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Anesth Analg 2001;92:650-655
© 2001 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

The Effects of Low-Flow Sevoflurane and Isoflurane Anesthesia on Renal Function in Patients with Stable Moderate Renal Insufficiency

Hideyuki Higuchi, MD*, Yushi Adachi, MD{dagger}, Hiroki Wada, MD{dagger}, Masuyuki Kanno, MD*, and Tetsuo Satoh, MD{dagger}

*Department of Anesthesia, Self Defense Force Central Hospital, Tokyo, Japan; and {dagger}Department of Anesthesiology, National Defense Medical College, Saitama, Japan

Address correspondence and reprint requests to Hideyuki Higuchi, MD, Department of Anesthesia, Self Defense Force Central Hospital, 1-2-24 Ikejiri, Setagaya, Tokyo 154-8532, Japan. Address e-mail to higu-chi{at}ka2.so-net.ne.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Sevoflurane degrades to Compound A, which is nephrotoxic in rats. Therefore, the renal effects of Compound A is an area of intense debate. We investigated the effects of low-flow sevoflurane and isoflurane anesthesia on renal function in patients with stable renal insufficiency. Seventeen patients with a serum creatinine level of more than 1.5 mg/dL were anesthetized with sevoflurane or isoflurane at a total flow of 1 L/min. Serum creatinine and blood urea nitrogen were measured before anesthesia and again 1, 2, 3, 5, 7, and 14 days after anesthesia. The 24-h creatinine clearance was measured before anesthesia and 7 days after anesthesia. There were no significant differences in the blood urea nitrogen levels, serum creatinine concentrations, or creatinine clearance before and after anesthesia within each group. These results suggest that sevoflurane and isoflurane have similar effects on renal function in patients with moderately impaired renal function. Further study of the effects of low-flow sevoflurane anesthesia on impaired renal function with a larger sample size than ours is required to resolve the issue of sevoflurane safety in patients with renal insufficiency.

Implications: The serum creatinine and blood urea nitrogen data indicate that, for exposures of <130 ppm/h in Compound A inspired area under the curve, renal effects of low-flow sevoflurane are similar to those of isoflurane in patients with stable renal insufficiency.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Many studies have investigated the renal effect of high-flow and low-flow or closed-circuit sevoflurane anesthesia because of the biodegradation of sevoflurane to fluoride ions and the degradation of sevoflurane to Compound A, which is nephrotoxic in rats (1–15). None of the studies, however, have demonstrated clinically significant renal effects as assessed by blood urea nitrogen (BUN) and serum creatinine concentrations in humans with normal renal function anesthetized with either high-flow or low-flow sevoflurane anesthesia, although some studies of humans report increased renal excretion of biochemical markers, such as {alpha}-glutathione-S-transferase, protein (albumin), and glucose after low-flow sevoflurane anesthesia (10,14,15). In patients with renal insufficiency, there is no significant difference in renal function between high-flow sevoflurane (4–6 L/min) and control anesthetics. Such high inflow rates, however, limit rebreathing and thereby minimize the respired concentration of Compound A (16–19). Recently, Mazze et al. (20) retrospectively analyzed 3436 surgical patients anesthetized with either sevoflurane (n = 1941) or one of three reference anesthetics (n = 1495), including 161 patients (sevoflurane; n = 88) with renal insufficiency (serum creatinine >=1.5 mg/dL). Mazze et al. reported that the influence of sevoflurane on serum creatinine levels did not differ from that of the control anesthetics. These authors, however, did not report the Compound A concentrations or the methods used to administer fresh gas flow rates in the patients with renal insufficiency. Thus, the effects of low-flow sevoflurane in surgical patients with stable renal failure have not been fully investigated. We therefore designed this prospective study to compare the effect of low-flow sevoflurane anesthesia with that of isoflurane anesthesia on renal function in surgical patients with impaired renal function, replicating the study by Mazze et al. (20).


