Living donor liver transplantation (LDLT) is an accepted treatment modality for end-stage liver disease. Although LDLT provides a survival benefit and reduced waiting time for the recipients,1,2 significant donor morbidity remains the greatest barrier.3,4 Moreover, the cosmetic and functional demands of donors are increasing. Therefore, a minimally invasive laparoscopic approach has been proposed as an ideal method for previously healthy donors.
Since the first pure laparoscopic donor hepatectomy for adult-to-pediatric LDLT in 2002,5 there have been consistent reports on pure laparoscopic left lateral sectionectomy demonstrating similar donor safety and graft results compared to the open technique.6-8 Although the right lobe graft is preferred because of the graft size, a limited number of studies have reported the outcomes of pure laparoscopic living donor right hepatectomy (LLDRH).9-13 This is because pure LLDRH has not yet been widely performed even in large volume centers since it requires significant experience in both LDLT and laparoscopic liver surgery.
Our institution implemented a pure LLDRH program in May 2013, and we have reported the results of the initial 54 cases.14 In this study, we enrolled 91 consecutive cases from the start of our pure LLDRH program and compared the incidence of complications to that observed in 197 cases of open living donor right hepatectomy (OLDRH) during the same period. We also evaluated covariates associated with complications in donors for pure LLDRH. To the best of our knowledge, this is the largest series to date, and sharing our results may benefit centers that are launching laparoscopic programs for donor hepatectomy.
MATERIALS AND METHODS
Study Population and Data Collection
This study was approved by the Institutional Review Board of Samsung Medical Center (IRB No. 2017-10-112) and conducted according to the principles of the Declaration of Helsinki. We retrospectively reviewed the medical records of the study population derived from our liver transplantation database. From May 2013 to July 2017, G-S.C. and D.C.H.K. performed 288 right lobe hepatectomy procedures for LDLT. During this period, 91 donors who were indicated and consented underwent pure LLDRH, and the remaining 197 donors underwent OLDRH.
Our donor selection criteria have been described previously.15,16 Indications for open technique were adult <65 years, body mass index <35, biochemistries within normal range, adequate graft size, and expected remnant liver >30%. Donors with any condition related to increased surgical risk were excluded. At the beginning of the pure LLDRH program, we applied more conservative criteria for donor selection. Our initial criteria for donors have also been described previously.15 We selected patients under 60 years old and with a remnant liver >35%. After confirming eligibility, we verified biliary anatomy with magnetic resonance cholangiopancreatography (MRCP) and excluded patients with anatomical variations such as bile ducts other than type 1, which require technical sophistication for the laparoscopic approach. After completing an initial 20 cases in March 2014, we began expanding to other types of bile duct. In June 2017, we adopted the same anatomical criteria and accepted any variation for indication for pure LLDRH. Donor selection criteria for open and laparoscopic techniques at the beginning of the program are summarized in Table S1 (SDC, http://links.lww.com/TP/B759).
Study End Points and Definitions
The primary end point was major complications in donors, defined as grade IIIa–V according to Clavien Dindo classification, during a 90-day follow-up period. All complications, including minor ones, were also presented according to Clavien Dindo classification as follows: I, any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic, or radiological interventions other than antiemetics, antipyretics, analgesics, diuretics, electrolytes, and physiotherapy; II, requiring pharmacological treatment with drugs other than those allowed for in grade I; IIIa, complications requiring intervention not under general anesthesia; IIIb, complications requiring interventions under general anesthesia; IV, life-threatening complications; and V, death.17 The secondary end points were the comprehensive complication index (CCI), which was obtained by an online calculator (www.assessurgery.com), duration of hospital stay, readmission, need for additional patient-controlled analgesia (PCA), and postoperative blood tests (aspartate transaminase, alanine aminotransferase, creatinine, and total bilirubin). We also compared intraoperative factors such as operative duration, estimated blood loss, and graft weight. Regarding recipients, the incidence of death, graft failure (defined as death or retransplantation), and each grade of complications was compared. To evaluate covariates associated with postoperative complications, anatomical variations on preoperative MRCP were verified by a single operator (G-S.C.). The length of the common channel of the right hepatic duct was defined as the length from the convergence of the right anterior and posterior ducts to the confluence level of the right and left hepatic ducts on preoperative MRCP as shown in Figure 1.
