LIVER TRANSPLANTATION 21:180–186, 2015
ORIGINAL ARTICLE
Glycemic Responses to Intermittent Hepatic Inflow Occlusion in Living Liver Donors Sangbin Han,1 Justin Sangwook Ko,1 Sang-Man Jin,2 Jong Man Kim,3 Soo Joo Choi,1 Jae-Won Joh,3 Yang Hoon Chung,1 Suk-Koo Lee,3 Mi Sook Gwak,1 and Gaabsoo Kim1 1 Department of Anesthesiology and Pain Medicine, 2Division of Endocrinology and Metabolism, Department of Medicine; and 3Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
The occurrence of glycemic disturbances has been described for patients undergoing intermittent hepatic inflow occlusion (IHIO) for tumor removal. However, the glycemic responses to IHIO in living liver donors are unknown. This study investigated the glycemic response to IHIO in these patients and examined the association between this procedure and the occurrence of hyperglycemia (blood glucose > 180 mg/dL). The data from 154 living donors were retrospectively reviewed. The decision to perform IHIO was made on the basis of the extent of bleeding that occurred during parenchymal dissection. One round of IHIO consisted of 15 minutes of clamping and 5 minutes of unclamping the hepatic artery and portal vein. Blood glucose concentrations were measured at predetermined time points, including the start and end of IHIO. Repeated hyperglycemic episodes occurred after unclamping. The mean maximum intraoperative blood glucose concentration was greater in donors who underwent 3 rounds of IHIO versus those who underwent 1 or 2 rounds (169 6 30 versus 149 6 31 mg/dL, P 5 0.005). The incidence of intraoperative hyperglycemia was also greater in donors who underwent 3 rounds of IHIO versus those who underwent 1 or 2 rounds (38.7% versus 7.7%, odds ratio 5 7.1, 95% confidence interval 5 2.5-20.4, P < 0.001). Donors who did not undergo IHIO and those who underwent 1 or 2 rounds of IHIO exhibited similar maximum glucose concentrations and similar incidence rates of hyperglycemia. In conclusion, IHIO induced repeated hyperglycemic responses in living donors, and donors who underwent 3 rounds of IHIO were more likely to experience intraoperative hyperglycemia. These results provide additional information on the risks and benefits of IHIO in living donors. C 2014 AASLD. Liver Transpl 21:180-186, 2015. V Received June 13, 2014; accepted October 12, 2014. Intermittent hepatic inflow occlusion (IHIO) effectively reduces the amount of blood lost during liver resection and can prevent the need for a blood transfusion. Recent studies have suggested that IHIO-induced ischemic preconditioning can increase the ability of the liver to tolerate ischemia and reperfusion injury by promoting cellular repair/protection mechanisms and improving intrahepatic microcirculation.1 Despite these potential benefits and the widespread use of IHIO during liver surgery, the maneuver has not been extensively adopted in living donor liver transplantation because of a lack of understanding of the effects of repeated hepatic ischemia and reperfusion in these
subjects. In particular, the glycemic response of living donors is poorly understood.2 The liver plays a prominent role in maintaining blood glucose levels within a narrow range. Accordingly, patients undergoing liver resection are at high risk for experiencing a glycemic disturbance resulting from surgical injuries and hepatocyte loss. Furthermore, IHIO has been shown to induce repeated hyperglycemia in patients undergoing liver resection to remove tumors.2 Glycemic responses to IHIO in living liver donors have never been assessed, and a better understanding of these responses will help clinicians to understand the risks and benefits of performing IHIO in living donors.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; IHIO, intermittent hepatic inflow occlusion. Potential conflict of interest: Nothing to report. Address reprint requests to Gaabsoo Kim, M.D., Ph.D., Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-Dong, Gangnam-Gu, Seoul 135-710, Korea. Telephone: 82-2-3410-2470; FAX: 82-2-34100361; E-mail: [email protected] DOI 10.1002/lt.24029 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2014 American Association for the Study of Liver Diseases. V
LIVER TRANSPLANTATION, Vol. 21, No. 2, 2015
Thus, we evaluated the glycemic responses of living donors undergoing IHIO and assessed the incidence rate and magnitude of hyperglycemia in these patients.
