ORIGINAL ARTICLE. Mauricio Sainz-Barriga, 1 Luigia Scudeller, 2 Maria Gabriella Costa, 3 Bernard de Hemptinne, 1 and Roberto Ivan Troisi 1

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1 LIVER TRANSPLANTATION 17: , 2011 ORIGINAL ARTICLE Lack of a Correlation Between Portal Vein Flow and Pressure: Toward a Shared Interpretation of Hemodynamic Stress Governing Inflow Modulation in Liver Transplantation Mauricio Sainz-Barriga, 1 Luigia Scudeller, 2 Maria Gabriella Costa, 3 Bernard de Hemptinne, 1 and Roberto Ivan Troisi 1 1 Department of General and Hepatobiliary Surgery, Liver Transplantation Service, Ghent University Hospital and Medical School, Ghent, Belgium; 2 Clinical Epidemiology and Biometric Unit, IRCCS Policlinico San Matteo, Pavia, Italy; and 3 Clinic of Anesthesia and Intensive Care Medicine, Department of Clinical and Experimental Medical Sciences, Medical School of the University of Udine, Udine, Italy The portal vein flow (PVF), portal vein pressure (PVP), and hepatic venous pressure gradient (HVPG) were prospectively assessed to explore their relationships and to better define hyperflow and portal hypertension (PHT) during liver transplantation (LT). Eighty-one LT procedures were analyzed. No correlation between PVF and PVP was observed. Increases in the central venous pressure (CVP) were transmitted to the PVP (58%, range ¼ 25%-91%, P ¼ 0.001). Severe PHT (HVPG 15 mm Hg) showed a significant reciprocal association with high PVF (P ¼ 0.023) and lower graft survival (P ¼ 0.04). According to this initial experience, an HVPG value 15 mm Hg is a promising tool for the evaluation of hemodynamic stress potentially influencing outcomes. An algorithm for graft inflow modulation based on flows, gradients, and systemic hemodynamics is provided. In conclusion, the evaluation of PHT severity with PVP could be delusive because of the influence of CVP. PVF and PVP do not correlate and should not be used individually to assess hyperflow and PHT during LT. Liver Transpl 17: , VC 2011 AASLD. Received September 16, 2010; accepted February 26, The liver has no active role in regulating portal inflow; this function is provided by resistance vessels at the splanchnic arteriolar level. Hence, the liver is a passive recipient of fluctuating blood flows. The large capacity of the splanchnic venous system can encompass a wide range of portal vein flows (PVFs) with minimal effects on the pressure in the portal system [ie, the portal vein pressure (PVP)]. 1-4 However, veins have limited elasticity once they are fully distended, and at this point, PVP increases rapidly with increased volume. 5 After liver transplantation (LT), PVF increases to double the flow observed in healthy subjects because of the loss of normal vascular tone and the persistence of abnormal splanchnic hemodynamics. 6-9 This increased PVF can reduce the hepatic artery flow (HAF) through an intrahepatic arterial buffer response In fact, in clinical LT, the PVF/ HAF ratio increases after reperfusion, and in more than half of cases, PVF accounts for 93% of the total liver flow. 9 As for partial liver grafts, the blood flow Abbreviations: AST, aspartate aminotransferase; cpht, clinical portal hypertension; CVP, central venous pressure; DRI, donor risk index; Epi, epinephrine; FS, full size; GGT, gamma-glutamyl transpeptidase; GIM, graft inflow modulation; GRWR, graft-torecipient weight ratio; HAF, hepatic artery flow; HVPG, hepatic venous pressure gradient; IQR, interquartile range; I/R, ischemia/ reperfusion; LDC, low-dose catecholamine; LT, liver transplantation; LW, liver weight; MAP, mean arterial pressure; Ne, norepinephrine; PCS, portocaval shunt; PGI 2, prostacyclin; PHT, portal hypertension; POD, postoperative day; PV, portal vein; PVF, portal vein flow; PVP, portal vein pressure; SA, splenic artery; SAL, splenic artery ligation. Address reprint requests to Roberto Ivan Troisi, M.D., Ph.D. Liver Transplantation Service, Department of General and Hepatobiliary Surgery, Ghent University Hospital and Medical School, De Pintelaan 185, 9000 Ghent, Belgium. Telephone: þ ; FAX: þ ; roberto.troisi@ugent.be DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases VC 2011 American Association for the Study of Liver Diseases.

