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Intraoperative Massive Transfusion Decreases Survival After Liver Transplantation
Intraoperative Massive Transfusion Decreases Survival After Liver Transplantation I.F.S.F. Boin, M.I. Leonardi, A.C.M. Luzo, A.R. Cardoso, C.A. Caruy, and L.S. Leonardi
ABSTRACT Patients undergoing liver transplantation often experience coagulopathy and massive intraoperative blood loss that can lead to morbidity and reduced survival. The aim of this study was to verify the survival rate and discover predictive factors for death among liver transplant patients who received massive intraoperative blood transfusions. This cohort study was based on prospective data collected retrospectively from January 2004 to July 2006. The 232 patients were distributed according to their blood requirements, (namely, more or less than 6 units), including red blood cell saver. The statistical analyses were performed using Student t test, Cox hazard regression, and the Kaplan-Meier method (log-rank test). The massively transfused cohort displayed higher Child-Pugh classifications (10.2 vs 9.6; P ⫽ .03); model for end-stage liver disease (MELD) scores (19 vs 17; P ⫽ .02); recipient weights (75.4 vs 71 kg; P ⫽ .03); as well as warm ischemia times (70.7 vs 56.4 minutes; P ⬍ .001) and surgery times (584.6 vs 503.4 minutes; P ⬍ .05). The proportional hazard (Cox) regression analysis showed that the risk of death increased 2.1% for each unit of donor sodium and 1.6% for each additional year of donors age over 50. The survival rates at 6, 12, 60, and 120 months for ⱖ6 vs ⬍6 U of blood transfusion of 63.8% vs 83.3%; 53.9% vs 76.3%; 40% vs 60%; 34.5% vs 49.2%. In conclusion, we observed that patients receiving over 6 red blood cell units intraoperatively displayed reduced survival. Predictive factors for this risk factor were high donor level of sodium and of age.
P
ATIENTS UNDERGOING liver transplantation often present with coagulopathy and massive intraoperative blood loss requiring large amounts of blood transfusions. Massive transfusion has been correlated with morbidity and reduced survival. Various surgical and anesthesic procedures have been used during the last 20 years to prevent excessive bleeding and reduce blood usage. Presently, almost 40% of surgeries are performed without blood transfusion.1–3 Despite the fact that massive transfusion is related to hazards in the postoperative period, there has not been a defined relationship between the number of packed red cells transfused and survival.4,5 Xia et al retrospectively analyzing a cohort of 124 patients undergoing liver transplantation concluded that high model for end-stage liver disease (MELD) scores were related to large amounts of blood transfusions and vasoactive drug use. The comorbidities described in their study to be associated with massive transfusion were hepatorenal syndrome, hepatic encephalopathy, and esophagogastric varices.6 © 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 40, 789 –791 (2008)
In order to analyze whether the number of packed red cell transfusions was a predictive factor for survival and to evaluate other correlated factors, we prospectively analyzed intraoperative blood usage of liver transplant surgeries performed from January 1994 to July 2006.
MATERIALS AND METHODS This is a cohort study based on prospective data collected retrospectively from January 2004 to July 2006. We analyzed all patients undergoing liver transplantation during the period, excluding those who were less than 18 years old, who received split grafts, or had acute hepatic insufficiency. All recipients were allocated organs by chronological criteria until July 2006. From the Unit of Liver Transplantation, Hospital de Clínicas, State University of Campinas, Campinas/SP, Brazil. Address reprint requests to Ilka de Fátima Santana Ferreira Boin, Rua Aldo Oliveira Barbosa 184 – Parque das Universidades, CEP 13086-030, Campinas/SP, Brazil. E-mail: [email protected] 0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.02.058 789
790
BOIN, LEONARDI, LUZO ET AL
The 232 patients underwent liver transplantation using the piggyback technique. They were categorized according to their blood requirements, including packed red cells obtained from the cell saver system, namely, more or less than 6 units of packed red cells. The cell saver system was utilized in all surgeries, except when the patient had hepatocellular carcinoma. Intraoperative massive blood transfusion was considered when we transfused 6 or more units of packed red cells. Blood transfusions were administered based on clinical and hemodynamic criteria. The desired hemoglobin ranged from 8.0 to 10.0 g/dL. The replacement of other hemocomponents was not analyzed; volemic reposition was performed with crystalloid and colloid solutions. The anesthetic induction and maintenance was performed with a combination of endovenous drugs; propofol, fentanyl, and pancuronium. Hemodynamic monitoring consisted of an arterial line and a pulmonary artery catheter. Body temperature was maintained with warming blankets and intravenous fluid warmers. The analyzed variables for recipients were: age, sex, disease, Child-Turcotte-Pagh (CTP) classification, weight (kg), height (cm), warm ischemic time, cold ischemic time, hepatectomy time, surgical time, ward care time, pretransplantation MELD score, serum sodium, and transfusion group (ⱖ6 U); For donors they were: age, time of orotracheal tube, and plasma sodium values. During the first 7 days the creatinine clearance and alanine aminotransferase (ALT) variables were analyzed to characterize graft dysfunction (ALT ⬎2000 IU/L). Statistical analyses were performed using Student t test, Cox hazard regression, and the Kaplan-Meier method (log-rank test).
