Can pretransplant TIPS be harmful in liver transplantation? A propensity score matching analysis

Surgery xxx (2020) 1e7

Contents lists available at ScienceDirect

Surgery journal homepage: www.elsevier.com/locate/surg

Can pretransplant TIPS be harmful in liver transplantation? A propensity score matching analysis Hajime Matsushima, MD, PhDa, Masato Fujiki, MD, PhDa, Kazunari Sasaki, MDa, Jacek B. Cywinski, MDb, Giuseppe D’Amico, MDa, Teresa Diago Uso, MDa, Federico Aucejo, MDa, Choon Hyuck David Kwon, MD, PhDa, Bijan Eghtesad, MDa, Charles Miller, MDa, Cristiano Quintini, MDa, Koji Hashimoto, MD, PhDa,* a b

Department of General Surgery, Digestive Disease & Surgery Institute, Cleveland Clinic, Cleveland, OH, USA Department of General Anesthesiology, Transplant Center and Outcomes Research, Anesthesiology Institute, Cleveland Clinic, Cleveland, OH, USA

a r t i c l e i n f o

a b s t r a c t

Article history: Accepted 18 February 2020 Available online xxx

Background: Transjugular intrahepatic portosystemic shunt has been established as an effective treatment for complicated portal hypertension. This retrospective study investigated the effect of pretransplant transjugular intrahepatic portosystemic shunt placement on intraoperative graft hemodynamics and surgical outcomes after liver transplantation. Methods: Of 1,081 patients who underwent liver transplantation between January 2007 and June 2017 at Cleveland Clinic (OH, USA), 130 patients had transjugular intrahepatic portosystemic shunt placement before liver transplant. We performed a 1:2 propensity score matching to compare intraoperative graft hemodynamics and surgical outcomes between the transjugular intrahepatic portosystemic shunt group (n ¼ 130) and the no-transjugular intrahepatic portosystemic shunt group (n ¼ 260). Results: The transjugular intrahepatic portosystemic shunt did not increase operative time, the volume of blood transfusion, duration of hospital stay, or complication rates. Graft and patient survivals were similar between the groups. Mean intraoperative cardiac output and graft portal flow in the transjugular intrahepatic portosystemic shunt group were greater than in the no-transjugular intrahepatic portosystemic shunt group (P ¼ .03 and P ¼ .003, respectively). In multivariate analysis, male sex, younger age, low platelet count, absence of portal vein thrombosis, and pretransplant transjugular intrahepatic portosystemic shunt placement were independently associated with increased portal flow volume (P < or ¼ 0.03 each). Transjugular intrahepatic portosystemic shunt malposition was observed in 17 patients (13.1%). The 1-year patient survival was 70.6% with transjugular intrahepatic portosystemic shunt malposition and 92.0% without transjugular intrahepatic portosystemic shunt malposition (P ¼ .01). Conclusion: Our findings suggest that pretransplant transjugular intrahepatic portosystemic shunt placement increases graft portal flow but does not compromise surgical outcomes after liver transplantation. Transjugular intrahepatic portosystemic shunt malposition, however, is not uncommon and may increase the complexity of transplantation. © 2020 Elsevier Inc. All rights reserved.

Introduction

Hajime Matsushima, MD, PhD and Koji Hashimoto, MD, PhD conceptualized the idea and design of the study. All authors participated equally in data collection, analysis, and interpretation. Hajime Matsushima, MD, PhD, and Koji Hashimoto, MD, PhD, wrote the article. All authors participated in revising the article and approving the final draft. * Reprint requests: Koji Hashimoto, MD, PhD, Department of General Surgery, Digestive Disease & Surgery Institute, Cleveland Clinic, 9500 Euclid Ave, A100, Cleveland, OH, 44195, USA. E-mail address: [email protected] (K. Hashimoto). https://doi.org/10.1016/j.surg.2020.02.017 0039-6060/© 2020 Elsevier Inc. All rights reserved.

Currently, liver transplantation (LT) is the only curative treatment for end-stage liver disease. With the evolution of surgical techniques and postoperative management, patient survival after LT has improved. Lack of available organs attributable to donor shortages, however, continues to be a serious problem that results in high mortality of patients on the waitlist.1 Candidates often drop off the waitlist for a variety of factors, including clinical deterioration of their medical condition and life-threatening complications such as portal hypertension with acute variceal bleeding.2,3