As our institutional OLDRH procedures have been described elsewhere,16 this study will focus on pure LLDRH procedures. The donor was positioned in the supine French position, and a 3-dimensional laparoscope (Olympus Co, Tokyo, Japan) was used. The locations and sizes of the ports and the positions of the surgeon and assistants are shown in Figure 2. Intra-abdominal pressure was maintained around 10 mm Hg with carbon dioxide gas. First, intraoperative biopsy was performed to determine the suitability of the organ for transplantation. The liver was sufficiently mobilized to identify the right hepatic vein at the cephalad direction and the vena cava at the caudal direction. A hanging maneuver was not necessarily applied. The cystic duct was resected, and the remnant duct at the biliary side was preserved for traction, while dissecting the right hepatic artery and vein. After dissection of the vessels, a temporary vessel clamp was applied to identify a demarcation line. Liver transection was performed after confirming the pathologic report. During the initial parenchymal separation, proper traction was maintained by pulling the fundus of the gall bladder to the right side and the teres ligament to the left side. During parenchymal separation, our direction was from the caudal side to the cephalad side because it was fast and safe. For transection, we started with the Harmonic Ace (Ethicon Endosurgery, United States) or Sonicision (Covidien, Mansfield, MA) until we reached the middle hepatic vein level (in dorsal view from the abdominal wall). After passing the middle hepatic vein level, we switched to the Cavitron Ultrasonic Surgical Aspirator (Integra, Plainsboro, NJ) to reduce unnecessary damage to the adjacent tissues. The portal vein and artery were taped with vessel loops and tracted to the abdominal wall while dissecting the caudate lobe. The isolated bile duct was incised and then encircled with a silk thread. Afterward, it was dissected under guidance of intraoperative cholangiogram or ultrasonography. Intraoperative ultrasound was used after temporarily clamping the common bile duct to induce congestion to dilate the bile duct for easier detection and identification.18 After completing the parenchymal transection, the small hepatic veins to the right of the liver were clipped, while the large veins were preserved. The graft was then wrapped in an endo-bag (LapBag; Sejong Medical, Gyeonggi-do, Korea) and a Pfannenstiel incision was made. When the incision was completed, pneumoperitoneum was again established with the incision clipped by the forceps. The hepatic artery, portal vein, and inferior hepatic vein were ligated with a Hem-o-lock clip. After ligating the right hepatic vein, the graft was extracted from the peritoneal cavity through the Pfannenstiel incision. After graft removal and incision closure, the pneumoperitoneum was again established to investigate bleeding or bile leakage. Finally, we anchored the remaining left falciform ligament and inserted a drain. Main surgical procedures are also provided as a Supplemental video.
Intraoperative and Postoperative Pain Management
Our institutional pain control regimen for donor hepatectomy has previously been described.19,20 In brief, after applying standard monitoring devices, intrathecal morphine sulfate (400 μg in 4 mL of a preservative-free 0.9% saline solution) was given preoperatively at the L3-L4 or L4-L5 level using a 27-gauge Whitacre spinal needle with the donor in a lateral decubitus position. In some donors selected in the previous randomized controlled trials for postoperative pain control, intrathecal morphine was omitted.21 Remifentanil was selectively used in donors with uncontrolled hemodynamic responses. Intravenous PCA with fentanyl was side-connected at the end of surgery in all donors. The PCA regimen was 1500 μg of fentanyl in normal saline 100 mL (15 μg/mL) and programmed for bolus, lockout time, and basal rate of 1 mL, 15 minutes, and 1 mL/h, respectively. An additional PCA was applied when needed.
