LIVER TRANSPLANTATION 21:738–752, 2015

REVIEW ARTICLE

Comparison Between Minimally Invasive and Open Living Donor Hepatectomy: A Systematic Review and Meta-Analysis Giammauro Berardi, Federico Tomassini, and Roberto Ivan Troisi Department of General Hepatobiliary and Liver Transplantation Surgery, Medical School, Ghent University Hospital, Ghent, Belgium

Living donor liver transplantation is a valid alternative to deceased donor liver transplantation, and its safety and feasibility have been well determined. Minimally invasive living donor hepatectomy (MILDH) has taken some time to be accepted because of inherent technical difficulties and the highly demanding surgical skills needed to perform the procedure, and its role is still being debated. Because of the lack of data, a systematic review and meta-analysis comparing MILDH and open living donor hepatectomy (OLDH) was performed. A systematic literature search was performed with PubMed, Embase, Scopus, and Cochrane Library Central. Treatment outcomes, including blood loss, operative time, hospital stay, analgesia use, donor-recipient morbidity and mortality, and donor procedure costs, were analyzed. There were 573 articles, and a total of 11, dated between 2006 and 2014, fulfilled the selection criteria and were, therefore, included. These 11 studies included a total of 608 adult patients. Blood loss [mean difference (MD) 5 –46.35; 95% confidence interval (CI) 5 –94.04-1.34; P 5 0.06] and operative times [MD 5 19.65; 95% CI 5 –4.28-43.57; P 5 0.11] were comparable between the groups, whereas hospital stays (MD 5 –1.56; 95% CI 5 –2.63 to 20.49; P 5 0.004), analgesia use (MD 5 –0.54; 95% CI 5 –1.04 to 20.03; P 5 0.04), donor morbidity rates [odds ratio (OR) 5 0.62; 95% CI 5 0.40-0.98; P 5 0.04], and wound-related complications (OR 5 0.41; 95% CI 5 0.17-0.97; P 5 0.04) were significantly reduced in MILDH. MILDH for right liver procurement was associated with a significantly reduced hospital stay (OR 5 –0.92; 95% CI 5 0.17-0.97; P 5 0.04). In conclusion, MILDH is associated with intraoperative results that are comparable to results for OLDH and with surgical outcomes that are no C 2015 AASLD. worse than those for the open procedure. Liver Transpl 21:738-752, 2015. V Received November 28, 2014; accepted March 14, 2015. Living donor liver transplantation (LDLT) is a therapeutic modality alternative to liver transplantation with a deceased donor. The first procedure was described in 1989 by Raia et al.,1 and Strong et al.2 performed the first successful pediatric LDLT in 1990. Its safety and feasibility have been well documented over the past several decades, and it is con-

sidered a valid and lifesaving procedure, especially in countries where there are few or no options for deceased organ donation. However, LDLT is accompanied by a certain donor morbidity risk that has hindered adoption of the procedure for routine use worldwide.3-5 Morbidity still represents an important issue, with rates ranging between 20% and 40%; it

Additional Supporting Information may be found in the online version of this article. Abbreviations: 2ICCLLS, 2nd International Consensus Conference on Laparoscopic Liver Surgery; CI, confidence interval; LDLT, living donor liver transplantation; LH, left hepatectomy; LLR, laparoscopic liver resection; LLS, left lateral sectionectomy; MD, mean difference; M-H, Mantel-Haenszel; MILDH, minimally invasive living donor hepatectomy; NR, not reported; OLDH, open living donor hepatectomy; OR, odds ratio; PCA, patient-controlled analgesia; RCT, randomized controlled trial; RH, right hepatectomy; SD, standard deviation. Financial support: Nothing to report. Potential conflict of interest: Nothing to report. Address reprint requests to Roberto Ivan Troisi, M.D., Ph.D., F.E.B.S., Department of General Hepatobiliary and Liver Transplantation Surgery, Medical School, Ghent University Hospital, De Pintelaan 185, 2K12 IC, Ghent 9000 Belgium. Telephone: 132-9-332-5519; FAX: 132-9-332-3891; E-mail: [email protected] DOI 10.1002/lt.24119 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