2

H. Matsushima et al. / Surgery xxx (2020) 1e7

The use of transjugular intrahepatic portosystemic shunt (TIPS) has been proposed as a bridge to LT in patients with severe portal hypertension, particularly for those who experience refractory ascites or variceal bleeding. A large cohort analysis using the registry of the United Network for Organ Sharing reported that patients with TIPS had a lesser mortality rate on the waiting list compared with patients without TIPS.4 Although several studies investigated the outcomes of patients who underwent TIPS placement before LT, the effect of TIPS on subsequent LT remains undetermined and controversial.5-9 The implantation of TIPS decreases portal venous pressure, resulting in decompression of the venous collaterals by redirecting blood flow to the portal vein.10-13 During the transplant operation, however, portal clamping often causes bowel congestion and hypotension. In addition, malposition or migration of the TIPS stent into the distal main portal vein, vena cava, and right atrium can make recipient hepatectomy difficult. In addition, the portal vein and hepatic vein may become unsuitable for anastomosis because of mechanical wall damage. Accordingly, we hypothesized that pretransplant TIPS placement can increase the risk of surgical complications, resulting in unfavorable outcomes after LT. The aim of the current study was to investigate the effect of pretransplant TIPS placement on surgical outcomes after LT. We also evaluated the influence of TIPS on the hemodynamics of the new liver graft. Methods This retrospective study included 1,081 patients who underwent deceased donor, whole LT between January 2007 and June 2017 at Cleveland Clinic (OH, USA). Patients who underwent retransplantation or simultaneous other-organ transplantation, as well as pediatric cases, were excluded. Of the 1,081 patients reviewed, 130 (12.0%) underwent TIPS placement before LT. The patency of the TIPS was evaluated by Doppler ultrasonography. Recipient variables assessed were age, sex, body mass index (BMI), model for end-stage liver disease (MELD) score, etiology of underlying liver disease, serum bilirubin level, international normalized ratio (INR), platelet count, serum creatinine level, and the presence of portal vein thrombosis at the time of LT. Donor variables assessed were age, sex, BMI, donor risk index, and type of donor (donation after brain death or donation after cardiac death). From the remaining 951 patients who had no TIPS placement, 260 patients were selected as the control group (no TIPS placement), using 1:2 propensity score matching to decrease the heterogeneity of patient characteristics. In the matched cohort, graft and patient survival, surgical outcomes, graft function, and graft hemodynamics were analyzed. Surgical outcomes included cold and warm ischemic time, operative time, volume of blood transfusion, use of bypass, venous reconstruction, graft hemodynamics, graft weight, duration of hospital stay, and complications (portal vein thrombosis, biliary complications, hepatic artery thrombosis, and acute cellular rejection). Aspartate aminotransferase, alanine aminotransferase, bilirubin level, and INR within 7 postoperative days were used to evaluate graft function. With regard to graft hemodynamics, graft portal flow and hepatic artery flow were assessed. Portal and hepatic artery flows were measured intraoperatively before biliary reconstruction, using a transit time flowmeter with 2-channel flow probes.14,15 The 8-, 10-, or 12-mm flow probes were used for the portal vein, and the 4- or 6-mm flow probes were used for the hepatic artery. Cardiac output was measured at the same time as hepatic flow. Splenic artery ligation was performed for portal inflow modulation when hepatic artery flow demonstrated diastolic reversal during flow measurement. In patients who underwent splenic artery ligation, the flow data obtained before ligation were used in the analyses. Proximal splenic artery embolization was performed postoperatively when diastolic reversal of

hepatic artery on Doppler ultrasonography or refractory ascites was observed.16,17 With regard to operative complications, biliary complications included biliary anastomotic stricture or bile leak that required interventions. Primary nonfunction was defined as primary graft failure resulting in retransplantation or patient death within 14 days after liver transplantation. In patients with TIPS, the position of the TIPS stent at the time of transplant was evaluated. TIPS malposition was defined as follows: (1) the proximal edge of a TIPS stent is located in the suprahepatic vena cava or right atrium, (2) the distal edge of a TIPS stent is located in the distal main portal vein close to or beyond the confluence of splenic vein. Subgroup analysis was performed to investigate the influence of TIPS malposition on surgical outcomes. This study was approved by the Cleveland Clinic Institutional Review Board and conducted according to the Declaration of Helsinki. Statistical analysis The data for continuous and categorical variables are expressed as means þ the standard deviation and as the number of cases with percentages, respectively. Statistical analyses were performed using JMP v 12 (SAS Institute Inc, Cary, NC, USA) and STATA v 15 (Stata Corp, College Station, TX, USA). Categorical variables were compared using the Pearson c2 statistic or Fisher exact probability test. The continuous variables were compared using t tests. Propensity score matching was performed using a caliper width of 0.20. The propensity score was calculated according to recipient sex, age, MELD score, presence of hepatocellular carcinoma, presence of hepatitis C virus infection, donor sex and age, and donor type (donation after brain death or cardiac death). Graft and patient survivals were analyzed using the Kaplan-Meier method and a loglank test. In the propensity score-matched cohort, the predictors for the volume of graft portal flow were determined using the least squares regression model. A P-value of <.05 was considered statistically significant. Results Baseline demographics of patients before and after propensity score matching The demographics of patients before and after propensity score matching are presented in Table I. Before matching, the rate of hepatocellular carcinoma and infection with hepatitis C virus in the no-TIPS group was greater than in the TIPS group (P < .001 and P ¼ .048, respectively). In contrast, the rate of alcoholic liver disease and nonalcoholic steatohepatitis in the TIPS group was greater than in the no-TIPS group (P ¼ .04 and P ¼ .01, respectively). The MELD score and serum bilirubin level in the TIPS group was greater than in the no-TIPS group (21.8 þ 9.4 vs 19.2 þ 9.9, P ¼ .01, and 9.6 þ 11.7 mg/dL vs 7.6 þ 10.5 mg/dL, P ¼ .046). Platelet count in the TIPS group was lesser than in the no-TIPS group (76.7 þ 42.1 [103/mL] vs 95.1 þ 73.1 [103/mL], P < .01). With regard to donor factors, although there were no differences between the no-TIPS group and TIPS group, the rate of donation after cardiac death tended to be greater in the TIPS group (P ¼ .06). After propensity score matching, all variables were well-balanced except for the rate of primary biliary cholangitis or primary sclerosing cholangitis and platelet count. The indications for TIPS placement included ascites and/or hydrothorax (75 cases), variceal bleeding (51 cases), and recanalization of portal vein thrombosis (1 case) (Table II). The median duration from TIPS placement to LT was 392 days (range: 4e5,072 days). The malposition of the TIPS stent was observed in 17 patients (13.1%). The proximal edge of the TIPS was seen in suprahepatic vena cava in 12 patients. Of these, the stent extended to right atrium in 1