Statistical analyses were performed with SAS 9.4 (SAS Institute Inc., Cary, NC). Continuous variables are presented as mean ± SD or median ± interquartile range and compared using the t test or the Mann-Whitney test. We used χ2 or Fisher exact test for categorical variables. To overcome selection bias and potential confounding factors, rigorous adjustments were performed using propensity scores of age, sex, body mass index, preoperative blood tests (aspartate transaminase, alanine aminotransferase, creatinine, albumin, platelet, and hemoglobin), and intraoperative procedures (cholecystectomy, Pringle maneuver, and intrathecal morphine). Binary logistic regression was used to estimate propensity scores. The caliper width was 0.2 SDs of the logit-transformed propensity score. After propensity matching, a standard mean difference <10% suggested an appropriate balance between the 2 groups. In the propensity-matched population, conditional logistic regression analysis and the Mann-Whitney test were used to compare outcomes. Odds ratios (ORs) with 95% confidence intervals (CIs) and P values are presented. Covariates associated with postoperative complications in the LLDRH group were identified using logistic regression analysis. Two different multivariate models were created considering the small number of events. Covariates with P < 0.15 and P < 0.05 were retained in the adjustment models 1 and 2, respectively. All tests were 2-tailed, and P < 0.05 was considered statistically significant.
Among 288 living right donor hepatectomies, 91 cases were performed using pure LLDRH and 159 cases by OLDRH. The baseline characteristics of donors are summarized in Table 1. Among the 91 pure LLDRH cases, 5 required open conversion and were analyzed as LLDRH on an intention-to-treat basis. The reasons for open conversion are summarized in Table S2 (SDC, http://links.lww.com/TP/B759). The donors in the LLDRH group were younger (32 versus 27; P = 0.009). Pringle maneuver (71.6% versus 36.6%; P < 0.001) and intrathecal morphine injection (90.4% versus 68.1%; P < 0.001) were less frequently used in the LLDRH group than the OLDRH group. A total of 72 pairs of matched data sets were generated by 1:1 individual matching without replacement, using propensity score (Table 1).
LLDRH Versus OLDRH
The incidence and type of complications in the entire population are presented in Table 2. The incidence of major complications was significantly higher in the LLDRH group (6.6% versus 15.4%; P = 0.017) (Table 2), but was not significantly different between the 2 groups after propensity score matching (11.1% versus 13.9%; OR, 1.29; 95% CI, 0.47-3.51; P = 0.617) (Table 3). The differences in CCI were not statistically significant in both populations. In the entire population, the incidence of additional PCA requirement was lower in the LLDRH group (19.8% versus 8.8%; P = 0.018). Operative duration was significantly longer in the LLDRH group (326 versus 365 min; P < 0.001) (Table 2). Operative duration of the pure LLDRH is shown chronologically in Figure 3.
Postoperative Complications in Pure LLDRH
Annual data on the incidence of major complications are presented in Figure 4. Starting from initiation of the pure LLDRH program, 14 of 91 donors showed major complications within the 90-day follow-up period. Among these 14 cases, 3 donors underwent reoperation under general anesthesia due to portal vein thrombosis, postoperative bleeding, and leakage from the cystic duct. The remaining 11 cases were all biliary complications requiring endoscopic interventions. The type of complications and treatment modalities in the LLDRH group are summarized in Table S3 (SDC, http://links.lww.com/TP/B759).
In univariate analysis, a right hepatic duct <1 cm and presence of multiple hepatic veins other than the right hepatic vein were predictors. A right hepatic duct <1 cm was consistently associated with postoperative complications in both multivariate models (OR, 4.31; 95% CI, 1.11-16.67; P = 0.034; OR, 4.05; 95% CI, 1.11-14.88; P = 0.035) (Table 4). Complications in donors with a right hepatic duct <1 cm are summarized in Table S4 (SDC, http://links.lww.com/TP/B759).
The main findings of the present study are (1) in our initial 91 cases of pure LLDRH, the incidence of major complications was 15.4% while the incidence of major complications was 6.6% in OLDRH during the same period; (2) in propensity score analysis, the incidence of donor complications was not significantly different compared to OLDRH; and (3) a right hepatic duct <1 cm on preoperative MRCP was independently associated with complications in pure LLDRH. These findings may be helpful for clinicians in selecting donors and safely performing pure LLDRH.
