Minimally Invasive Donors Right Hepatectomy versus Open Donors Right Hepatectomy: A Meta-Analysis

Background: How to obtain a donor liver remains an open issue, especially in the choice of minimally invasive donors right hepatectomy versus open donors right hepatectomy (MIDRH versus ODRH). We conducted a meta-analysis to clarify this question. Methods: A meta-analysis was performed in PubMed, Web of Science, EMBASE, Cochrane Central Register, and ClinicalTrials.gov databases. Baseline characteristics and perioperative outcomes were analyzed. Results: A total of 24 retrospective studies were identified. For MIDRH vs. ODRH, the operative time was longer in the MIDRH group (mean difference [MD] = 30.77 min; p = 0.006). MIDRH resulted in significantly less intraoperative blood loss (MD = −57.86 mL; p < 0.00001), shorter length of stay (MD = −1.22 days; p < 0.00001), lower pulmonary (OR = 0.55; p = 0.002) and wound complications (OR = 0.45; p = 0.0007), lower overall complications (OR = 0.79; p = 0.02), and less self-infused morphine consumption (MD = −0.06 days; 95% CI, −1.16 to −0.05; p = 0.03). In the subgroup analysis, similar results were observed in pure laparoscopic donor right hepatectomy (PLDRH) and the propensity score matching group. In addition, there were no significant differences in post-operation liver injury, bile duct complications, Clavien–Dindo ≥ 3 III, readmission, reoperation, and postoperative transfusion between the MIDRH and ODRH groups. Discussion: We concluded that MIDRH is a safe and feasible alternative to ODRH for living donators, especially in the PLDRH group.


Introduction
Liver transplantation (LT) is an established treatment for patients suffering from endstage liver disease. Due to a paucity of deceased donors, particularly in Asian countries, living donor liver transplantation (LDLT) has become an important alternative [1]. The LDLT has drawn criticism for the risk it poses to healthy people who will have a major operation without any potential health benefits, including the risk of death. As donor safety is the cornerstone of LDLT, a surgery scheme with less perioperative complication occurrence is crucial.
Open donor liver resection has long been accepted as the classic procedure for obtaining liver for transplant recipients. However, with the conceptualization of minimally invasive liver surgery and the accumulation of laparoscopic techniques, minimally invasive donor left lateral hepatectomy (MIDLH) is considered as standard practice, once the team has fulfilled the adequate learning, because it is minimally invasive and results in less intraoperative blood loss, more rapid postoperative recovery, and a higher level of comfort to patients [2]. Previous physicians had struggled to perform laparoscopic-assisted living donor right hepatectomy, and [3] the first case of pure laparoscopic donor right liver resection (PLDRH) was not reported until 2013 [4] due to the highly complex procedure and 2 of 18 intricate anatomy of the human liver. Because surgeons were concerned for the safety of the donor, they were hesitant to employ PLDRH in clinical settings. As a result, the application of minimally invasive donor right hepatectomy (MIDRH) is relatively lagging behind. It should be noted that recent investigations indicated that clinicians prefer MIDRH, in particular, PLDRH, more than open donor right hepatectomy (ODRH) when performing LT [5][6][7]. However, the choice between MIDRH and ODRH remains highly controversial in the liver surgeons' community.
Therefore, the current meta-analysis was carried out to thoroughly assess the potential advantages of MIDRH over ODRH in LDLT. Our conclusions provide evidence for the selection of clinical strategy that may be advantageous to clinical practitioners as well as patients.

Search Strategy and Study Selection
This study followed the PRISMA guidelines [8]. Published studies which compared MIDRH and ODRH for right liver donor were systematically searched in PubMed, Web of Science, EMBASE, Cochrane Central Register, and ClinicalTrials.gov databases before 30 April 2022, by two independent researchers (CWC, CYM). The combinations of the following key terms were used: laparoscopic, open, conventional, living donor, liver donor, minimally invasive. In order to find additional studies, the references of eligible studies were manually searched.

Inclusion and Exclusion Criteria
Two researchers (JHW, JH) individually screened all titles and abstracts to find papers that qualified: (1) studies focused on comparing MIDRH and ODRH; (2) types of studies that included randomized controlled trials (RCTs), retrospective studies, cohort studies, and case-control studies; (3) articles published in English. The exclusion criteria were as follows: (1) non-English or experimental studies; (2) studies without sufficient data; (3) the publication type was editorials, abstracts, letters, case reports, and expert opinion.