2 LIVER TRANSPLANTATION, Vol. 17, No. 7, 2011 SAINZ-BARRIGA ET AL. 837 that the liver has to accommodate is further increased because the vascular bed of such grafts is reduced. Indeed, higher intraoperative and postoperative PVPs have been significantly correlated with lower graft weights 13 ; likewise, in small partial liver grafts, portal hyperperfusion or high PVPs have been associated with increased cholestasis and reduced graft survival To overcome this hemodynamic stress, the use of PVF or PVP to tailor graft inflow modulation (GIM) surgical techniques in living donor LT has been reported. 13,18-21 The goal of GIM is to improve the function and outcome through a reduction of excessive hyperflow to the liver without deterioration of liver function or, in partial liver grafts, without hindering regeneration by excessive shunting By reducing PVF, we can obtain a concomitant improvement in HAF. 19 The PVP threshold for GIM in LT has not been established yet but seems to be between 15 and 20 mm Hg. 13,20,25 Additionally, the superior risk flow margin appears to be 4 times the flows measured in healthy subjects [360 ml minute g of liver weight (LW) 1 ]. 16 Although grafts of different types and qualities may tolerate higher PVFs, full size (FS) grafts have shown a median flow of 130 ml minute g of LW 1 after reperfusion, whereas the median flow observed in partial liver grafts has been higher at 180 ml minute g of LW 1. 9 The aims of this study were to explore the relationships between PVF, PVP, and hepatic venous pressure gradient (HVPG) values during LT and to better define hyperflow and portal hypertension (PHT) during LT. PATIENTS AND METHODS We performed an analysis of 81 LT procedures performed in 77 patients with 65 FS grafts (80.2%) and 16 partial grafts (19.8%) from September 2007 to September After institutional board review (approval number 2007/292), informed consent was obtained from all adult LT candidates when their eligibility for transplantation was confirmed. In this prospective study, all types of indications (acute and chronic end-stage liver diseases) and grafts (whole and partial) were included. Clinical evidence of PHT [ie, clinical portal hypertension (cpht)], such as splenomegaly, a transjugular intrahepatic portosystemic shunt, grade 2 to 3 esophageal varices, and refractory ascites, was assessed before LT. 26 The presence of these parameters is in most cases compatible with clinically significant PHT The anesthetic management was standardized. All recipients were in a supine position during flow and pressure measurements; the zero reference was at the midaxillary line. Surgical Technique The caval vein was preserved in all cases. An end-toside temporary portocaval shunt (PCS) was routinely applied to drain splanchnic blood during total hepatectomy and was removed during engraftment after the completion of the caval anastomosis. All types of grafts were implanted with a broad end-to-side cavocaval anastomosis technique An end-to-end arterial reconstruction was performed in most cases. Other technical variations have been previously described. 19,21,33,34 Intraoperative Hepatic Flow Measurements The protocol has been previously described in detail. 