PATIENTS AND METHODS Subjects In all, 154 adult living donors who underwent open right hepatectomies between December 2010 and August 2012 were included in the study. Routine pretransplant evaluations of the donors included biochemical tests, abdominal ultrasound, computed tomography, angiography, and magnetic resonance cholangiopancreatography to detect undiagnosed diseases and assess the liver function, parenchymal fatty changes, anatomy of the biliary/vascular system, and liver volume. Acceptable donors were considered to have 30% macrosteatosis without any type of hepatitis and a remnant liver volume 30%.3 There were no specific exclusion criteria for the study. The institutional review board of Samsung Medical Center approved this retrospective study (SMC 2014-05-079) and waived the requirement for written informed consent. All data were obtained from computerized medical records.
Monitoring and Anesthesia Intraoperative anesthetic management was performed according to the standardized protocol for living donor hepatectomy, which included standard anesthetic monitoring (peripheral capillary oxygen saturation, 3lead electrocardiography, and noninvasive arterial blood pressure measurement). Morphine sulfate (400 lg) was intrathecally administered to alleviate postoperative pain.4 Anesthesia was induced with sodium thiopental (5 mg/kg) and maintained with isoflurane. An intra-arterial catheter was placed in the right radial artery for direct blood pressure monitoring and blood sampling. Remifentanil was infused intravenously at a rate of 0.05 to 0.20 lg/kg/minute according to the hemodynamic response of each individual. Vecuronium was used as a muscle relaxant to facilitate endotracheal intubation and intraoperative muscle relaxation. Ventilation was controlled to obtain a tidal volume of 8 mL/kg and to maintain normocapnea, and the fraction of inspired oxygen was maintained at 0.5. Circulation was managed to achieve a target mean arterial pressure of 70 mm Hg and a pulse pressure variation of 12%.5 Hartmann’s solution was administered primarily to maintain normovolemia, and a colloid solution was administered for intravascular volume expansion after liver parenchymal dissection. A red blood cell transfusion was indicated when the blood hemoglobin concentration of the patient was 200 mg/dL. A 5% dextrose solution was postoperatively infused at a rate of 80 mL/hour in combination with a 40 mL/ hour infusion of Hartmann’s solution. Oral intake was allowed on the third day after surgery.
Study Objectives and Parameters The primary objectives of this study were to evaluate the glycemic response to IHIO in living liver donors and to investigate the contribution of IHIO to the development of intraoperative hyperglycemia (blood glucose concentration > 180 mg/dL).7 The secondary objective was to explore the association between intraoperative hyperglycemia and posttransplant donor complications, which were graded on the basis of the modified Clavien-Dindo classification.8 Grade III complications were those requiring surgical, endoscopic, or radiological interventions without (IIIa) or with general anesthesia (IIIb). Grade IV complications included
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TABLE 1. Clinical Data of 154 Study Donors Variable Age (years)* Female sex [n (%)] Body mass index (kg/m2)* Hypertension [n (%)] Diabetes mellitus [n (%)] Dyslipidemia [n (%)] Never smoker [n (%)] Fasting glucose (mg/dL)* Macrosteatosis (%)† Microsteatosis (%)† Remnant liver volume (%)† Total IHIO rounds: 0, 1 or 2, and 3 [n (%)] Cumulative IHIO time (minutes)† Operative time (minutes)* Crystalloid (mL/hour)* Blood loss (mL)†‡
Descriptive Statistic 34 6 11 58 (37.7) 23.1 6 3.2 6 (3.9) 0 (0) 28 (18.2) 104 (67.5) 95 6 9 5 (0-10) 10 (0-15) 35 (33-40) 53 (34.4), 26 (16.9), and 75 (48.7) 33 (0-50) 379 6 57 371 6 93 165 (84-270)
*The data are presented as means and standard deviations. The data are presented as medians and interquartile ranges. ‡ Calculated with the perioperative hematocrit change and the estimated plasma volume. †
life-threatening complications necessitating intensive care unit management, and grade V complications were those that resulted in patient death. According to the Centers for Disease Control definition of surgical infection, surgical site infections included superficial/deep incisional infections and organ/space infections.9 We also analyzed the relationship between blood glucose concentrations and transaminase concentrations.
