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Comparison of Two Different Inhalation Anesthetics on Grafted Kidney Function in Patients Undergoing Renal Transplantation Surgery: Desflurane or Sevoflurane?
Comparison of Two Different Inhalation Anesthetics on Grafted Kidney Function in Patients Undergoing Renal Transplantation Surgery: Desflurane or Sevoflurane? M.S. Karadeniza,*, H.S. Ciftcib, T. Tefikc, O. Mammadova, H. Yazıcıd, I. Nanec, A. Turkmend, F. Oguzb, and K.M. Tugrula a Department of Anesthesiology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey; bDepartment of Medical Biology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey; cDepartment of Urology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey; and dDepartment of Nephrology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
ABSTRACT Background. Anesthetic management of patients during renal transplantation is vitally important for ensuring proper functioning of kidneys that have undergone ischemiareperfusion damage. The goal of this prospective study was to compare the effects of 2 different inhalation agents (sevoflurane and desflurane) on grafted kidney function in renal transplantation surgery. Methods. Sixty-five patients who were scheduled for living donor renal transplantation were enrolled in the study. General anesthesia was performed on all patients. Thirty-five pairs of recipients and donors were anesthetized with sevoflurane (group S) and 30 pairs of recipients and donors were anesthetized with desflurane (group D). Each patient’s demographic characteristics, immunologic and clinical data, and hemodynamic parameters were recorded. The estimated glomerular filtration rate was calculated in the preoperative period and on postoperative days 1 and 7. The blood samples were collected before the operation and on postoperative days 1 and 7 for measurement of serum creatinine, neutrophil gelatinase-associated lipocalin, and interleukin 18. Results. There were no significant differences in demographic characteristics or immunologic data between group D and group S. Intraoperative heart rate and mean arterial blood pressure were the same between groups. Creatinine, estimated glomerular filtration rate, neutrophil gelatinase-associated lipocalin, and interleukin 18 values did not differ between groups (P > .05) in the preoperative period and postoperative days 1 and 7. Conclusions. Sevoflurane and desflurane had no adverse effects on grafted kidney functions according to short-term graft outcomes in patients undergoing living donor renal transplantation.
A
NESTHETIC management of patients during renal transplant surgeries is vitally important for ensuring proper functioning of kidneys that have undergone ischemia-reperfusion damage. Intraoperative hemodynamic stabilization must be maintained, and anesthetic agents that have adverse effects on kidneys are to be avoided. Sevoflurane and desflurane are the most frequently used inhalation agents in modern anesthesia [1]. It is well known that neither of these drugs has toxic effects on the kidneys unless the safe dose range is exceeded. However, some studies 0041-1345/17 http://dx.doi.org/10.1016/j.transproceed.2017.01.014
448
The study was supported by the Scientific Research Projects Coordination Unit (BAP) of Istanbul University (project number 37511). *Address correspondence to Meltem Savran Karadeniz, Istanbul University, Medical Faculty of Istanbul, Department of Anesthesiology, Millet cad Cerrahi monoblok Giris kati, 34093 Fatih/Istanbul, Turkey. E-mail: [email protected] ª 2017 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 49, 448e453 (2017)
COMPARISON OF INHALATION ANESTHETICS
have suggested that compound A, which emerges with the interaction of carbon dioxide absorbents and inorganic fluoride ions as the byproduct of sevoflurane metabolism, causes nephrotoxic effects in rats [2e4]. In renal transplantation surgery, a limited number of studies have emphasized the effects of inhalation agents on transplanted kidney function [5,6]. Blood urea nitrogen (BUN), serum creatinine, and creatinine clearance were used in the evaluation of kidney function in these studies. However, those parameters are affected by several factors (eg, diet, sex, body mass index), and they take at least 24 to 48 hours to increase in the event of kidney dysfunction; thus, diagnosis may be delayed. Currently, interleukin 18 (IL-18) and neutrophil gelatinase-associated lipocalin (NGAL), which increase within a few hours of ischemic kidney damage, are used for early diagnosis of acute renal injury. The goal of the present prospective study was to compare the effects of 2 different inhalation agents (sevoflurane and desflurane) on grafted kidney function in renal transplantation recipients by measuring serum NGAL, IL-18, and creatinine levels and estimated glomerular filtration rate (eGFR) in the perioperative period. PATIENTS AND METHODS We enrolled 70 patients between 18 and 45 years of age who were diagnosed with end-stage renal disease and scheduled for living donor kidney transplant. This prospective, randomized clinical study was conducted between April 2013 and October 2015. Approval for the study was obtained from the Ethics Committee of Istanbul Medical Faculty (2013/1073), and written informed consent was obtained from the patients 1 day before the surgery. Before renal transplantation, immunologic factors (eg, a number of matched [HLA]-A, -B, -DR, crossmatch test, pretransplant and posttransplant HLA antibodies) that affect grafted kidney function were analyzed in all patients. Two different inhalation anesthetic agents were administered to the recipients. The patients were divided into group S (sevoflurane) and group D (desflurane) using a computerized single block randomization. Similarly, the same volatile anesthetic agents were administered to donors. Routine motorization was provided by using electrocardiograms, invasive blood pressure, and pulse oximetry. An intravenous 5 mL/kg/h 0.9% NaCl infusion was started in the operating room. Anesthesia was induced using 0.03 mg/kg of midazolam, 2 mg/kg of propofol, 0.2 mg/kg of remifentanil, and 0.5 mg/kg of rocuronium. After insertion of an endotracheal tube, mechanical ventilation was started with a tidal volume of 8 mL/kg, a respiratory rate of 10 to 12 breaths/min, and a positive end-expiratory pressure of 4 cm H2O; it was then targeted to achieve an end-tidal carbon dioxide concentration of 32 to 35 mm Hg throughout the operation. General anesthesia was maintained with 4% to 6% desflurane in group D and 2% to 3% sevoflurane in group S with a mixture of 50% oxygen and 50% air with 2 L of fresh gas flow. We aimed to keep the end-tidal volatile anesthetic concentration of 1.2 to 1.4 MAC for anesthesia maintenance. The goal was to maintain intraoperative blood pressure within 20% of preoperative values. If hypotension occurred, the patients were treated with volume replacement and incremental ephedrine doses of 5 mg.
