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The Effects of Desflurane and Isoflurane on Hepatic and Renal Functions After Right Hepatectomy in Living Donors
The Effects of Desflurane and Isoflurane on Hepatic and Renal Functions After Right Hepatectomy in Living Donors J.S. Ko, G. Kim, Y.H. Shin, M.S. Gwak, G.S. Kim, C.H.D. Kwon, and J.W. Joh ABSTRACT Purpose. Considering the severe nature of living donor right hepatectomy (removal of two thirds of the original liver), identification of an anesthetic agent having a minimal impact on postoperative organ function seems important. We compared postoperative hepatic and renal functions between 2 inhalational anesthetics, desflurane (Des) and isoflurane (Iso) among living donors undergoing right hepatectomy. Method. Sixty-four adult donors included in this retrospective study were divided into a Des group (n ⫽ 32) and an Iso group (n ⫽ 32). Before the induction of anesthesia, morphine sulfate (400 g) was injected intrathecally. Anesthesia was maintained with 1 minimum alveolar concentration (MAC) of Des or Iso plus intravenous remifentanil. Hepatic and renal function tests were analyzed preoperatively, immediately after operation, and on the first, second, third, fifth, seventh, and thirtieth postoperative days (POD). Results. Total bilirubin showed significant elevations on POD 1, 5, 7, and 30 in the Des group. Estimated glomerular filtration rate was significantly lower immediately after operation and on POD 1 in the Des group. The postoperative complication rates were similar between the 2 groups, and no patient developed hepatic or renal failure. Conclusion. The present study showed better postoperative hepatic and renal function tests with Iso than Des at an equivalent dose of 1 MAC among living donors undergoing right hepatectomy. ARIOUS inhalation anesthetics have been used during hepatobiliary surgery including living donor operations.1,2 However, considering the severe nature of living donor right hepatectomy (removal of two thirds of the original liver) with subsequent alterations in postoperative liver function,3 the identification of an anesthetic agent with minimal impact on postoperative organ function seems important. The present study compared postoperative hepatic and renal functions of subjects receiving isoflurane (Iso) versus desflurane (Des), which show similar structural properties and minimal metabolism.
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METHODS After obtaining Institutional Review Board approval, we retrospectively reviewed the medical records of 64 living donors who underwent right hepatectomy from May 2008 to December 2010. The donors were divided into a Des group (n ⫽ 32) and an Iso group (n ⫽ 32). No premedication was given. Before induction of anesthesia, morphine sulfate (400 g) was injected intrathecally for postoperative pain control.4 During the operation, the inspired Des or Iso 0041-1345/12/$–see front matter doi:10.1016/j.transproceed.2012.01.016 442
concentration was titrated to maintain an end-tidal 1 minimum alveolar concentration (MAC). Continuous infusion of remifentanil was titrated to maintain intraoperative blood pressure (BP) and heart rate (HR) within 20% of preoperative values. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TB), blood urea nitrogen (BUN), creatinine (Cr), BUN/Cr ratio, and estimated glomerular filtration rate (eGFR, calculated using Modification of Diet in Renal Disease Study Equation)5 were analyzed preoperatively, immediately after the operation, and on the first, second, third, fifth, seventh, and thirtieth postoperative days (POD).
From the Department of Anesthesiology and Pain Medicine (J. S. K., G. K., Y. H. S., M. S. G., G. S. K.), and Department of Surgery (C.H.D. K., J.W. J.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Address reprint requests to Gaab Soo Kim, MD, PhD, Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Ilwon-Dong, Kangnam-Ku, Seoul, Korea 135-710. E-mail: [email protected] © 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 44, 442– 444 (2012)
EFFECTS OF DESFLURANE AND ISOFLURANE For continuous variables, Student t or Mann-Whitney rank sum test with Bonferroni correction was used to compare intergroup differences, and chi-square test was used for categorical variables. A difference was regarded to be statistically significant when P ⬍ .05. Statistical analyses were performed with SAS/Genetics (SAS 3.1.3; SAS Institute Inc., Cary, NC, United States).