Statistical Analyses Continuous variables are expressed as means and standard deviations or medians and interquartile ranges according to probability distributions and were analyzed with a 1-way analysis of variance or the Kruskal-Wallis test. Categorical variables are expressed as numbers and percentages and were analyzed with the v2 test, Fisher’s exact test, or logistic regression analysis. The results of the logistic regression analysis are described as odds ratios with 95% confidence intervals. Repeatedly measured data were analyzed with a mixed model with Bonferroni correction. Pearson correlations were used to analyze the degree of linear dependence between 2 continuous variables. All reported P values are 2-sided, and P < 0.05 was considered statistically significant. SPSS 19.0 (SPSS, Inc., Chicago, IL) was used for all statistical analyses.
RESULTS The characteristics of the study population are given in Table 1. All 154 donors underwent standard right hepatectomy without the middle hepatic vein trunk. No donors received any blood products during surgery. Overall, 101 donors (65.6%) underwent at least
Figure 1. Blood glucose concentrations measured immediately after the clamping and unclamping of the hepatoduodenal ligament. C and U indicate clamping and unclamping, respectively; I indicates immediately after the induction of anesthesia; and 1h and 2h indicate 1 and 2 hours, respectively, after liver resection.
1 round of IHIO during parenchymal dissection. Six donors (3.9%) underwent 1 round, 20 donors (13.0%) underwent 2 rounds, 41 donors (26.6%) underwent 3 rounds, 22 donors (14.3%) underwent 4 rounds, 7 donors (4.5%) underwent 5 rounds, and 5 donors (3.2%) underwent 6 rounds. A median of 8 glucose measurements were taken during surgery. The donors’ detailed glycemic responses to IHIO are shown in Fig. 1. Up-and-down glycemic disturbances were repeatedly observed during IHIO. Blood glucose concentrations decreased during the 15 minutes of clamping and rose during the 5 minutes of unclamping, and they gradually decreased for 2 hours after liver resection. Blood glucose concentrations were significantly greater at the start of the second clamping (at the end of the first unclamping) versus the first
LIVER TRANSPLANTATION, Vol. 21, No. 2, 2015
Figure 2. Scatter plot of increases in blood glucose concentrations during each IHIO reperfusion period. The lines indicate the mean values.
Figure 3. Association between the total number of IHIO rounds performed during parenchymal dissection and (A) the maximal intraoperative blood glucose concentrations and (B) the incidence rate of intraoperative hyperglycemia (blood glucose concentration > 180 mg/dL).
HAN ET AL. 183
Figure 4. Changes in the blood glucose concentration in hepatectomized donors who underwent 0 to 2 rounds and 3 rounds of IHIO.
clamping. In contrast, blood glucose concentrations at the second, third, and fourth clampings were not significantly different from one another. As shown in Fig. 2, the degree to which glucose levels increased was significantly greater during the first unclamping period versus the second. In contrast, the degrees to which glucose levels increased during the second, third, and fourth unclamping periods were not significantly different from one another. There were no significant differences in the degrees to which glucose levels decreased during the first and second clamping periods (20 6 17 versus 22 6 15 mg/dL, respectively; P 5 0.37) and thereafter (Fig. 1). As shown in Fig. 3, maximum intraoperative blood glucose concentrations were greater in donors who underwent 3 rounds of IHIO (169 6 30 mg/dL) versus those who underwent 1 or 2 rounds (149 6 31 mg/dL, P 5 0.005). In contrast, there was no significant difference in the maximal blood glucose concentration between donors who did not undergo IHIO (135 6 23 mg/dL) and those who underwent 1 or 2 rounds of IHIO (149 6 31 mg/dL, P 5 0.10). The incidence of hyperglycemia was greater in donors who underwent 3 rounds of IHIO (38.7%) versus those who underwent 1 or 2 rounds (odds ratio 5 7.1, 95% confidence interval 5 2.5-20.4, P < 0.001). In contrast, the incidence of hyperglycemia was similar in donors who did not undergo IHIO and those who underwent 1 or 2 rounds of IHIO (odds ratio 5 2.1, 95% confidence interval 5 0.3-16.0, P 5 0.46). The degree to which blood glucose levels increased during unclamping periods was significantly greater in donors who developed intraoperative hyperglycemia versus those who did not [first unclamping, 64 6 23 versus 38 6 17 mg/dL (P 5 0.001); second unclamping, 30 6 23 versus 20 6 16 mg/dL (P 5 0.04); third unclamping, 32 6 19 versus 20 6 16 mg/dL (P 5 0.02)]. This result suggests that the donors who developed hyperglycemia responded differently to IHIO in comparison with the donors who did not develop hyperglycemia.