C 2015 American Association for the Study of Liver Diseases. V

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consists mainly of biliary complications and a certain degree of transient liver failure that prolongs hospital stays.6,7 Mortality risk is the most dramatic event, and the rate has been estimated to be approximately 0.13% for donation of a left lateral sector and 0.2% to 0.5% in adult LDLT.4,8 Minimally invasive liver surgery has been widely used for the treatment of different liver diseases. According to a recent survey, at least 5388 laparoscopic liver resections (LLRs) have been carried out in all liver segments to date (including 1184 major LLRs).9 In comparison with standard liver surgery, the laparoscopic approach has the advantage of reducing surgical morbidity, postoperative pain, and recovery time.10-12 Further developments in laparoscopic surgery have demonstrated its technical feasibility in living donor hepatectomy.13-15 The first laparoscopic LDLT procedure was described in 2002, and since then, this procedure has taken some time to be accepted, most likely because of inherent technical difficulties and the highly demanding surgical skills require to perform it.13 In the past several years, specialized units have performed minimally invasive living donor hepatectomy (MILDH) with either the pure (full laparoscopic) technique or the hybrid technique (including hand-assisted procedures and single-port incision).14-18 Furthermore, different types of graft harvesting, including left lateral sectionectomies (LLSs), left hepatectomies (LHs), and right hepatectomies (RHs), have been performed.19-21 Comparative analyses of conventional surgery and minimally invasive techniques for living donor graft retrieval have previously been described.22-24 However, because of the limited number of reports comparing both techniques and especially because of the low number of patients, it is still not yet clear which method is more beneficial to the donor. Because of the lack of consensus on this topic, the objective of this study was to perform a systematic review and meta-analysis of MILDH and open living donor hepatectomy (OLDH) with a look at the available literature. The primary outcome measures included estimated blood loss, operative time, hospital stay, analgesia use, and morbidity and mortality rates. Morbidity was further analyzed in terms of minor and major complications according to the Clavien-Dindo classification25 and specific complications (biliary and wound-related). A subgroup analysis concerning right lobe donors (blood loss, operative time, hospital stay, and morbidity) was then performed. Secondary outcomes included recipient morbidity, recipient 90-day mortality, and donor procedure costs.

MATERIALS AND METHODS Literature Search The study protocol recieved a priori approval by the institutional review committee. Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines for conducting and reporting

BERARDI ET AL. 739

meta-analyses were followed. The research protocol was registered at the International Prospective Register of Systematic Reviews (http://www. crd.york.ac.uk/ PROSPERO) with the following registration number: CRD42014013631. A systematic literature search was performed independently by 2 of the manuscript’s authors (G.B. and F.T.) with PubMed, Embase, Scopus, and Cochrane Library Central. The search was limited to studies in humans and to those reported in the English language. No restrictions were set for the type of publication, date, or publication status. Participants of any age and sex who underwent MILDH or OLDH were considered. The search strategy was based on different combinations of words for each database. For the PubMed database, the following combination was used: (laparoscopic OR laparoscopy OR laparoscopically OR minimally invasive OR minimally invasive OR hybrid OR hand-assisted OR hand assisted OR single-site OR robotic OR robotically OR robot OR robot assistance OR robot-assisted OR robotic-assisted) AND (living OR live) AND (donor OR donation OR transplant OR transplantation) AND (liver resection OR liver resections OR hepatectomy OR hepatectomies OR hepatic resection OR hepatic resections OR liver surgery). The same key words were inserted into the search manager fields of Scopus, Embase, and Cochrane Library Central (see Supporting Text 1). Extensive crosschecking of the reference lists of all retrieved articles that fulfilled the inclusion criteria further broadened the search. For all of the databases, the last search was run on September 14, 2014.

Study Selection The same 2 authors independently screened the titles and abstracts of the primary studies that were identified in the electronic search. Duplicate studies were excluded. The following criteria were set for inclusion in this meta-analysis: 1. Studies comparing MILDH and OLDH. Robotic, laparoscopic, single-site, hand-assisted, or hybrid procedures were considered minimally invasive. Patients undergoing LLS, LH (with or without the middle hepatic vein), and RH for graft harvesting were included. 2. Studies reporting at least 1 perioperative outcome 3. If more than 1 study was reported by the same institute, only the most recent or highest quality study was included. The following exclusion criteria were set: (1) original studies assessing the outcome of either only MILDH or only OLDH; (2) review articles, letters, comments, and case reports; and (3) studies from which it was impossible to retrieve or calculate data of interest. The Cohen kappa statistic was used to quantify agreement between the investigators.