449 Bradycardia (heart rate [HR] <50 beats/min) was treated with 0.01 mg/kg of atropine. All patients received continuous infusion of remifentanil (0.1e0.2 mg/kg) throughout the operation. Soda lime was used as a carbon dioxide absorbent. An anesthetics gas analyzer (Datex-Ohmeda, Helsinki, Finland) was used to measure the end-tidal volatile anesthetic concentration. After induction of anesthesia, invasive arterial and central venous pressure monitorization was applied to all patients. We administered 0.9% NaCl to maintain central venous pressure at 12 to 15 mm Hg throughout the operation, and 15 mg/kg of methylprednisolone was administered to patients before reperfusion. All surgeries were performed by the same surgical team. At the end of surgery, residual muscle relaxants were reversed with neostigmine, and all patients were extubated. The recipients were transported to the postanesthesia care unit after endotracheal extubation, and 1.5 mg/kg of intravenous tramadol and 1 g of paracetamol were administered for postoperative pain control. The patients were transferred to a transplantation ward when the discharge criteria were met. Immunosuppressive therapy for renal transplant patients in the postoperative period consisted of a combination of tacrolimus with mycophenolate mofetil/mycophenolate sodium and prednisolone. Demographic characteristics of all patients, duration of surgery and anesthesia, warm and cold ischemia time, intraoperative hemodynamic data (eg, HR, mean arterial pressure), and the amount of intravenous fluids were recorded. eGFR were calculated by using the Modification Diet in Renal Disease Study equation in the preoperative period and postoperative days 1 and 7. Acute rejection and graft loss within 1 month of transplantation were also documented.
Collection of the Samples Blood samples were obtained for the measurement of serum creatinine, NGAL, and IL-18. The samples were collected before the operation and on postoperative days 1 and 7. Specimens were centrifuged at 2600g for 10 minutes to remove the sediment. Serum samples were frozen in 1-mL aliquots at 20 C.
Determination of Serum NGAL and IL-18 Levels Serum levels of NGAL and IL-8 were evaluated by using a commercial enzyme-linked immunosorbent assay kit (Bioassay Technology Laboratory, Korean Biotech Co, Ltd) by following the manufacturer’s instructions.
Statistical Methods The creatinine level was 1.5 0.5 mg/dL on postoperative day 7 with desflurane in this pilot study. We calculated that a minimum of 27 patients would be required for each group to obtain an SD of 0.4 with a and b errors of 0.05 and 0.2, respectively. We therefore chose to include 35 patients in each group in case of dropouts. All statistical analyses were performed by using SPSS version 21.0 (IBM SPSS Statistics, IBM Corporation, Armonk, NY, United States), and P values < .05 were considered significant. The KolmogorovSmirnov test was performed to assess the deviation from normal distribution. Quantitative variables were summarized as mean SD. The Student t test was used for parametric data in the comparison of groups, and the Wilcoxon signed-rank test was used for paired data. The c2 test and the Fisher exact test were used to identify the frequency and rate in categorical variables and to calculate variations between the groups.
450
KARADENIZ, CIFTCI, TEFIK ET AL Table 1. Demographic and Clinical Data Characteristic
Desflurane Group (n ¼ 30)
Sevoflurane Group (n ¼ 35)
Age, y 39.30 13.82 34.63 11.90 Male/female, no. 22/8 18/17 Weight, kg 68.05 12.98 64.27 14.44 Duration of 298 43.10 282 40 anesthesia, min Duration of surgery, min 287 39.14 270 34.89 Warm ischemia time, min 6.13 2.03 6.30 2.90 Cold ischemia time, min 56.61 18 62.03 23.7 Fluid intake, mL 2073.33 706.58 2157 829.34
P
.1 .08 .2 .1 .6 .7 .3 .4
Data are expressed as mean SD unless otherwise indicated.
higher on postoperative days 1 and day 7 compared with the preoperative value (P < .001 and P < .001) (Fig 4). Serum NGAL levels in both groups on postoperative day 7 were significantly lower compared with the level on postoperative day 1 (P < .001) (Fig 5). The serum IL-18 level in both groups on postoperative day 7 was significantly lower compared with the level at the preoperative period and on postoperative day 1 (both, P < .01) (Fig 6). No statistically significant difference was observed among the patients in terms of acute rejection episodes (7 patients in group D, 8 patients in group S) or graft loss within 1 month of transplantation among the groups (Table 2) (P > .05).