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TABLE 2. Postoperative Outcomes of Donors With and Without Intraoperative Hyperglycemia Nonhyperglycemic (n 5 121)
Hyperglycemic (n 5 33)
P Value
64 (52.9) 9 (7.4) 1 (0.8) 0 10 (8.3) 4 (3.3) 4 (3.3) 13 (10-20) 49 (40.5)
19 (57.6) 5 (15.2) 0 0 6 (18.2) 2 (6.1) 4 (12.1) 12 (10-21) 13 (39.4)
0.63 0.18 >0.99 — 0.11 0.61 0.07 0.90 0.91
Overall complications [n (%)] Grade IIIa complication [n (%)] Grade IIIb complication [n (%)] Grade IV/V complication [n (%)] Bile leakage [n (%)] Biliary stricture [n (%)] Surgical site infection [n (%)] Hospital stay (days)* Hospital stay > 14 days [n (%)]
*The data are presented as medians and interquartile ranges.
Posttransplant donor glycemic changes were comparable in donors who underwent 0 to 2 rounds of IHIO and those who underwent 3 rounds of IHIO (P 5 0.72; Fig. 4). Fasting blood glucose concentrations ranged from 60 to 150 mg/dL in all of the study donors on postoperative day 7. None of the donors required insulin or glucose to manage postoperative hyper- or hypoglycemia, respectively. The patients were followed postoperatively for a mean duration of 3 months. The incidences of overall, grade IIIa, and biliary complications were not significantly different for donors who experienced intraoperative hyperglycemia and those who did not (Table 2). Those who developed intraoperative hyperglycemia had a nonsignificant but elevated risk of surgical site infections in comparison with those who did not develop intraoperative hyperglycemia (12.1% versus 3.3%, P 5 0.07).
DISCUSSION This article describes the glycemic responses of living liver donors after IHIO during parenchymal dissection. The intermittent hepatic ischemia and reperfusion produced by IHIO induced repeated hyperglycemic disturbances in the donors. The degree to which blood glucose levels increased during intermittent reperfusions was greater in donors who developed intraoperative hyperglycemia versus those who did not. Accordingly, prolonged IHIO (3 rounds) was determined to be significantly associated with the occurrence of intraoperative hyperglycemia. We observed that blood glucose levels decreased during hepatic ischemia and rose after liver reperfusion. The net effect of glycemic disturbances tended toward hyperglycemia. Several mechanisms are thought to be involved in these hyperglycemic disturbances. First, hepatic inflow occlusion decreases intracellular energy levels and glucose delivery to hepatocytes. The metabolic result of this phenomenon is massive glycogenolysis and leakage of accumulated glucose out of the hepatocytes (spontaneously or through structurally disrupted cell membranes). Subsequent hepatic reperfusion causes the released glucose to flow into the systemic circulation.10
Figure 5. Association between maximum intraoperative and postoperative concentrations of (A) AST and (B) ALT within the first week after liver resection.