Data Extraction The same 2 authors extracted the main data as follows: (1) first author, year of publication, and study

740 BERARDI ET AL.

type; (2) number and characteristics of patients of the MILDH and OLDH groups as well as the type of hepatectomy performed; and (3) treatment outcomes, including blood loss, operative time, hospital stay, analgesia use, donor procedure-related morbidity according to the Clavien-Dindo classification,25 and mortality. Furthermore, recipient morbidity, recipient 90-day mortality, and donor procedure costs were extracted. All relevant texts, tables, and figures were reviewed for data extraction, and whenever further information was required, the corresponding authors of the articles were contacted by e-mail. Discrepancies between the 2 reviewers were resolved by consensus discussion.

Risk of Bias The Newcastle-Ottawa scale was used to assess the quality of the studies, and funnel plots were constructed to assess the risk of publication bias across series for all outcome measures.

Statistical Analysis The meta-analysis was performed with RevMan software, version 5.1. Odds ratios (ORs) were used as a summary measure of efficacy for dichotomous data, and the mean difference (MD) between groups was used for continuous variables. A 95% confidence interval (CI) was reported for both measures. If the study provided medians and interquartile ranges instead of means and standard deviations (SDs), the means and SDs were imputed as described by Hozo et al.26 The fixed-effect model was used when no heterogeneity was detected among studies, whereas the random-effect model was preferred when variance was present. Statistical heterogeneity was evaluated with the I2 statistic. I2 values of 0% to 25%, 26% to 50%, and >51% were considered to be indicative of homogeneity, moderate heterogeneity, and high heterogeneity, respectively. All statistical data were considered with a P < 0.05 level of significance.

RESULTS Study Selection The literature search yielded 573 articles; after duplicates were removed, 344 titles and abstracts were reviewed (Fig. 1). Of these, 328 articles were excluded for the following reasons: 145 did not concern living donor hepatectomy, 178 did not compare techniques, 1 was a review article, 1 was a letter to the editor, and 1 comment and 2 conference abstracts were not supported by fully published results. The latter 2 were excluded according to the Agency for Healthcare Research and Quality guidelines.27 Finally, 16 articles10,15,18,22-24,28-37 were selected for full-text review, and of these, 5 articles were excluded for the following reasons: 1 article37 was excluded because it did not compare the results of donor patients (only recipient intraoperative data were evaluated); 2

LIVER TRANSPLANTATION, June 2015

articles10,35 were excluded because they were composed of a series of hepatectomies for different diseases without the description of a separate analysis of living donor procedures; 1 article36 was excluded because the procedure described was not considered to be a minimally invasive technique; and another34 was excluded because it was redundant and included lower quality series from the same institute. There was no disagreement regarding the eligibility of full-text articles (Cohen kappa 5 1). Finally, a total of 11 articles dated between 2006 and 2014 fulfilled the selection criteria and were, therefore, included in this meta-analysis; this pool of articles consisted of 3 case-controlled23,24,29 and 8 comparative studies.15,18,22,28,30-33 These 11 studies included a total of 608 adult patients: 254 were treated by minimally invasive procedures, and 354 were treated by the open technique. The minimally invasive group comprised 27 patients undergoing pure laparoscopic donor hepatectomies and 227 patients treated with hybrid techniques (including procedures using a pure laparoscopy, hand-assisted, or single-port approach for liver mobilization followed by open continuation of the operation). As for the type of graft retrieval, in the MILDH group, 52 patients underwent LLS, 171 underwent RH, and 24 underwent LH; in the OLDH group, 64 patients underwent LLS, 223 underwent RH, and 59 underwent LH. Data from 1 article concerning the type of hepatectomy were impossible to calculate because of the lack of subdivision into RH, LH, and LLS groups.23 The characteristics of the included studies are summarized in Table 1. Two corresponding authors were contacted by email to obtain unpublished or unclear data, and none of these responded or addressed the questions posed. The outcomes of interest of each single study are summarized in Tables 2 and 3.

Estimated Blood Loss All of the included studies reported results concerning blood loss in both groups. An overall trend of a significant reduction in blood loss was observed in the minimally invasive group versus the open group (MD 5 –46.35; 95% CI 5 –94.041.34; P 5 0.06; Fig. 2).

Operative Time All the articles contributed to determining the overall effect concerning the operative time. No statistically significant differences were observed between the MILDH and OLDH groups (MD 5 19.65; 95% CI 5 – 4.28-43.57; P 5 0.11; Fig. 3).