9 In short, serial HAF and PVF readings were taken under stable conditions after portal and arterial reperfusion with ultrasound transit time flow measurements. We used different probe sizes to better fit the vessel diameters, which ranged from 2 to 12 mm. The average flow values (ml minute 1 ) were determined. At the same time, PVP was measured by direct puncture of the portal vein (PV) with a 25-gauge needle after the absence of air in the tubing and the establishment of the zero level at the height of the PV were ascertained. Before each measurement, the set was flushed again, and the zero level was checked for drifting. HAF, PVF, and PVP were simultaneously recorded (VeriQ 4122, MediStim ASA, Oslo, Norway). We used the central venous pressure (CVP), which was measured at the same time as PVP, to calculate HVPG (HVPG ¼ PVP CVP). PVP was measured at the origin of the recipient PV proximally to the anastomosis. When HVPG was 10 mm Hg, a second measurement was taken distally to the PV anastomosis to exclude the presence of stenosis if flow or pressure gradients were absent. Concomitantly, a Doppler ultrasound assessment of the hepatic venous outflow was performed to exclude a compromised outflow (ProSound SSD-4000, Aloka NV/SA, Mechelen, Belgium). To avoid the misinterpretation of data and the bias due to the different sizes and types of grafts, we defined liver perfusion as the amount of flow normalized by LW (ml minute g of LW 1 ). In a previous prospective study, 9 we identified the median PVF values to be 130 ml minute g of LW 1 (range ¼ ml minute g of LW 1 ) for FS grafts and 180 ml minute g of LW 1 (range ¼ ml minute g of LW 1 ) for partial liver grafts. Taking into account the expected better quality of the grafts used for partial LT and our previous flow results, we divided the patients into 2 groups: patients with FS grafts (the FS group) and patients with partial grafts (the partial graft group). The FS group included 59 FS grafts from deceased donors and 6 donation after cardiac death grafts, whereas the partial graft group included 12 split liver grafts and 4 living donor grafts. The donor warm ischemia times for the donation after cardiac death grafts were not included in the warm ischemia times for the FS grafts. For the outcome analysis, all patients were categorized according to PVF (3 groups: <90, 90 to <270, and 270 ml minute g of LW 1 ), PVP (3 groups: <15, 15 to <20, and 20 mm Hg), and HVPG values (3 groups: <10, 10 to <15, and 15 mm Hg). Liver Tests The peak aspartate aminotransferase (AST) level as a marker of ischemia/reperfusion (I/R) injury and the

3 838 SAINZ-BARRIGA ET AL. LIVER TRANSPLANTATION, July 2011 TABLE 1. Study Population FS Grafts Partial Grafts Overall (n ¼ 81) (n ¼ 65)* (n ¼ 16) P Value Recipient characteristics Male gender 57 (70%) 48 (74%) 9 (56%) 0.22 Age (years) 60 ( ) 59 ( ) 61 (53-65) 0.61 cpht 67 (83%) 57 (88%) 10 (63%) Indication for LT Alcohol 30 (37%) 26 (40%) 4 (25%) 0.85 Cirrhosis 30 (37%) 22 (34%) 8 (50%) Secondary biliary cirrhosis 6 (7%) 5 (8%) 1 (6%) Acute hepatic failure 5 (6%) 4 (6%) 1 (6%) Cholestatic 3 (4%) 3 (5%) 0 Other 7 (9%) 5 (8%) 2 (13%) Lab Model for End-Stage Liver Disease score 16 ( ) 17 (11-24) 13 (9-16.7) Donor characteristics Male gender 47 (58%) 38 (58%) 9 (56%) 1 Age (years) 45 (29-53) 47 (33-54) 29 ( ) Intensive care unit stay > 7 days 13 (16%) 10 (15%) 3 (19%) 0.96 DRI Macrosteatosis (%) 4 (0-6.3) 4 (0-10) 0 (0-5) 0.53 Body mass index (kg/m 2 ) 24 (22-26) 24 ( ) 23 ( ) 0.35 University of Wisconsin solution 55 (67.9%) 47 (72.3%) 8 (50%) 0.13 Histidine tryptophan ketoglutarate solution 26 (32.1%) 18 (27.7%) 8 (50%) Intraoperative and graft characteristics Cold ischemia time (minutes) 495 ( ) 490 ( ) 526 ( ) 0.49 Warm ischemia time (minutes) 45 (35-60) 45 (33-55) 52 (35-75) 0.23 Operation time (minutes) 540 ( ) 510 ( ) 615 ( ) Graft weight (mg) < GRWR < Graft volume to standard liver volume ratio (%) < NOTE: The results are presented as numbers and percentages, medians and IQRs, or means and SDs. *FS LT and donation after cardiac death. Living donor LT and split LT. Four living donors were excluded from the analysis. serum bilirubin and gamma-glutamyl transpeptidase (GGT) levels as markers of cholestasis were collected during the first postoperative month. Thirty-two LT procedures (39.5%) were excluded solely from the laboratory comparative data analysis whenever one of the following circumstances arose during the first month after transplantation: early biliary complications (n ¼ 8), acute cellular rejection (n ¼ 7), donation after cardiac death (n ¼ 6), hepatic artery stenosis or thrombosis (n ¼ 5), graft failure or patient death (n ¼ 4), and sepsis (n ¼ 2). Statistical Analysis Unless otherwise specified, values are expressed as means and standard deviations for normally distributed variables and as medians and interquartile ranges (IQRs) in other cases. Comparisons of recipient, donor, and operative characteristics between groups were made with the Mann-Whitney test for continuous variables (the Kruskall-Wallis test was used for more than 2 groups) and with Fisher s exact test for categorical data. The Pearson correlation coefficient (or the Spearman correlation coefficient for nonnormal distributions) was calculated to assess correlations of (1) the graft-to-recipient weight ratio (GRWR) with PVP and HVPG, (2) PVF with PVP and HVPG, and (3) CVP with PVP. Graft survival was estimated according to the Kaplan-Meier method (for deaths not due to graft failure, grafts were censored at patients deaths). Linear regression in univariate and multivariate models was used to explore factors influencing flows, pressures, and gradients. Statistical analysis was performed with Stata 11 for Windows and with GraphPad Prism 5.0c for Macintosh. RESULTS Study Population Recipient, donor, and intraoperative characteristics are reported in Table 1. FS graft recipients and partial graft recipients were comparable except for a greater frequency of cpht in the FS group versus the partial graft group (88% versus 63%, P ¼ 0.027). The donor risk index (DRI) penalized partial liver grafts; this was shown by the higher index values for this group (2.13

4 LIVER TRANSPLANTATION, Vol. 17, No. 7, 2011 SAINZ-BARRIGA ET AL. 839 TABLE 2. Systemic and Hepatic Hemodynamics During LT Overall (n ¼ 81) (n ¼ 65) (n ¼ 16) P Value Systemic hemodynamics CVP (mm Hg) 8 (6-10) 8 (6-10) 8.5 (6.8-10) 0.8 MAP (mm Hg) 70 (62-77) 68 ( ) 77 ( ) Hepatic hemodynamics HAF (ml minute 1 ) 205 ( ) 249 ( ) 112 ( ) HAF (ml minute g of LW 1 ) 15.6 ( ) 16 (8.2-23) 14.1 (8.5-19) 0.5 PVF (ml minute 1 ) 1621 ( ) 1690 ( ) 1618 ( ) 0.3 PVF (ml minute g of LW 1 ) 122 (77-171) ( ) ( ) PVP (mm Hg) 15 (12-18) 15 ( ) 15.5 ( ) 0.9 HVPG (mm Hg)* 7 (4-10) 7 (4-9.6) 6.9 (5-10.3) 0.69 Portal blood flow to arterial 7.7 ( ) 6.6 ( ) 15.4 (7-20.6) blood flow ratio NOTE: The results are expressed as medians and IQRs. *HVPG ¼ PVP CVP. FS Grafts Partial Grafts for the partial graft group versus for the FS group, P ¼ ; 4 living donors were excluded from the DRI calculation for the partial graft group). As expected, the graft weights, GRWRs, and graft volume to standard liver volume ratios were higher in the FS group. Transplant Population Flow, Pressure, and Gradient Distributions Hepatic hemodynamics and systemic hemodynamics were simultaneously measured approximately 90 minutes after graft revascularization for the whole data set. This time was longer for partial grafts (120 minutes, IQR ¼ minutes) versus FS grafts (81 minutes, IQR ¼ minutes, P ¼ 0.009). The results are reported in Table 2. When PVF was indexed by the graft weight, significantly higher perfusion was observed in partial grafts versus FS grafts (168.5 versus ml minute g of LW 1, P ¼ 0.023). Conversely, the median HAF measurement for FS grafts was twice the measurement for partial grafts (249 versus 112 ml minute 1, P ¼ 0.001). The median HVPG value after reperfusion was 7 mm Hg (IQR ¼ 4-10 mm Hg), and this showed persistent PHT with which the newly grafted liver had to comply. No difference between flow and pressure measurements proximal or distal to the PV anastomosis was observed in any high-hvpg cases. Likewise, all Doppler ultrasound hepatic vein controls showed excellent pulsatility and backflow (triphasic waveform) in the spectral tracing. Relationship Between PVF, PVP, and HVPG No correlation was found between PVF and PVP (Fig. 1A,B) or between PVF and HVPG (Fig. 1C,D). PVPs 20 mm Hg were found for 19.7% of the patients (16/81). Noticeably, 25% of these patients (4/16) had low PVFs (<90 ml minute g of LW 1 ). The same low PVFs were observed in 27.3% of the patients (12/44) with PVPs 15 mm Hg. High PVFs were observed in 3% of the patients (2/65) with PVPs < 20 mm Hg. In the group with HVPGs 15 mm Hg, only 1 patient had a low PVF (14.3% or 1/7), whereas none of the patients with HVPGs < 15 mm Hg had high PVFs (Fig. 1D). The results of linear regression in univariate and multivariate models are presented in Table 3. In the univariate analysis, the DRI showed an association with higher PVPs (P ¼ 0.036). CVP increases were transmitted to the PVP (58%, range ¼ 25%-91%, P ¼ 0.001). In the multivariate analysis, cpht showed a significant association with higher PVPs (P ¼ 0.009) and a trend toward higher HVPGs (P ¼ 0.08). Partial grafts were associated only with higher PVF values (P ¼ 0.004) and not with PVP or HVPG (P ¼ 0.89 and P ¼ 0.9, respectively). PVFs 270 ml minute g of LW 1 showed an association with higher HVPGs (P ¼ 0.04). Reciprocally, HVPGs 15 mm Hg showed an association with higher PVFs (P ¼ 0.023). Hyperflow and PHT No correlation between GRWR and PVP was found (FS grafts: r ¼ 0.19, P ¼ 0.12; partial grafts: r ¼ 0.109, P ¼ 0.68). Smaller FS grafts showed a correlation with higher HVPGs (FS grafts: r ¼ 0.303, P ¼ 0.014; partial grafts: r ¼ 0.25, P ¼ 0.33). Four patients (4.9%) had high PVFs (270 ml minute g of LW 1 ); 2 (12.5%) received partial liver grafts, and 2 (3.1%) received FS grafts (P ¼ 0.36; Fig. 1). Only 1 patient who underwent transplantation with a partial graft presented with hyperflow (360 ml minute g of LW 1 ). Exceptionally, no GIM was performed in this patient because we deemed the HAF value to be adequate (>100 ml minute 1 ) with correct hepatic venous outflow. Eighty-three percent of the patients (67/81) had a diagnosis of cpht. The mean spleen diameter of the cpht patients indicated splenomegaly (>13 cm) and

5 840 SAINZ-BARRIGA ET AL. LIVER TRANSPLANTATION, July 2011 Figure 1. Relationship between PVP, PVF and HVPG (HVPG ¼ PVP CVP). No correlation was found (A) between the portal pressure and the portal flow (FS grafts: r ¼ 0.13, P ¼ 0.33; partial grafts: r ¼ 0.31, P ¼ 0.2), (B) between the portal pressure and the portal perfusion (FS grafts: r ¼ 0.15, P ¼ 0.22; partial grafts: r ¼ 0.48, P ¼ 0.058), (C) between the hepatic venous gradient and the portal flow (FS grafts: r ¼ 0.08, P ¼ 0.5; partial grafts: r ¼ 0.19, P ¼ 0.48), or (D) between the hepatic venous gradient and the portal perfusion (FS grafts: r ¼ 