RESULTS
Demographic data, graft status, as well as surgical and anesthetic data were similar between the 2 groups, except for the amount of intraoperative remifentanil, which was significantly less in the Iso than the Des group (1.16 ⫾ 0.65 vs 1.54 ⫾ 0.64 g, respectively). Intraoperative BP and HR were comparable between 2 groups (data not shown). Mean values of AST, ALT, and TB reached a maximum at POD 2 showing gradual reductions thereafter, achieving measurements close to the preoperative levels by POD 30. TB was generally higher in the Des than the Iso group with significance on POD 1, 5, 7, and 30 (Fig 1). BUN, Cr, and BUN/Cr ratio remained decreased until POD 5, showing an increasing trend toward preoperative values from POD 7 to POD 30. The eGFR was generally lower in the Des group with significantly lower levels immediately after the operation and on POD 1. There was no significant difference in the number of donors who experienced postoperative complications between the 2 groups: 17 versus 16 in the Des and Iso groups, respectively. One donor in the Des group displayed bile duct leakage. Minor postoperative complications, including
443
atelectasis, pleural effusion, and wound problems, were comparable between the 2 groups (46% vs 49%, respectively). There was no case of sustained hepatic dysfunction, hepatic failure, renal failure, thromboembolism, sepsis, or death among our donors.
DISCUSSION
The halogenated inhalational anesthetics have been reported to induce variable degrees of hepatic injury, producing mild elevations of postoperative liver function test results.6 – 8 Although the exact mechanisms of hepatotoxicity have not been elucidated, the putative causes have been purported to be the biotransformation of toxic metabolites and alterations in hepatic blood flow.9 –11 Among the inhalational anesthetics, both Iso and its structural analog, Des, have been reported to undergo minimal metabolism (⬍0.2% and ⬍0.02%, respectively). The degree of biotransformation of inhalational anesthetics is measured based on serum and urine fluoride levels because fluoride has been implicated in organ toxicity after inhalational anesthesia.12 Smiley et al13 found that plasma concentrations of fluoride at the end of surgery were minimal after both Des and Iso anesthesia (4.17 ⫾ 1.09 and 5.12 ⫾ 1.18 mol/L, respectively). These values were substantially ⬍50 mol/L, which is the threshold for potential organ toxicity. Therefore, the hepatotoxic effects of metabolites from the 2 inhalational agents have been deduced to be both similar and negligible.
Fig 1. Serial changes in perioperative AST, ALT, and TB. Values are expressed as mean ⫾ SD. *P ⬍ .05 compared with Iso group.
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There are 2 main blood flows to the liver; the portal venous outflow from the splanchnic viscera constitutes two thirds of the liver blood supply. But it is significantly less oxygenated than the hepatic artery, which supplies the remaining one third of the liver blood flow. Most currently available inhalational anesthetics have been shown to decrease total hepatic blood flow (THBF) secondary to depressed cardiac output and to alter portal venous and hepatic arterial vascular resistances.9,11 In this respect, several experimental studies have demonstrated variable effects of Iso and Des on THBF in dose-dependent manners.11,14 Merin et al14 showed that, at equivalent doses, hepatic arterial blood flow was increased by Iso, whereas, it was only maintained by Des. Hepatic vascular resistance was decreased only by Iso. Moreover, Hartman et al11 reported that high-dose Des was superior to preserve THBF, but at low-dose Iso was slightly better. In our study using low doses of each inhalational anesthetic (1 MAC), the structural liver damage was similar between the 2 groups; however, the greater elevations of TB implied that liver functions were compromised to a greater extent after anesthesia with Des than Iso. The reason for this outcome may be ascribed, in part, to a selectively greater increase in well-oxygenated blood flow via the hepatic artery by Iso. However, the anesthetic factor alone cannot be viewed as the predominant one for alterations in hepatic and renal functions, because other important