RESULTS
There were 142 patients (61.2%) in the large transfusion cohort (ⱖ6 U) versus 90 patients transfused with less than 6 U of packed red cells (38.8%). There was no need for blood transfusion among 8.6% of patients. Of the patients, 73.3% were men and 53.3% had hepatitis C. Table 1. Comparison of Recipient and Donor Variables (Means) Between Patients Who Had >6 Vs <6 U of Blood Transfusion
The high transfusion group (ⱖ6 U) displayed higher mean Child-Pugh classifications (10.2 vs 9.6; P ⫽ .03); MELD scores (19 vs 17; P ⫽ .02); recipient weight (75.4 vs 71 kg; P ⫽ .03); as well as warm ischemia times (70.7 vs 56.4 minutes; P ⬍ .001) and surgery times (584.6 vs 503.4 minutes; P ⬍ .05). Other variable results are shown in Table 1. The proportional hazard (Cox) regression analysis showed that the predictive values related to survival were donor age and donor sodium plasma value. The risk of death was increased 2.1% for each elevation of 1 unit in donor sodium plasma value and 1.6% for each additional year of donor age over 50. The survival rates at 6, 12, 60, and 120 months were (ⱖ6 vs ⬍6 U): 63.8% vs 83.3%; 53.9% vs 76.3%; 40% vs 60%; 34.5% vs 49.2%. The high transfusion group showed a lower survival over the short and long terms (Fig 1). DISCUSSION
Variable
ⱖ6 U
⬍6 U
P
Age R (y) CTP classification* MELD* Weight R (kg)* Height R (cm) Warm ischemia time (min)* Cold ischemia time (min) Hepatectomy time (min)* Surgical time (min)* ICU time (d) Ward care time (d) Creatinine clearance ALT R (IU/L)* Sodium D Orotracheal tube D (h) Age D (y)
47.4 ⫾ 9.4 10.2 ⫾ 1.9 18.9 ⫾ 4.6 75.4 ⫾ 15.5 168.6 ⫾ 8.2 70.7 ⫾ 31.8 724.6 ⫾ 174.3 254.6 ⫾ 78.9 584.6 ⫾ 142.2 14.17 ⫾ 28.7 21.7 ⫾ 31.9 54.5 ⫾ 26.8 3108 ⫾ 3946 149.2 ⫾ 13.6 85.2 ⫾ 64.5 32.3 ⫾ 12.1
45 ⫾ 11.6 9.6 ⫾ 2.0 17.5 ⫾ 4.7 71.0 ⫾ 14.8 167.6 ⫾ 9.4 56.42 ⫾ 17.5 688.6 ⫾ 188.5 233.9 ⫾ 58.5 503.3 ⫾ 118.8 10.0 ⫾ 10.0 18.2 ⫾ 13.4 71.6 ⫾ 31.7 1988 ⫾ 2584 151.1 ⫾ 14.0 93.9 ⫾ 77.9 33.5 ⫾ 1.42
.09 .03 .02 .03 .40 .0001 .13 .03 .0001 .19 .33 .0001 .01 .32 .36 .06
R, recipient; D, donor. *P ⬍ .05.