0.13, P ¼ 0.3; partial grafts: r ¼ 0.1, P ¼ 0.68). Solid circles represent partial liver grafts, and open circles represent FS grafts. The lines reflect currently applied threshold levels with clinical relevance for PHT. was significantly larger than the mean diameter of the non-cpht patients ( versus cm, P ¼ ). After revascularization, the proportion of patients with HVPGs 10 mm Hg was 26% (21/81). Thus, 46 of the 67 patients with cpht before LT no longer showed it after LT, and this represented an improvement in PHT immediately after revascularization in 68.6% of the patients (46/67). The distributions of patients with HVPGs 10 mm Hg were similar for the partial graft group (31.2% or 5/16) and the FS group (24.6% or 16/ 65, P ¼ 0.75). Severe PHT (HVPG 15 mm Hg) was observed in 33% of these patients (7/21) and was 3 times more frequent in patients with partial grafts (18.7% or 3/ 16) versus patients with FS grafts (6% or 4/65, P ¼ 0.27). GIM Three LT patients (2 partial grafts and 1 FS graft) underwent splenic artery ligation (SAL) because of low HAF (<100 ml minute 1 ). A successful 60% reduction of PVF was obtained, and this was followed by a 57.2% improvement in HAF. In 1 partial graft, the HVPG value was reduced from 13 to 5 mm Hg. In the other 2 grafts, our previous experience 35 was confirmed: little or no effect of SAL on PVP or HVPG (a stable gradient of 9 mm Hg and a reduction from 7 to 6 mm Hg) was observed. Liver Tests in the PVF, PVP, and HVPG Groups The I/R damage (the peak AST level divided by the graft weight) was compared between the PVF, PVP, and HVPG groups separately for each type of graft (Fig. 2). The highest AST peak was observed in the low-pvf group (<90 ml minute g of LW 1 ), whereas the higher PVF groups displayed lower peaks with both FS and partial grafts (P ¼ and P ¼ 0.21, respectively). This suggests either that greater I/ R damage was responsible for the lower PVFs or, conversely and more likely, that lower flows predisposed the patients to greater I/R damage. Similar results have been observed by others. 36 In Fig. 3, we can see the curves for the total bilirubin levels. A trend toward normalization at the end of the first month after LT was observed in all groups. In the severe PHT group, we observed nonsignificantly higher AST and GGT peaks in the patients with FS grafts (Figs. 2 and 4). This may suggest a combined effect of I/R and HVPG on cholestasis. The evolution of total bilirubin and GGT levels in partial liver grafts paradoxically showed lower cholestasis with high flows and high gradients. Although the beneficial effect of higher flows within safe limits has been previously described, 22,37 the positive effect of higher gradients might resemble the effect of I/R on partial grafts because the groups with higher AST peaks had higher levels of cholestasis (Figs. 2-4). Graft Survival With a median follow-up of 25 months (range ¼ months), the overall 1-year graft survival rate was 93.5%. No significant differences were observed

6 LIVER TRANSPLANTATION, Vol. 17, No. 7, 2011 SAINZ-BARRIGA ET AL. 841 TABLE 3. Linear Regression Analysis of the Variables Influencing PVF, PVP, and HVPG PVF (ml Minute g of LW 1 ) PVP (mm Hg) HVPG (mm Hg)* 95% Confidence Coefficient Interval P Value Coefficient 95% Confidence Interval P Value Coefficient 95% Confidence Interval P Value Univariate analysis cpht (yes versus no) to to to DRI to to to Partial graft versus to to to FS graft Lab Model for End-Stage to to to Liver Disease score Cold ischemia time (minutes) to to to Warm ischemia time (minutes) to to