H. Matsushima et al. / Surgery xxx (2020) 1e7

3

Table I Demographics of patients with or without TIPS before and after propensity score matching* Variables

Recipient Sex, female Age, y Body mass index, kg/m2 Etiology of liver disease Hepatocellular carcinoma Hepatitis C virus Alcohol disease NASH Autoimmune PBC or PSC MELD score Bilirubin, mg/dL INR Platelet count, 103/mL Serum creatinine, mg/dL Portal vein thrombosis Donor Sex, female Age, y Body mass index, kg/m2 Donor risk index Donation after cardiac death Year of transplant 2007e2010 2011e2014 2015e2017 Follow-up duration, days

Before matching

After matching

No TIPS (n ¼ 951)

TIPS (n ¼ 130)

P

No TIPS (n ¼ 260)

TIPS (n ¼ 130)

P

267 (28.1) 55.9 þ 10.2 29.5 þ 6.5

44 (33.9) 57.5 þ 9.2 30.2 þ 6.0

.18 .09 .22

107 (41.2) 57.1 þ 9.1 29.1 þ 6.7

44 (33.9) 57.5 þ 9.2 30.2 þ 6.0

.16 .70 .11

261 (27.4) 363 (38.2) 97 (10.2) 109 (11.5) 22 (2.3) 96 (10.1) 19.2 þ 9.9 7.6 þ 10.5 1.59 þ 1.07 95.1 þ 73.1 1.40 þ 1.04 140 (14.7)

12 (9.2) 38 (29.2) 21 (16.2) 26 (20) 1 (0.8) 8 (6.2) 21.8 þ 9.4 9.6 þ 11.7 1.64 þ 0.48 76.7 þ 42.1 1.50 þ 1.15 17 (13.1)

< .001 .048 .04 .01 .41 .20 .01 .046 .60 <.01 .34 .62

23 (8.9) 83 (31.9) 29 (11.2) 44 (16.9) 6 (2.3) 41 (15.7) 21.1 þ 9.3 8.5 þ 10.5 1.69 þ 1.77 90.1 þ 66.5 1.54 þ 1.17 45 (17.3)

12 (9.2) 38 (29.2) 21 (16.2) 26 (20) 1 (0.8) 8 (6.2) 21.8 þ 9.4 9.6 þ 11.7 1.64 þ 0.48 76.7 þ 42.1 1.50 þ 1.15 17 (13.1)

.90 .59 .16 .46 .50 .01 .51 .38 .71 .04 .74 .31

402 (42.3) 43.4 þ 15.8 28.3 þ 6.6 1.50 þ 0.41 107 (11.3)

56 (43.1) 42.5 þ 16.2 29.4 þ 7.7 1.53 þ 0.46 22 (16.9)

.86 .53 .08 .55 .06 .44

118 (45.4) 43.8 þ 16.0 28.3 þ 6.77 1.56 þ 0.47 44 (16.9)

56 (43.1) 42.5 þ 16.2 29.4 þ 7.70 1.53 þ 0.46 22 (16.9)

.67 .47 .14 .51 1 .48

399 (42.0) 338 (35.5) 214 (22.5) 1,946 þ 1,235

47 (36.2) 50 (38.4) 33 (25.4) 1,868 þ 1,214

110 (42.3) 71 (27.3) 79 (30.4) 1,909 þ 1,265

47 (36.2) 50 (38.4) 33 (25.4) 1,868 þ 1,214

.50

.76

TIPS, transjugular intrahepatic portosystemic shunting; NASH, nonalcoholic fatty liver disease; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; MELD, model for end-stage liver disease. * The data are presented as mean þ SD for continuous variables and numbers (%) for categorical variables

Operative factors and surgical outcomes after LT in the matched population

Table II Indications for TIPS* Indications for TIPS placement Ascites/hydrothorax Gastrointestinal bleeding Portal vein thrombosis Others Days from TIPS to liver transplantation Stent malposition to main portal vein to suprahepatic vena cava TIPS patency at the time of liver transplantation