Fig 1. Survival curves with Kaplan-Meier method and log-rank test show that patients with intraoperative massive blood transfusions (ⱖ6 U) presented lower survival rates than patients with ⬍6 U in the short and long terms (P ⫽ .0009).
Despite the fact that major blood usage has been related to a reduced survival rate after liver transplantation, massive transfusion has not been considered to be an independent predictive factor of prognosis in the postoperative period.4,7–10 The aim of this study was to detect predictive factors that could anticipate massive bleeding in the intraoperative period and thereby prevent some hazards in the postoperative period. Knowledge of these factors could permit a more rational utilization of blood components as well as the use of antifibrinolytic drugs and procoagulant factors like aprotinin and recombinant factor VIIa.11–13 Some wellknown factors that correlate with hazard in this period, such as the presence of ascites, portal hypertension, and late abdominal surgeries, were not analyzed in our study. McCluskey et al4 associated MELD score with massive transfusion. They observed independent risk factors, before multivariable analysis, to be renal function, preoperative hematocrit, CTP score at the time of transplan-
INTRAOPERATIVE MASSIVE BLOOD TRANSFUSIONS
tation, cold ischemia time, and surgical technique. The results of our study agree with those authors. We observed that patients with high MELD and CTP scores as well as elevated weights used more packed red cells at surgery. They also showed the impact of longer times of warm ischemia, hepatectomy, and surgery. These patients experienced decreased renal function and greater graft dysfunction in the postoperative period. The proportional hazard (Cox) regression analysis demonstrated that donor age and donor sodium plasma values were predictive factors. Patients undergoing multiple transfusions displayed lower survival rates, in agreement with Yuasa et al11 and other authors.7,10,11 In conclusion, massive transfusion in the intraoperative period of liver transplantation was responsible for a lower survival rate among these patients. Donor age and sodium plasma values were predictive factors for massive bleeding. REFERENCES 1. Cacciarelli TV, Keeffe EB, Moore DH, et al: Primary liver transplantation without transfusion of red blood cells. Surgery 120:698, 1996 2. Ramos E, Dalmau A, Sabate A, et al: Intraoperative red blood cell transfusion in liver transfusion: influence on patient outcome, prediction of requirements, and measures to reduce them. Liver Transpl 9:1320, 2003 3. Mor E, Jennings L, Gonwa TA, et al: The impact of operative bleeding on outcome in transplantation of the liver. Surg Gynecol Obstet 176:219, 1993
791 4. McCluskey AS, Karkouti K, Wijeysundera DN, et al: Derivation of a risk index for the prediction of massive blood transfusion in liver transplantation. Liver Transpl 12:1584, 2006 5. Massicotte L, Sassine MP, Lenis S, et al: Survival rate changes with transfusion of blood products during liver transplantations. Can J Anesth 52:148, 2005 6. Xia VW, Du B, Braunfeld M, et al: Preoperative characteristics and intraoperative transfusion and vasopressor requirements in patients with low vs high MELD scores. Liver Transpl 12:614, 2006 7. Steib A, Freys G, Lehmann C, et al: Intraoperative blood losses and transfusion requirements during adult liver transplantation remain difficult to predict. Can J Anesth 48:1075, 2001 8. Cacciarelli TV, Keeffe EB, Moore DH, et al: Effect of intraoperative blood transfusion on patient outcome in hepatic transplantation. Arch Surg 134:25, 1999 9. Hendriks HG, van der Meer J, Klompmaker IJ, et al: Blood loss in orthotopic liver transplantation: a retrospective analysis of transfusion requirements and the effects of autotransfusion of cell saver blood in 164 consecutive patients. Blood Coagul Fibrinolysis 11 (suppl 1):S87, 2000 10. Findlay JY, Rettke SR: Poor prediction of blood transfusion requirements in adult liver transplantations from preoperative variables. J Clin Anesth 12:319, 2000 11. Yuasa T, Niwa N, Kimura S, et al: Intraoperative blood loss during living donor liver transplantation: an analysis of 635 recipients at a single center. Transfusion 45:879, 2005 12. Niemann CU, Behrends M, Quan D, et al: Recombinant factor VIIa reduces transfusion requirements in liver transplant patients with high MELD scores. Transfus Med 16:93, 2006 13. de Boer MT, Molenaar IQ, Hendriks HGD, et al: Minimizing blood loss in liver transplantation: progress through research and evolution techniques. Dig Surg 22:265, 2005