contributing elements include donor- and surgery-related factors pertaining to the living donor right hepatectomy. Therefore, further study is warranted to determine the dose-related effects of inhalational anesthetics on THBF and, subsequently, the clinical implication of altered postoperative hepatic and renal functions after living donor right hepatectomy. Our study was inherently associated with all of the limitations of a retrospective analyses. Also, more specific markers for hepatic and renal injury might have further elucidated the contributing effect of each anesthetic on postoperative hepatic and renal functions. Future studies should be directed to these issues. In conclusion, the present study showed better postoperative hepatic and renal function tests with Iso than Des at
KO, KIM, SHIN ET AL
the equivalent dose of 1 MAC among living donors undergoing right hepatectomy. REFERENCES 1. Chhibber A, Dziak J, Kolano J, et al: Anesthesia care for adult live donor hepatectomy: our experiences with 100 cases. Liver Transpl 13:537, 2007 2. Siniscalchi A, Begliomini B, De Pietri L, et al: Increased prothrombin time and platelet counts in living donor right hepatectomy: implications for epidural anesthesia. Liver Transpl 10: 1144, 2004 3. Schumann R, Zabala L, Angelis M, et al: Altered hematologic profiles following donor right hepatectomy and implications for perioperative analgesic management. Liver Transpl 10:363, 2004 4. Ko JS, Choi SJ, Gwak MS, et al: Intrathecal morphine combined with intravenous patient-controlled analgesia is an effective and safe method for immediate postoperative pain control in live liver donors. Liver Transpl 15:381, 2009 5. Levey AS, Bosch JP, Lewis JB, et al: A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461, 1999 6. Bito H, Ikeda K: Renal and hepatic function in surgical patients after low-flow sevoflurane or isoflurane anesthesia. Anesth Analg 82:173, 1996 7. Reichle FM, Conzen PF: Halogenated inhalational anaesthetics. Best Pract Res Clin Anaesthesiol 17:29, 2003 8. Stachnik J: Inhaled anesthetic agents. Am J Health Syst Pharm 63:623, 2006 9. Frink EJ, Jr., Morgan SE, Coetzee A, et al: The effects of sevoflurane, halothane, enflurane, and isoflurane on hepatic blood flow and oxygenation in chronically instrumented greyhound dogs. Anesthesiology 76:85, 1992 10. Gelman S: General anesthesia and hepatic circulation. Can J Physiol Pharmacol 65:1762, 1987 11. Hartman JC, Pagel PS, Proctor LT, et al: Influence of desflurane, isoflurane and halothane on regional tissue perfusion in dogs. Can J Anaesth 39:877, 1992 12. Mazze RI, Calverley RK, Smith NT: Inorganic fluoride nephrotoxicity: prolonged enflurane and halothane anesthesia in volunteers. Anesthesiology 46:265, 1977 13. Smiley RM, Ornstein E, Pantuck EJ, et al: Metabolism of desflurane and isoflurane to fluoride ion in surgical patients. Can J Anaesth 38:965, 1991 14. Merin RG, Bernard JM, Doursout MF, et al: Comparison of the effects of isoflurane and desflurane on cardiovascular dynamics and regional blood flow in the chronically instrumented dog. Anesthesiology 74:568, 1991
V
METHODS After obtaining Institutional Review Board approval, we retrospectively reviewed the medical records of 64 living donors who underwent right hepatectomy from May 2008 to December 2010. The donors were divided into a Des group (n ⫽ 32) and an Iso group (n ⫽ 32). No premedication was given. Before induction of anesthesia, morphine sulfate (400 g) was injected intrathecally for postoperative pain control.4 During the operation, the inspired Des or Iso 0041-1345/12/$–see front matter doi:10.1016/j.transproceed.2012.01.016 442
concentration was titrated to maintain an end-tidal 1 minimum alveolar concentration (MAC). Continuous infusion of remifentanil was titrated to maintain intraoperative blood pressure (BP) and heart rate (HR) within 20% of preoperative values. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TB), blood urea nitrogen (BUN), creatinine (Cr), BUN/Cr ratio, and estimated glomerular filtration rate (eGFR, calculated using Modification of Diet in Renal Disease Study Equation)5 were analyzed preoperatively, immediately after the operation, and on the first, second, third, fifth, seventh, and thirtieth postoperative days (POD).