Hospital Stay Nine articles reported assessable results concerning hospital stays.15,18,22-24,29,31-33

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Figure 1.

BERARDI ET AL. 741

Study selection.

An overall statistically significant reduction in the length of stay was observed in the MILDH group versus the OLDH group (MD 5 –1.56; 95% CI 5 –2.63 to 20.49; P 5 0.004; Fig. 4).

Analgesia Use Patient-controlled analgesia (PCA) use (measured in days) was considered to be an indicator of postoperative pain in the 5 articles reporting on this outcome. A significant reduction in PCA use was observed in the MILDH group versus the OLDH group (MD 5 –0.54; 95% CI 5 –1.04 to 20.03; P 5 0.04; Fig. 5).

Donor Mortality and Morbidity No perioperative mortality for donors was recorded in the reports included in this meta-analysis. As for overall donor morbidity, 10 studies15,18,22-24,28-31,33 reported data, and a significant reduction was observed in the MILDH group (OR 5 0.62; 95% CI 5 0.40-0.98; P 5 0.04; Fig. 6). Analyzing donor morbidity according to the ClavienDindo classification,25 we found no statistically signif-

icant difference between the 2 groups for both minor (grade I-II) complications (OR 5 0.65; 95% CI 5 0.381.10; P 5 0.11) and major (grade III-V) complications (OR 5 0.75; 95% CI 5 0.41-1.37; P 5 0.35; Fig. 7). Furthermore, wound-related complications and biliary leaks were separately analyzed: the woundrelated complications that were reported accounted for infections, hematomas, and incisional hernias. A statistically significant reduction of these was observed in the MILDH group (OR 5 0.41; 95% CI 5 0.17-0.47; P 5 0.04; Fig. 8). As for biliary complications (including biliary leaks and stenosis), no statistically significant difference was seen between the 2 approaches, although a trend favoring MILDH was evidenced (OR 5 0.74; 95% CI 5 0.29-1.90; P 5 0.53; Fig. 9).

Secondary Outcomes Recipient patients included 27 children and 126 adults for the MILDH group and 25 children and 140 adults for the OLDH group; in 3 articles, these data were not specified.18,29,31

RH LLS

66 22

United Comparative States Korea Comparative

RH RH

150 34 40 110

50 50

Korea Comparative

United Comparative States Korea Case-control

Japan Comparative

China Case-control

India Comparative

RH

RH

LH-LLS

RH

30

United Case-control States

MILDH

Hybrid

Pure Laparoscopic

Hybrid

Hybrid

Hybrid

Hybrid

Hybrid

Hybrid

Hybrid

33.9 6 8.9

29.6 6 5.7

37 6 10.3

29 6 5

39 6 12

26

25

31

20

4

27.4 6 9.4

37.2 6 8.7

35.8 6 8.4

25 6 5.5

43.2 6 3.7

13/13

13/12

13/18

11/9

3/1

35/25

7/8

1/10

15/18

10/6

8/5

32 6 5

31 6 10

29 6 11.1

38.6 6 9.4

36.8 6 12

35.7 6 8

35.2 6 3.8

24

32.4 6 8.4

25 37.4 6 10.5

79 37.8 6 10.1

20

30

90

15

11

18/6

14/11

54/25

17/3

9/21

58/32

6/9

6/5

13/20

9/5

9/4

Donor Age, Male/ Years Female

OLDH

33 39.1 6 11.1

14

13

Donor Age, Male/ Number of Years Female Patients

60 31.2 6 10.3

15

11

33

16

13

Type of Number MILDH of Patients

Pure Laparoscopic RH-LH-LLS Hybrid

LLS

30

France Comparative

RH-LH

26

Japan Comparative

Country

*According to the Newcastle-Ottawa scale.

Kurosaki et al.15 (2006) Soubrane et al.33 (2006) Baker et al.28 (2009) Kim et al.22 (2011) Thenappan et al.23 (2011) Choi et al.18 (2012) Nagai et al.32 (2012) Ha et al.29 (2013) Marubashi et al.31 (2013) Zhang et al.24 (2014) Makki et al.30 (2014)

Study

Type of Number Type of Study of Patients Hepatectomy

Total

TABLE 1. Characteristics of Included Studies

8

8

7

8

7

8

8

8

9

8

8

Study Quality*

Score of

742 BERARDI ET AL. LIVER TRANSPLANTATION, June 2015

330 6 68 312 6 67.8

396 6 72

1033 6 1096

590 6 493.3 313.5 6 80.6

*SD is NR.