Laparoscopic hepatectomy has recently become popular because it offers less pain, shorter hospital stay, earlier recovery to normal life, and is more cosmetically acceptable.22 Although previous comparative studies have shown that the laparoscopic approach is a feasible option for left donor hepatectomy,8,23 only limited data have been reported on the right side graft. This is because right donor hepatectomy is more technically demanding and is associated with increased donor morbidity, even with the open approach.16 Indeed, it is the most difficult application of the laparoscopic approach, especially when inflow of both graft and remnant liver until graft retrieval is essential for transplantation.9,24 Recently, a study showed comparable results between the open and the laparoscopic approach in donors mostly undergoing right hepatectomy,11,13 but our study benefits in that it is a comparative study using propensity score matching in the largest cohort consisting of only right grafts. By limiting participants to pure LLDRH, we were also able to evaluate covariates associated with pure LLDRH. In addition, we evaluated complications for a longer follow-up period of 90 days, because the 30-day follow-up in previous studies may have led to an underestimate of morbidity in hepatic resection.12 We also calculated CCI, a recently proposed continuous score to summarize overall burden of procedure, to account for less serious morbidity based on a do-no-harm principle for donors.25
The overall incidence of donor complications was 20.9%, and the major complications (grade IIIa–V) rate was 15.4%, which is comparable to previously reported incidences of overall complications (10.0%–33.3%) and major complications (2.9%–12.6%) in open donor hepatectomy.4,14 However, it was significantly higher than that of OLDRH during the same period in our institution. CCI and operative duration of the LLDRH group were also higher in the entire population. Although this difference vanished after propensity score matching, the difference may exist due to insufficient sample size; according to backward power calculation based on our results, 2189 patients in each group are needed to properly evaluate a difference of 3%. Statistical data suggest that this change after score matching may be related to intraoperative Pringle maneuver use. Intraoperative Pringle maneuver in living donor hepatectomy has been reported to lessen blood loss and improve remnant function, shorter recovery period, and shorter hospital stay.26-28 Whether Pringle maneuver benefits clinical outcome of pure LLDRH remains uncertain in this study, and additional studies are needed. A difference in donor selection criteria between OLDRH and pure LLDRH may also be related to this change, but the incidence of complications decreased in the later cases of pure LLDRH despite an expansion of criteria, suggesting that this explanation is less likely.
A learning curve effect was evident throughout our experience as shown by improvements in complication rate and operative duration, despite a progressive increase in the proportion of laparoscopic approaches and expansion of donor selection criteria. Also, to ensure safety and avoid harm for donors, the priority before initiating the pure LLDRH program was sufficient experience of surgeons in both living donor hepatectomy and laparoscopic hepatectomy. G.-S. Choi had performed >100 cases of laparoscopic hepatectomy, and >30 cases were performed by D.C.H.K.. They also had sufficient experience in performing living donor hepatectomy without causing severe morbidity. In addition to the experience of the surgeon, we believe that multidisciplinary teamwork is an important factor for stability, reproducibility, and standardization of our institutional protocol, as shown in previous studies.9-11,15 Establishing an international donor hepatectomy registry could also be helpful for beginning centers in the future.
Selecting donors with adequate anatomical criteria is another issue. Unlike OLDRH, in which most anatomical variations can be managed safely by surgical modifications,29 we were extremely cautious at the beginning of the program and limited our donors to those with normal anatomy. Our first expansion of anatomical criteria after an initial 7 cases resulted in an increase of major complications depending on anatomical variation, and we again restricted donors to those with normal anatomy. However, with accumulating experience of 20 cases, we became relatively confident and started to gradually expand anatomical indication as mentioned in the Methods section. Meanwhile, 69 donors with biliary anatomical variations (40 donors with type 2, 23 donors with type 3, and 6 donors with type 4) were excluded from pure LLDRH. By June 2017, we started to apply the same donor selection criteria for pure LLDRH and OLDRH.
In this study, we identified the covariates associated with operative complications. Among preoperatively verified anatomical variations that surgeons felt were difficult to manage, a common trunk of the right hepatic duct <1 cm was independently associated with complications of pure LLDRH. The short neck of the hepatic duct may be mostly associated with biliary complications. When surgical clips cannot be used, a laparoscopic suture on the short neck of the hepatic duct may not completely close the duct, resulting in biliary leakage. The short neck of the hepatic duct may also cause an increased number of bile duct openings or a double barrel bile duct, which are fragile to biliary complications. Anatomical variations might be further associated with complications, because an excessive dissection of the bile duct to obtain a clear view can cause incidental stripping leading to damage on the blood supply at the end of bile duct. So, when dissecting the bile duct, we used an intraoperative ultrasound after inducing a congestion by clamping the common bile duct.18 Based on our results, we suggest the use of preoperative MRCP for donor selection and that beginning centers may want to consider excluding donors with right hepatic duct <1 cm. Other anatomical variations could not be evaluated in this study because they showed too low incidence for analysis owing to a strict anatomical indication at the beginning phase. Therefore, further studies with expanded anatomical criteria are needed to investigate other at-risk anatomical variations, because a wise donor selection cannot be overemphasized for success of the program.
