not released until it had undergone extensive testing, which although it revealed that fluoride production exceeds that of enflurane, was not able to detect any clinically significant deterioration in renal function (3,4).

In the January issue of ANESTHESIA AND ANALGESIA, Eger et al reexamine the question of sevoflurane-induced nephrotoxicity, in direct comparison with desflurane. They focus not only on fluoride toxicity, but on another potential toxic metabolite of sevoflurane - the so-called Compound A, a vinyl ether formed by degradation in carbon dioxide absorbents, which can produce renal damage in rats. The present package labeling recommends the use of fresh gas flow of at least 2 liters/min sevoflurane to avoid inhalation of Compound A (by prevention of rebreathing, cooling of the absorbent to reduce its formation, and wash out of any Compound A formed). They subjected 12 volunteers to a crossover study of eight hours of 1.25 minimum alveolar concentration (MAC) sevoflurane or desflurane.

In contrast to desflurane (which produced no discernible effects), sevoflurane was associated with transient injury to the glomerulus (revealed by albuminuria), the proximal tubule (glycosuria, increased urinary alpha-glutathione-S-transferase) and distal tubule (increased urinary pi-glutathione-S-transferase). However, serum creatinine, BUN and urinary concentrating ability (a sensitive measure of fluoride-induced nephrotoxicity) remained unchanged.

What does this all mean? Eger et al conclude that their findings implicate renal injury due to Compound A accumulating during prolonged sevoflurane anesthesia, despite fresh gas flows within the lowest limit recommended by the package guidelines. They recommend that when sevoflurane is used a flow exceeding 6 liters/min would ensure elimination of Compound A.

How should we interpret this? Well, first let's look at some of the limitations of the study. Because several volunteers refused to be anesthetized twice, only seven subjects actually received both anesthetics - three received only sevoflurane and two only desflurane. This should be taken in the context of the dramatic variation in nephrotoxic effects seen in different patients - for example, a 150-fold difference between the lowest and highest value for albumin excretion. Thus, data extrapolated from patients exposed to only one anesthetic agent must be viewed with caution. Second, we still do not exactly understand the correlation between tubular enzymuria and proteinuria and subsequent renal dysfunction, For example, cardiopulmonary bypass consistently induces tubular enzymuria even with the use of pulsatile perfusion (5), yet the incidence of clinically important acute renal failure after uncomplicated bypass remains quite rare.

Third, is there an age-related susceptibility to sevoflurane induced nephrotoxicity - in other words, is the pediatric population, where sevoflurane is widely used, more or less susceptible to tubular enzymuria? Fourth, are high fresh gas flows necessary when sevoflurane is used for short procedures? How relevant is this eight hour anesthetic study to current practice? And finally, although Dr. Eger is a respected, indeed venerated, investigator in the field of volatile anesthesia, it must be acknowledged - as it is in the article - that he and one of the other authors are paid consultants to the company which manufactures desflurane, which is locked in a fierce battle for market position with the manufacturer of sevoflurane.

Readers are encouraged to carefully examine this paper - which raises more questions than it answers - and to draw their own conclusions.

References

1. Cousins MJ and Mazze RI. Methoxyflurane nephrotoxicity: A study of dose response in man. JAMA 1973;225:1611-1616.
2. Eichhorn JH, Hedley-White J, Steinman TI et al. Renal failure following enflurane anesthesia. Anesthesiology 1976;45:557-560.
3. Tsukamoto N, Hiribayashi Y, Shimuzu R and Mitsuhata H. The effects of sevoflurane and isoflurane anesthesia on renal tubular function in patients with moderately impaired renal function. Anesth Analg 1996;82:909-13.
4. Frink EJJ, Malan TPJ, Isner RJ et al. Renal concentrating function with prolonged sevoflurane or enflurane anesthesia in volunteers. Anesth Analg 1994;80:1019-25.
5. Canivet JL, Larbuisson R, Damas P, et al. Plasma renin activity and urine beta 2-microglobulin during and after cardiopulmonary bypass: pulsatile vs non-pulsatile perfusion. Eur Heart J 1990;11:1079-82.