75 (57.7) 51 (39.2) 1 (0.8) 3 (2.3) 392 (4e5,072) 17 (13.1) 5 (3.8) 12 (9.2) 127 (97.7)

* The data are presented as median (range) continuous variables and numbers (%) for categorical variables.

patient (Fig 1, A). In 5 patients, the distal edge of the stent was observed in the distal main portal vein. In 1 patient, the stent extended to the superior mesenteric vein (Fig 1, B). In 28 patients, revision of TIPS was performed because of its occlusion. The patency rate of TIPS at the time of LT was 97.7%. Graft function, graft, and patient survival in the matched population Liver function within 7 postoperative days was compared between the 2 groups (Supplementary Fig 1). Aspartate aminotransferase, alanine aminostransferase, bilirubin level, and INR were similar between the groups during the period. Graft survival was also similar at 1, 3, and 5 years (86.9%, 82.7%, and 75.5%, respectively) for the no-TIPS group and 88.5%, 80.5%, and 76.1%, respectively, for the TIPS group (P ¼ .47) (Fig 2, A). The overall patient survival was also similar at 1, 3, and 5 years (87.7%, 83.4%, and 76.2%, respectively) for the no-TIPS group and 89.2%, 81.1%, and 76.7%, respectively for the TIPS group (P ¼ .57) (Fig 2, B).

Cold and warm ischemic time was comparable between the noTIPS group and the TIPS group (P ¼ .30 and P ¼ .87, respectively) (Table III). Operative time and transfusion volume were similar between the 2 groups. Venovenous bypass during LT was used in 15 cases in the no-TIPS group (5.8%) and 9 patients in the TIPS group (6.9%) (P ¼ .66). The rate of venous reconstruction with the piggyback technique was similar between the 2 groups. Intraoperative cardiac output in the TIPS group was greater than in the no-TIPS group (10.5 þ 2.8 L/min vs 9.7 þ 3.3 L/min, P ¼ .03). Graft portal flow after reperfusion in the TIPS group was greater than in the noTIPS group (1,947 þ 808 mL/min vs 1,688 þ 759 mL/min, P ¼ .003). No difference was observed in hepatic artery flow between the groups (P ¼ .85). The frequency of portal inflow modulation by splenic artery ligation and splenic artery embolization was similar between the groups (P ¼ 1.00 and P ¼ .91, respectively). The mean duration of hospital stay was 12.9 days in the no-TIPS group and 13.9 days in the TIPS group (P ¼ .32). The rate of postoperative complications, including portal vein thrombosis, hepatic artery thrombosis, biliary complication, and acute rejection, was comparable between the 2 groups. Retransplantation was performed in 5 patients in the no-TIPS group and in 2 in the TIPS group (P ¼ .79). Predictive factors for the volume of graft portal flow in the matched population To analyze the effect of TIPS placement before LT on portal flow into the graft, least squares regression analysis was conducted. The results of univariate and multivariate analyses of factors associated with graft portal flow are shown in Table IV. In the univariate

4

H. Matsushima et al. / Surgery xxx (2020) 1e7

Fig 1. Radiologic images of patients with malpositioned TIPS. (A) X-ray of patient whose TIPS malposition is in the right atrium. (B) Computed tomography of patient whose TIPS malposition (white arrows) is in the superior mesenteric vein.

Table III Perioperative variables and surgical outcomes after liver transplantation in patients with or without TIPS* Variables

No TIPS (n ¼ 260)

TIPS (n ¼ 130)

P

Cold ischemic time, h Warm ischemic time, min Operative time, min Transfusion, unit Red blood cells Fresh frozen plasma Platelets Venovenous bypass Venous reconstruction Piggyback Conventional Cardiac output, L/min Portal flow, mL/min Hepatic artery flow, mL/min Graft weight, g Splenic artery ligation Postoperative splenic artery embolization Duration of hospital stay, days Portal vein thrombosis Hepatic artery thrombosis Biliary complication Acute rejection Retransplantation

6.9 þ 1.8 44.2 þ 12.4 420 þ 129

6.7 þ 1.9 44.4 þ 11.1 425 þ 95

.30 .87 .74

8.2 þ 7.0 7.6 þ 8.8 10.3 þ 11.9 15 (5.8)

8.8 þ 6.7 7.4 þ 7.1 11.1 þ 9.6 9 (6.9)

.44 .76 .49 .66 .63

184 (70.8) 76 (29.2) 9.7 þ 3.3 1,688 þ 759 297 þ 278 1,705 þ 384 12 (4.6) 27 (10.4)

95 (73.1) 35 (26.9) 10.5 þ 2.8 1,947 þ 808 292 þ 192 1,733 þ 351 6 (4.6) 14 (10.8)

.03 .003 .85 .48 1.00 .91

12.9 þ 8.8 10 (3.8) 10 (3.8) 59 (22.7) 59 (22.7) 5 (1.9)

13.9 þ 11.4 5 (3.8) 2 (1.5) 26 (20) 27 (20.8) 2 (1.5)

.32 1.00 .35 .54 .67 .79

* The data are presented as mean þ SD for continuous variables and numbers (%) for categorical variables.