to CVP (mm Hg) to to Not applicable HAF (ml minute 1 ) to to to PVF (ml minute g of LW 1 ) < to to to <270 Not applicable Reference group Reference group to to PVP (mm Hg) <15 Reference group 15 to < to Not applicable Not applicable to HVPG (mm Hg) <10 Reference group 10 to < to Not applicable Not applicable Multivariate analysis cpht (yes versus no) to to to Partial graft versus FS graft to to to Cold ischemia time (minutes) to to to Warm ischemia time (minutes) to to to PVF (ml minute g of LW 1 ) <90 Not applicable to to to <270 Reference group Reference group to HVPG (mm Hg)* <10 Reference group 10 to < to Not applicable Not applicable *HVPG ¼ PVP CVP.

7 842 SAINZ-BARRIGA ET AL. LIVER TRANSPLANTATION, July 2011 Figure 2. I/R damage as AST peak according to the type of graft. The median values of peak aspartate AST levels divided by the graft weight are compared for the flow, pressure, and gradient groups according to the graft type. A significantly higher AST peak was found only in the low-pvf group (<90 ml minute g of LW 1 ) within FS grafts. Boxes represent IQRs, and whiskers represent minimum and maximum values. The number of patients in each group is presented in parentheses. *P ¼ Figure 3. Cholestasis according to the type of graft. The median bilirubin values during the first month after LT are compared for the flow, pressure, and gradient groups according to the graft type. Gray bands represent the normal range of bilirubin values. Circles represent PVF groups (white, <90 ml minute g of LW 1 ; gray, 90 to <270 ml minute g of LW 1 ; black, 270 ml minute g of LW 1 ). Squares represent PVP groups (white, <15 mm Hg, gray, 15 to <20 mm Hg; black, 20 mm Hg). Triangles represent HVPG groups (white, <10 mm Hg; gray, 10 to <15 mm Hg; black, 15 mm Hg).

8 LIVER TRANSPLANTATION, Vol. 17, No. 7, 2011 SAINZ-BARRIGA ET AL. 843 Figure 4. Cholestasis according to the type of graft. The median GGT values during the first month after LT are compared for the flow, pressure, and gradient groups according to the graft type. Gray bands represent the normal range of GGT values. Circles represent PVF groups (white, <90 ml minute g of LW 1 ; gray, 90 to <270 ml minute g of LW 1 ; black, 270 ml minute g of LW 1 ). Squares represent PVP groups (white, <15 mm Hg, gray, 15 to <20 mm Hg; black, 20 mm Hg). Triangles represent HVPG groups (white, <10 mm Hg; gray, 10 to <15 mm Hg; black, 15 mm Hg). between the PVF, PVP, and HVPG groups. Although a trend toward lower graft survival in the severe PHT group (HVPG 15 mm Hg) could be hypothesized (Fig. 5), we experienced 6 graft losses; 2 were late graft losses and were, therefore, unlikely related to hepatic hemodynamics. Graft failure was recorded only in the FS group; details of the 6 graft losses are presented in Table 4. DISCUSSION Figure 5. Estimated graft survival according to HVPG groups. A shorter survival can be hypothesized for those with HVPG levels 15 mm Hg (overall P value ¼ 0.042). The number of patients at risk at time 0, 3 and 6 months are provided. One of the main findings of our study is the lack of a correlation between PVF and PVP. High PVPs (20 mm Hg) were distributed throughout the entire spectrum of flows and perfusions in our study population (Fig. 1A,B). Our results confirm in a prospective way the absence of a correlation between direct PVF measurements and PVP, which has also been observed by others. 