Data Extraction and Quality Assessment
The original data from all candidate articles were independently assessed and extracted by two reviewers (CYM, CWC) by using a unified datasheet which included the following: baseline characteristics (first author, country, publication year, research design, sample size, and mean age, gender, body mass index (BMI), PGV), intraoperative (intraoperative and operative time) and postoperative outcomes (peak AST, peak ALT, peak TB, hospital stay, self-infused morphine consumption, pulmonary complications, bile leak, Clavien-Dindo grade ≥ III, re-hospitalization, reoperation, biliary stricture, postoperative transfusion, wound, postoperative bleeding, and total complications). The Newcastle-Ottawa Scale (NOS) [9] was used to evaluate the quality of included studies and a NOS score ≥ 6 was considered as a high quality article.

Statistical Analysis
Statistical analysis was performed by using Review Manager 5.3 software. The weighted mean difference (WMD) with the 95% confidence interval (CI) and odds ratio (OR) were used to compare continuous variables and dichotomous, respectively. The method of converting medians with ranges into means with standard deviations was in accordance with a prior study carried by Hozo et al. [10] The Higgins I 2 index was used to quantify the statistical heterogeneity [11]. When heterogeneity is low or moderate (I 2 < 50%), the fixed-effects model (FEM) was adopted. In contrast, the random-effects model (REM) was adopted when the heterogeneity is high (I 2 ≥ 50%).

Other Outcomes
Our analysis revealed that the MIDRH group and ODRH group were similar with rehospitalization (MIDRH vs. ODRH:6.5% vs. 3 Table  3).

Publication Bias
Begg's funnel plot was drawn for each outcome and adopted to investigate publication bias. All studies lie inside the 95% CI in the funnel plot that indicated no obvious publication bias.

Discussion
Living donor right hepatectomy is currently the most common donor surgery in adult-to-adult living donor liver transplantation [32,33], in which about two-thirds of the working liver is removed from the donator [34]. Concerns about donor safety and ethical issues have persisted since the procedure was performed in 1996 [34]. Ensuring the safety of the donor is the cornerstone of LDLT. The safety and superiority of minimally invasive hepatectomy have been proved in liver tumor resection [35][36][37][38], and previous studies have also reflected the feasibility and safety of minimally invasive hepatectomy in donor liver resection [39][40][41][42][43]. Moreover, the consensus [2] on minimally invasive donor hepatectomy for living donor liver transplantation stated that "pure laparoscopic" donor hepatectomy is applicable to left lateral hepatectomy and should be considered standard practice once the team has fulfilled the adequate learning. But there is still a lack of high-level evidence to explain the advantages and disadvantages of laparoscopic or open hepatectomy for living right hepatectomy.
In our study, the demographic data showed that the donors who underwent MIDRH were younger and had a female predominance, which was consistent with previous research [44][45][46][47][48][49]. It is easy to understand this phenomenon because the MIDRH has the advantages of quick postoperative recovery, light pain, beautiful appearance, and minimal trauma, and is more favored by the younger and female. Reduced intraoperative blood loss and shorter LOS were found in the MIDRH group, and the average amount of estimated intra-operation blood loss from our pooled data was 283.6 ± 221.8 mL, and 431.4 ± 342.0 mL in the MIDRH and ODRH group. These results were similar to previous studies Figure 11. Forest plot and funnel plot comparison of MIDRH versus ODRH for self-infused morphine pump (days) [12,16,19,21].

Other Outcomes
Our analysis revealed that the MIDRH group and ODRH group were similar with rehospitalization (MIDRH vs. ODRH: 6.5% vs. 3 Table 3).

Publication Bias
Begg's funnel plot was drawn for each outcome and adopted to investigate publication bias. All studies lie inside the 95% CI in the funnel plot that indicated no obvious publication bias.