Causes of graft failure or patient death

Fig 2. Kaplan-Meier curves for graft and survival in patients with or without TIPS. (A) Graft patient survival in the TIPS and the no-TIPS groups. The log-rank test found no difference in graft survival between the 2 groups (P ¼ .47). (B) Survivals of patients in the TIPS and the no-TIPS groups. The log-rank test found no difference in patient survival between the 2 groups (P ¼ .57).

During the follow-up period, graft failure was observed in 72 patients in the no-TIPS group (27.7%) and 32 patients in the TIPS group (24.6%) (P ¼ .52) (Table V). The incidence of graft failure attributable to primary nonfunction in the no-TIPS group tended to be greater than in the TIPS group (4.2% vs 0.8%, P ¼ .07, respectively). Graft failure attributable to infection or multiple organ failure, hepatic artery thrombosis, and biliary complication was comparable between 2 groups. Surgical outcomes in patients with TIPS malposition

analysis, recipient sex (male), younger age, lesser platelet count, absence of portal vein thrombosis, and pretransplant TIPS placement were associated with increased graft portal flow (P  0.02 each) Likewise, in the multivariate analysis, recipient sex (male), younger age, , lesser platelet count, absence of portal vein thrombosis, and pretransplant TIPS placement were independently associated with increased graft portal flow (P  0.03 each).

Subgroup analysis was performed for patients with TIPS. Perioperative variables and surgical outcomes were compared between the patients with or without TIPS malposition (Table VI). With regard to operative time and blood transfusion requirements, there were no differences between the groups. Furthermore, graft hemodynamics and surgical complications were comparable. Graft

H. Matsushima et al. / Surgery xxx (2020) 1e7 Table IV Univariate and multivariate analysis for correlations between perioperative variables and graft portal flow Variables

Recipient factor Sex, male Age, y Body mass index, kg/m2 Hepatocellular carcinoma Hepatitis C virus MELD score Bilirubin, mg/dL INR Platelet count, 103/mL Serum Creatinine, mg/dL Portal vein thrombosis TIPS prior to liver transplantation Donor factor Sex, male Age, y Body mass index, kg/m2 Donor risk index Donation after cardiac death Operative factor Cold ischemic time, h Warm ischemic time, min Operative time, min Red blood cell transfusion, unit Bypass Graft weight, g

Univariate

Multivariate

F

P

F

P

12.88 12.71 2.11 0.23 0.16 0.06 1.97 0.92 9.69 2.31 5.66 9.15

< .001 < .001 .15 .63 .69 .82 .16 .34 .002 .13 .02 .003

11.58 10.41

< .001 < .001

3.11 0.86 0.06 0.13 0.48

.08 .06 .81 .72 .49

1.14 < 0.001 0.07 0.25 0.03 1.22

.29 .98 .79 .62 .86 .27

7.12

.01

4.67 6.17

.03 .01

Table V Causes of graft failure or patient death* No TIPS (n ¼ 260) TIPS (n ¼ 130) P 72 (27.7) 11 (4.2) 22 (8.5) 1 (0.4) 0 (0) 1 (0.4) 17 (6.5) 7 (2.7) 5 (1.9) 4 (1.5) 4 (1.5)

Table VI Perioperative variables and surgical outcomes after liver transplantation in patients with or without TIPS malposition* Variables

TIPS (n ¼ 113)

TIPS malposition (n ¼ 17)

P

Cold ischemic time, h Warm ischemic time, min Operative time, min Transfusion, unit Red blood cells Fresh frozen plasma Platelets Venovenous bypass Venous reconstruction Piggyback Conventional Cardiac output Portal flow, mL/min Hepatic artery flow, mL/min Duration of hospital stay, days Portal vein thrombosis Hepatic artery thrombosis Biliary complication Acute rejection Retransplantation

6.7 þ 1.8 44.0 þ 11.0 420 þ 88

6.4 þ 2.2 47.2 þ 12.0 455 þ 129

.47 .26 .16

9.0 þ 7.1 7.7 þ 7.4 11.2 þ 9.8 9 (8.0)

7.2 þ 3.4 5.0 þ 4.0 10.3 þ 8.3 0 (0)

.32 .14 .71 .60 .78

83 (73.4) 30 (26.6) 10.5 þ 2.8 1,946 þ 781 284 þ 196 13.4 þ 8.8 4 (3.5) 2 (1.8) 22 (19.5) 22 (19.5) 2 (1.8)

12 (70.6) 5 (29.4) 10.4 þ 2.7 1,948 þ 986 338 þ 161 17.8 þ 22.0 1 (5.9) 0 (0) 4 (23.5) 5 (29.4) 0 (0)

.90 .99 .29 .14 .51 1.00 .75 .35 1.00

* The data are presented as mean þ SD for continuous variables and numbers (%) for categorical variables

MELD, model for end-stage liver disease; TIPS, transjugular intrahepatic portosystemic shunting.