11.9 6 3.9

265 6 48

417 6 217

702.5 6 124

NR

7 6 1.4

378.4 6 112 385.9 6 47.4

336.5 6 89.4

10.3 6 3.3

435 6 103

10.7 6 2.6

290.1 6 66.9 335.5 6 93.6

353 6 396

6.3 6 1.3

6.9 6 0.3

4.3*

7.5 6 2.3

389 6 69

350 6 174

662

320 6 67

18.7 6 44.2

11 6 2.7

363 6 32.7

302 6 191

Kurosaki et al.15 (2006) Soubrane et al.33 (2006) Baker et al.28 (2009) Kim et al.22 (2011) Thenappan et al.23 (2011) Choi et al.18 (2012) Nagai et al.32 (2012) Ha et al.29 (2013) Marubashi et al.31 (2013) Zhang et al.24 (2014) Makki et al.30 (2014)

Donor

Donor

NR

2.4 6 1

NR

NR

NR

2.4 6 1

2 6 0.9

NR

NR

2 6 0.9

1.2 6 1.2

15.3

16

9.7

5

NR

20

13.3

0

21.2

18.7

0

(%) 283 6 371

733 6 457

464 6 78

550 6 305

456 6 347

250 6 111.3

316 6 121

0 395.8 6 125.7

0 422.6 6 139.3

0

0

NR

0 531.7 6 322.5

NR

0

0

Operative

675.2 6 117

378.1 6 59

NR

NR

2.2 6 0.9

3.8 6 2.8

(Days)

10.9 6 2.5

NR

8.7 6 2.4

NR

3.2 6 1

NR

NR

NR

12 6 3.6 2.55 6 1.1 7.8 6 2.3

Donor

Donor

20.8

28

21.5

10

23

23.3

26.6

9

21.2

35.7

0

(%)

0

0

0

0

NR

0

NR

0

0

0

0

(%)

Use Morbidity Mortality

Analgesia

6.4 6 3.7 2.36 6 1.7

9.8 6 0.9

3.9*

8.1 6 3

12.8 6 4.9

(Days)

Stay

Hospital

OLDH

383 6 73 18.3 6 16.7

305.4 6 88.1

363 6 53

303.2 6 61.4

324 6 105.6

306 6 29

316 6 61

244 6 55

320 6 67.9

(mL) Time (Minutes)

Loss

Blood

0 199.2 6 185.4

0

(%)

Analgesia Morbidity Mortality

(Minutes) Stay (Days) Use (Days)

Hospital

Loss (mL)

Time

Operative

Study

Blood

MILDH

TABLE 2. Raw Data of Each Included Study

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TABLE 3. Raw Data for Each Included Study MILDH

Study

OLDH

Recipient

Recipient

Recipient

Recipient

Morbidity (%)

Mortality (%)

Costs ($)

Morbidity (%)

Mortality (%)

Costs ($)

NR

23

12,130 6 1085*

NR

NR

11,492 6 1634*

43.7

6.2

NR

50

7.1

NR

51.5 18.1 60

18.1† 0 0

1107‡ 5997 6 1131§ NR

57.5 27.2 33

12.1† 9 6.6

1000‡ 6100 6 1145§ NR

NR NR NR NR

NR NR NR 0

NR NR NR NR

NR 36.7 NR NR

NR NR NR NR

NR NR NR NR

16 7.6

0 3.8

7652.5 6 1291.2* NR

28 16.6

8 4.1

6540.8 6 1113* NR

Kurosaki et al.15 (2006) Soubrane et al.33 (2006) Baker et al.28 (2009) Kim et al.22 (2011) Thenappan et al.23 (2011) Choi et al.18 (2012) Nagai et al.32 (2012) Ha et al.29 (2013) Marubashi et al.31 (2013) Zhang et al.24 (2014) Makki et al.30 (2014) *Total in-hospital cost. One-year overall survival. ‡ SD is NR. § Out-of-pocket costs to donors. †

Figure 2.

Meta-analysis forest plot concerning blood loss (milliliters).