RESULTS
DISCUSSION
Seventy patients who underwent living related-donor renal transplantation were included in the study. Five patients in group D were excluded because of errors in blood sampling. There were no significant differences in demographic characteristics, immunologic data, or immunosuppressive regimens between group D and group S (Tables 1 and 2). The results of flow cytometry cross-match (FXCM) test and complement-dependent cytotoxicity (CDC) test, were negative for all patients. HR and mean arterial pressure values did not differ between groups in any measurement (P > .05) (Figs 1 and 2). Creatinine, eGFR, NGAL, and IL-18 values did not differ between groups D and S in the preoperative period or postoperative day 1 and day 7 (P > .05). The creatinine values of group S and group D were significantly lower on postoperative days 1 and 7 compared with preoperative values (both, P < .001 and P < .001) (Fig 3). The eGFR values of group S and group D were significantly
This prospective, randomized study found no differences between groups S and D in terms of eGFR, serum creatinine, NGAL, or IL-18 levels on postoperative days 1 and 7. We suggest that these agents do not cause kidney dysfunction in the perioperative period, and thus they can be safely used in renal transplant surgeries. Anesthesia management of patients undergoing renal transplant is a compelling process because patients with a history of end-stage kidney disease may have problems due to metabolic and systemic diseases [1]. In addition to the immunologic preparation and intraoperative surgical approach, anesthetic management has the utmost importance in preventing acute renal injury and graft loss. In this study, preoperative immunologic data and the postoperative immunosuppressive regimens of both groups were comparable. Intraoperative hemodynamic instability is also an important factor that affects transplanted kidney function. In our study, neither agent caused hypotensive episodes in the intraoperative period. In living donor kidney transplant surgeries, 2 different inhalation agents (sevoflurane and desflurane) have generally been used for many years. Sevoflurane has been used in clinical settings for w20 years, and its reliability has been verified despite some adverse effects. The most significant metabolite, compound A, develops as a consequence of degradation of sevoflurane with alkaline carbon dioxide absorbents [7]. Some experimental studies suggest that these agents have nephrotoxic effects in rats [8]. The topic of controversy for years is to what extent the nephrotoxic effects of compound A on humans differ depending on the exposure time and concentration [9]. Researchers in some publications stated that the nephrotoxic effects of sevoflurane would not cause renal damage in humans, and most of them were individually resistant with administration at a flow rate <2 L/min [10]. However, other investigators reported that inhalation agents even at minimal levels might cause renal damage and a temporary increase in biochemical markers. Low flow 1 L/min anesthesia of sevoflurane caused albuminuria, enzymuria, and glycosuria compared with isoflurane [11e13]. Eger et al [14] suggested that administration of sevoflurane 1.25 MAC, 2 L/min flow for 8 hours caused temporary renal
Table 2. Preoperative and Postoperative Immunologic Data and Postoperative Immunosuppressive Regimens Variable
Desflurane Group (n ¼ 30)
HLA mismatch 0 1 (3.3%) 0e5 21 (70.0%) 6 8 (26.7%) Pretransplant HLA antibody status Negative 23 (76.7%) Positive 7 (23.3%) Posttransplant HLA antibody status Negative 25 (83.3%) Positive 5 (16.7%) Total acute rejection within 1 mo No 23 (76.7%) Yes 7 (23.3%) Graft loss within 1 mo 0 Immunosuppressive regimen Tacrolimus þ MMF þ 19 (63.3%) prednisolone Tacrolimus þ MYF þ 11 (36.7%) prednisolone
Sevoflurane Group (n ¼ 35)
P
1 (2.9%) 29 (82.9%) 5 (14.3%)
.450
27 (77.1%) 8 (22.9%)
.964
26 (82.9%) 6 (17.1%)
.959
27 (77.1%) 8 (22.9%) 0
.964
26 (74.3%)
.340
9 (25.7%)
Abbreviations: MMF, mycophenolate mofetil; MYF, mycophenolate sodium.
COMPARISON OF INHALATION ANESTHETICS
451
Fig 1. Heart rate follow-up in the desflurane group (group D) and the sevoflurane group (group S) throughout the intraoperative period.
damage compared with desflurane. Different studies reported that sevoflurane with the same concentration and exposure time produced minimal enzymatic changes, and those changes fell to normal levels on days 5 to 7 in healthy volunteers [15,16]. Fluoride ion, which is another unwanted product of sevoflurane metabolism, might cause renal damage in humans. As indicated in the earlier study, sevoflurane may lead to slight and temporary proteinuria and an increase in N-acetyl-b-D-glucosaminidase levels [13]. However, no studies have reported that sevoflurane causes
deterioration in routine clinical renal function tests (BUN, creatinine, or creatinine clearance) [5]. Many studies showed that even high fluoride concentrations >50 mmol/L caused no nephrotoxic effects on humans based on the dose and time period [17,18]. Furthermore, sevoflurane did not cause renal dysfunction even in patients with stable renal insufficiency [19]. Desflurane has pharmacokinetic characteristics similar to those of sevoflurane; numerous studies reported that it is highly stable and undergoes significantly less biotransformation than sevoflurane, however [14,20,21].
Fig 2. Mean arterial pressure follow-up in the desflurane group (group D) and the sevoflurane group (group S) throughout the intraoperative period. Abbreviation: Preop, preoperative.
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KARADENIZ, CIFTCI, TEFIK ET AL
Fig 3. Serum creatinine (Cr) levels in the desflurane group (group D) and the sevoflurane group (group S) on the preoperative (preop) day and postoperative days 1 and 7. ***P < .001 compared with the preoperative value, þþP < .01 compared with postoperative day 1.
Fig 5. Serum neutrophil gelatinase-associated lipocalin (NGAL) levels in the desflurane group (group D) and the sevoflurane group (group S) on the preoperative (preop) day and postoperative days 1 and 7. *P < .05 compared with the preop value, þþþ P < .001 compared with postoperative day 1.
In the present study, the recipient and the donor were taken to the operating room simultaneously, and the same inhalation agent was administered to both for the maintenance of anesthesia. The anesthesia exposure period of the transplanted kidney was w4.5 to 5 hours in both groups. Fresh gas flow was 2 L/min, and the MAC value was between 1.2 and 1.4. The concentrations administered to the study patients were similar to the concentrations administered to healthy volunteers in the studies discussed earlier [15]. A limited number of studies have investigated the effects of inhalation agents on kidney function in patients undergoing renal transplant. Teixeira et al [6] reported that sevoflurane and isoflurane had similar effects on serum creatinine levels and diuresis. Park et al [5] found that sevoflurane and desflurane had similar effects on graft functions over a 1-year period in patients who received a kidney transplant from living donors. Neither agent caused deterioration in serum BUN, creatinine, or eGFR values. However, there are no data regarding MAC values of inhalation agents and fresh gas flow, which are the most important factors that affect concentrations of compound A and serum fluoride in these retrospective studies. There is also no information available about hemodynamic factors that affect kidney function during the preoperative period.
Compared with previous studies, in addition to creatinine and eGFR, we evaluated more specific biomarkers (serum NGAL and IL-18), which provide early findings for renal tubular damage in the evaluation of grafted kidney function. However, although not used as a routine clinical test, serum NGAL levels, according to researchers in many studies, enabled early diagnosis of graft dysfunction; these levels correlate with the increase in serum creatinine and have a prognostic role within the first 12 hours [22,23]. Proinflammatory cytokine IL-18 and NGAL have important roles in determining the need for dialysis within 24 hours postoperatively [24]. Both biomarkers are important indicators because they correlate with kidney function of the recipient and also reveal delayed graft functions in the initial period [25]. No significant difference between sevoflurane and desflurane was found in our study in terms of effect on the recipients’ serum NGAL and IL-18 levels. In the evaluation of change between groups, both serum NGAL and IL-18 levels were correlated with the decrease in creatinine levels and an increase in eGFR, and the levels were significantly lower on postoperative day 7 compared with postoperative day 1. We therefore suggest that sevoflurane may be used as safely as desflurane in kidney transplant surgeries.