Graft failure, total Primary nonfunction Infection or/and multiple organ failure Hepatic artery thrombosis Biliary complication Rejection Malignancy Recurrence of primary liver disease Cardiac event Cerebrovascular event Other

5

32 (24.6) 1 (0.8) 10 (7.7) 0 (0) 0 (0) 2 (1.5) 6 (4.6) 1 (0.8) 6 (4.6) 1 (0.8) 5 (3.9)

.52 .07 .79 1.00 NA .26 .45 .28 .19 .67 .17

TIPS transjugular intrahepatic portosystemic shunting * The data are presented as numbers (%) for categorical variables

survival at 1 year was 91.2% for patients without TIPS malposition but 70.6% for the patients with TIPS malposition (P ¼ .01) (Fig 3, A). The overall patient survival at 1 year was 92.0% for the patients without TIPS malposition and 70.6% for the patients with TIPS malposition (P ¼ .01) (Fig 3, B). The cause of graft loss or patient death is shown in Table VII.

Discussion In the current study, we analyzed LT data from a single center to determine the influence of earlier TIPS placement on surgical and graft outcomes including graft hemodynamics using propensity score matching. In this, the largest study of its kind, we found that pretransplant TIPS placement did not impair operative outcomes and graft survival for LT patients. Furthermore, the graft portal flow of patients with TIPS was greater than that of patients without TIPS, and multivariate analysis revealed that pretransplant TIPS

placement was independently associated with increased graft portal flow. Of note, however, the patients with TIPS malposition demonstrated poorer graft and patient survival compared with those without TIPS malposition. Earlier studies have reported the effect of TIPS on LT outcomes. Guerrini et al6 reported that patients with TIPS had a lesser risk of mortality 1 year after LT compared with those without TIPS.6 In contrast, other studies found no difference in terms of graft outcomes.7-9,18 These conflicting results might be attributed to the heterogeneity of baseline patient characteristics without propensity score matching. Patients who underwent TIPS before LT were potentially sicker than those who did not undergo TIPS. In our cohort, before propensity score matching, underlying liver disease was more severe in patients with TIPS compared with those without TIPS, as characterized by greater MELD scores, greater serum bilirubin levels, and lesser platelet counts. In addition, the presence of hepatocellular carcinoma or hepatitis C virus, which negatively affects graft survival, was observed less frequently in patients with TIPS. Although there were no differences in terms of operative time and blood transfusion requirements, malposition or migration of a TIPS stent into the suprahepatic vena cava, right atrium, or main portal vein potentially complicates native hepatectomy and graft implantation.19-22 In our cohort, malposition of TIPS was seen in 13.1% of patients. Although all misplaced stents were removed successfully, intimal damage of vessels where TIPS stents were located was of concern. Although the poor quality of these veins potentially increases the risk of anastomotic thrombosis, our results demonstrated that patients with TIPS had a similar incidence of venous anastomotic thrombosis compared with those without TIPS. The similar thrombotic risk may be that patients with TIPS had greater portal flows, which may have neutralized the risk of portal vein thrombosis. In cases of severe damage to the main portal vein, however, the use of an interposition vein graft should be considered.23 In our study, patients with TIPS demonstrated greater intraoperative cardiac output and graft portal flow. TIPS placement alters both portal and systemic hemodynamics in patients with cirrhosis. Diversion of portal blood flow to the systemic venous

6

H. Matsushima et al. / Surgery xxx (2020) 1e7 Table VII Causes of graft failure or patients death in patients with TIPS*

Primary nonfunction Infection or/and multiple organ failure Hepatic artery thrombosis Biliary complication Rejection Malignancy Recurrence of primary liver disease Cardiac event Cerebrovascular event Other

TIPS (n ¼ 113)

TIPS malposition (n ¼ 17)

P

1 7 0 0 1 6 1 4 1 5

0 3 0 0 1 0 0 2 0 0

1.00 .12 NA NA .25 1.00 1.00 .18 1.00 1.00

(0.9) (6.2) (0) (0) (0.9) (5.3) (0.9) (3.5) (0.9) (4.4)

(0) (17.7) (0) (0) (5.9) (0) (0) (11.8) (0) (0)

TIPS, transjugular intrahepatic portosystemic shunting. * The data are presented as numbers (%) for categorical variables

Fig 3. Kaplan-Meier curves for graft and patient survival in patients with or without TIPS malposition. (A) The 1-y graft survival of patients with TIPS malposition was worse than those without TIPS malposition (P ¼ .01). (B) The 1-y survival of patients with TIPS malposition was worse than those without TIPS malposition (P ¼ .01).