This hypothesis is further supported by a positive correlation between maximum intraoperative glucose concentrations and postoperative transaminase concentrations (Fig. 5). Hepatic enzymes leak out of injured hepatocytes in the same manner as glucose; therefore, transaminase concentrations are considered to be markers of structural hepatocyte injury
LIVER TRANSPLANTATION, Vol. 21, No. 2, 2015
during hepatectomy. Second, nonhepatic glucose production might be induced during hepatic vascular occlusion to compensate for the lack of glucose released from the liver.11 This response is hormonal, and some of the effects may be sustained after reperfusion. We previously showed that living donors who underwent
ORIGINAL ARTICLE
Glycemic Responses to Intermittent Hepatic Inflow Occlusion in Living Liver Donors Sangbin Han,1 Justin Sangwook Ko,1 Sang-Man Jin,2 Jong Man Kim,3 Soo Joo Choi,1 Jae-Won Joh,3 Yang Hoon Chung,1 Suk-Koo Lee,3 Mi Sook Gwak,1 and Gaabsoo Kim1 1 Department of Anesthesiology and Pain Medicine, 2Division of Endocrinology and Metabolism, Department of Medicine; and 3Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
The occurrence of glycemic disturbances has been described for patients undergoing intermittent hepatic inflow occlusion (IHIO) for tumor removal. However, the glycemic responses to IHIO in living liver donors are unknown. This study investigated the glycemic response to IHIO in these patients and examined the association between this procedure and the occurrence of hyperglycemia (blood glucose > 180 mg/dL). The data from 154 living donors were retrospectively reviewed. The decision to perform IHIO was made on the basis of the extent of bleeding that occurred during parenchymal dissection. One round of IHIO consisted of 15 minutes of clamping and 5 minutes of unclamping the hepatic artery and portal vein. Blood glucose concentrations were measured at predetermined time points, including the start and end of IHIO. Repeated hyperglycemic episodes occurred after unclamping. The mean maximum intraoperative blood glucose concentration was greater in donors who underwent 3 rounds of IHIO versus those who underwent 1 or 2 rounds (169 6 30 versus 149 6 31 mg/dL, P 5 0.005). The incidence of intraoperative hyperglycemia was also greater in donors who underwent 3 rounds of IHIO versus those who underwent 1 or 2 rounds (38.7% versus 7.7%, odds ratio 5 7.1, 95% confidence interval 5 2.5-20.4, P < 0.001). Donors who did not undergo IHIO and those who underwent 1 or 2 rounds of IHIO exhibited similar maximum glucose concentrations and similar incidence rates of hyperglycemia. In conclusion, IHIO induced repeated hyperglycemic responses in living donors, and donors who underwent 3 rounds of IHIO were more likely to experience intraoperative hyperglycemia. These results provide additional information on the risks and benefits of IHIO in living donors. C 2014 AASLD. Liver Transpl 21:180-186, 2015. V Received June 13, 2014; accepted October 12, 2014. Intermittent hepatic inflow occlusion (IHIO) effectively reduces the amount of blood lost during liver resection and can prevent the need for a blood transfusion. Recent studies have suggested that IHIO-induced ischemic preconditioning can increase the ability of the liver to tolerate ischemia and reperfusion injury by promoting cellular repair/protection mechanisms and improving intrahepatic microcirculation.1 Despite these potential benefits and the widespread use of IHIO during liver surgery, the maneuver has not been extensively adopted in living donor liver transplantation because of a lack of understanding of the effects of repeated hepatic ischemia and reperfusion in these
subjects. In particular, the glycemic response of living donors is poorly understood.2 The liver plays a prominent role in maintaining blood glucose levels within a narrow range. Accordingly, patients undergoing liver resection are at high risk for experiencing a glycemic disturbance resulting from surgical injuries and hepatocyte loss. Furthermore, IHIO has been shown to induce repeated hyperglycemia in patients undergoing liver resection to remove tumors.2 Glycemic responses to IHIO in living liver donors have never been assessed, and a better understanding of these responses will help clinicians to understand the risks and benefits of performing IHIO in living donors.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; IHIO, intermittent hepatic inflow occlusion. Potential conflict of interest: Nothing to report. Address reprint requests to Gaabsoo Kim, M.D., Ph.D., Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-Dong, Gangnam-Gu, Seoul 135-710, Korea. Telephone: 82-2-3410-2470; FAX: 82-2-34100361; E-mail: [email protected] DOI 10.1002/lt.24029 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2014 American Association for the Study of Liver Diseases. V
LIVER TRANSPLANTATION, Vol. 21, No. 2, 2015
Thus, we evaluated the glycemic responses of living donors undergoing IHIO and assessed the incidence rate and magnitude of hyperglycemia in these patients.