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The study was conducted at the Self Defense Force Central Hospital in Tokyo, Japan. The study was approved by the hospital ethics committee. Before participation in the study, each patient signed an informed consent form. We studied 17 patients with moderately impaired renal function who were not receiving hemodialysis. Serum creatinine values were more than 1.5 mg/dL. Patients were randomly assigned to one of two groups: a Sevoflurane group (n = 8) and an Isoflurane group (n = 9). The types of surgery and antibiotics were varied ( Table 1).


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  		Table 1. Disease, Surgical Procedure, Coexisting Renal Disease, Antibiotics, Anesthetic dose, and Compound A Inspired Area Under the Curve (AUC)
 
Thirty minutes after receiving an IM injection of atropine (0.5 mg), each patient was given an IV injection of fentanyl (100–200 µg), thiopental (3–5 mg/kg), and vecuronium (0.1 mg/kg) to facilitate tracheal intubation. Anesthesia was then maintained with sevoflurane or isoflurane, N2O (4 L/min), and oxygen (2 L/min). After 5 min, the fresh gas flow rate was reduced to 1 L/min; the flow rates of both N2O and oxygen were set at 500 mL/min. The flow rates of N2O and oxygen were adjusted to maintain the inspiratory oxygen concentration at approximately 40% to 50%. Percutaneous arterial blood oxygen saturation was monitored throughout anesthesia and maintained >98%. Ventilation was controlled with a tidal volume of 8 to 10 mL/kg, and the ventilatory rate was adjusted to maintain an end-tidal PCO2 of 30 to 40 mm Hg. End-tidal concentrations of sevoflurane were analyzed with a Capnomac Ultima gas analyzer (Capnomac, Datex, Finland) that was calibrated immediately before each study. A semiclosed-circuit with a soda lime absorbent (Drägersorb 800; Dräger, Luebeck, Germany) was used to absorb CO2. The soda lime absorbent was changed before the administration of anesthetics to each patient. The anesthesia machine was an Ohmeda EXCEL 210 (Madison, WI). The sevoflurane (0.4%–3.0%) or isoflurane (0.2%–1.5%) concentration was adjusted by the anesthesiologist to maintain the mean arterial blood pressure within ±25% of baseline by administering fentanyl (50–100 µg) IV. Crystalloids, fresh frozen plasma, and blood were administered as required. If it was not possible to maintain the mean arterial blood pressure within ±25% of baseline, continuous dopamine or nitroglycerin and a bolus of ephedrine (5–10 mg) or nicardipine (1–2 mg) was administered. Hourly urine output was maintained at more than 25 mL by the administration of IV furosemide. After skin closure, the anesthetic administration was discontinued, and the fresh gas inflow rate was changed to 6 L/min of oxygen. Once the patient opened his or her eyes and took a deep breath on verbal command, the endotracheal tube was removed.

Clinical laboratory studies, such as BUN, serum creatinine, and potassium concentrations, were performed immediately before the administration of anesthesia and again at 1, 2, 3, 5, 7, and 14 days (when possible) after initiation of anesthesia. The 24-h creatinine clearance was measured before anesthesia and 7 days after initiation of anesthesia.

Gas samples were obtained from the inspiratory limbs of the anesthetic circuit distal to the one-way valves via a capped stopcock port, with gas-tight glass syringes for Compound A analysis. Inspiratory limb gas samples were obtained from the inspiratory limb every 60 min after intubation and at the end of anesthesia by using a gas-tight locking syringe. The gas was injected into a gas chromatograph (GC-14A, Shimazu, Tokyo, Japan). A glass column 5 m long, 3-mm internal diameter, packed with 20% dioctyl phthalate on a Chromosorb WAW (GL Science Co, Tokyo, Japan) 80/100 mesh, was maintained at 110°C in the gas chromatogram. The injection port was maintained at 130°C. A carrier stream of nitrogen flowing at 30 mL/min was delivered through the column to a hydrogen flame ionization detector. The gas chromatograph was calibrated by preparing standard calibration gases from stock solutions of Compound A supplied by Maruishi Pharmaceutical (Osaka, Japan).