system further promotes a hyperdynamic status, as characterized by an increase of cardiac output and a decrease in peripheral vascular resistance.12,24,25 Lotterer et al12 reported that gastroesophageal collateral flow decreases as portal vein pressure decreases after TIPS placement. Similarly, our study confirmed that pretransplant TIPS placement helps secure sufficient portal flow into the liver graft. In our study cohort, the rate of venovenous bypass used during LT was similar between the TIPS group and the no-TIPS group. Decompression of venous collaterals can cause congestion of the gastrointestinal tract and hypotension during portal clamping. During our center’s early experience, from 2007 to 2010, venovenous bypass was used frequently to maintain systemic hemodynamics in patients with TIPS. As we gained experience, the majority of patients were transplanted successfully without the use of venovenous bypass. Although our center does not use a temporary portocaval shunt during the anhepatic phase, the creation of a temporary shunt might help prevent bowel congestion and hypotension, as other studies have advocated.26,27 In subgroup analysis according to TIPS malposition, patients with malpositioned TIPS had statistically significantly lesser graft and patient survivals compared with those without malposition. Similarly, Guerrini et al6 reported that 5-year graft survival was 58.5% in patients with malpositioned TIPS, and 5-year graft survival was 78.3% in patients without TIPS malposition. Although our study

did not observe an association between TIPS malposition and risk of vascular complication after liver transplantation, malposition apparently increases the complexity of transplantation.19,20,28-30 In fact, 1 of our patients with a malpositioned TIPS required extensive dissection of suprahepatic vena cava and right atrium to extract the stent (Fig 1, A). Although no patients experienced technical failure such as unrepairable vascular injury, unfavorable consequences with TIPS malposition should not be underestimated. This study has several limitations. First, this is a retrospective study, and there were differences in patient characteristics between the patients who underwent TIPS and those who did not undergo TIPS. Therefore, propensity score matching was performed to minimize a selection bias, although propensity score matching can also have limitations depending on the parameters chosen to match. Second, we found a statistically significant association between pretransplant TIPS placement and graft portal flow. Although these findings could be explained by decompression of portosystemic shunts as discussed earlier in this report, the alteration of shunts after TIPS placement was not evaluated. Recognition of graft hemodynamics in patients who underwent pretransplant TIPS placement, however, may be helpful in surgical planning, because graft portal flow is an important prognostic factor in LT.31-33 In conclusion, our findings indicate that pretransplant TIPS placement is associated with increased graft portal flow and does not compromise surgical outcomes of subsequent LT. It should be noted, however, that malposition of TIPS is not uncommon and may increase the complexity of transplantation. Funding/Support The authors declare that no funding/financial support was received. Conflict of interest/Disclosures The authors declare no conflict of interests. Acknowledgments The authors would like to acknowledge Ms. Sally Garrett Karyo for her editorial assistance. Supplementary data Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.1016/j.surg.2020. 02.017.

H. Matsushima et al. / Surgery xxx (2020) 1e7

References 1. Kim WR, Lake JR, Smith JM, et al. OPTN/SRTR 2016 Annual Data Report: liver. Am J Transplant. 2018;18(Suppl 1):172e253. 2. Imperiale TF, Chalasani N. A meta-analysis of endoscopic variceal ligation for primary prophylaxis of esophageal variceal bleeding. Hepatology. 2001;33: 802e807. 3. Garcia-Pagan JC, Caca K, Bureau C, et al. Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med. 2010;362:2370e2379. 4. Berry K, Lerrigo R, Liou IW, Ioannou GN. Association between transjugular intrahepatic portosystemic shunt and survival in patients with cirrhosis. Clin Gastroenterol Hepatol. 2016;14:118e123. 5. Tripathi D, Therapondos G, Redhead DN, Madhavan KK, Hayes PC. Transjugular intrahepatic portosystemic stent-shunt and its effects on orthotopic liver transplantation. Eur J Gastroenterol Hepatol. 2002;14:827e832. 6. Guerrini GP, Pleguezuelo M, Maimone S, et al. Impact of tips preliver transplantation for the outcomes posttransplantation. Am J Transplant. 2009;9: 192e200. 7. Levi Sandri GB, Lai Q, Lucatelli P, et al. Transjugular intrahepatic portosystemic shunt for a wait list patient is not a contraindication for orthotopic liver transplant outcomes. Exp Clin Transplant. 2013;11:426e428. 8. Barbier L, Hardwigsen J, Borentain P, et al. Impact of transjugular intrahepatic portosystemic shunting on liver transplantation: 12-year single-center experience. Clin Res Hepatol Gastroenterol. 2014;38:155e163. 9. Mumtaz K, Metwally S, Modi RM, et al. Impact of transjugular intrahepatic porto-systemic shunt on post liver transplantation outcomes: study based on the United Network for Organ Sharing database. World J Hepatol. 2017;9: 99e105. 10. Toomey PG, Ross SB, Golkar FC, et al. Outcomes after transjugular intrahepatic portosystemic stent shunt: a “bridge” to nowhere. Am J Surg. 2013;205: 441e446. 11. Buechter M, Manka P, Theysohn JM, Reinbolt M, Canbay A, Kahraman A. Spleen stiffness is positively correlated with HVPG and decreases significantly after TIPS implantation. Dig Liver Dis. 2018;50:54e60. 12. Lotterer E, Wengert A, Fleig WE. Transjugular intrahepatic portosystemic shunt: short-term and long-term effects on hepatic and systemic hemodynamics in patients with cirrhosis. Hepatology. 1999;29:632e639. 13. Stankovic Z, Rossle M, Euringer W, et al. Effect of TIPS placement on portal and splanchnic arterial blood flow in 4-dimensional flow MRI. Eur Radiol. 2015;25: 2634e2640. 14. Hashimoto K, Miller CM, Quintini C, et al. Is impaired hepatic arterial buffer response a risk factor for biliary anastomotic stricture in liver transplant recipients? Surgery. 2010;148:582e588. 15. Matsushima H, Fujiki M, Sasaki K, et al. Predictive value of hepatic venous pressure gradient for graft hemodynamics in living donor liver transplantation. Liver Transpl. 2019;25:1034e1042. 16. Quintini C, D’Amico G, Brown C, et al. Splenic artery embolization for the treatment of refractory ascites after liver transplantation. Liver Transpl. 2011;17:668e673. 17. Presser N, Quintini C, Tom C, et al. Safety and efficacy of splenic artery embolization for portal hyperperfusion in liver transplant recipients: a 5-year experience. Liver Transpl. 2015;21:435e441.

