Pure laparoscopic versus open left lateral hepatectomy in pediatric living donor liver transplantation: a review and meta-analysis

The meta-analysis was conducted to evaluate the safety and feasibility of pure laparoscopic left lateral hepatectomy in comparison with open approach for pediatric living donor liver transplantation (LDLT). A systemic literature survey was performed by searching the PubMed, EMBASE and Cochrane Library databases for articles that compared pure laparoscopic left lateral living donor hepatectomy (LLDH) and open left lateral living donor hepatectomy (OLDH) by November 2021. Meta-analysis was performed to assess donors’ and recipients’ perioperative outcomes using RevMan 5.3 software. A total of five studies involving 432 patients were included in the analysis. The results demonstrated that LLDH group had significantly less blood loss (WMD = −99.28 ml, 95%CI −152.68 to −45.88, p = 0.0003) and shorter length of hospital stay (WMD = −2.71d, 95%CI −3.78 to −1.64, p < 0.00001) compared with OLDH group. A reduced donor overall postoperative complication rate was observed in the LLDH group (OR = 0.29, 95%CI 0.13–0.64, p = 0.002). In the subgroup analysis, donor bile leakage, wound infection and pulmonary complications were similar between two groups (bile leakage: OR = 1.31, 95%CI 0.43–4.02, p = 0.63; wound infection: OR = 0.38, 95%CI 0.10–1.41, p = 0.15; pulmonary complications: OR = 0.24, 95%CI 0.04–1.41, p = 0.11). For recipients, there were no significant difference in perioperative outcomes between the LLDH and OLDH group, including mortality, overall complications, hepatic artery thrombosis, portal vein and biliary complications. LLDH is a safe and effective alternative to OLDH for pediatric LDLT, reducing invasiveness and benefiting postoperative recovery. Future large-scale multi-center studies are expected to confirm the advantages of LLDH in pediatric LDLT.


Introduction
Pediatric liver transplantation is the most effective treatment for children with end-stage liver disease [1].For pediatric patients, living donor liver transplantation (LDLT) which procedures liver graft of the left lateral lobe can meet the demand [2,3].Since the first successful pediatric LDLT of a left lateral lobe graft in 1989 [4], the life-saving technique greatly increased the availability of organs and improved survival rates of children.
Meng Sha, Zhi-peng Zong and Chuan Shen have contributed equally to this work.
Conventionally, left lateral hepatectomy was performed through open procedure of subcostal incision with a midline extension [5].The postoperative pain, huge scar and long period of recovery often caused stress and anxiety among donors [6].With the increasing demand of minimizing physiological and psychological damage, laparoscopic surgery has been applied to living donor hepatectomy.In 2002, Cherqui et al. first reported the laparoscopic left lateral hepatectomy for pediatric LDLT [7].Since then, several studies have described the outcomes of the minimal invasive surgery in pediatric LDLT [8,9].Compared with open surgery, less trauma and more rapid recovery were revealed by the laparoscopic surgery [10].However, because living donors are healthy adults, ensuring donor safety is greatly challenged by advocates of open surgery.
Since pure laparoscopic left lateral hepatectomy for pediatric LDLT is performed only at highly experienced centers, no consensus has now been reached.It remains unclear which types of surgery benefits donors and recipients most.Under this circumstance, we conducted a systematic review and meta-analysis to compare the safety and feasibility between pure laparoscopic and open left lateral hepatectomy in pediatric LDLT.

Literature search
A systematic literature search of the PubMed, EMBASE and Cochrane Library databases was performed in November 2021 by 2 investigators (M.Sha and Z. Zong) independently.The literature search was conducted to identify comparative studies evaluating perioperative outcomes between pure laparoscopic vs. open left lateral hepatectomy in pediatric living donor liver transplantation.All retrieved articles were manually searched for further studies.No restrictions were set for publication date, status or language.

Inclusion and exclusion criteria
Randomized or comparative studies that evaluated perioperative outcomes between pure laparoscopic vs. open left lateral hepatectomy in pediatric liver transplantation were included for the meta-analysis.The exclusion criteria were: (1) case reports, letters, reviews, editorials and non-comparative studies; (2) studies that did not report the operative data or postoperative outcomes; (3) studies in which it was impossible to calculate or retrieve mean and standard deviation; (4) if multiple studies were reported by the same institution, only the most recent or highest quality study was included.