Overall results for recipient morbidity (OR 5 0.81; 95% CI 5 0.47-1.42; P 5 0.46) and 90-day mortality (OR 5 0.43; 95% CI 5 0.12-1.57; P 5 0.20) were compared, and no statistically significant differences were noted between MILDH and OLDH for either outcome (Fig. 10). One study was not included in the mortality analysis because only 1 year of overall survival was reported without specification of mortality at 90 days.28 The costs of the donor procedure were also evaluated: 4 articles reported data, but 1 was excluded because it considered only out-of-pocket costs to donors.22 In 1 article, no SD was reported, and the article was, therefore, not included.28 The remaining 2 articles were not considered sufficient to assess the overall effect.

Subgroup Analysis In 3 articles reporting results for more than 1 type of donor hepatectomy, no subcategorization of results was specified, and the articles were, therefore, not included in the subgroup analysis.15,23,31 When we considered only the results of donors who underwent RH graft retrieval, the primary outcome results remained similar for blood loss, operative time, and hospital stay, whereas statistical significance was lost for donor morbidity (OR 5 0.75; 95% CI 5 0.44-1.28; P 5 0.30; Fig. 11). Because of the low number of cases undergoing LLS and LH for graft retrieval and because of difficult data extraction, no separate analysis was performed for these 2 subgroups.

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BERARDI ET AL. 745

Figure 3.

Meta-analysis forest plot concerning operative time (minutes).

Figure 4.

Meta-analysis forest plot concerning hospital stay (days).

Publication Bias Funnel plots were constructed for each outcome, and these showed symmetry and suggested that publication bias was not substantial and was unlikely to drive any conclusions made (Fig. 12).

DISCUSSION LDLT is considered a safe and effective alternative to deceased donor liver transplantation. The shortage of cadaveric liver grafts has renewed interest in this type of procedure in countries where there is limited access to deceased organ donation. Conversely, the risks of donor morbidity and mortality and the availability of deceased cardiac death organ donors, in addition to MELD-driven allocation, lead to a very critical and limited approach to LDLT in many Western countries.38,39 Furthermore, the recent success that the minimally invasive technique for liver surgery has gained worldwide has led to the notion that this approach is feasible in living donor surgery. The main putative advantages of the application of minimally invasive surgery to living donors are similar to other indications: less morbidity, shorter hospital stay, less postoperative pain, and an obvious reduction in the length of scars (more evident with the pure tech-

nique). Guided by this principle, several specialized units have decided to implement MILDH, and they have highlighted good results and encouraged different perspectives. In all the reports, safety and feasibility were underlined. However, several articles comparing MILDH and OLDH have been published, with different outcome evaluations and results among series, and this has led to difficulty not only in the interpretation of data but also in the drawing of final conclusions about the 2 approaches. The metaanalysis as a quantitative technique for therapeutic evaluation may be used to elucidate the state of the art when controversy persists. This is the first systematic review and meta-analysis in the available literature comparing the minimally invasive technique and the standard open technique for living donor hepatectomy. In this analysis, we included 11 studies covering 608 patients, and this may represent the largest body of information available for the comparison of MILDH and ODLH in the literature to date. Raia et al.1 described the first living donor hepatectomy in 1989, whereas Cherqui et al.13 presented the first minimally invasive hepatectomy for donor graft procurement in 2002 in a report on a purely laparoscopic technique. Four years later, Koffron et al.14 proposed the hybrid technique for right lobe retrieval,

746 BERARDI ET AL.

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Figure 5.

Meta-analysis forest plot concerning analgesia use (days)

Figure 6.

Meta-analysis forest plot concerning overall donor morbidity.

and Kurosaki et al.15 described the first study comparing the 2 techniques. Since then, we have observed a progressive increase in publications over the years, and this suggests a growing interest in the comparison of the 2 approaches. The world’s first full laparoscopic left liver procurement for adult LDLT was presented by Troisi et al.40 at the 10th World Congress of the International Hepato-Pancreato Biliary Association in 2012. Subsequently, small case reports that included the first right liver graft followed.19,20 Different techniques have been described, but there is a clear predominance of hybrid procedures among these reports. Although case series, case reports, and original articles concerning pure laparoscopic living donor hepatectomies have already been described, only 2 studies comparing OLDH and the pure laparoscopic technique are currently available.22,33 In these 2 reports, the procedure is performed from the beginning to the end with the use of the pneumoperitoneum and with laparoscopic instruments. In the other series, laparoscopic and/or hand-assisted techniques are mainly used for liver mobilization, with a switch to an open parenchymal division under direct view. The vast majority of graft procurements are performed with RH, with 6 articles describing only RH,18,24,28-30,32 2 describing LLS,22,33 and 3 describing a mix of RH, LH, and LLS.15,23,31