Fig 4. Estimated glomerular filtration rate (eGFR) in the desflurane group (group D) and the sevoflurane group (group S) on the preoperative (preop) day and postoperative days 1 and 7. ***P < .001 compared with the preop value, þþþP < .001 compared with postoperative day 1.
Fig 6. Serum interleukin 18 (IL-18) levels in the desflurane group (group D) and the sevoflurane group (group S) on the preoperative (preop) day and postoperative days 1 and 7. **P < .01 compared with the preop value, þþP < .01 compared with postoperative day 1.
COMPARISON OF INHALATION ANESTHETICS
The limitation of our study is the fact that we did not evaluate the levels of compound A or serum inorganic fluoride ions. CONCLUSIONS
Sevoflurane and desflurane had no adverse effects on grafted kidney functions according to short-term graft outcomes in these patients undergoing living donor renal transplantation surgery. REFERENCES [1] Baxi V, Jain A, Dasgupta D. Anesthesia for renal transplantation: an update. Indian J Anaesth 2009;53:139e47. [2] Hert SD, Moerman A. Sevoflurane. F1000Res 2015;4:626. [3] Keller KA, Callan C, Prokocimer P, Delgado-Herrera L, Friedman MB, Hoffman GM, et al. Inhalation toxicity study of haloalkane degradant of sevoflurane. Compound A (PIFE) in Sprague-Dawley rats. Anesthesiology 1995;83:1220e32. [4] Kharasch ED, Thorning D, Garton K, Hankins DC, Kilty CG. Role of renal cystein conjugate beta-lyase in mechanism of compound A nephrotoxicity in rats. Anesthesiology 1997;86:160e71. [5] Park JH, Lee JH, Joo DJ, Song KJ, Kim YS, Koo BN. Effects of sevoflurane on grafted kidney function in renal transplantation. Korean J Anesthesiol 2012;62:529e35. [6] Teixeira S, Costa G, Costa F, da Silva Viana J, Mota A. Sevoflurane versus isoflurane: does it matter in renal transplantation? Transplant Proc 2007;39:2486e8. [7] Artru AA. Renal effects of sevoflurane during conditions of possible increased risk. J Clin Anesth 1998;10:531e8. [8] Gonsowski CT, Laster MJ, Eger 2nd EI, Ferrell LD, Kerschmann RL. Toxicity of compound A in rats. Effect of 3-hour administration. Anesthesiology 1994;80:556e65. [9] Gentz BA, Malan Jr TP. Renal toxicity with sevoflurane: a storm in a teacup? Drugs 2001;61:2155e62. [10] Bito H, Ikeda K. Closed-circuit anesthesia with sevoflurane in humans. Effects on renal and hepatic functions and concentration of breakdown products with sodalime in the circuit. Anesthesiology 1994;80:71e6. [11] Kharasch ED, Frink Jr EJ, Zager R, Bowdle TA, Artru A, Nogami WM. Assessment of low-flow sevoflurane and isoflurane effects on renal function using sensitive markers of tubular toxicity. Anesthesiology 1997;86:1238e53. [12] Biko H, Ikeuchi Y, Ikeda K. Effects of low-flow sevoflurane anesthesia on renal function: comparison with high-flow sevoflurane
453 anesthesia and low-flow isoflurane anesthesia. Anesthesiology 1997;86:1231e7. [13] Higuchi H, Sumita S, Wada H, Ura T, Ikemato T, Nakai T, et al. Effects of sevoflurane and isoflurane on renal function and possible markers of nephrotoxicity. Anesthesiology 1998;89:307e22. [14] Eger 2nd EI, Koblin DD, Bowland T, Ionescu P, Laster JM, Fang Z, et al. Nephrotoxicity of sevoflurane versus desflurane anesthesia in volunteers. Anesth Analg 1997;84:160e8. [15] Ebert TJ, Messana LD, Uhrich TD, Staacke TS. Absence of renal and hepatic toxicity after four hours of 1.25 minimum alveolar concentration sevoflurane anesthesia in volunteers. Anesth Analg 1998;86:662e7. [16] Goldberg ME, Cantillo J, Gratz I, Deal E, Vekeman D, McDougall R, et al. Dose of compound A, not sevoflurane, determines changes in the biochemical markers of renal injury in health volunteers. Anesth Analg 1999;88:437e45. [17] Kharasch ED, Hankins DC, Thummel KE. Human kidney methoxyflurane and sevoflurane metabolism. Intrarenal fluoride production as a possible mechanism of methoxyflurane nephrotoxicity. Anesthesiology 1995;82:689e99. [18] Kharash ED. Adverse drug reactions with halogenated anesthetics. Clin Pharmacol Ther 2008;84:158e62. [19] Conzen PF, Kharash ED, Czerner SF, Artru AA, Reichle FM, Michalowski P, et al. Low-flow sevoflurane compared with low-flow isoflurane anesthesia in patients with stable renal insufficiency. Anesthesiology 2002;97:578e84. [20] Kim MS, Lee JR, Kim MS, Ham SY, Choi SH. Kidney function in living donors undergoing nephrectomy by sevoflurane or desflurane anesthesia. Yonsei Med J 2013;54:1266e72. [21] Ko JS, Gwak MS, Choi SM, Yang M, Kim MJ, Lee JY, et al. The effects of desflurane and sevoflurane on hepatic and renal functions after right hepatectomy in living donors. Transpl Int 2010;23:736e44. [22] Lohkamp LN, Öllinger R, Chatzigeorgiou A, Illigens BM, Siepman T. Intraoperative biomarkers in renal transplantation. Nephrology (Carlton) 2016;21:188e99. [23] Pezeshgi A, Azar SA, Ghasemi H, Kamali K, Esmaeilzadeh A, Hajsalimi B, et al. Role of plasma neutrophil gelatinase-associated lipocalin as an emerging biomarker of acute renal failure following kidney transplantation and its correlation with plasma creatinine. J Renal Inj Prev 2016;5:98e103. [24] Hall IE, Yarlagadda SG, Coca SG, Wang Z, Doshi M, Deverajan P, et al. IL-18 and urinary NGAL predict dialysis and graft recovery after kidney transplantation. J Am Soc Nephrol 2010;21:189e97. [25] Sung WC, Yu HP, Tsai YF, Chung PC, Lin CC, Lee WC. The ratio of plasma interleukin-18 is a sensitive biomarker for acute kidney injury after liver transplantation. Transplant Proc 2014;46: 816e7.