Data extraction
Data were extracted from the studies included in the metaanalysis by two independent investigators.The following information was collected: (1) first author, year, country and study type; (2) patient demographics and number of patients included in each arm; (3) operative data including operative time, blood loss and conversion; (4) postoperative outcomes including donor and recipient complications and hospital stay.

Quality assessment
The quality of included studies was evaluated according to Newcastle-Ottawa scale (NOS) which consists of patient selection, comparability of study groups and measurement of outcomes [11].Articles with Newcastle-Ottawa scale (NOS) scores ≥ 6 were considered to be of high quality.

Statistical analysis
The meta-analysis was analyzed using Review Manager version 5.3 (Revman, The Cochrane Collaboration, Oxford, UK).If median and range is provided by selected studies, the mean and SD were calculated as described by Hozo et al. [12].Odds ratios (OR) with a 95% confidence interval (CI) was used for dichotomous variables and weighted mean differences (WMD) with 95% CI were performed for continuous variables.Statistical heterogeneity among studies was evaluated with Cochrane Q and Higgins I 2 statistics.A fixedeffect model was used when I 2 < 50%, while random-effect model was recommended when high heterogeneity was present.The results obtained were analyzed using Review Manager version 5.3 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.p values of < 0.05 were considered to be statistically significant.

Study selection and eligibility
As shown in the flow chart (Fig. 1), the search strategy initially generated 82 studies.We excluded 29 of these studies because of irrelevance or duplication.Another 48 studies 1 3 were excluded because of improper study type or insufficient data after a full-text review.Finally, 5 studies met the metaanalysis's inclusion criteria.
A total of 432 patients in 5 countries between 2006 and 2021 were included in the analysis [13][14][15][16][17].The main characteristics of the included studies are summarized in Table 1.166 donors underwent pure laparoscopic left lateral living donor hepatectomy (LLDH) and 266 underwent open left lateral living donor hepatectomy (OLDH) for pediatric liver transplantation.One paper was conducted in Korea, one in France, one in Russia, one in Belgium and one in Brazil.The main operative parameters analyzed included operative time, blood loss, ischemic time and conversion.Donor and recipient complications and hospital stay were compared for postoperative outcomes.NOS shows that the five included studies had scores of 7 or more, demonstrating the satisfactory research quality.

Meta-analysis results
The results are presented in Figs. 2, 3, Supplementary Figs. 1, 2 and summarized in Table 2 and 3.

Operative time
All included studies reported operation (Fig. 2a).Though no significant difference was observed between two groups, the operation time tended to be longer in the LLDH group compared to the OLDH group (WMD = 30.48min, 95%CI: −5.42 to 66.38, p = −0.10).

Ischemic time
Three studies evaluated data for warm or total ischemic time.The total ischemic time from graft procurement to perfusion was similar between two groups (WMD = −0.85min, 95%CI −16.48 to 14.78, p = 0.92) (Fig. 2c).For warm ischemic time, the OLDH group showed a tendency of less time compared to the LLDH group, though no significant difference was observed (WMD = 2.66 min, 95%CI −0.08 to 5.40, p = 0.06) (Fig. 2d).

Length of hospital stay
Length of hospital stay was reported in three studies (Fig. 2e).Significantly shorter hospital stay was found in the LLDH group versus the OLDH group (WMD = −2.71d,95%CI −3.78 to −1.64, p < 0.00001).

Postoperative outcomes of recipients
All liver grafts in the included studies were successfully transplanted.Only one study reported two cases of perioperative graft failure, one in each group.The recipient perioperative mortality was comparable between two groups (OR = 1.78, 95%CI 0.54-5.92,p = 0.34) (Fig. 3b).