PATIENTS AND METHODS Subjects In all, 154 adult living donors who underwent open right hepatectomies between December 2010 and August 2012 were included in the study. Routine pretransplant evaluations of the donors included biochemical tests, abdominal ultrasound, computed tomography, angiography, and magnetic resonance cholangiopancreatography to detect undiagnosed diseases and assess the liver function, parenchymal fatty changes, anatomy of the biliary/vascular system, and liver volume. Acceptable donors were considered to have 30% macrosteatosis without any type of hepatitis and a remnant liver volume 30%.3 There were no specific exclusion criteria for the study. The institutional review board of Samsung Medical Center approved this retrospective study (SMC 2014-05-079) and waived the requirement for written informed consent. All data were obtained from computerized medical records.
Monitoring and Anesthesia Intraoperative anesthetic management was performed according to the standardized protocol for living donor hepatectomy, which included standard anesthetic monitoring (peripheral capillary oxygen saturation, 3lead electrocardiography, and noninvasive arterial blood pressure measurement). Morphine sulfate (400 lg) was intrathecally administered to alleviate postoperative pain.4 Anesthesia was induced with sodium thiopental (5 mg/kg) and maintained with isoflurane. An intra-arterial catheter was placed in the right radial artery for direct blood pressure monitoring and blood sampling. Remifentanil was infused intravenously at a rate of 0.05 to 0.20 lg/kg/minute according to the hemodynamic response of each individual. Vecuronium was used as a muscle relaxant to facilitate endotracheal intubation and intraoperative muscle relaxation. Ventilation was controlled to obtain a tidal volume of 8 mL/kg and to maintain normocapnea, and the fraction of inspired oxygen was maintained at 0.5. Circulation was managed to achieve a target mean arterial pressure of 70 mm Hg and a pulse pressure variation of 12%.5 Hartmann’s solution was administered primarily to maintain normovolemia, and a colloid solution was administered for intravascular volume expansion after liver parenchymal dissection. A red blood cell transfusion was indicated when the blood hemoglobin concentration of the patient was 200 mg/dL. A 5% dextrose solution was postoperatively infused at a rate of 80 mL/hour in combination with a 40 mL/ hour infusion of Hartmann’s solution. Oral intake was allowed on the third day after surgery.
Study Objectives and Parameters The primary objectives of this study were to evaluate the glycemic response to IHIO in living liver donors and to investigate the contribution of IHIO to the development of intraoperative hyperglycemia (blood glucose concentration > 180 mg/dL).7 The secondary objective was to explore the association between intraoperative hyperglycemia and posttransplant donor complications, which were graded on the basis of the modified Clavien-Dindo classification.8 Grade III complications were those requiring surgical, endoscopic, or radiological interventions without (IIIa) or with general anesthesia (IIIb). Grade IV complications included
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TABLE 1. Clinical Data of 154 Study Donors Variable Age (years)* Female sex [n (%)] Body mass index (kg/m2)* Hypertension [n (%)] Diabetes mellitus [n (%)] Dyslipidemia [n (%)] Never smoker [n (%)] Fasting glucose (mg/dL)* Macrosteatosis (%)† Microsteatosis (%)† Remnant liver volume (%)† Total IHIO rounds: 0, 1 or 2, and 3 [n (%)] Cumulative IHIO time (minutes)† Operative time (minutes)* Crystalloid (mL/hour)* Blood loss (mL)†‡
Descriptive Statistic 34 6 11 58 (37.7) 23.1 6 3.2 6 (3.9) 0 (0) 28 (18.2) 104 (67.5) 95 6 9 5 (0-10) 10 (0-15) 35 (33-40) 53 (34.4), 26 (16.9), and 75 (48.7) 33 (0-50) 379 6 57 371 6 93 165 (84-270)
*The data are presented as means and standard deviations. The data are presented as medians and interquartile ranges. ‡ Calculated with the perioperative hematocrit change and the estimated plasma volume. †
life-threatening complications necessitating intensive care unit management, and grade V complications were those that resulted in patient death. According to the Centers for Disease Control definition of surgical infection, surgical site infections included superficial/deep incisional infections and organ/space infections.9 We also analyzed the relationship between blood glucose concentrations and transaminase concentrations.