ABSTRACT Background. Anesthetic management of patients during renal transplantation is vitally important for ensuring proper functioning of kidneys that have undergone ischemiareperfusion damage. The goal of this prospective study was to compare the effects of 2 different inhalation agents (sevoflurane and desflurane) on grafted kidney function in renal transplantation surgery. Methods. Sixty-five patients who were scheduled for living donor renal transplantation were enrolled in the study. General anesthesia was performed on all patients. Thirty-five pairs of recipients and donors were anesthetized with sevoflurane (group S) and 30 pairs of recipients and donors were anesthetized with desflurane (group D). Each patient’s demographic characteristics, immunologic and clinical data, and hemodynamic parameters were recorded. The estimated glomerular filtration rate was calculated in the preoperative period and on postoperative days 1 and 7. The blood samples were collected before the operation and on postoperative days 1 and 7 for measurement of serum creatinine, neutrophil gelatinase-associated lipocalin, and interleukin 18. Results. There were no significant differences in demographic characteristics or immunologic data between group D and group S. Intraoperative heart rate and mean arterial blood pressure were the same between groups. Creatinine, estimated glomerular filtration rate, neutrophil gelatinase-associated lipocalin, and interleukin 18 values did not differ between groups (P > .05) in the preoperative period and postoperative days 1 and 7. Conclusions. Sevoflurane and desflurane had no adverse effects on grafted kidney functions according to short-term graft outcomes in patients undergoing living donor renal transplantation.
A
NESTHETIC management of patients during renal transplant surgeries is vitally important for ensuring proper functioning of kidneys that have undergone ischemia-reperfusion damage. Intraoperative hemodynamic stabilization must be maintained, and anesthetic agents that have adverse effects on kidneys are to be avoided. Sevoflurane and desflurane are the most frequently used inhalation agents in modern anesthesia [1]. It is well known that neither of these drugs has toxic effects on the kidneys unless the safe dose range is exceeded. However, some studies 0041-1345/17 http://dx.doi.org/10.1016/j.transproceed.2017.01.014
448
The study was supported by the Scientific Research Projects Coordination Unit (BAP) of Istanbul University (project number 37511). *Address correspondence to Meltem Savran Karadeniz, Istanbul University, Medical Faculty of Istanbul, Department of Anesthesiology, Millet cad Cerrahi monoblok Giris kati, 34093 Fatih/Istanbul, Turkey. E-mail: [email protected] ª 2017 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 49, 448e453 (2017)
COMPARISON OF INHALATION ANESTHETICS
have suggested that compound A, which emerges with the interaction of carbon dioxide absorbents and inorganic fluoride ions as the byproduct of sevoflurane metabolism, causes nephrotoxic effects in rats [2e4]. In renal transplantation surgery, a limited number of studies have emphasized the effects of inhalation agents on transplanted kidney function [5,6]. Blood urea nitrogen (BUN), serum creatinine, and creatinine clearance were used in the evaluation of kidney function in these studies. However, those parameters are affected by several factors (eg, diet, sex, body mass index), and they take at least 24 to 48 hours to increase in the event of kidney dysfunction; thus, diagnosis may be delayed. Currently, interleukin 18 (IL-18) and neutrophil gelatinase-associated lipocalin (NGAL), which increase within a few hours of ischemic kidney damage, are used for early diagnosis of acute renal injury. The goal of the present prospective study was to compare the effects of 2 different inhalation agents (sevoflurane and desflurane) on grafted kidney function in renal transplantation recipients by measuring serum NGAL, IL-18, and creatinine levels and estimated glomerular filtration rate (eGFR) in the perioperative period. PATIENTS AND METHODS We enrolled 70 patients between 18 and 45 years of age who were diagnosed with end-stage renal disease and scheduled for living donor kidney transplant. This prospective, randomized clinical study was conducted between April 2013 and October 2015. Approval for the study was obtained from the Ethics Committee of Istanbul Medical Faculty (2013/1073), and written informed consent was obtained from the patients 1 day before the surgery. Before renal transplantation, immunologic factors (eg, a number of matched [HLA]-A, -B, -DR, crossmatch test, pretransplant and posttransplant HLA antibodies) that affect grafted kidney function were analyzed in all patients. Two different inhalation anesthetic agents were administered to the recipients. The patients were divided into group S (sevoflurane) and group D (desflurane) using a computerized single block randomization. Similarly, the same volatile anesthetic agents were administered to donors. Routine motorization was provided by using electrocardiograms, invasive blood pressure, and pulse oximetry. An intravenous 5 mL/kg/h 0.9% NaCl infusion was started in the operating room. Anesthesia was induced using 0.03 mg/kg of midazolam, 2 mg/kg of propofol, 0.2 mg/kg of remifentanil, and 0.5 mg/kg of rocuronium. After insertion of an endotracheal tube, mechanical ventilation was started with a tidal volume of 8 mL/kg, a respiratory rate of 10 to 12 breaths/min, and a positive end-expiratory pressure of 4 cm H2O; it was then targeted to achieve an end-tidal carbon dioxide concentration of 32 to 35 mm Hg throughout the operation. General anesthesia was maintained with 4% to 6% desflurane in group D and 2% to 3% sevoflurane in group S with a mixture of 50% oxygen and 50% air with 2 L of fresh gas flow. We aimed to keep the end-tidal volatile anesthetic concentration of 1.2 to 1.4 MAC for anesthesia maintenance. The goal was to maintain intraoperative blood pressure within 20% of preoperative values. If hypotension occurred, the patients were treated with volume replacement and incremental ephedrine doses of 5 mg.
