Donor Safety and Remnant Liver Volume in Living Donor Liver Transplantation

Transcription

1 LIVER TRANSPLANTATION 14: , 2008 ORIGINAL ARTICLE Donor Safety and Remnant Liver Volume in Living Donor Liver Transplantation C. Burcin Taner, Murat Dayangac, Baris Akin, Deniz Balci, Suleyman Uraz, Cihan Duran, Refik Killi, Omer Ayanoglu, Yildiray Yuzer, and Yaman Tokat Department of Surgery and Transplantation, Florence Nightingale Hospital, Istanbul Science University, Istanbul, Turkey Living donor liver transplantation is now a common practice in countries in which the availability of cadaveric organs is limited. The preoperative preparation, intraoperative surgical technique, and postoperative care of donors and recipients have evolved in recent years. We retrospectively compared 67 donors with a remnant liver volume equal to or more than 30% (group 1) with 14 donors who had less than 30% remnant liver volume (group 2) for donor outcomes. All the complications in donors were systematically classified. Donors with less than 30% remnant liver volume showed significantly higher peak aspartate aminotransferase, alanine aminotransferase, international normalized ratio, and bilirubin levels. There were 6 complications in group 1 and 4 complications in group 2. The difference between the 2 groups in terms of donor complications did reach statistical significance (P 0.043); donors with a remnant liver volume 30% had a 4 times greater relative risk of morbidity. In conclusion, the use of donors with less than 30% remnant liver volume is highly debatable as donor safety should be of utmost importance in living donor liver transplantation. Liver Transpl 14: , AASLD. Received November 26, 2007; accepted May 11, Living donor liver transplantation (LDLT) is now an accepted treatment modality for end-stage liver disease. It has become an alternative in the era of organ shortage. This procedure is possible because of the segmental structure of the liver and the regeneration potential of the transplanted and remnant parts. After years of extensive experience in adult-to-child left-lobe liver transplantation, right donor hepatectomy has become a common practice in centers performing adult-to-adult LDLT. Despite impressive results, right-lobe LDLT involves one of the most complicated and technically demanding surgical procedures and has created considerable controversy with respect to donor safety. To date, there have been 17 donor deaths reported, and the morbidity is reported to be in the range of 20% to 30%. 1-3 Since its start, the technique, donor and recipient selection, and postoperative care have evolved. In adult-to-adult LDLT, a right donor hepatectomy is performed in most cases in order to meet the metabolic demands of the recipient. It is well known that the graft-to-recipient body weight ratio should be at least 0.8% to prevent small-for-size syndrome in the recipient. 4 On the other hand, a large enough left lobe should remain in the donors to meet metabolic demand until the remnant regenerates to a sufficient size. There has been a relatively small number of publications in English literature specifically addressing remnant volume and associated morbidity. 5 Initial experience in the past suggested leaving a remnant of not less than 30%. 6 In countries in which living donors are the major source for livers, with growth of experience, transplant teams now attempt to perform the donor hepatectomy even if the remnant liver volume is less than the suggested 30%. Considering the controversy regarding safety and the extent of remnant liver volume in right-lobe LDLT, we decided to analyze our own data. We retrospectively examined the remnant liver volume in our donors and Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CI, confidence interval; CT, computerized tomography; F, female; GRWR, graft-to-recipient weight ratio; ICU, intensive care unit; INR, international normalized ratio; LDLT, living donor liver transplantation; M, male; MHV, middle hepatic vein; NS, not significant; POD, postoperative day; RR, relative risk. Address reprint requests to C. Burcin Taner, Department of Surgery and Transplantation, Florence Nightingale Hospital, Istanbul Science University, Abide-i Hurriyet Caddesi No. 290, Istanbul, Turkey Telephone: ; tanerburcin@yahoo.com DOI /lt Published online in Wiley InterScience ( American Association for the Study of Liver Diseases.