Statistical Analyses Continuous variables are expressed as means and standard deviations or medians and interquartile ranges according to probability distributions and were analyzed with a 1-way analysis of variance or the Kruskal-Wallis test. Categorical variables are expressed as numbers and percentages and were analyzed with the v2 test, Fisher’s exact test, or logistic regression analysis. The results of the logistic regression analysis are described as odds ratios with 95% confidence intervals. Repeatedly measured data were analyzed with a mixed model with Bonferroni correction. Pearson correlations were used to analyze the degree of linear dependence between 2 continuous variables. All reported P values are 2-sided, and P < 0.05 was considered statistically significant. SPSS 19.0 (SPSS, Inc., Chicago, IL) was used for all statistical analyses.
RESULTS The characteristics of the study population are given in Table 1. All 154 donors underwent standard right hepatectomy without the middle hepatic vein trunk. No donors received any blood products during surgery. Overall, 101 donors (65.6%) underwent at least
Figure 1. Blood glucose concentrations measured immediately after the clamping and unclamping of the hepatoduodenal ligament. C and U indicate clamping and unclamping, respectively; I indicates immediately after the induction of anesthesia; and 1h and 2h indicate 1 and 2 hours, respectively, after liver resection.
1 round of IHIO during parenchymal dissection. Six donors (3.9%) underwent 1 round, 20 donors (13.0%) underwent 2 rounds, 41 donors (26.6%) underwent 3 rounds, 22 donors (14.3%) underwent 4 rounds, 7 donors (4.5%) underwent 5 rounds, and 5 donors (3.2%) underwent 6 rounds. A median of 8 glucose measurements were taken during surgery. The donors’ detailed glycemic responses to IHIO are shown in Fig. 1. Up-and-down glycemic disturbances were repeatedly observed during IHIO. Blood glucose concentrations decreased during the 15 minutes of clamping and rose during the 5 minutes of unclamping, and they gradually decreased for 2 hours after liver resection. Blood glucose concentrations were significantly greater at the start of the second clamping (at the end of the first unclamping) versus the first
LIVER TRANSPLANTATION, Vol. 21, No. 2, 2015
Figure 2. Scatter plot of increases in blood glucose concentrations during each IHIO reperfusion period. The lines indicate the mean values.
Figure 3. Association between the total number of IHIO rounds performed during parenchymal dissection and (A) the maximal intraoperative blood glucose concentrations and (B) the incidence rate of intraoperative hyperglycemia (blood glucose concentration > 180 mg/dL).
HAN ET AL. 183
Figure 4. Changes in the blood glucose concentration in hepatectomized donors who underwent 0 to 2 rounds and 3 rounds of IHIO.
clamping. In contrast, blood glucose concentrations at the second, third, and fourth clampings were not significantly different from one another. As shown in Fig. 2, the degree to which glucose levels increased was significantly greater during the first unclamping period versus the second. In contrast, the degrees to which glucose levels increased during the second, third, and fourth unclamping periods were not significantly different from one another. There were no significant differences in the degrees to which glucose levels decreased during the first and second clamping periods (20 6 17 versus 22 6 15 mg/dL, respectively; P 5 0.37) and thereafter (Fig. 1). As shown in Fig. 3, maximum intraoperative blood glucose concentrations were greater in donors who underwent 3 rounds of IHIO (169 6 30 mg/dL) versus those who underwent 1 or 2 rounds (149 6 31 mg/dL, P 5 0.005). In contrast, there was no significant difference in the maximal blood glucose concentration between donors who did not undergo IHIO (135 6 23 mg/dL) and those who underwent 1 or 2 rounds of IHIO (149 6 31 mg/dL, P 5 0.10). The incidence of hyperglycemia was greater in donors who underwent 3 rounds of IHIO (38.7%) versus those who underwent 1 or 2 rounds (odds ratio 5 7.1, 95% confidence interval 5 2.5-20.4, P < 0.001). In contrast, the incidence of hyperglycemia was similar in donors who did not undergo IHIO and those who underwent 1 or 2 rounds of IHIO (odds ratio 5 2.1, 95% confidence interval 5 0.3-16.0, P 5 0.46). The degree to which blood glucose levels increased during unclamping periods was significantly greater in donors who developed intraoperative hyperglycemia versus those who did not [first unclamping, 64 6 23 versus 38 6 17 mg/dL (P 5 0.001); second unclamping, 30 6 23 versus 20 6 16 mg/dL (P 5 0.04); third unclamping, 32 6 19 versus 20 6 16 mg/dL (P 5 0.02)]. This result suggests that the donors who developed hyperglycemia responded differently to IHIO in comparison with the donors who did not develop hyperglycemia.