449 Bradycardia (heart rate [HR] <50 beats/min) was treated with 0.01 mg/kg of atropine. All patients received continuous infusion of remifentanil (0.1e0.2 mg/kg) throughout the operation. Soda lime was used as a carbon dioxide absorbent. An anesthetics gas analyzer (Datex-Ohmeda, Helsinki, Finland) was used to measure the end-tidal volatile anesthetic concentration. After induction of anesthesia, invasive arterial and central venous pressure monitorization was applied to all patients. We administered 0.9% NaCl to maintain central venous pressure at 12 to 15 mm Hg throughout the operation, and 15 mg/kg of methylprednisolone was administered to patients before reperfusion. All surgeries were performed by the same surgical team. At the end of surgery, residual muscle relaxants were reversed with neostigmine, and all patients were extubated. The recipients were transported to the postanesthesia care unit after endotracheal extubation, and 1.5 mg/kg of intravenous tramadol and 1 g of paracetamol were administered for postoperative pain control. The patients were transferred to a transplantation ward when the discharge criteria were met. Immunosuppressive therapy for renal transplant patients in the postoperative period consisted of a combination of tacrolimus with mycophenolate mofetil/mycophenolate sodium and prednisolone. Demographic characteristics of all patients, duration of surgery and anesthesia, warm and cold ischemia time, intraoperative hemodynamic data (eg, HR, mean arterial pressure), and the amount of intravenous fluids were recorded. eGFR were calculated by using the Modification Diet in Renal Disease Study equation in the preoperative period and postoperative days 1 and 7. Acute rejection and graft loss within 1 month of transplantation were also documented.
Collection of the Samples Blood samples were obtained for the measurement of serum creatinine, NGAL, and IL-18. The samples were collected before the operation and on postoperative days 1 and 7. Specimens were centrifuged at 2600g for 10 minutes to remove the sediment. Serum samples were frozen in 1-mL aliquots at 20 C.
Determination of Serum NGAL and IL-18 Levels Serum levels of NGAL and IL-8 were evaluated by using a commercial enzyme-linked immunosorbent assay kit (Bioassay Technology Laboratory, Korean Biotech Co, Ltd) by following the manufacturer’s instructions.
Statistical Methods The creatinine level was 1.5 0.5 mg/dL on postoperative day 7 with desflurane in this pilot study. We calculated that a minimum of 27 patients would be required for each group to obtain an SD of 0.4 with a and b errors of 0.05 and 0.2, respectively. We therefore chose to include 35 patients in each group in case of dropouts. All statistical analyses were performed by using SPSS version 21.0 (IBM SPSS Statistics, IBM Corporation, Armonk, NY, United States), and P values < .05 were considered significant. The KolmogorovSmirnov test was performed to assess the deviation from normal distribution. Quantitative variables were summarized as mean SD. The Student t test was used for parametric data in the comparison of groups, and the Wilcoxon signed-rank test was used for paired data. The c2 test and the Fisher exact test were used to identify the frequency and rate in categorical variables and to calculate variations between the groups.
450
KARADENIZ, CIFTCI, TEFIK ET AL Table 1. Demographic and Clinical Data Characteristic
Desflurane Group (n ¼ 30)
Sevoflurane Group (n ¼ 35)
Age, y 39.30 13.82 34.63 11.90 Male/female, no. 22/8 18/17 Weight, kg 68.05 12.98 64.27 14.44 Duration of 298 43.10 282 40 anesthesia, min Duration of surgery, min 287 39.14 270 34.89 Warm ischemia time, min 6.13 2.03 6.30 2.90 Cold ischemia time, min 56.61 18 62.03 23.7 Fluid intake, mL 2073.33 706.58 2157 829.34
P
.1 .08 .2 .1 .6 .7 .3 .4
Data are expressed as mean SD unless otherwise indicated.
higher on postoperative days 1 and day 7 compared with the preoperative value (P < .001 and P < .001) (Fig 4). Serum NGAL levels in both groups on postoperative day 7 were significantly lower compared with the level on postoperative day 1 (P < .001) (Fig 5). The serum IL-18 level in both groups on postoperative day 7 was significantly lower compared with the level at the preoperative period and on postoperative day 1 (both, P < .01) (Fig 6). No statistically significant difference was observed among the patients in terms of acute rejection episodes (7 patients in group D, 8 patients in group S) or graft loss within 1 month of transplantation among the groups (Table 2) (P > .05).
RESULTS
DISCUSSION
Seventy patients who underwent living related-donor renal transplantation were included in the study. Five patients in group D were excluded because of errors in blood sampling. There were no significant differences in demographic characteristics, immunologic data, or immunosuppressive regimens between group D and group S (Tables 1 and 2). The results of flow cytometry cross-match (FXCM) test and complement-dependent cytotoxicity (CDC) test, were negative for all patients. HR and mean arterial pressure values did not differ between groups in any measurement (P > .05) (Figs 1 and 2). Creatinine, eGFR, NGAL, and IL-18 values did not differ between groups D and S in the preoperative period or postoperative day 1 and day 7 (P > .05). The creatinine values of group S and group D were significantly lower on postoperative days 1 and 7 compared with preoperative values (both, P < .001 and P < .001) (Fig 3). The eGFR values of group S and group D were significantly
This prospective, randomized study found no differences between groups S and D in terms of eGFR, serum creatinine, NGAL, or IL-18 levels on postoperative days 1 and 7. We suggest that these agents do not cause kidney dysfunction in the perioperative period, and thus they can be safely used in renal transplant surgeries. Anesthesia management of patients undergoing renal transplant is a compelling process because patients with a history of end-stage kidney disease may have problems due to metabolic and systemic diseases [1]. In addition to the immunologic preparation and intraoperative surgical approach, anesthetic management has the utmost importance in preventing acute renal injury and graft loss. In this study, preoperative immunologic data and the postoperative immunosuppressive regimens of both groups were comparable. Intraoperative hemodynamic instability is also an important factor that affects transplanted kidney function. In our study, neither agent caused hypotensive episodes in the intraoperative period. In living donor kidney transplant surgeries, 2 different inhalation agents (sevoflurane and desflurane) have generally been used for many years. Sevoflurane has been used in clinical settings for w20 years, and its reliability has been verified despite some adverse effects. The most significant metabolite, compound A, develops as a consequence of degradation of sevoflurane with alkaline carbon dioxide absorbents [7]. Some experimental studies suggest that these agents have nephrotoxic effects in rats [8]. The topic of controversy for years is to what extent the nephrotoxic effects of compound A on humans differ depending on the exposure time and concentration [9]. Researchers in some publications stated that the nephrotoxic effects of sevoflurane would not cause renal damage in humans, and most of them were individually resistant with administration at a flow rate <2 L/min [10]. However, other investigators reported that inhalation agents even at minimal levels might cause renal damage and a temporary increase in biochemical markers. Low flow 1 L/min anesthesia of sevoflurane caused albuminuria, enzymuria, and glycosuria compared with isoflurane [11e13]. Eger et al [14] suggested that administration of sevoflurane 1.25 MAC, 2 L/min flow for 8 hours caused temporary renal
Table 2. Preoperative and Postoperative Immunologic Data and Postoperative Immunosuppressive Regimens Variable
Desflurane Group (n ¼ 30)
HLA mismatch 0 1 (3.3%) 0e5 21 (70.0%) 6 8 (26.7%) Pretransplant HLA antibody status Negative 23 (76.7%) Positive 7 (23.3%) Posttransplant HLA antibody status Negative 25 (83.3%) Positive 5 (16.7%) Total acute rejection within 1 mo No 23 (76.7%) Yes 7 (23.3%) Graft loss within 1 mo 0 Immunosuppressive regimen Tacrolimus þ MMF þ 19 (63.3%) prednisolone Tacrolimus þ MYF þ 11 (36.7%) prednisolone
Sevoflurane Group (n ¼ 35)
P
1 (2.9%) 29 (82.9%) 5 (14.3%)
.450
27 (77.1%) 8 (22.9%)
.964
26 (82.9%) 6 (17.1%)
.959
27 (77.1%) 8 (22.9%) 0
.964
26 (74.3%)
.340
9 (25.7%)
Abbreviations: MMF, mycophenolate mofetil; MYF, mycophenolate sodium.