The results of the present meta-analysis showed a tendency toward a substantial reduction in bleeding in MILDH. The role of vision magnification (3- to 4-fold magnification) is a matter of fact in the case of fully laparoscopic techniques but also hybrid techniques. However, this does not concern the parenchymal transection step, which is done, in the majority of hybrid procedure cases, under direct vision. Indeed, only the mobilization of the chosen lobe (usually the right one) is performed under a fully laparoscopic view. However, surgeons performing laparoscopic major hepatectomies find the mobilization of the right lobe from the diaphragm and the inferior vena cava easier with the minimally invasive technique. The magnified view is an evident advantage for dissection and bleeding control. Manuscripts describing this technique and, therefore, included in this metaanalysis in fact confirm this result and show extremely low blood loss values (especially with a fully laparoscopic approach; Table 2). Furthermore, the high intra-abdominal pressure reached by pneumoperitoneum use, a common technical feature in all MILDH procedures, has been described as a contributor to decreasing blood loss because of the hemostatic effect.41 Surgical times were not significantly different between the groups, although the forest plot highlighted a favorable effect

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Figure 7. Meta-analysis forest plots concerning minor and major complications in donors according to the Clavien-Dindo classification.

Figure 8.

Meta-analysis forest plot concerning wound-related complications (including infections, hematomas, and hernias).

toward a reduction in the OLDH operative time. A learning curve effect must be considered. According to the statements of the 2nd International Consensus Conference on Laparoscopic Liver Surgery (2ICCLLS), major hepatectomies should still be considered innovative procedures in the learning phase (Balliol 2b classification, “the exploration phase”): blood loss is reported to be less, pending questions on the methodology used.42,43 The reduction of cold ischemia is a characteristic of LDLT, and teams will often coordinate and extend the donor procedure to minimize the cold ischemia time for the graft. This is, however, true for either standard

or laparoscopic approaches and, therefore, represents, in our opinion, not a comparison bias (the aim of a meta-analysis) but rather the single specific MILDH and OLDH results themselves. Whatever it is, the weighted overall mean value of the operative time outcome for both techniques should be carefully interpreted. Overall results concerning hospital stay, morbidity rate, and analgesia use were significantly in favor of MILDH, and this revealed and confirmed what is already known about minimally invasive surgery. These results could give significant strength to past evidence showing that the minimally invasive approach

748 BERARDI ET AL.

Figure 9.

Figure 10.

LIVER TRANSPLANTATION, June 2015

Meta-analysis forest plot concerning overall biliary complications.

Meta-analysis forest plots concerning recipient morbidity and mortality.

could be applicable to living donor hepatectomy, maintain efficacy, and reduce the impact of surgical stress on patients. A possible bias of the postoperative analgesia use outcome could be the fact that the MILDH group was composed of various types and lengths of incisions: more specifically, some articles describe a 2- to 3-trocar technique with a midline epigastric incision,23,24,28,30-32 others describe a 1- to 3-trocar technique with a subcostal incision,15,18,29 whereas 2 articles describe a 5-trocar technique with a Pfannenstiel incision.22,33 The association of 2 or 3 trocars still allows for a significant reduction to what would be the length of the standard incision. The Pfannenstiel incision is then usually made without a section of the abdominal wall muscles (a less painful scar). Additional

limits of such results could be related to the different center policies and outcome measures concerning analgesia. This heterogeneity could have influenced the strength of this result, although we used a randomeffects model for estimation. Unlike the intraoperative data, which are quite comparable between groups, the postoperative outcomes undeniably favor MILDH. A reduction in hospital stay, morbidity rates, and analgesia use are all factors related to high patient satisfaction and reduced inhospital costs. Furthermore, it is important to highlight that when we considered separately the articles included in this review, donor morbidity was not significantly different between the groups, but when we pooled all the single effects of articles in the cumulative

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Figure 11.