7

18. Pateria P, Jeffrey GP, Garas G, et al. Tranjugular intrahepatic portosystemic shunt: indications, complications, survival and its use as a bridging therapy to liver transplant in Western Australia. J Med Imaging Radiat Oncol. 2017;61: 441e447. 19. Khan TT, Reddy KS, Johnston TD, et al. Transjugular intrahepatic portosystemic shunt migration in patients undergoing liver transplantation. Int Surg. 2002;87: 279e281. 20. Rumi MN, Schumann R, Freeman RB, Rohrer RJ, Fairchild RB. Acute transjugular intrahepatic portosystemic shunt migration into pulmonary artery during liver transplantation. Transplantation. 1999;67:1492e1494. 21. Salvalaggio PR, Koffron AJ, Fryer JP, Abecassis MM. Liver transplantation with simultaneous removal of an intracardiac transjugular intrahepatic portosystemic shunt and a vena cava filter without the utilization of cardiopulmonary bypass. Liver Transpl. 2005;11:229e232. 22. Clavien PA, Selzner M, Tuttle-Newhall JE, Harland RC, Suhocki P. Liver transplantation complicated by misplaced TIPS in the portal vein. Ann Surg. 1998;227:440e445. 23. Farney AC, Gamboa P, Payne WD, Gruessner RW. Donor iliac vein interposition during liver transplantation in a patient with a migrated transjugular intrahepatic portosystemic shunt. Transplantation. 1998;65:572e574. 24. Azoulay D, Castaing D, Dennison A, Martino W, Eyraud D, Bismuth H. Transjugular intrahepatic portosystemic shunt worsens the hyperdynamic circulatory state of the cirrhotic patient: preliminary report of a prospective study. Hepatology. 1994;19:129e132. 25. Rodriquez-Laiz JM, Banares R, Echenaqusia A, et al. Effects of transjugular intrahepatic portasystemic shunt (TIPS) on splanchnic and systemic hemodynamics, and hepatic function in patients with portal hypertension. Preliminary results. Dig Dis Sci. 1995;40:2121e2127. 26. Figueras J, Llado L, Ramos E, et al. Temporary portocaval shunt during liver transplantation with vena cava preservation. Results of a prospective randomized study. Liver Transpl. 2001;7:904e911. 27. Margarit C, de Cenarruzabeitia I, Lazaro J, et al. Portocaval shunt and inferior vena cava preservation in orthotopic liver transplantation. Transplant Proc. 2005;37:3896e3898. 28. Goldberg MS, Weppler D, Khan FA, et al. Dose transjugular intrahepatic portosystemic shunting facilitate or complicate liver transplantation? Transplant Proc. 1997;29:557e559. 29. Meyer C, Odeh M, Herrera JJ, et al. Orthotopic liver transplantation with a suprahepatic vena caval anastomosis over a transjugular intrahepatic portosystemic shunt. J Am Coll Surg. 1998;187:217e220. 30. Hutchins RR, Patch D, Tibballs J, Burrouqhs A, Davidson BR. Liver transplantation complicated by embedded transjugular intrahepatic portosystemic shunt: a new method for portal anastomosis- a surgical salvage procedure. Liver Transpl. 2000;6:237e238. 31. Troisi R, Cammu G, Militerno G, et al. Modulation of portal graft flow: a necessity in adult livingdDonor liver transplantation? Ann Surg. 2003;237:429e436. 32. Spitzer AL, Dick AA, Bakthavatsalam R, et al. Intraoperative portal vein blood flow predicts allograft and patient survival following liver transplantation. HPB (Oxford). 2010;12:166e173. 33. Matsushima H, Sasaki K, Fujiki M, et al. Too much, too little, or just right? The importance of allograft portal flow in deceased donor liver transplantation [e-pub ahead of print]. Transplantation. https://doi.org/10.1097/TP. 0000000000002968, Accessed September 18, 2019