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TABLE 2. Postoperative Outcomes of Donors With and Without Intraoperative Hyperglycemia Nonhyperglycemic (n 5 121)
Hyperglycemic (n 5 33)
P Value
64 (52.9) 9 (7.4) 1 (0.8) 0 10 (8.3) 4 (3.3) 4 (3.3) 13 (10-20) 49 (40.5)
19 (57.6) 5 (15.2) 0 0 6 (18.2) 2 (6.1) 4 (12.1) 12 (10-21) 13 (39.4)
0.63 0.18 >0.99 — 0.11 0.61 0.07 0.90 0.91
Overall complications [n (%)] Grade IIIa complication [n (%)] Grade IIIb complication [n (%)] Grade IV/V complication [n (%)] Bile leakage [n (%)] Biliary stricture [n (%)] Surgical site infection [n (%)] Hospital stay (days)* Hospital stay > 14 days [n (%)]
*The data are presented as medians and interquartile ranges.
Posttransplant donor glycemic changes were comparable in donors who underwent 0 to 2 rounds of IHIO and those who underwent 3 rounds of IHIO (P 5 0.72; Fig. 4). Fasting blood glucose concentrations ranged from 60 to 150 mg/dL in all of the study donors on postoperative day 7. None of the donors required insulin or glucose to manage postoperative hyper- or hypoglycemia, respectively. The patients were followed postoperatively for a mean duration of 3 months. The incidences of overall, grade IIIa, and biliary complications were not significantly different for donors who experienced intraoperative hyperglycemia and those who did not (Table 2). Those who developed intraoperative hyperglycemia had a nonsignificant but elevated risk of surgical site infections in comparison with those who did not develop intraoperative hyperglycemia (12.1% versus 3.3%, P 5 0.07).
DISCUSSION This article describes the glycemic responses of living liver donors after IHIO during parenchymal dissection. The intermittent hepatic ischemia and reperfusion produced by IHIO induced repeated hyperglycemic disturbances in the donors. The degree to which blood glucose levels increased during intermittent reperfusions was greater in donors who developed intraoperative hyperglycemia versus those who did not. Accordingly, prolonged IHIO (3 rounds) was determined to be significantly associated with the occurrence of intraoperative hyperglycemia. We observed that blood glucose levels decreased during hepatic ischemia and rose after liver reperfusion. The net effect of glycemic disturbances tended toward hyperglycemia. Several mechanisms are thought to be involved in these hyperglycemic disturbances. First, hepatic inflow occlusion decreases intracellular energy levels and glucose delivery to hepatocytes. The metabolic result of this phenomenon is massive glycogenolysis and leakage of accumulated glucose out of the hepatocytes (spontaneously or through structurally disrupted cell membranes). Subsequent hepatic reperfusion causes the released glucose to flow into the systemic circulation.10
Figure 5. Association between maximum intraoperative and postoperative concentrations of (A) AST and (B) ALT within the first week after liver resection.
This hypothesis is further supported by a positive correlation between maximum intraoperative glucose concentrations and postoperative transaminase concentrations (Fig. 5). Hepatic enzymes leak out of injured hepatocytes in the same manner as glucose; therefore, transaminase concentrations are considered to be markers of structural hepatocyte injury
LIVER TRANSPLANTATION, Vol. 21, No. 2, 2015
during hepatectomy. Second, nonhepatic glucose production might be induced during hepatic vascular occlusion to compensate for the lack of glucose released from the liver.11 This response is hormonal, and some of the effects may be sustained after reperfusion. We previously showed that living donors who underwent