COMPARISON OF INHALATION ANESTHETICS
451
Fig 1. Heart rate follow-up in the desflurane group (group D) and the sevoflurane group (group S) throughout the intraoperative period.
damage compared with desflurane. Different studies reported that sevoflurane with the same concentration and exposure time produced minimal enzymatic changes, and those changes fell to normal levels on days 5 to 7 in healthy volunteers [15,16]. Fluoride ion, which is another unwanted product of sevoflurane metabolism, might cause renal damage in humans. As indicated in the earlier study, sevoflurane may lead to slight and temporary proteinuria and an increase in N-acetyl-b-D-glucosaminidase levels [13]. However, no studies have reported that sevoflurane causes
deterioration in routine clinical renal function tests (BUN, creatinine, or creatinine clearance) [5]. Many studies showed that even high fluoride concentrations >50 mmol/L caused no nephrotoxic effects on humans based on the dose and time period [17,18]. Furthermore, sevoflurane did not cause renal dysfunction even in patients with stable renal insufficiency [19]. Desflurane has pharmacokinetic characteristics similar to those of sevoflurane; numerous studies reported that it is highly stable and undergoes significantly less biotransformation than sevoflurane, however [14,20,21].
Fig 2. Mean arterial pressure follow-up in the desflurane group (group D) and the sevoflurane group (group S) throughout the intraoperative period. Abbreviation: Preop, preoperative.
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KARADENIZ, CIFTCI, TEFIK ET AL
Fig 3. Serum creatinine (Cr) levels in the desflurane group (group D) and the sevoflurane group (group S) on the preoperative (preop) day and postoperative days 1 and 7. ***P < .001 compared with the preoperative value, þþP < .01 compared with postoperative day 1.
Fig 5. Serum neutrophil gelatinase-associated lipocalin (NGAL) levels in the desflurane group (group D) and the sevoflurane group (group S) on the preoperative (preop) day and postoperative days 1 and 7. *P < .05 compared with the preop value, þþþ P < .001 compared with postoperative day 1.
In the present study, the recipient and the donor were taken to the operating room simultaneously, and the same inhalation agent was administered to both for the maintenance of anesthesia. The anesthesia exposure period of the transplanted kidney was w4.5 to 5 hours in both groups. Fresh gas flow was 2 L/min, and the MAC value was between 1.2 and 1.4. The concentrations administered to the study patients were similar to the concentrations administered to healthy volunteers in the studies discussed earlier [15]. A limited number of studies have investigated the effects of inhalation agents on kidney function in patients undergoing renal transplant. Teixeira et al [6] reported that sevoflurane and isoflurane had similar effects on serum creatinine levels and diuresis. Park et al [5] found that sevoflurane and desflurane had similar effects on graft functions over a 1-year period in patients who received a kidney transplant from living donors. Neither agent caused deterioration in serum BUN, creatinine, or eGFR values. However, there are no data regarding MAC values of inhalation agents and fresh gas flow, which are the most important factors that affect concentrations of compound A and serum fluoride in these retrospective studies. There is also no information available about hemodynamic factors that affect kidney function during the preoperative period.
Compared with previous studies, in addition to creatinine and eGFR, we evaluated more specific biomarkers (serum NGAL and IL-18), which provide early findings for renal tubular damage in the evaluation of grafted kidney function. However, although not used as a routine clinical test, serum NGAL levels, according to researchers in many studies, enabled early diagnosis of graft dysfunction; these levels correlate with the increase in serum creatinine and have a prognostic role within the first 12 hours [22,23]. Proinflammatory cytokine IL-18 and NGAL have important roles in determining the need for dialysis within 24 hours postoperatively [24]. Both biomarkers are important indicators because they correlate with kidney function of the recipient and also reveal delayed graft functions in the initial period [25]. No significant difference between sevoflurane and desflurane was found in our study in terms of effect on the recipients’ serum NGAL and IL-18 levels. In the evaluation of change between groups, both serum NGAL and IL-18 levels were correlated with the decrease in creatinine levels and an increase in eGFR, and the levels were significantly lower on postoperative day 7 compared with postoperative day 1. We therefore suggest that sevoflurane may be used as safely as desflurane in kidney transplant surgeries.
Fig 4. Estimated glomerular filtration rate (eGFR) in the desflurane group (group D) and the sevoflurane group (group S) on the preoperative (preop) day and postoperative days 1 and 7. ***P < .001 compared with the preop value, þþþP < .001 compared with postoperative day 1.