2 DONOR SAFETY AND REMNANT LIVER VOLUME 1175 compared donors with less than 30% remnant liver volume to donors who had a remnant liver volume equal to or more than 30%. Our aim was to reach a conclusion about whether it is safe to leave less than a 30% remnant liver volume after a right-lobe living donor hepatectomy. To the best of our knowledge, this is the first study that systematically evaluates morbidity in such donors after right-lobe donation. PATIENTS AND METHODS Between July 2005 and December 2006, we performed 81 LDLTs. Data were obtained from a medical record review. Follow-up was complete as of September Preoperative and postoperative biochemical, hematological, coagulation profile, intraoperative and postoperative transfusion requirement, postoperative complication, hospital stay, and readmission data for all donors were collected. Preoperative Evaluation Once the indication for liver transplant is established, the recipients are placed on our cadaveric liver transplantation list, and a workup is started for their living donors as a low number of cadaveric organs limits our practice. Donor evaluation is 3-fold: biochemical and serological tests, medical and social/psychiatric evaluation, and anatomical imaging studies. All donors are evaluated by a hepatologist, a transplant surgeon, and a psychiatrist before a decision about eligibility. Acceptance criteria for living donors include an age between 18 and 65 years, a relationship to the recipient within the fourth degree of consanguinity, negative results of serological tests for hepatitis B and C viruses, and normal hematologic, liver, and renal functions. We consider only ABO-identical or ABO-compatible donors to be acceptable. All eligible donors undergo imaging studies, including chest radiography, abdominal ultrasonography, computerized tomography (CT), and magnetic resonance imaging for exclusion of any unrecognized diseases, evaluation of the degree of hepatosteatosis, and delineation of vascular and biliary anatomy. Liver biopsy is performed selectively when greater than a mild fatty change is shown on ultrasonographic examination. The standard liver volume of the recipient is calculated by an experienced radiologist using contrastenhanced multidetector CT via the Cavalieri method as described previously. 7 The remnant liver volume is calculated from the volumetric study and expressed as the percentage of the total liver volume. In our practice, the decision of middle hepatic vein (MHV) inclusion in right donor hepatectomy is complex. In addition to the consideration of hepatic volume requirements for the recipient, we include MHV in cases of a dominant MHV draining the majority of the right lobe combined with adequate drainage of segment 4B via a separate venous branch. All imaging studies are reviewed preoperatively by the donor surgeon. Once all the tests are complete, each donor-recipient pair is reviewed at our weekly liver transplant selection conference. We specifically pay attention to the metabolic demand of the recipient and the volume and vascular/biliary anatomy of the donor liver. Operative Procedure The donors and recipients are admitted to the hospital the night before the planned transplantation. The donors receive an epidural catheter for postoperative pain management immediately before general anesthesia with endotracheal intubation. A J-shaped or bilateral subcostal incision with an upper midline extension is used. After an intraoperative ultrasound evaluation of the vascular structures and cholecystectomy, cholangiography through the cystic duct stump for evaluation of the biliary tree is performed. A cavitron ultrasonic surgical aspirator (CUSA System 200 macrodissector; Cavitron Surgical Systems, Stamford, CT) is used for parenchymal division. Heparin sodium (2000 units) is given intravenously before the clamping of the vessels after transection of the parenchyma. The liver graft is first weighed and then washed with University of Wisconsin solution at the back-table. After removal of the graft, vessel stumps are closed with continuous, nonabsorbable sutures. The stump of the right biliary duct is closed with continuous, absorbable sutures. Dilute methylene blue is then injected gently through the cystic duct stump to check for any leaks in the biliary tree. Before closure of the abdomen, a silastic drain is placed in the right upper quadrant, which is brought out through a stab incision in the right lower quadrant. On the recipient side, cava-sparing total hepatectomy is performed. Once the graft is ready, the inferior vena cava is clamped, the middle/left hepatic vein opening is sutured, and the right hepatic vein stump is tailored to a larger triangular opening. The graft right/middle hepatic vein is sutured to this opening. Any inferior hepatic veins in the graft are sutured to a separate opening in the inferior vena cava. Anastomosis of the donor right portal vein to the recipient main portal vein is performed, and the graft is subsequently reperfused. Hepatic artery reconstruction is performed under surgical microscopy. Biliary anastomosis is then performed under loupe magnification. Postoperative Care Donors are extubated in the operating room and remain in the surgical intensive care unit (ICU) overnight. The epidural catheter is removed once the international normalized ratio (INR) falls below 1.5. Pain control is then accomplished with intravenous and/or oral narcotics according to the individual patient s need. Donors are started on ambulation and a clear liquid diet on postoperative day 2. The diet is advanced slowly on postoperative days 3 and 4. For recipients, the ICU stay depends on their recovery from the anesthesia. The postoperative diet and ambulation regimen are similar to those of the donors. Immunosuppression is established with corticosteroids, tacrolimus, and mycophenolate mofetil.