The laparoscopic approach in hepatectomy has been found to decrease pain, yield early recovery with minimal wound complications, and shorten hospital stay,22 but only a cosmetic benefit with minimal wound issues was shown in this study. Postoperative pain was measured as additional PCA requirement, and was less frequent in the LLDRH group than in the entire population, despite reduced use of intrathecal morphine. However, this was not significantly different after propensity score matching. A comparison with numerical pain score might have changed the results, but this could not be done because numerical pain score was not routinely recorded. Early recovery could also not be accurately compared due to an institutional protocol recommending hospitalization of donors for a certain period of time, especially in the beginning of the LLDRH program. Even with the largest number of cases to date, surgeon inexperience in the beginning of the program may have influenced the results. Therefore, this study does not conclude that pure LLDRH only offers cosmetic benefit. We believe that, in the future, a well-designed study with a larger number of cases will show an improved result.
This study had limitations. First, this is a retrospective review of single-center data. Despite the rigorous adjustment with propensity score matching, an unmeasured confounding factor may have influenced the results. Second, as described above, this study lacks sufficient data to show beneficial effects of pure LLDRH. Nevertheless, our results on clinical outcomes should not be considered as equivalent considering type 2 error in small sample size and the difference in the entire population. Third, since this study contains cases from the very beginning of the program, we updated the donor selection criteria during the study period. As anatomical variation was one of the major indications of pure LLDRH in the beginning phase, the difference in anatomical variation between the 2 groups could not be adjusted, and only one type of anatomical variation could be evaluated as a predictor of complication. Fourth, operations during this study were started by a single surgeon (D.C.H.K.) and followed by another one (G-S.C.). So, a comparison before and after a certain learning curve could not be made, and variance in surgical factors by different surgeons could have also affected the results. Last, data on recipient outcomes may not be sufficient or accurately analyzed. Although we showed no differences in major complication rates, a more accurate study of recipient outcomes over long-term follow-up is needed. Despite these limitations, this study was the first to compare donor safety and graft results between pure LLDRH and OLDRH using propensity score matching in a large cohort and may contribute to the foundation of future studies.
During the initial 91 cases in our pure LLDRH program, the incidence of major complications was 15.4% in the pure LLDRH group and 6.6% in the OLDRH group. The difference in complication rates was not statistically significant on propensity-matched analysis. A right hepatic duct size <1 cm verified on preoperative MRCP was significantly associated with donor complications in the pure LLDRH group. Further studies on donor and recipient outcomes with pure LLDRH are needed.