Fig 6. Serum interleukin 18 (IL-18) levels in the desflurane group (group D) and the sevoflurane group (group S) on the preoperative (preop) day and postoperative days 1 and 7. **P < .01 compared with the preop value, þþP < .01 compared with postoperative day 1.
COMPARISON OF INHALATION ANESTHETICS
The limitation of our study is the fact that we did not evaluate the levels of compound A or serum inorganic fluoride ions. CONCLUSIONS
Sevoflurane and desflurane had no adverse effects on grafted kidney functions according to short-term graft outcomes in these patients undergoing living donor renal transplantation surgery. REFERENCES [1] Baxi V, Jain A, Dasgupta D. Anesthesia for renal transplantation: an update. Indian J Anaesth 2009;53:139e47. [2] Hert SD, Moerman A. Sevoflurane. F1000Res 2015;4:626. [3] Keller KA, Callan C, Prokocimer P, Delgado-Herrera L, Friedman MB, Hoffman GM, et al. Inhalation toxicity study of haloalkane degradant of sevoflurane. Compound A (PIFE) in Sprague-Dawley rats. Anesthesiology 1995;83:1220e32. [4] Kharasch ED, Thorning D, Garton K, Hankins DC, Kilty CG. Role of renal cystein conjugate beta-lyase in mechanism of compound A nephrotoxicity in rats. Anesthesiology 1997;86:160e71. [5] Park JH, Lee JH, Joo DJ, Song KJ, Kim YS, Koo BN. Effects of sevoflurane on grafted kidney function in renal transplantation. Korean J Anesthesiol 2012;62:529e35. [6] Teixeira S, Costa G, Costa F, da Silva Viana J, Mota A. Sevoflurane versus isoflurane: does it matter in renal transplantation? Transplant Proc 2007;39:2486e8. [7] Artru AA. Renal effects of sevoflurane during conditions of possible increased risk. J Clin Anesth 1998;10:531e8. [8] Gonsowski CT, Laster MJ, Eger 2nd EI, Ferrell LD, Kerschmann RL. Toxicity of compound A in rats. Effect of 3-hour administration. Anesthesiology 1994;80:556e65. [9] Gentz BA, Malan Jr TP. Renal toxicity with sevoflurane: a storm in a teacup? Drugs 2001;61:2155e62. [10] Bito H, Ikeda K. Closed-circuit anesthesia with sevoflurane in humans. Effects on renal and hepatic functions and concentration of breakdown products with sodalime in the circuit. Anesthesiology 1994;80:71e6. [11] Kharasch ED, Frink Jr EJ, Zager R, Bowdle TA, Artru A, Nogami WM. Assessment of low-flow sevoflurane and isoflurane effects on renal function using sensitive markers of tubular toxicity. Anesthesiology 1997;86:1238e53. [12] Biko H, Ikeuchi Y, Ikeda K. Effects of low-flow sevoflurane anesthesia on renal function: comparison with high-flow sevoflurane
453 anesthesia and low-flow isoflurane anesthesia. Anesthesiology 1997;86:1231e7. [13] Higuchi H, Sumita S, Wada H, Ura T, Ikemato T, Nakai T, et al. Effects of sevoflurane and isoflurane on renal function and possible markers of nephrotoxicity. Anesthesiology 1998;89:307e22. [14] Eger 2nd EI, Koblin DD, Bowland T, Ionescu P, Laster JM, Fang Z, et al. Nephrotoxicity of sevoflurane versus desflurane anesthesia in volunteers. Anesth Analg 1997;84:160e8. [15] Ebert TJ, Messana LD, Uhrich TD, Staacke TS. Absence of renal and hepatic toxicity after four hours of 1.25 minimum alveolar concentration sevoflurane anesthesia in volunteers. Anesth Analg 1998;86:662e7. [16] Goldberg ME, Cantillo J, Gratz I, Deal E, Vekeman D, McDougall R, et al. Dose of compound A, not sevoflurane, determines changes in the biochemical markers of renal injury in health volunteers. Anesth Analg 1999;88:437e45. [17] Kharasch ED, Hankins DC, Thummel KE. Human kidney methoxyflurane and sevoflurane metabolism. Intrarenal fluoride production as a possible mechanism of methoxyflurane nephrotoxicity. Anesthesiology 1995;82:689e99. [18] Kharash ED. Adverse drug reactions with halogenated anesthetics. Clin Pharmacol Ther 2008;84:158e62. [19] Conzen PF, Kharash ED, Czerner SF, Artru AA, Reichle FM, Michalowski P, et al. Low-flow sevoflurane compared with low-flow isoflurane anesthesia in patients with stable renal insufficiency. Anesthesiology 2002;97:578e84. [20] Kim MS, Lee JR, Kim MS, Ham SY, Choi SH. Kidney function in living donors undergoing nephrectomy by sevoflurane or desflurane anesthesia. Yonsei Med J 2013;54:1266e72. [21] Ko JS, Gwak MS, Choi SM, Yang M, Kim MJ, Lee JY, et al. The effects of desflurane and sevoflurane on hepatic and renal functions after right hepatectomy in living donors. Transpl Int 2010;23:736e44. [22] Lohkamp LN, Öllinger R, Chatzigeorgiou A, Illigens BM, Siepman T. Intraoperative biomarkers in renal transplantation. Nephrology (Carlton) 2016;21:188e99. [23] Pezeshgi A, Azar SA, Ghasemi H, Kamali K, Esmaeilzadeh A, Hajsalimi B, et al. Role of plasma neutrophil gelatinase-associated lipocalin as an emerging biomarker of acute renal failure following kidney transplantation and its correlation with plasma creatinine. J Renal Inj Prev 2016;5:98e103. [24] Hall IE, Yarlagadda SG, Coca SG, Wang Z, Doshi M, Deverajan P, et al. IL-18 and urinary NGAL predict dialysis and graft recovery after kidney transplantation. J Am Soc Nephrol 2010;21:189e97. [25] Sung WC, Yu HP, Tsai YF, Chung PC, Lin CC, Lee WC. The ratio of plasma interleukin-18 is a sensitive biomarker for acute kidney injury after liver transplantation. Transplant Proc 2014;46: 816e7.