3 1176 TANER ET AL. TABLE 1. Characteristics of Donors with a Liver Remnant 30% (Group 1) and Donors with a Liver Remnant 30% (Group 2) Group 1 (n 67)* Group 2 (n 14)* P Value Age (years) NS Gender (M/F) 31/36 8/6 NS Donor BMI NS Estimated total liver volume (ml) NS Estimated right-lobe volume (ml) NS Estimated remnant volume (%) Intraoperative right-lobe weight (g) Estimated right-lobe volume/intraoperative right-lobe weight (%) NS Estimated blood loss (ml) NS Transection time (minutes) Right-lobe graft with MHV ( / ) 31/36 8/6 NS GRWR (%) NS Abbreviations: BMI, body mass index; F, female; GRWR, graft-to-recipient weight ratio; M, male; MHV, middle hepatic vein; NS, not significant. *Mean standard deviation. Postoperative complications are defined as any event satisfying the classification of Broering et al. 8 For this study, donors were divided into 2 groups: group 1 consisted of donors with a remnant of the total liver volume of 30%, and group 2 consisted of donors with a remnant of the total liver volume of 30%. For statistical analysis, continuous parameters in each group were compared by an independent sample T test, and categorical parameters were compared with the chi-square test. All analyses were performed with SPSS 14.0 for Windows (SPSS, Chicago, IL), and differences were considered significant at a P value of Values of measured variables were expressed as means the standard deviation or as ranges. RESULTS There were 67 patients in group 1 and 14 patients in group 2 (Table 1). The mean postoperative follow-up was 15 months. Donor characteristics (age, gender, and body mass index) were similar between the study groups. No livers with more than 15% steatosis were used in either group. There was no difference between the groups in preoperative total liver volume estimation. Although preoperative right volume estimations in group 2 were higher, the difference did not reach statistical significance. In group 2, the intraoperative weight of the right lobe measured at the back-table was significantly higher. The ratio of the estimated rightlobe volume to the intraoperative, immediate post right lobectomy actual weight was similar between the groups. The range of remnant liver ratios was 31.1% to 45.1% for group 1 and 27.6% to 29.6% for group 2. The ratio of grafts with MHV in either group was not different. The parenchymal transection time was significantly higher in group 2; however, estimated blood loss during the operation remained similar. Even though the mean graft weight was higher in group 2, there was no statistically significant difference in the graft-to-recipient weight ratio between the 2 groups. Postoperative follow-up showed significantly higher peak aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, and INR levels in group 2 patients (Table 2). Patients with a small remnant showed higher postoperative day 7 total bilirubin levels, but the INR levels returned to normal in both groups. Group 2 patients stayed in the hospital on average 3 days longer; the length of ICU stay was not different. In group 2, peak ALT and AST levels were higher in donors with MHV-included grafts, although this did not reach statistical significance. Peak INR and total bilirubin levels were similar between these 2 subgroups (data not shown). There were no deaths in either group. There were 6 complications in group 1 and 4 complications in group 2 (Table 3). In group 1, 2 patients developed surgical site infections, which were treated with intravenous antibiotics and drainage of the incision at bedside; 1 patient developed pneumonia in the first postoperative week; 1 patient had a biliary leak diagnosed during the first postoperative week, which required endoscopic biliary stent placement; and 2 patients developed an incisional hernia. Prolonged hyperbilirubinemia, defined as a total bilirubin level 2 mg/dl by the end of the second postoperative week, occurred only in group 2 patients (2 patients); at the 1-month follow-up, both patients had normal total bilirubin levels. One postoperative hemorrhage in this group required a return to the operating room on postoperative day 1. This patient did not need a blood transfusion. One patient had a pulmonary embolism diagnosed on postoperative day 8, which required systemic anticoagulation for 6 months. No grade 4 (life-threatening) complication occurred in either group. Although the overall rate of donor morbidity was lower than that of previously reported series, the difference between the 2 groups in