ABSTRACT Patients undergoing liver transplantation often experience coagulopathy and massive intraoperative blood loss that can lead to morbidity and reduced survival. The aim of this study was to verify the survival rate and discover predictive factors for death among liver transplant patients who received massive intraoperative blood transfusions. This cohort study was based on prospective data collected retrospectively from January 2004 to July 2006. The 232 patients were distributed according to their blood requirements, (namely, more or less than 6 units), including red blood cell saver. The statistical analyses were performed using Student t test, Cox hazard regression, and the Kaplan-Meier method (log-rank test). The massively transfused cohort displayed higher Child-Pugh classifications (10.2 vs 9.6; P ⫽ .03); model for end-stage liver disease (MELD) scores (19 vs 17; P ⫽ .02); recipient weights (75.4 vs 71 kg; P ⫽ .03); as well as warm ischemia times (70.7 vs 56.4 minutes; P ⬍ .001) and surgery times (584.6 vs 503.4 minutes; P ⬍ .05). The proportional hazard (Cox) regression analysis showed that the risk of death increased 2.1% for each unit of donor sodium and 1.6% for each additional year of donors age over 50. The survival rates at 6, 12, 60, and 120 months for ⱖ6 vs ⬍6 U of blood transfusion of 63.8% vs 83.3%; 53.9% vs 76.3%; 40% vs 60%; 34.5% vs 49.2%. In conclusion, we observed that patients receiving over 6 red blood cell units intraoperatively displayed reduced survival. Predictive factors for this risk factor were high donor level of sodium and of age.
P
ATIENTS UNDERGOING liver transplantation often present with coagulopathy and massive intraoperative blood loss requiring large amounts of blood transfusions. Massive transfusion has been correlated with morbidity and reduced survival. Various surgical and anesthesic procedures have been used during the last 20 years to prevent excessive bleeding and reduce blood usage. Presently, almost 40% of surgeries are performed without blood transfusion.1–3 Despite the fact that massive transfusion is related to hazards in the postoperative period, there has not been a defined relationship between the number of packed red cells transfused and survival.4,5 Xia et al retrospectively analyzing a cohort of 124 patients undergoing liver transplantation concluded that high model for end-stage liver disease (MELD) scores were related to large amounts of blood transfusions and vasoactive drug use. The comorbidities described in their study to be associated with massive transfusion were hepatorenal syndrome, hepatic encephalopathy, and esophagogastric varices.6 © 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 40, 789 –791 (2008)
In order to analyze whether the number of packed red cell transfusions was a predictive factor for survival and to evaluate other correlated factors, we prospectively analyzed intraoperative blood usage of liver transplant surgeries performed from January 1994 to July 2006.
MATERIALS AND METHODS This is a cohort study based on prospective data collected retrospectively from January 2004 to July 2006. We analyzed all patients undergoing liver transplantation during the period, excluding those who were less than 18 years old, who received split grafts, or had acute hepatic insufficiency. All recipients were allocated organs by chronological criteria until July 2006. From the Unit of Liver Transplantation, Hospital de Clínicas, State University of Campinas, Campinas/SP, Brazil. Address reprint requests to Ilka de Fátima Santana Ferreira Boin, Rua Aldo Oliveira Barbosa 184 – Parque das Universidades, CEP 13086-030, Campinas/SP, Brazil. E-mail: [email protected] 0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.02.058 789
790
BOIN, LEONARDI, LUZO ET AL
The 232 patients underwent liver transplantation using the piggyback technique. They were categorized according to their blood requirements, including packed red cells obtained from the cell saver system, namely, more or less than 6 units of packed red cells. The cell saver system was utilized in all surgeries, except when the patient had hepatocellular carcinoma. Intraoperative massive blood transfusion was considered when we transfused 6 or more units of packed red cells. Blood transfusions were administered based on clinical and hemodynamic criteria. The desired hemoglobin ranged from 8.0 to 10.0 g/dL. The replacement of other hemocomponents was not analyzed; volemic reposition was performed with crystalloid and colloid solutions. The anesthetic induction and maintenance was performed with a combination of endovenous drugs; propofol, fentanyl, and pancuronium. Hemodynamic monitoring consisted of an arterial line and a pulmonary artery catheter. Body temperature was maintained with warming blankets and intravenous fluid warmers. The analyzed variables for recipients were: age, sex, disease, Child-Turcotte-Pagh (CTP) classification, weight (kg), height (cm), warm ischemic time, cold ischemic time, hepatectomy time, surgical time, ward care time, pretransplantation MELD score, serum sodium, and transfusion group (ⱖ6 U); For donors they were: age, time of orotracheal tube, and plasma sodium values. During the first 7 days the creatinine clearance and alanine aminotransferase (ALT) variables were analyzed to characterize graft dysfunction (ALT ⬎2000 IU/L). Statistical analyses were performed using Student t test, Cox hazard regression, and the Kaplan-Meier method (log-rank test).