1. Kawasaki S, Makuuchi M, Matsunami H, et al. Living related liver transplantation in adults.Ann Surg1998227269–274
2. Shah SA, Levy GA, Greig PD, et al. Reduced mortality with right-lobe living donor compared to deceased-donor liver transplantation when analyzed from the time of listing.Am J Transplant20077998–1002
3. Hall EC, Boyarsky BJ, Deshpande NA, et al. Perioperative complications after live-donor hepatectomy.JAMA Surg2014149288–291
4. Ghobrial RM, Freise CE, Trotter JF, et al.; A2ALL Study GroupDonor morbidity after living donation for liver transplantation.Gastroenterology2008135468–476
5. Cherqui D, Soubrane O, Husson E, et al. Laparoscopic living donor hepatectomy for liver transplantation in children.Lancet2002359392–396
6. Soubrane O, Cherqui D, Scatton O, et al. Laparoscopic left lateral sectionectomy in living donors: safety and reproducibility of the technique in a single center.Ann Surg2006244815–820
7. Kim KH, Jung DH, Park KM, et al. Comparison of open and laparoscopic live donor left lateral sectionectomy.Br J Surg2011981302–1308
8. Soubrane O, de Rougemont O, Kim KH, et al. Laparoscopic living donor left lateral sectionectomy: a new standard practice for donor hepatectomy.Ann Surg2015262757–61discussion 761
9. Kim KH, Kang SH, Jung DH, et al. Initial outcomes of pure laparoscopic living donor right hepatectomy in an experienced adult living donor liver transplant center.Transplantation20171011106–1110
10. Rotellar F, Pardo F, Benito A, et al. Totally laparoscopic right hepatectomy for living donor liver transplantation: analysis of a preliminary experience on 5 consecutive cases.Transplantation2017101548–554
11. Suh KS, Hong SK, Lee KW, et al. Pure laparoscopic living donor hepatectomy: focus on 55 donors undergoing right hepatectomy.Am J Transplant201818434–443
12. Egger ME, Ohlendorf JM, Scoggins CR, et al. Assessment of the reporting of quality and outcome measures in hepatic resections: a call for 90-day reporting in all hepatectomy series.HPB (Oxford)201517839–845
13. Samstein B, Griesemer A, Halazun K, et al. Pure laparoscopic donor hepatectomies: ready for widespread adoption?Ann Surg2018268602–609
14. Kwon CHD, Choi GS, Kim JM, et al. Laparoscopic donor hepatectomy for adult living donor liver transplantation recipients.Liver Transpl2018241545–1553
15. Kwon CHD, Joh JW. Aseni P, Grande AM, De Carlis L. Totally laparoscopic right hepatectomy for living donors.In: Multiorgan Procurement for Transplantation2016Cham, SwitzerlandSpringer239–245
16. Shin M, Song S, Kim JM, et al. Donor morbidity including biliary complications in living-donor liver transplantation: single-center analysis of 827 cases.Transplantation201293942–948
17. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.Ann Surg2004240205–213
18. Rhu J, Choi GS, Kim JM, et al. Intraoperative ultrasonography as a guidance for dividing bile duct during laparoscopic living donor hepatectomy.Ann Transplant201924115–122
19. Ko JS, Gwak MS, Choi SJ, et al. The effects of desflurane and sevoflurane on hepatic and renal functions after right hepatectomy in living donors*.Transpl Int201023736–744
20. 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 Transpl200915381–389
21. Lee SH, Gwak MS, Choi SJ, et al. Prospective, randomized study of ropivacaine wound infusion versus intrathecal morphine with intravenous fentanyl for analgesia in living donors for liver transplantation.Liver Transpl2013191036–1045
22. Dagher I, Di Giuro G, Dubrez J, et al. Laparoscopic versus open right hepatectomy: a comparative study.Am J Surg2009198173–177
23. Yu YD, Kim KH, Jung DH, et al. Laparoscopic live donor left lateral sectionectomy is safe and feasible for pediatric living donor liver transplantation.Hepatogastroenterology2012592445–2449
24. Buell JF, Cherqui D, Geller DA, et al.; World Consensus Conference on Laparoscopic SurgeryThe international position on laparoscopic liver surgery: the Louisville statement, 2008.Ann Surg2009250825–830doi: 10.1097/sla.0b013e3181b3b2d8
25. Slankamenac K, Graf R, Barkun J, et al. The comprehensive complication index: a novel continuous scale to measure surgical morbidity.Ann Surg20132581–7
26. Imamura H, Takayama T, Sugawara Y, et al. Pringle’s manoeuvre in living donors.Lancet20023602049–2050
27. Miller CM, Masetti M, Cautero N, et al. Intermittent inflow occlusion in living liver donors: impact on safety and remnant function.Liver Transpl200410244–247
28. Park JB, Joh JW, Kim SJ, et al. Effect of intermittent hepatic inflow occlusion with the Pringle maneuver during donor hepatectomy in adult living donor liver transplantation with right hemiliver grafts: a prospective, randomized controlled study.Liver Transpl201218129–137
29. Nakamura T, Tanaka K, Kiuchi T, et al. Anatomical variations and surgical strategies in right lobe living donor liver transplantation: lessons from 120 cases.Transplantation2002731896–1903