4 DONOR SAFETY AND REMNANT LIVER VOLUME 1177 TABLE 2. Postoperative Characteristics of Donors with a Liver Remnant 30% (Group 1) and Donors with a Liver Remnant 30% (Group 2). Group 1 (n 67)* Group 2 (n 14)* P Value Peak AST (U/L) Peak ALT (U/L) Peak total bilirubin (mg/dl) Peak INR POD 7 total bilirubin (mg/dl) POD 7 INR NS ICU stay (days) NS Hospital stay (days) Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ICU, intensive care unit; INR, international normalized ratio; POD, postoperative day. *Mean standard deviation. TABLE 3. Postoperative Complications of Donors with a Liver Remnant 30% (Group 1) and Donors with a Liver Remnant 30% (Group 2) Group 1 (n 67) Group 2 (n 14) P Value Grade 1 Surgical site infection (n 2) Prolonged hyperbilirubinemia (n 2) Grade 2 Pneumonia (n 1) Pulmonary embolism (n 1) Grade 3 Biliary leak (n 1) Postoperative hemorrhage (n 1) Incisional hernia (n 2) Grade 4 None None Overall 6/67 (9%) 4/14 (28%) P RR 4.00 ( , 95% CI) Abbreviations: CI, confidence interval; RR, relative risk. TABLE 4. Overall Comparison of Donors With Postoperative Complications and Donors Without Complications Donors With Complications (n 10)* Donors Without Complications (n 71)* P Value Remnant (%) Age (years) NS Body mass index NS *Mean standard deviation. terms of donor complications did reach statistical significance (P 0.043); donors with a remnant liver volume 30% had a 4 times greater relative risk of morbidity (relative risk 4.00, 95% confidence interval ). 9 A subgroup analysis in group 1 showed that none of the donors with more than 40% remnant volume (n 12) had any morbidity. In fact, when the donor morbidity data were individually examined, none of the donors with a remnant volume 37% had complications. When the donors with morbidity in both groups (n 10) were compared with donors who had no morbidity (n 71), there was a statistically significant difference in the remnant volumes but no difference in the ages or body mass indices (Table 4). There were no intraoperative or postoperative blood transfusions in either group. During the same study period, another 60 potential donors were evaluated and were found to be ineligible for donation for different anatomical, medical, and/or social reasons. Ten of these patients were denied because of a remnant volume of less than 30% and availability of other donors for their respective recipients. DISCUSSION Adult LDLT has been an essential addition to liver transplantation practice in countries in which organ availability from brain-dead patients has been scarce. A

5 1178 TANER ET AL. vast amount of experience has accumulated since the first adult-to-pediatric LDLT in The expansion of the practice to adult recipients was a natural evolution as many countries in the eastern hemisphere depend almost solely on living liver donors. Since the first adult-to-adult LDLT in 1994 in Japan, the practice has spread to other countries in the world. The preoperative preparation of donors, surgical technique for both donor and recipient operations, and postoperative care have continuously evolved. With increasing experience together with an ever increasing need for liver donors, liver transplant teams have been pushed to use more marginal donors such as the ones with a small remnant liver volume after donation. In adult LDLT using the right lobe, the volume of the remnant liver in the donor is a major concern. On the basis of the data presented in this article, 24 (out of 141) potential donors with a remnant volume 30% were evaluated during the same study period. Fourteen of those individuals were the only potential donors for their respective recipients. Because a small remnant is a relatively common problem in countries in which LDLT is a common practice, it is essential to minimize the intraoperative and postoperative morbidity and to characterize the postoperative course and complications. In donors undergoing right hepatectomy compared to those undergoing left hepatectomy or left lateral segmentectomy, serious complications resulting from hepatic parenchymal loss occur more frequently. 