From the Department of Anesthesiology and Pain Medicine (J. S. K., G. K., Y. H. S., M. S. G., G. S. K.), and Department of Surgery (C.H.D. K., J.W. J.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Address reprint requests to Gaab Soo Kim, MD, PhD, Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Ilwon-Dong, Kangnam-Ku, Seoul, Korea 135-710. E-mail: [email protected] © 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 44, 442– 444 (2012)
EFFECTS OF DESFLURANE AND ISOFLURANE For continuous variables, Student t or Mann-Whitney rank sum test with Bonferroni correction was used to compare intergroup differences, and chi-square test was used for categorical variables. A difference was regarded to be statistically significant when P ⬍ .05. Statistical analyses were performed with SAS/Genetics (SAS 3.1.3; SAS Institute Inc., Cary, NC, United States).
RESULTS
Demographic data, graft status, as well as surgical and anesthetic data were similar between the 2 groups, except for the amount of intraoperative remifentanil, which was significantly less in the Iso than the Des group (1.16 ⫾ 0.65 vs 1.54 ⫾ 0.64 g, respectively). Intraoperative BP and HR were comparable between 2 groups (data not shown). Mean values of AST, ALT, and TB reached a maximum at POD 2 showing gradual reductions thereafter, achieving measurements close to the preoperative levels by POD 30. TB was generally higher in the Des than the Iso group with significance on POD 1, 5, 7, and 30 (Fig 1). BUN, Cr, and BUN/Cr ratio remained decreased until POD 5, showing an increasing trend toward preoperative values from POD 7 to POD 30. The eGFR was generally lower in the Des group with significantly lower levels immediately after the operation and on POD 1. There was no significant difference in the number of donors who experienced postoperative complications between the 2 groups: 17 versus 16 in the Des and Iso groups, respectively. One donor in the Des group displayed bile duct leakage. Minor postoperative complications, including
443
atelectasis, pleural effusion, and wound problems, were comparable between the 2 groups (46% vs 49%, respectively). There was no case of sustained hepatic dysfunction, hepatic failure, renal failure, thromboembolism, sepsis, or death among our donors.
DISCUSSION
The halogenated inhalational anesthetics have been reported to induce variable degrees of hepatic injury, producing mild elevations of postoperative liver function test results.6 – 8 Although the exact mechanisms of hepatotoxicity have not been elucidated, the putative causes have been purported to be the biotransformation of toxic metabolites and alterations in hepatic blood flow.9 –11 Among the inhalational anesthetics, both Iso and its structural analog, Des, have been reported to undergo minimal metabolism (⬍0.2% and ⬍0.02%, respectively). The degree of biotransformation of inhalational anesthetics is measured based on serum and urine fluoride levels because fluoride has been implicated in organ toxicity after inhalational anesthesia.12 Smiley et al13 found that plasma concentrations of fluoride at the end of surgery were minimal after both Des and Iso anesthesia (4.17 ⫾ 1.09 and 5.12 ⫾ 1.18 mol/L, respectively). These values were substantially ⬍50 mol/L, which is the threshold for potential organ toxicity. Therefore, the hepatotoxic effects of metabolites from the 2 inhalational agents have been deduced to be both similar and negligible.
Fig 1. Serial changes in perioperative AST, ALT, and TB. Values are expressed as mean ⫾ SD. *P ⬍ .05 compared with Iso group.
