Anesth Analg 2001;93:1210-1213
© 2001 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
The Effect of Ketorolac and Sevoflurane Anesthesia on Renal Glomerular and Tubular Function
Merja Laisalmi, MD*,
Anna-Maija Teppo, MSc ,
Anna-Maria Koivusalo, MD PhD*,
Eero Honkanen, MD PhD,
Päivi Valta, MD PhD*, and
Leena Lindgren, MD PhD*
*Department of Anaesthesia and Intensive Care Medicine and Department of Medicine, Division of Nephrology, Surgical Hospital, Helsinki University Central Hospital, Helsinki, Finland
Address correspondence and reprint requests to Merja Laisalmi, MD, Department of Anaesthesiology and Intensive Care Medicine, The Surgical Hospital, PO Box 263, 00029 HUS, Finland.
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Abstract
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We assessed the renal effects of the combination of ketorolac and sevoflurane anesthesia by using sensitive and specific markers of renal proximal and distal tubular and glomerular function. Thirty women (ASA physical status I and II) undergoing breast surgery received either ketorolac 30 mg IM or saline at premedication, at the end, and 6 h after anesthesia maintained with sevoflurane. Peak levels of serum fluoride at 2 h after the end of anesthesia were 30.1 µmol/L (21.0–50.0 µmol/L) in the Ketorolac group and 33.3 µmol/L (13.0–38.0 µmol/L) in the Control group (mean and range, not significant). Urine  1-microglobulin indexed to urine creatinine was increased from 2 h after the start of anesthesia until the first postoperative day in the Ketorolac group (peak level, 0.8 ± 0.4 mg/mmol; upper limit of normal, 0.7 mg/mmol) but did not change in the Control group. Urine glutathione-S-transferase (GST)- indexed to urine creatinine (GST-/creatinine) and GST- /creatinine were increased 2 h after anesthesia and returned to baseline values thereafter in both groups. There were no changes in serum cystatin C and urine kallikrein or urine output per hour between groups. The perioperative administration of ketorolac to healthy, well hydrated patients anesthetized with sevoflurane did not produce renal glomerular or tubular dysfunction.
IMPLICATIONS: Ketorolac 90 mg IM, given in divided doses over approximately 10 h to patients anesthetized with sevoflurane with a fresh gas flow rate of 4–6 L/min, did not result in clinically significant changes in renal glomerular or tubular function.
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Introduction
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The nonsteroidal antiinflammatory drug ketorolac nonselectively inhibits the function of cyclooxygenase enzymes and the synthesis of renal vasodilating prostaglandins, and this can impair renal blood flow (1). Serum inorganic fluoride (F-) released during the metabolism of sevoflurane may increase to levels associated with nephrotoxicity, and renal tubular dysfunction has been reported in patients anesthetized with sevoflurane (2). In a previous study (3) we assessed the renal effects of sevoflurane anesthesia and ketorolac by using conventional measures of renal function. We now report the renal effects of this combination with new, more sensitive markers of renal glomerular and tubular function.
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Methods
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The additional data were obtained from the same patients who participated in our earlier study (3). The double-blinded, placebo-controlled study was approved by the hospital ethics committee. Thirty women, ASA physical status I and II, having elective breast surgery were enrolled to the study after giving informed, written consent.
Ketorolac 30 mg, or an equal volume of saline, was given IM together with the premedication (oral diazepam) at the end of surgery and again 6 h after the end of surgery by a trained nurse not participating in the perioperative care of the patients. The patients were randomized to either the Ketorolac or Control group, by using sealed envelopes, by a doctor not participating in the study. The patients received standardized anesthesia with propofol and alfentanil, and cisatracurium was given to facilitate intubation of the trachea. Anesthesia was maintained with sevoflurane in oxygen and air (fraction of inspired oxygen, 0.4) with a fresh gas flow of 4–6 L/min (3). Ventilation of the lungs was adjusted to maintain end-tidal CO2 between 4.5 and 5.5 kPa.
Blood and urine samples for measurement of serum F-, urine creatinine, 1-microglobulin, and glutathione-S-transferase (GST)- and - were collected before surgery, 2 h after the start of anesthesia, 2 and 12 h after the end of anesthesia, and on the first postoperative day (POD). Urine kallikrein concentrations were measured after 2 h of anesthesia and 2 h after the end of anesthesia. Samples for the assays of serum and urine phosphate concentrations were taken before surgery and on the first and second PODs. Serum cystatin C was measured before surgery and on the second POD in 10 randomly selected patients from each group.