RESULTS
There were 142 patients (61.2%) in the large transfusion cohort (ⱖ6 U) versus 90 patients transfused with less than 6 U of packed red cells (38.8%). There was no need for blood transfusion among 8.6% of patients. Of the patients, 73.3% were men and 53.3% had hepatitis C. Table 1. Comparison of Recipient and Donor Variables (Means) Between Patients Who Had >6 Vs <6 U of Blood Transfusion
The high transfusion group (ⱖ6 U) displayed higher mean Child-Pugh classifications (10.2 vs 9.6; P ⫽ .03); MELD scores (19 vs 17; P ⫽ .02); recipient weight (75.4 vs 71 kg; P ⫽ .03); as well as warm ischemia times (70.7 vs 56.4 minutes; P ⬍ .001) and surgery times (584.6 vs 503.4 minutes; P ⬍ .05). Other variable results are shown in Table 1. The proportional hazard (Cox) regression analysis showed that the predictive values related to survival were donor age and donor sodium plasma value. The risk of death was increased 2.1% for each elevation of 1 unit in donor sodium plasma value and 1.6% for each additional year of donor age over 50. The survival rates at 6, 12, 60, and 120 months were (ⱖ6 vs ⬍6 U): 63.8% vs 83.3%; 53.9% vs 76.3%; 40% vs 60%; 34.5% vs 49.2%. The high transfusion group showed a lower survival over the short and long terms (Fig 1). DISCUSSION
Variable
ⱖ6 U
⬍6 U
P
Age R (y) CTP classification* MELD* Weight R (kg)* Height R (cm) Warm ischemia time (min)* Cold ischemia time (min) Hepatectomy time (min)* Surgical time (min)* ICU time (d) Ward care time (d) Creatinine clearance ALT R (IU/L)* Sodium D Orotracheal tube D (h) Age D (y)
47.4 ⫾ 9.4 10.2 ⫾ 1.9 18.9 ⫾ 4.6 75.4 ⫾ 15.5 168.6 ⫾ 8.2 70.7 ⫾ 31.8 724.6 ⫾ 174.3 254.6 ⫾ 78.9 584.6 ⫾ 142.2 14.17 ⫾ 28.7 21.7 ⫾ 31.9 54.5 ⫾ 26.8 3108 ⫾ 3946 149.2 ⫾ 13.6 85.2 ⫾ 64.5 32.3 ⫾ 12.1
45 ⫾ 11.6 9.6 ⫾ 2.0 17.5 ⫾ 4.7 71.0 ⫾ 14.8 167.6 ⫾ 9.4 56.42 ⫾ 17.5 688.6 ⫾ 188.5 233.9 ⫾ 58.5 503.3 ⫾ 118.8 10.0 ⫾ 10.0 18.2 ⫾ 13.4 71.6 ⫾ 31.7 1988 ⫾ 2584 151.1 ⫾ 14.0 93.9 ⫾ 77.9 33.5 ⫾ 1.42
.09 .03 .02 .03 .40 .0001 .13 .03 .0001 .19 .33 .0001 .01 .32 .36 .06
R, recipient; D, donor. *P ⬍ .05.
Fig 1. Survival curves with Kaplan-Meier method and log-rank test show that patients with intraoperative massive blood transfusions (ⱖ6 U) presented lower survival rates than patients with ⬍6 U in the short and long terms (P ⫽ .0009).