4,10,11 Therefore, as a first step, a precise evaluation of the donor remnant liver volume before the operation is imperative for preventing unexpected hepatic insufficiency or other morbidity in the donor. At our center, we routinely intend to ensure a minimum remnant liver volume of 30% for donor safety. However, in the case of a single suitable donor with a marginal remnant liver volume, we do not reject the donor without re-evaluation of CT volumetry and further discussion with the donor and the family about possible associated morbidity. As described previously and also shown in this study, accurate preoperative volumetric measurements are especially important in the subgroup of patients in which a possibility of a critical small remnant exists. 7 In our practice, all the volumetric measurements are performed by a single experienced radiologist and reviewed by the donor surgeon to ensure accurate preoperative planning that is as realistic to the intraoperative parenchymal dissection plane as possible. The similarity of the preoperative estimated volume and intraoperative weight measurement in this study reflects the close communication between the radiologist and the donor surgeon. Based on the results of studies on major hepatic resection for primary and secondary liver malignancies, a critical percentage of RLV of 27% was identified to stand for a threshold in terms of severe hepatic dysfunction. 12,13 However, donor hepatectomy in a healthy population, in which no mortality is acceptable, should be taken as a situation different from that encountered in the oncologic field. Thus, the remnant liver volume must be sufficient so that the donor is not at risk of developing liver failure post-donation. Fan et al. 6 recommended a 30% residual liver volume of the total liver volume in a nonfatty liver to increase donor safety. However, in a recent review, the same group cited 17 of 178 donors who had a left-lobe remnant volume less than 30% and found no statistical difference in postoperative liver function as measured by INR between this group of donors and those with a larger remnant liver volume. 14 In this study, the postoperative biochemistry and coagulation profile showed significant differences in peak AST, ALT, total bilirubin, and INR levels in donors who were left with a small remnant. By postoperative day 7, all except total bilirubin levels returned to normal levels. Patients with a small remnant liver volume had delayed clearance of bilirubin levels, but all had recovered synthetic function as observed with the normal INR levels on postoperative day 7. In fact, 2 patients in group 2 were the only ones with prolonged hyperbilirubinemia beyond the first postoperative week. At the 1-month follow-up, both patients had normal total bilirubin levels. Higher peak INR values in group 2 did not have any observed clinical significance. Although the overall rate of donor morbidity was lower for the whole group than that of previously reported series, the difference between the 2 groups in terms of donor complications did reach statistical significance, and donors with a small remnant had a 4 times greater relative risk of morbidity (relative risk 4.00, 95% confidence interval ). 9,14-16 Hospital stay was prolonged in group 2 patients as a result of associated complications in this group. One donor in this group presented to the hospital during the second postoperative week with shortness of breath and was diagnosed with pulmonary embolus. He was readmitted for anticoagulation. Teams should have a low threshold for suspecting any complications, especially in this group of patients. In countries in which the practice of liver transplantation depends on living donors, there is a push for using more marginal donors. Even though there was no mortality in our donors, a donor death would be too late to change donor selection principles and practice. We believe that the experience and data in the international transplant community are still too limited for concluding what percentage of liver volume can be left in a donor without the donor s life being put into jeopardy. In this regard, other donor characteristics such as age, medical comorbidity, and steatosis in the liver should be taken into consideration separately in each case. This article alone cannot address minimal acceptable remnant liver volume in donors; however, it is clear that morbidity increases with smaller remnants as none of the donors with remnants 37% had any morbidity. It should be emphasized that using donors with a small remnant liver volume should be practiced by experienced teams only. In fact, our practice, which started in 1999, has now accumulated more than 350 LDLTs. Initial experience between 1999 and 2004 did not involve any donors with a remnant below 35%. We