Discussion
Living donor right hepatectomy is currently the most common donor surgery in adult-to-adult living donor liver transplantation [32,33], in which about two-thirds of the working liver is removed from the donator [34]. Concerns about donor safety and ethical issues have persisted since the procedure was performed in 1996 [34]. Ensuring the safety of the donor is the cornerstone of LDLT. The safety and superiority of minimally invasive hepatectomy have been proved in liver tumor resection [35][36][37][38], and previous studies have also reflected the feasibility and safety of minimally invasive hepatectomy in donor liver resection [39][40][41][42][43]. Moreover, the consensus [2] on minimally invasive donor hepatectomy for living donor liver transplantation stated that "pure laparoscopic" donor hepatectomy is applicable to left lateral hepatectomy and should be considered standard practice once the team has fulfilled the adequate learning. But there is still a lack of high-level evidence to explain the advantages and disadvantages of laparoscopic or open hepatectomy for living right hepatectomy.
In our study, the demographic data showed that the donors who underwent MIDRH were younger and had a female predominance, which was consistent with previous research [44][45][46][47][48][49]. It is easy to understand this phenomenon because the MIDRH has the advantages of quick postoperative recovery, light pain, beautiful appearance, and minimal trauma, and is more favored by the younger and female. Reduced intraoperative blood loss and shorter LOS were found in the MIDRH group, and the average amount of estimated intra-operation blood loss from our pooled data was 283.6 ± 221.8 mL, and 431.4 ± 342.0 mL in the MIDRH and ODRH group. These results were similar to previous studies [44,47,50]. The small amount of estimated intra-operation blood loss may be attributed to the fine dissection, which facilitates the identification and processing of tiny structures. And there were no significant differences in postoperative bleeding and postoperative blood transfusion events between the two groups.
Different from other meta-analyses [44,46,50,51], we found that the procedure time was longer in the MIDRH group than in the ODRH group, especially in PLDRH. However, in the PSM subgroup, the operation time showed no difference. In the encompassing literature, several studies [12,26,29,30] reported a shorter operation time in the PLDRH group than the ODRH group, which included a larger number of cases and is consistent with another study of Lai et al. [52]. This result may be caused by some small sample studies included in our analysis. Due to some limitations of laparoscopic surgery such as motion, visualization, and tactile sensation [53], the learning process for laparoscopy is relatively long. Currently, there are serval reports about the learning curve of PLDRH. Rhu et al. [26] thought that it was possible to reduce the operating time only after more than 50 PLDRH procedures. Lee et al. reported that operating time was stabilized for ODRH after 17 cases and for PLDRH after 15 cases [22]. In our study, there were only two studies with fewer than 15 PLDRH. Meanwhile, the operation time was also affected by the patient's own conditions. And in cases of tissue structure variation or other anatomical abnormalities, laparoscopy may lead to increased postoperative morbidity [54][55][56]. In general, the operation time of PLDRH will be reduced and the laparoscopic-related complications will be overcome with the accumulation of laparoscopic surgery experience.
Our pooled data indicated that MIDRH had fewer analgesic requirements than ODRH, which was in accordance with the results of previous studies [44][45][46][47][48][49]. MIDRH has a smaller incision without cutting the subcostal nerve and muscle which preserves the integrity of the abdominal wall as much as possible. Regardless of the differences between the operator and the patient, a small incision could promote postoperative rehabilitation, reduce postoperative pain, and improve respiratory status. Meanwhile, our study revealed that MIDRH demonstrated a better surgical incision; this seems to be more evident in PLDRH, with lower wound complication rates. Apparently, it was associated with the hidden benefits of small incision, such as reducing the psychological burden on patients, the rate of infection, and long-term discomfort at the incision site after surgery.
Our study found that the PLDRH group had a favorable advantage in pulmonary complications, which is consistent with previous studies [45,46,51]. This may be associated with the delicate operation being minimally invasive, producing light postoperative pain, and reducing irritation to the chest cavity. Meanwhile, our study found that there was no difference in peak AST, peak ALT, peak TB, bile leak, biliary stricture, Clavien-Dindo grade ≥ III, rehospitalization, and reoperation between MIDRH and ODRH. These indicators had not been investigated in previous studies [46][47][48][49][50][51].
Cost-benefit analysis between MIDRH and ODRH was also important. Riquelme et al. [56] have shown that upfront intraoperative costs associated with ODRH were lower, but the overall costs between ODRH and PLDRH were equivalent after 3 months of followup. In our study, data of cost were not reported in the included studies, so we could not conduct a specific analysis on this issue.
There are some limitations in our study. All the articles were retrospective studies without randomized controlled trials. Potential bias exists in the intrinsic retrospective study. Due to time and the fact that times of liver blockage could not be obtained, it was impossible to conduct hierarchical analysis of this research. Some studies had small samples and the outcomes may have been affected by the learning curve. A high level of evidence is still needed to explore the merits of the two surgery procedures.

Conclusions
In conclusion, MIDRH is a safe and feasible alternative approach in donor right hepatectomy for its better performance in intra-operation blood loss, pulmonary complications, length of stay, postoperative pain, wound complications, and overall complications.