Despite the fact that major blood usage has been related to a reduced survival rate after liver transplantation, massive transfusion has not been considered to be an independent predictive factor of prognosis in the postoperative period.4,7–10 The aim of this study was to detect predictive factors that could anticipate massive bleeding in the intraoperative period and thereby prevent some hazards in the postoperative period. Knowledge of these factors could permit a more rational utilization of blood components as well as the use of antifibrinolytic drugs and procoagulant factors like aprotinin and recombinant factor VIIa.11–13 Some wellknown factors that correlate with hazard in this period, such as the presence of ascites, portal hypertension, and late abdominal surgeries, were not analyzed in our study. McCluskey et al4 associated MELD score with massive transfusion. They observed independent risk factors, before multivariable analysis, to be renal function, preoperative hematocrit, CTP score at the time of transplan-
INTRAOPERATIVE MASSIVE BLOOD TRANSFUSIONS
tation, cold ischemia time, and surgical technique. The results of our study agree with those authors. We observed that patients with high MELD and CTP scores as well as elevated weights used more packed red cells at surgery. They also showed the impact of longer times of warm ischemia, hepatectomy, and surgery. These patients experienced decreased renal function and greater graft dysfunction in the postoperative period. The proportional hazard (Cox) regression analysis demonstrated that donor age and donor sodium plasma values were predictive factors. Patients undergoing multiple transfusions displayed lower survival rates, in agreement with Yuasa et al11 and other authors.7,10,11 In conclusion, massive transfusion in the intraoperative period of liver transplantation was responsible for a lower survival rate among these patients. Donor age and sodium plasma values were predictive factors for massive bleeding. REFERENCES 1. Cacciarelli TV, Keeffe EB, Moore DH, et al: Primary liver transplantation without transfusion of red blood cells. Surgery 120:698, 1996 2. Ramos E, Dalmau A, Sabate A, et al: Intraoperative red blood cell transfusion in liver transfusion: influence on patient outcome, prediction of requirements, and measures to reduce them. Liver Transpl 9:1320, 2003 3. Mor E, Jennings L, Gonwa TA, et al: The impact of operative bleeding on outcome in transplantation of the liver. Surg Gynecol Obstet 176:219, 1993
791 4. McCluskey AS, Karkouti K, Wijeysundera DN, et al: Derivation of a risk index for the prediction of massive blood transfusion in liver transplantation. Liver Transpl 12:1584, 2006 5. Massicotte L, Sassine MP, Lenis S, et al: Survival rate changes with transfusion of blood products during liver transplantations. Can J Anesth 52:148, 2005 6. Xia VW, Du B, Braunfeld M, et al: Preoperative characteristics and intraoperative transfusion and vasopressor requirements in patients with low vs high MELD scores. Liver Transpl 12:614, 2006 7. Steib A, Freys G, Lehmann C, et al: Intraoperative blood losses and transfusion requirements during adult liver transplantation remain difficult to predict. Can J Anesth 48:1075, 2001 8. Cacciarelli TV, Keeffe EB, Moore DH, et al: Effect of intraoperative blood transfusion on patient outcome in hepatic transplantation. Arch Surg 134:25, 1999 9. Hendriks HG, van der Meer J, Klompmaker IJ, et al: Blood loss in orthotopic liver transplantation: a retrospective analysis of transfusion requirements and the effects of autotransfusion of cell saver blood in 164 consecutive patients. Blood Coagul Fibrinolysis 11 (suppl 1):S87, 2000 10. Findlay JY, Rettke SR: Poor prediction of blood transfusion requirements in adult liver transplantations from preoperative variables. J Clin Anesth 12:319, 2000 11. Yuasa T, Niwa N, Kimura S, et al: Intraoperative blood loss during living donor liver transplantation: an analysis of 635 recipients at a single center. Transfusion 45:879, 2005 12. Niemann CU, Behrends M, Quan D, et al: Recombinant factor VIIa reduces transfusion requirements in liver transplant patients with high MELD scores. Transfus Med 16:93, 2006 13. de Boer MT, Molenaar IQ, Hendriks HGD, et al: Minimizing blood loss in liver transplantation: progress through research and evolution techniques. Dig Surg 22:265, 2005