444
There are 2 main blood flows to the liver; the portal venous outflow from the splanchnic viscera constitutes two thirds of the liver blood supply. But it is significantly less oxygenated than the hepatic artery, which supplies the remaining one third of the liver blood flow. Most currently available inhalational anesthetics have been shown to decrease total hepatic blood flow (THBF) secondary to depressed cardiac output and to alter portal venous and hepatic arterial vascular resistances.9,11 In this respect, several experimental studies have demonstrated variable effects of Iso and Des on THBF in dose-dependent manners.11,14 Merin et al14 showed that, at equivalent doses, hepatic arterial blood flow was increased by Iso, whereas, it was only maintained by Des. Hepatic vascular resistance was decreased only by Iso. Moreover, Hartman et al11 reported that high-dose Des was superior to preserve THBF, but at low-dose Iso was slightly better. In our study using low doses of each inhalational anesthetic (1 MAC), the structural liver damage was similar between the 2 groups; however, the greater elevations of TB implied that liver functions were compromised to a greater extent after anesthesia with Des than Iso. The reason for this outcome may be ascribed, in part, to a selectively greater increase in well-oxygenated blood flow via the hepatic artery by Iso. However, the anesthetic factor alone cannot be viewed as the predominant one for alterations in hepatic and renal functions, because other important contributing elements include donor- and surgery-related factors pertaining to the living donor right hepatectomy. Therefore, further study is warranted to determine the dose-related effects of inhalational anesthetics on THBF and, subsequently, the clinical implication of altered postoperative hepatic and renal functions after living donor right hepatectomy. Our study was inherently associated with all of the limitations of a retrospective analyses. Also, more specific markers for hepatic and renal injury might have further elucidated the contributing effect of each anesthetic on postoperative hepatic and renal functions. Future studies should be directed to these issues. In conclusion, the present study showed better postoperative hepatic and renal function tests with Iso than Des at
KO, KIM, SHIN ET AL
the equivalent dose of 1 MAC among living donors undergoing right hepatectomy. REFERENCES 1. Chhibber A, Dziak J, Kolano J, et al: Anesthesia care for adult live donor hepatectomy: our experiences with 100 cases. Liver Transpl 13:537, 2007 2. Siniscalchi A, Begliomini B, De Pietri L, et al: Increased prothrombin time and platelet counts in living donor right hepatectomy: implications for epidural anesthesia. Liver Transpl 10: 1144, 2004 3. Schumann R, Zabala L, Angelis M, et al: Altered hematologic profiles following donor right hepatectomy and implications for perioperative analgesic management. Liver Transpl 10:363, 2004 4. Ko JS, Choi SJ, Gwak MS, et al: Intrathecal morphine combined with intravenous patient-controlled analgesia is an effective and safe method for immediate postoperative pain control in live liver donors. Liver Transpl 15:381, 2009 5. Levey AS, Bosch JP, Lewis JB, et al: A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461, 1999 6. Bito H, Ikeda K: Renal and hepatic function in surgical patients after low-flow sevoflurane or isoflurane anesthesia. Anesth Analg 82:173, 1996 7. Reichle FM, Conzen PF: Halogenated inhalational anaesthetics. Best Pract Res Clin Anaesthesiol 17:29, 2003 8. Stachnik J: Inhaled anesthetic agents. Am J Health Syst Pharm 63:623, 2006 9. Frink EJ, Jr., Morgan SE, Coetzee A, et al: The effects of sevoflurane, halothane, enflurane, and isoflurane on hepatic blood flow and oxygenation in chronically instrumented greyhound dogs. Anesthesiology 76:85, 1992 10. Gelman S: General anesthesia and hepatic circulation. Can J Physiol Pharmacol 65:1762, 1987 11. Hartman JC, Pagel PS, Proctor LT, et al: Influence of desflurane, isoflurane and halothane on regional tissue perfusion in dogs. Can J Anaesth 39:877, 1992 12. Mazze RI, Calverley RK, Smith NT: Inorganic fluoride nephrotoxicity: prolonged enflurane and halothane anesthesia in volunteers. Anesthesiology 46:265, 1977 13. Smiley RM, Ornstein E, Pantuck EJ, et al: Metabolism of desflurane and isoflurane to fluoride ion in surgical patients. Can J Anaesth 38:965, 1991 14. Merin RG, Bernard JM, Doursout MF, et al: Comparison of the effects of isoflurane and desflurane on cardiovascular dynamics and regional blood flow in the chronically instrumented dog. Anesthesiology 74:568, 1991