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Meta-analysis forest plots concerning RH subgroup analysis.

analysis, statistical significance was reached. With this result, we can indeed see the major advantage of a meta-analysis, in which the large sample size allows us to make important conclusions. As for morbidity, the overall rate was significantly reduced in the MILDH group; when we stratified complications according to the Clavien-Dindo classifica-

tion, the results showed a tendency for favoring MILDH, although it was not statistically significant for minor (I-II) or major (III-V) complications. However, focusing on specific wound-related complications (including infections, hematomas, and incisional hernias), we found such morbidity to be significantly lower in the MILDH group. This could be explained by

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Figure 12. Meta-analysis funnel plot assessing publication bias (blood loss in the example).

the minor abdominal wall injury (small scars) in line with the advantages of minimally invasive surgery, which were shown for other indications. Liver-specific complications such as biliary fistulas and stenosis were not significantly different between the 2 groups (although a trend favoring MILDH was shown). In the subgroup analysis, we decided to analyze separately the single types of hepatectomies in order to minimize the bias generated by the presence of more than 1 hepatectomy in the cumulative group: only data concerning RH were eligible for analysis. What must be noted is that the donor morbidity rate lost significance. Blood loss and operative times remained similar between the groups, whereas the hospital stay was confirmed to be lower with MILDH. A donor procedure cost analysis was not performed because only 2 articles were eligible for inclusion and because a bias in cost standardization was considered likely. As for the recipients’ results, no overall differences were highlighted from this review in terms of morbidity and mortality, although a limitation to this result does exist: the vast majority of recipients were adult patients, but 17.6% in the OLDH group and 15.1% in the MILDH group were pediatric recipients. Further studies that allow the analysis of data with a homogeneous division of recipients are needed. This meta-analysis has some limitations. First, this study was conducted with retrospective studies, only 3 of which were case-controlled. However, an important percentage of the meta-analysis concerns nonrandomized controlled trials, mainly cohort and case-control studies.44 To date, despite the worldwide spread of this technique, there are only 7 running randomized controlled trials (RCTs) comparing laparoscopic and open liver surgery (https://www.clinicaltrials.gov/). The difficulties in conducting RCTs for laparoscopic liver surgery are mainly due to the acknowledged long learning curve and expertise in hepatobiliary surgery and the need for large-scale collaboration to accrue a relatively modest sample size. The functional recovery should be the primary outcome of such studies as recently stated

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at the 2nd International Consensus Conference on Laparoscopic Liver Surgery in Morioka, Japan. In view of this, prospective studies concerning open hepatectomy versus laparoscopic hepatectomy for living donors are even more difficult to perform beyond controversial issues. Therefore, we can conclude that meta-analyses composed of case-control or retrospective studies are common and appropriate in this setting. A word of caution should be written on the fact that certain numbers of negative experiences are missing because they were not reported in the literature, especially for a novel technique such as a minimally invasive approach for LDLT. However, this is a general problem with a meta-analysis. As for the issue of donor selection as another possible bias, we have to consider any suitable living donor as the result of a rigorous selection and workup, regardless of the chosen approach (standard or minimally invasive). Further selection based on the presence of a formal vascular and/or biliary anatomy could be pursued in the case of the laparoscopic approach and, therefore, cannot be excluded. Some of the outcomes were associated with significant heterogeneity among the studies: this is especially true for those outcomes that were strongly influenced by different center policies such as operative time, analgesia use, and hospital stay. According to the high I2 test value, we used a random-effects model when appropriate in order to minimize bias generated from this heterogeneity. Although reduced morbidity and no mortality have been reported with MILDH, there is still uncertainty about the true figures and the undefined risks; this procedure is actually classified as Balliol 2a: “development in progress.” The absence of an international registry on laparoscopic liver surgery and living donor hepatectomy (as stated during 2ICCLLS) makes it difficult to make final conclusions confirming these techniques as safe and useful for a select category of donors and patients.43 Future research should be directed toward performing studies with a larger patient number. Because of the difficulty inherent in setting up RCTs, casecontrolled analyses comparing MILDH to OLDH are most likely more feasible. In this case, a standardized cost analysis would be also advisable. In conclusion, the results of this meta-analysis comparing MILDH to OLDH, though with due caution as previously mentioned, show that the minimally invasive approach could result in a significant reduction in hospital stay, analgesia use, overall donor morbidity rates, and abdominal wall complications with similar recipient survival. MILDH for right liver procurement is associated with a significantly reduced hospital stay.

ACKNOWLEDGMENT The authors thank Roberto Montalti, M.D., Ph.D., for his critical evaluation of this article.

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