The concentrations of F- were determined by the method of Fry and Taves (4), by using an F--selective combination electrode. Serum cystatin C was determined with a Dako Cystatin C PET kit (Dako Inc., Copenhagen, Denmark) at United Laboratories Ltd., Helsinki, Finland. Urine 1-microglobulin was analyzed by radioimmunoassay (5). GST- was analyzed by enzyme immunoassay with NephkitTM-Alpha, and GST- was analyzed with Biotrin NephkitTM-Pi (Biotrin International Ltd., Dublin, Ireland). To eliminate the influence of variations in urine volume, 1-microglobulin, GST-, and GST- were normalized to urinary creatinine taken from spot samples. Urine kallikrein was determined by using the method of Amundsen et al. (6) and indexed to the urine output per hour. Urine creatinine levels were measured by modified Jaffe reactions, and serum and urine phosphate were measured by a photometric method. The reference values for 1-microglobulin/creatinine are 0.27 mg/mmol (0.04–0.70 mg/mmol) (mean and range), and for GST-/creatinine and GST-/creatinine they are 0.61 mg/mmol (0.10–1.93 mg/mmol) and 2.38 mg/mmol (0.25–7.41 mg/mmol), respectively. The 1-microglobulin/creatinine values were derived from 33 healthy individuals (23–63 yr), and GST-/creatinine and GST-/creatinine values were derived from 38 healthy individuals aged 18–46 yr.
Two-way analysis of variance for repeated measures, followed when indicated by Fisher’s protected least significance difference test or unpaired Student’s t-tests, was used to detect differences between the two groups. A value of P < 0.05 was considered statistically significant. Calculations were performed with Stat View 5.0.1 (SAS Institute, Inc., San Francisco, CA).
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Results
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The two groups were comparable with respect to demographic variables and perioperative data (Table 1). The serum F- peaked 2 h after the end of anesthesia (Table 2). Serum cystatin C levels remained unchanged throughout the study period (Table 3). In the Ketorolac group, the urine 1-microglobulin/creatinine ratio was increased from 2 h after the start of anesthesia until the first POD compared with the preoperative values, but it did not change significantly in the Control group (Table 3). The changes in urine GST-/creatinine and GST-/creatinine ratios are shown in Figure 1. Urine kallikrein increased during the anesthesia only in the Ketorolac group, although there were no significant differences between the groups (Table 3). There were no differences between the groups in the urine volumes (Table 2) or in the concentrations of serum or urine phosphate (Table 3).
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Discussion
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In the absence of preexisting renal disease, renal toxicity caused by nonsteroidal antiinflammatory drugs is most often associated with volume depletion and hypotension. Under these circumstances, the renal circulation is dependent on renal vasodilating prostaglandins (7). In our patients, in whom hydration was well maintained, the combination of ketorolac with sevoflurane anesthesia caused neither changes in the glomerular filtration rate nor renal tubular damage.
Serum concentrations of F- >50 µmol/L are considered toxic. In our study, the mean serum levels of F- were <34 µmol/L. Compound A, an F--containing product of sevoflurane degradation formed in carbon dioxide absorbers (8), is also potentially toxic to the kidneys. The formation of Compound A can be minimized by the use of novel nonreagent CO2 absorbers (9) or by the use of high gas flows. To avoid Compound A as a confounding factor in our study, we administered sevoflurane using high fresh gas flows. Serum cystatin C, an early marker of mild deterioration of glomerular filtration rate (10), did not change during our study period, indicating intact glomerular function.
The changes in 1-microglobulin in our study were small and without clinical significance. The urinary excretion of 1-microglobulin increases in cases of proximal tubular dysfunction even in the absence of any histologic damage (5,11).
Urine GST- is considered a marker of F- toxicity and of proximal tubular cell injury (12), and GST- is considered a marker of distal tubular damage (13). A slight increase in these markers was noted in our study. There are conflicting data about GST- and GST- in connection with low-flow sevoflurane anesthesia with or without changes in urine GST- or GST- (14,15).
Increases in urine 1-microglobulin, GST-, and GST- indicate transient, subclinical damage of proximal or distal tubular cells (16,17). However, information about the normal variation of these markers resulting from different kinds of stress, e.g., surgical or physiologic stress, is not available.
The kallikrein-kinin system is an essential element in acute renal vasodilatory response (18). A decrease in urinary kallikrein is regarded as a marker of distal tubular dysfunction. No indication of deterioration of tubular function was noticed in either of our study groups. Increased phosphate excretion into the urine is related to a defect in tubular reabsorption (19). It is interesting to note that urine phosphate levels decreased significantly and serum phosphate remained stable on the first POD in our groups, indicating intact tubular function.
In conclusion, we found that the administration of ketorolac to patients given high-flow sevoflurane anesthesia was not associated with evidence of renal toxicity, and this combination can be considered safe in healthy, well hydrated patients.
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Acknowledgments
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Supported by Helsinki University Central Hospital EVO Grant TKI4009.
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References
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Accepted for publication June 29, 2001.
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Abstract
Introduction