The anesthetic dose was calculated as minimum alveolar anesthetic concentration hours (MAC-h) (1 MAC = 1.71% for sevoflurane, 1.15% for isoflurane) (21,22). Compound A exposure was calculated from the areas under the curve (AUC) of Compound A concentration versus time by using the trapezoid rule. Values are expressed as the mean ± SD. Intragroup comparisons of laboratory data were performed with two-way repeated-measures analysis of variance with Student-Newman-Keuls post hoc test. Intergroup comparisons of patients’ demographic data were analyzed by using unpaired Student’s t-tests. P values of <0.05 were considered to be statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Disease, surgical procedure, and coexisting renal disease of all patients are indicated in Table 1. There were no differences between the groups in age, height, body weight, duration of anesthesia and surgery, fentanyl dose, and MAC-h ( Table 2). The maximum Compound A concentration in the Sevoflurane group was 17.5 ± 11.3 ppm, the mean was 11.2 ± 7.2 ppm, and the inspired Compound A AUC was 51.0 ± 41.6 ppm/h ( Table 3). There was a strong correlation between Compound A AUC and MAC-h (r2 = 0.88, P < 0.001; Fig. 1). There were no significant differences in BUN levels, serum creatinine concentrations, or 24-h creatinine clearance before and after anesthesia within each group ( Table 4). None of the patients required hemodialysis after anesthesia. Figure 2 indicates changes in serum creatinine levels during the study period in individual patients of each group. Two patients (one patient in each group) had a postoperative increase in serum creatinine of 20% or more after anesthesia ( Fig. 3). The BUN, serum creatinine, and 24-h creatinine clearance values returned toward control levels at the end of study.


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  		Table 2. Patient Demographics
 

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  		Table 3. Compound A Data in the Sevoflurane Group (n = 8)
 


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  		Figure 1. Relation between inspired Compound A area under the curve (AUC) and minimum alveolar anesthetic concentration hours (MAC-h) of sevoflurane. There was a strong correlation between Compound A AUC and MAC-h of sevoflurane (r2 = 0.88, P < 0.001).

 

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  		Table 4. Perioperative Blood Urea Nitrogen (BUN), Serum Creatinine Concentrations, and Creatinine Clearance
 


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  		Figure 2. Time courses of individual serum creatinine values during the study period in both sevoflurane ({circ} and isoflurane (•) groups. The horizontal bars represent the mean values for each group on each day. There was no significant difference between the Sevoflurane and Isoflurane groups.

 


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  		Figure 3. Serum creatinine concentration increases above the preanesthetic control of 20% or more. Two patients (one in the Sevoflurane group, left panel; one in the Isoflurane group, right panel) had a postoperative increase in serum creatinine of 20% or more.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
There were no differences in BUN levels, serum creatinine concentrations, and creatinine clearance after anesthesia between the two groups. These findings are consistent with those of other studies that investigated the effects of high-flow and low-flow or closed-circuit sevoflurane anesthesia on renal function (5–15,19,20), including those in patients with impaired renal function (16–18,20).

Compound A dose dependently induces corticomedullary renal necrosis in rats (2–4). Therefore, the possible nephrotoxic effects of Compound A in humans is the subject of intense debate, although clinically significant renal effects in surgical patients have not been demonstrated (10–15). In addition, clinical studies investigating the renal effects of low-flow sevoflurane have raised questions regarding the assessment of postoperative renal function in surgical patients: is it appropriate to measure urinary excretion of sensitive markers, such as protein (albumin), glucose, and N-acetyl-ß-glucosaminidase (10–15,23,24)? Some assert that serum creatinine is not a good marker of either increased glomerular permeability or tubular integrity and that even though serum creatinine is a powerful tool that reflects the glomerular filtration rate, it is not a sensitive enough indicator of abnormal renal function because tubular necrosis in rats appears at smaller doses of Compound A than those associated with increases in serum creatinine (2–4,10,24). Doses of Compound A associated with histologic evidence of tubular necrosis are also associated with proteinuria and enzymuria in rats (4). Others assert that measurements of BUN and serum creatinine are easily performed, inexpensive, and, most important, prognostically significant in clinical medicine. In contrast, the validity of sensitive markers as a reliable indicator of clinically significant renal injury has not been established. Further, the interpretations of the levels of sensitive markers are not straightforward, because urinary excretion of sensitive markers is not specific and is affected by many factors, such as surgical stress and antibiotics (12,13,20,23). Although the issue of how postoperative renal function should be assessed in surgical patients is still not resolved, we did not measure urinary excretion of sensitive markers. The surgical procedures and antibiotics administered were not uniform, unlike those in our previous studies (14).