6 DONOR SAFETY AND REMNANT LIVER VOLUME 1179 have attempted using donors with a small remnant only after overcoming the learning curve and decreasing the morbidity in donors. Even though a higher incidence of complications in small remnant patients is seen, the similar morbidity types between the groups might be a reflection of improved surgical technique and postoperative care, which come with experience. Although the follow-up period is relatively short, none of the morbidity in either group has caused long-term sequelae thus far. An alternative approach to donors with a potential small remnant liver volume is to use dual donors. 17 In our opinion, this practice should be considered only if the recipient has several donors, each with a potential small remnant liver volume after right-lobe graft donation. When the possibility of dual-lobe LDLT is entertained, the cumulative risk to both donors should be justified and discussed with both donors. In conclusion, the use of donors with less than 30% remnant liver volume is controversial. Our data show a significantly increased rate of morbidity. In countries in which liver transplantation practice depends on living donors, the increased morbidity and possibility of mortality in donors with small remnants should be fully discussed with donors and recipients. REFERENCES 1. Trotter JF, Adam R, Lo CM, Kenison J. Documented deaths of hepatic lobe donors for living donor liver transplantation. Liver Transpl 2006;12: Middleton PF, Duffield M, Lynch SV, Padbury RT, House T, Stanton P, et al. Living donor liver transplantation adult donor outcomes: a systematic review. Liver Transpl 2006; 12: Strong RW. Living-donor liver transplantation: an overview. J Hepatobiliary Pancr Surg 2006;13: Fujita S, Kim ID, Uryuhara K, Asonuma K, Egawa H, Kiuchi T, et al. Hepatic grafts from live donors: donor morbidity for 470 cases of live donation. Transpl Int 2000; 13: Ibrahim S, Chen CL, Wang CC, Wang SH, Lin CC, Liu YW, et al. Small remnant liver volume after right lobe living donor hepatectomy. Surgery 2006;140: Fan ST, Lo CM, Liu CL, Yong BH, Chan JK, Ng IO. Safety of donors in live donor liver transplantation using right lobe grafts. Arch Surg 2000;135: Duran C, Aydinli B, Tokat Y, Yuzer Y, Kantarci M, Akgun M, et al. Stereological evaluation of liver volume in living donor liver transplantation using MDCT via the Cavalieri method. Liver Transpl 2007;13: Broering DC, Wilms C, Bok P, Fischer L, Mueller L, Hillert C, et al. Evolution of donor morbidity in living related liver transplantation: a single center analysis of 165 cases. Ann Surg 2004;240: Beavers KL, Sandler RS, Shrestha R. Donor morbidity associated with right lobectomy for living donor liver transplantation to adult recipients: a systematic review. Liver Transpl 2002;8: Lo CM. Complications and long-term outcome of living liver donors: a survey of 1508 cases in five Asian centers. Transplantation 2003;15:75(suppl):S12 S Soejima Y, Harada N, Shimada M, Suehiro T, Minagawa R, Hiroshige S, et al. Perioperative management and complications in donors related to living-donor liver transplantation. Surgery 2002;131:S195 S Shirabe K, Shimada M, Gion T, Hasegawa H, Takenaka K, Utsunomiya T, Sugimachi K. Postoperative liver failure after major hepatic resection for hepatocellular carcinoma in the modern era with special reference to remnant liver volume. J Am Coll Surg 1999;188: Schindl MJ, Redhead DN, Fearon KC, Garden OJ, Wigmore SJ. The value of residual liver volume as a predictor of hepatic dysfunction and infection after major liver resection. Gut 2005;54: Fan ST, Lo CM, Liu CL, Wang WX, Wong J. Safety and necessity of including the middle hepatic vein in the right lobe graft in adult-to-adult live donor liver transplantation. Ann Surg 2003;238: Pomfret EA, Pomposelli JJ, Gordon FD, Erbay N, Lyn Price L, Lewis WD, Jenkins RL. Transplantation 2003;76: Lo CM, Fan ST, Liu CL, Yong BH, Chan JK, Wong J. Increased risk for living liver donors after extended right lobectomy. Transplant Proc 1999;31: Lee SG, Hwang S, Park KM, Kim KH, Ahn CS, Lee YJ, et al. Seventeen adult-to-adult living donor liver transplantations using dual grafts. Transplant Proc 2001;33: