Laparoscopy-Assisted versus Open Hepatectomy for Live Liver Donor: Systematic Review and Meta-Analysis

Objective To assess the feasibility, safety, and potential benefits of laparoscopy-assisted living donor hepatectomy (LADH) in comparison with open living donor hepatectomy (ODH) for liver transplantation. Background LADH is becoming increasingly common for living donor liver transplant around the world. We aim to determine the efficacy of LADH and compare it with ODH. Methods A systematic search on PubMed, Embase, Cochrane Library, and Web of Science was conducted in May 2017. Results Nine studies were suitable for this analysis, involving 979 patients. LADH seemed to be associated with increased operation time (WMD = 24.85 min; 95% CI: −3.01~52.78, P = 0.08), less intraoperative blood loss (WMD = −59.92 ml; 95% CI: −94.58~−25.27, P = 0.0007), similar hospital stays (WMD = −0.47 d; 95% CI: −1.78~0.83, P = 0.47), less postoperative complications (RR = 0.70, 95% CI: 0.51~0.94, P = 0.02), less analgesic use (SMD = −0.22; 95% CI: −0.44~−0.11, P = 0.04), similar transfusion rates (RR = 0.82; 95% CI: 0.24~3.12, P = 0.82), and similar graft weights (WMD = 7.31 g; 95% CI: −23.45~38.07, P = 0.64). Conclusion Our results indicate that LADH is a safe and effective technique and, when compared to ODH.


Introduction
Liver transplantation from living donors is a potential treatment for end-stage liver disease. And due, in part, to the limited number of available livers from deceased patients, living donor liver transplantation (LDLT) has become an established solution. Since the first successful LDLT for a child in 1989 [1], this life-saving procedure has developed rapidly, providing similar or even better outcomes, especially in children, in comparison with cadaver liver grafts [2]. Living donors are typically healthy adults; therefore the donor's safety is paramount.
Over the past two decades, laparoscopic surgery has been widely applied to liver surgery. In 2002, Cherqui et al. [3] reported the first case of laparoscopic living donor left lobectomy and laparoscopic LDLT was increasingly used in some centers. However, owing to technical difficulties, this procedure developed relatively slowly. The first case of laparoscopic-assisted hybrid living donor hepatectomy (LADH) was reported by Koffron et al. [4] in 2006, in which hands were introduced into the abdomen while still maintaining the pneumoperitoneum. In this procedure, a laparoscopic technique is employed for mobilization of liver and hilar dissection; however, the parenchymal transection is performed as an open procedure. As a result, this hybrid procedure achieved the advantage of avoiding a large subcostal incision while retaining the safety and familiarity of an open dissection and resection. In addition, laparoscopic-assisted surgeries offered surgeons an opportunity to accumulate expertise before converting to complete laparoscopic living donor hepatectomies.
Several studies have compared the outcome of laparoscopic-assisted living donor hepatectomy (LADH) with widely used open living donor hepatectomy (ODH). However, no consensus has been reached on this topic; it is still not clear which method is of more benefit to the donor. In

Data Extraction and Quality Assessment.
Two investigators (M. Y. Chen and H. P. Zhu) independently assessed publications for inclusion and extracted data from eligible studies, including the baseline characteristics, such as first author, publication year, country of region, study type, sample size, and operation outcomes (operation time and intraoperative estimated blood loss) and postoperative outcomes (overall complications and length of hospital stay). The primary outcomes of the study include blood loss, complications, and analgesic use. The secondary outcomes are operation time, transfusion, length of stay, and graft weights. We made attempts to contact corresponding authors for missing data points. Only one author provided requested data for analysis [5].
The quality of the researches was evaluated by The Newcastle-Ottawa Quality Assessment Scale (NOS). The scale ranged from 0 to 9 stars: studies achieving more than or equal to 6 are deemed as good methodologically.

Statistical Analysis.
All analyses were performed with Review Manager Version 5.3 (The Cochrane Collaboration, Oxford, United Kingdom). Risk ratio (RR) with a 95% confidence interval (CI) was used for the comparison analysis of dichotomous variables. The same continuous parameters were expressed as weighted mean difference (WMD) in the same unit or standard mean difference (SMD) for different unit with 95% CI. When data in individual studies was presented as median and a range, the means and standard deviations (SDs) were estimated by Hozo et al. [6]. The test of heterogeneity, which indicated between-study variance, was evaluated according to Cochran's test and Higgins-squared statistic [7]. Pooled effects were calculated using a randomeffects model, unless heterogeneity was less than 50% or < 0.05. Graphical funnel plots were generated to determine visual inspections for publication bias.
We conduct subgroup analyses in the studies focusing on right lobe hepatectomies (RH) and left lobe hepatectomies (LH).

Study Eligibility.
A flowchart of the search strategies, containing reasons for excluding studies, is shown in Figure 1. No randomized controlled trials were identified in the records. Nine studies were selected for the final meta-analysis. Five studies [8,10,12,14,15] compared laparoscopy-assisted and open donor right hepatectomy and one study [11] compared left hepatectomy. Two studies [5,13] had data for both right hepatectomy and left hepatectomy comparisons. One study [9] evaluated the safety and feasibility of mixed laparoscopicassisted donor right and left hepatectomies by comparing them with open donor hepatectomies.
A total of 979 patients were included in the analysis with 309 undergoing LADH (31.5%) and 670 undergoing OH (53.2%). Characteristics of included studies are summarized in Table 1. Four papers were conducted in Japan [5,10,11,13], two in the United States [8,9], one in China [15], one in Korea [14], and one in India [12]. Seven of the studies graded morbidity according to the Clavien-Dindo Classification. Four studies reported conversion in 10 cases, including diaphragmatic rupture (1 case), right hepatic vein injury (1 case), and IVC injury (1 case). And the other conversions were not documented in their respective studies. Three studies reported quality of life for donor in the followup period [11,12,14].
The quality of the research included was generally moderate to satisfactory. NOS shows that one out of the nine studies observed had 6 stars, six had 7 stars, and two had 8 stars. Table 2 shows the evaluation of quality according to NOS.
Analgesic Use. There are five studies that gave relevant information on analgesic use after surgery and postoperative pain was evaluated by the number of days of analgesic use or the dosage of analgesic. We found that analgesic use was significantly less in the LADH group (SMD = −0.22; 95% CI: −0.44∼−0.11, = 0.04) (Figure 4).

Publication Bias.
A funnel plot for studies reporting RRs of postoperative overall complications was used to detect publication bias. The plots standing for the studies distributed            symmetrically. This result suggested that the publication bias was acceptable (Figure 9).

Discussion
Minimally invasive donor surgery was developed to reduce the morbidity and decrease the impact on the donor, minimizing tissue trauma, and improving postoperative pain and cosmesis for patients. LADH with manual hand manipulation in the abdominal cavity, giving the surgeon enhanced tactile feedback of the liver, allowed for more precise mobilization and dissection of the targeted lobe. This technique is combined with smaller incision while preserving the maneuverability and safety of an open liver resection. LADH apparently leads to less wound-related morbidity and the best cosmetic result [16]. In a recent review, Xu et al. [17] examined laparoscopic versus open liver resection for liver transplantation, showing less blood loss, shortened hospital stay, and longer operation time. However, this review did not attempt to clarify the different types of laparoscopic      surgery. In our meta-analysis, we only included the studies of laparoscopy-assisted (hybrid) surgery. Our further subgroup analysis was done to learn how LADH affects surgery in different areas of the liver.
Our result confirms that blood loss was significantly less in the LADH group than in the ODH group. This is consistent with published results for laparoscopic hepatectomies, even when laparoscopy is only used for the hepatic mobilization [18]. In the subgroup analysis of single types of hepatectomy to minimize the bias, there was no difference between the types of donor hepatectomy. LADH is a potential technique to decrease blood loss, confirmed by the colorectal surgery [19] and prior analysis [20]. Hand-assisted surgery has been promoted by its advocates in decreased complication rate in the colorectal surgery [19]. Our analysis of LADH demonstrated favourable overall complication rates compared to ODH, similar to the previous analysis [20]. In the subgroup analysis, LH shows a significantly lower rate of complications in the LADH group, which accounts for the lower complication rate in the total group. However, the case volume is small in the left hepatectomy subgroup. In theory, it is easier to mobilize the right lobe from the diaphragm by laparoscopic technique and inferior vena cava with the help of manual manipulation. Adequate mobilization, improved visualization, and better manipulation contribute to the enhanced safety of the operation. Living donor mortality in ODH was reported as 0.2% (23/1153), mostly related to surgical procedure [21]. There was no mortality to be reported in the studies both in laparoscopy-assisted and open group for donor. In other words, LADH shows a better tendency toward in the outcome of morbidity to ODH.
Smaller and midline incisions in the supraumbilical area resulted in reduced disruption of abdominal muscles, deceased scar discomfort, and less postoperative analgesic use in our analysis, raising the possibility of better cosmetic results and, possibly, faster return to work and normal physical activities. However, it tended to have an increased operative time associated with hand-assisted surgery, though it did not reach statistical significance. The result could be explained by the application of laparoscopic instruments for the meticulous mobilization in the liver surgery. Furthermore, the transfusion rate was comparable between LADH and ODH in this analysis. Additionally, LOS demonstrated no inferiority for LADH. Interestingly, the prior meta-analysis of laparoscopic versus open hepatectomy for live liver donor has shown the significantly shorter hospital stay in the LADH group [17,20]. This may be ascribed to the methods of surgery and postoperation protocols and insurance policy. Regarding hospital cost, it was higher in the LADH. From published data, the overall cost of laparoscopic liver resection was lower than open liver resection [22].
After comparing laparoscopic-assisted operation and open operation, there was a high heterogeneity in the analysis, even in the subgroup analyses by type of surgery. These may result from differences in study designs, number of participants, donors' baseline characteristics, surgical techniques, and surgical types. In addition, some of the data estimated the mean and SD from median and range, which may result in inaccuracy. No random trials were included and most of the studies were cohort studies or case-control studies. Because of high-risk in the donor hepatectomy, a relative surgical abstention may present in the enrolled patients and their families. Based on these limitations, larger prospective studies and randomized trials are needed.

Conclusion
According to our data, laparoscopy-assisted living donor hepatectomy (LADH) is equally safe and effective technique. There was no increased risk of morbidity compared to ODH patients in our examined groups. Benefits of laparoscopy-assisted donor hepatectomy compared to open surgery have demonstrated improved short-term outcomes, especially lower intraoperative blood loss and complications. We conclude that LADH is an appropriate minimally invasive procedure for living donor hepatectomies, which needs to be selected by patients' and surgery' preferences.

Abbreviations
LADH: Laparoscopy-assisted living donor hepatectomy ODH: Open donor hepatectomy LLR: Laparoscopic liver resection WMD: Weighted mean difference SMD: Standard mean difference RR: Risk ratio SD: Standard deviation NOS: Newcastle-Ottawa Quality Assessment Scale RH: Right lobe hepatectomy LH: Left lobe hepatectomy ALT: Alanine aminotransferase AST: Aspartate aminotransferase TB: Total bilirubin LFT: Liver function test.