Novis et al. (25) reviewed 28 studies that examined preoperative risk factors for perioperative renal failure. Of 30 variables, preoperative risk factors such as increased serum creatinine, increased BUN levels, and existing renal dysfunction were found to predict postoperative renal dysfunction (25). Charlson et al. (26) reported that a postoperative serum creatinine increase of more than 20% above the preoperative value identified most patients whose creatinine clearance decreased by more than 50%. Among those patients with postoperative increases in serum creatinine that were sustained for 48 hours or more, more than one-third still had evidence of renal impairment when they left the hospital (26). Applying this definition of an increase in serum creatinine as more than 20%, we identified two patients (one patient in each group) who had a postoperative increase in serum creatinine after anesthesia. Although the serum creatinine increase (>20%) in one of the patients (Patient 14) after low-flow isoflurane anesthesia was for only one day, the increase in the other patient (Patient 1) after low-flow sevoflurane lasted for three days. This sustained increase in serum creatinine was probably caused by hypovolemia during and after anesthesia because of intraoperative bleeding and IV fluid volume restriction to prevent brain edema. Indeed, central venous pressure remained <4 mm Hg for three days. Thereafter, central venous pressure increased to 10 mm Hg. Similarly, the serum creatinine concentration decreased on Day 5 after anesthesia and returned to the preanesthetic value seven days after anesthesia.

There are limitations in this study. First, the statistical power is only 5%–20% because of the small sample size. Therefore, the present investigation lacks the power to adequately address the question regarding the safety of low-flow sevoflurane in patients with moderate renal insufficiency. Second, the anesthetic dose and inspired Compound A AUC were quite small. We did not provide a test for the effects of large doses of Compound A; this was also a problem in the study by Mazze et al. (20). In rats, Compound A AUC <50–180 ppm-h does not cause histologic evidence of necrosis, and increasing the AUC Compound A above this threshold induces necrosis (3,4,24). In humans, albuminuria, glucosuria, enzymuria, or a combination of these appear to be associated with inhaled doses of Compound A exceeding 160 ppm-h (10,14,15,24,27). Thus, the AUC for Compound A (51.0 ± 41.6 ppm-h) in this study would be far too small, compared with the threshold of Compound A nephrotoxicity in rats and the threshold for the increases in biochemical markers of renal injury in healthy humans. Further, we did not study the renal function in patients with severely impaired renal function, who required hemodialysis. Further study of the effects of prolonged low-flow sevoflurane anesthesia with a large sample size or in patients with severely impaired renal function is required to resolve the issue of sevoflurane safety in patients with renal insufficiency. A final and critical limitation of the present study, which is also applicable to the study by Mazze et al.(20), is the reliance on the gold standard, such as BUN and serum creatinine levels (24). This continues to be, however, a matter of debate, as mentioned above.

In summary, the effects of low-flow sevoflurane on renal function, as assessed with BUN and serum creatinine levels, did not differ from those of isoflurane in patients with stable renal insufficiency. Serum creatinine concentrations in all patients returned to preanesthetic values.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Kharasch ED, Thummel KE. Identification of cytochrome P4502E1 as the predominate enzyme catalyzing human liver microsomal defluorination of sevoflurane, isoflurane, and methoxyflurane. Anesthesiology 1993; 79: 795–807.[Web of Science][Medline]
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Accepted for publication November 2, 2000.





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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2001 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press