Discussion
Since the first implementation of laparoscopic approach for left lateral hepatectomy in pediatric LDLT in 2002 [7], the acquisition of grafts by laparoscopy has been carried out in many centers.The minimally invasive surgery was suggested to alleviate trauma and reduce postoperative pain for living donors [18].With the continuous development of laparoscopic technology, pure laparoscopic approach was innovated to provide more clear visualization of perihepatic spaces and intraparenchymal structures [19].However, for pediatric recipients with sophisticated anatomy, it is more important to maintain the integrity of the biliary tract, inflow and outflow tracts.In addition, the safety and effect of pure laparoscopic hepatectomy for donors also needs further verification [20].Therefore, we conducted the meta-analysis to evaluate the safety and feasibility of pure laparoscopic left lateral hepatectomy in pediatric LDLT.This meta-analysis showed that LLDH had a little longer operation time with no significant difference compared with OLDH approach.Since no big mobilization is needed for left lateral lobe of liver, the operation time difference might correlate with the dissection of the hilum under laparoscopy as well as surgeons' experience [21,22].The maximal distance between the surface of the lobe and the portal vein bifurcation is also reported to affect the operation time [23].For blood loss, LLDH group demonstrated significantly superior results compared with OLDH group, which is consistent with published results for laparoscopic hepatectomy [24].Better visual field and positive pressure pneumoperitoneum facilitated less blood loss in laparoscopic approach [25].Since laparoscopic procurement of liver graft requires an extension of lower abdominal incision, the warm ischemic time tended to be longer in the LLDH group.However, with the advanced experience of surgeons, the total ischemic time did not differ between two groups.
In LDLT, the safety of donor should always be of the first importance [26].Previous studies reported that donor hepatectomy resulted in a mortality of 0.1-0.2%[27] and an incidence rate of 25-35% [28] in healthy individuals.In this analysis, no donor mortality was found in neither of the groups.Two studies in LLDH group reported conversion in 4 cases, including 2 cases of middle hepatic vein injury, 1 case of hilum injury and 1 case of biliary injury.The overall incidence of complications of the LLDH group was significantly lower than those of the OLDH group.In subgroup analysis, although there was no significant difference in bile leakage, wound and pulmonary complications between two groups, incidence of wound infection and pulmonary complications shows a better tendency toward LLDH group.Subsequently, the length of hospital stay was shorter in the LLDH group, demonstrating faster postoperative recovery.The above results suggest that LLDH shows a better outcome of donor morbidity than OLDH.With respect to postoperative outcomes of recipients, there was no significant difference in the recipient prognosis including mortality and surgical complications between the two groups.This is attributed to complete preservation of anatomic structures by two approaches.
Preoperative selection of donors is another important issue to be noted.Anatomical abnormalities, such as multiple arterial supply, a right posterior bile duct draining into the left hepatic duct and double (separate) venous outflow, are generally considered to increase surgical difficulty and morbidity of complications [29].In the studies included above, no consensus of donor selection process was reached, however, the main contraindication to the laparoscopic procurement was the presence of two separate hepatic veins in the graft [15].For bile duct division, single bile duct arising from the left hepatic duct through evaluation of preoperative MRI biliary reconstruction is recommended.With the application of intraoperative cholangiography and indocyanine green fluorescence imaging, optimal bile duct division can be determined more precisely [30,31].Since pediatric LDLT is performed at highly experienced centers, donor selection is mainly based on experience of surgeons.Further exploration in large-scale, prospective studies is required to develop standardized donor selection criteria.
Although our analysis was the first to evaluate pure laparoscopic left lateral hepatectomy in pediatric LDLT, it has some potential limitations.First, our study mainly focused on pediatric LDLT, which only included a total of 5 studies.Because pure laparoscopic hepatectomy for pediatric LDLT is performed only at experienced centers, the limited availability of studies may cause selection bias for patients.Second, due to lack of randomized controlled trials, the included studies are cohort and case-control studies, which may cause another potential source of bias.In addition, certain heterogeneity was found in some results such as operation time and hospital stay, which is attributed to difference in sample sizes, surgical techniques and baseline characteristics.
Finally, it should be noted that living donors who underwent laparoscopic hepatectomy were selected with a favorable anatomy [32].This factor may favor LLDH approach in aspect of perioperative outcomes.
Despite the limitations described above, this meta-analysis included 432 patients to evaluate the safety and feasibility of pure laparoscopic left lateral hepatectomy in pediatric LDLT.Our results indicate that LLDH is a safe and effective alternative to OLDH for pediatric LDLT.The LLDH is believed to alleviate invasiveness and benefit postoperative recovery for living donors with no more complications.Future large-scale prospective randomized controlled studies are expected in more liver transplantation centers to confirm the superiority of LLDH in pediatric LDLT.

Fig. 1
Fig.1 The flow diagram of the search strategy

Fig. 2
Fig. 2 The operative time a, intraoperative blood loss b, total c and warm d ischemic time and length of hospital stay e in LLDH group versus OLDH group

Fig. 3
Fig. 3 The postoperative complication rate a of donors in LLDH group versus OLDH group.The perioperative mortality b and postoperative complication rate c of recipients in LLDH group versus OLDH group

Table 2
Intraoperative and postoperative outcomes of donors included in the meta-analysis

Table 3
Results of meta-analysis comparing pure laparoscopic versus open left lateral hepatectomy in pediatric transplantation