37,38 In our view, the lack of a correlation between PVF and PVP raises the question whether any decision regarding the need for modulating graft inflow should require an evaluation of both. Because the SAL and PCS techniques have direct effects on PVF reduction, this also raises the question of graft hypoperfusion. In our study, 25% of the patients with PVPs 20 mm Hg presented low PVF values (<90 ml minute g of LW 1 ) that were inferior than PVF measurements in healthy living donors. 9 In such patients, a decision to decrease PVF could potentially further reduce the portal inflow to the liver and risk hypoperfusion of the graft and, consequently, inferior outcomes. 37,39,40 If we were to apply the PVP threshold of 15 mm Hg, even more patients would be at risk for hypoperfusion. Also, contrary to the experience of Ito et al., 13 no correlation between GRWR and PVP was found. A similar lack of a correlation between the graft weight and PVP in living donor recipients has been observed by other groups. 25,37 The literature for GIM in partial LT abounds with reports on adequate levels of PVP for avoiding damage

9 TABLE 4. Specifics of Graft Failure Cause of Graft Loss Graft Survival (Days) HVPG (mm Hg)* PVP (mm Hg) HAF (ml Minute 1 PVF (ml Minute g of LW 1 ) HAF (ml Minute 1 ) 100 g of LW 1 ) PVF (ml Minute 1 ) Warm Ischemia Time (Minutes) Cold Ischemia Time (Minutes) Donor Age (Years) DRI GRWR Cardiac Index (L/minute/m 2 ) cpht Graft Number Disease Type 1 Cirrhosis FS 4.1 No PV thrombosis and hepatic artery thrombosis 2 Acute hepatic FS 5.4 No I/R and failure cholestasis FS 6.7 Yes Hepatic artery thrombosis 3 Primary sclerosing cholangitis FS 5.6 Yes Ischemic-type biliary lesions 4 Alcoholic cirrhosis FS 4.5 Yes PHT and chronic rejection 5 Alcoholic cirrhosis FS 5.6 Yes Secondary biliary cirrhosis 6 Hepatitis C cirrhosis *HVPG ¼ PVP CVP. Lupus Anticoagulans: risk factor for hepatic artery thrombosis. to liver grafts. An arbitrary PVP threshold of 20 mm Hg was initially proposed for applying GIM according to the higher PVPs observed in the recipients of small living donor grafts (GRWR < 0.8) and their negative influence on patient survival. 13 This threshold has recently been challenged because of failures observed under this cutoff level; after single-center reports, 41 the Kyoto group described the first retrospective series and proposed a PVP threshold of 15 mm Hg. 25 Besides the already mentioned risk of hypoperfusion, our data suggest that high PVFs may be found in 3% of LT patients with PVPs < 20 mm Hg. This could explain the graft failures reported in the literature with PVPs < 20 mm Hg. Such patients may benefit from GIM and will remain unknown if pressures alone are used to make a decision. The relationship between PVF and PVP could be better clarified by Ohm s law, which states that the current equals the voltage difference divided by the resistance. When we relate Ohm s law to fluid flow, the current is the blood flow, the voltage difference is the pressure difference or pressure gradient (HVPG), and the resistance is the resistance to flow offered by the blood vessel and its interactions with the flowing blood (PVF ¼ PVP CVP/resistance). This indicates a linear and proportionate relationship between PVF and PVP that is modulated by CVP. We have observed a significant association between CVP and PVP (Table 3). Similarly to our results, in experimental in vivo studies, 60% of the CVP increase was transmitted to the PVP. 42 When the CVP was markedly elevated, 90% was transmitted to the PVP, and 64% was transmitted to the capsule 43 ; this suggests that the compliance of the capacitance vessels may also be related to the distensibility of the liver tissue because the capacitance vessels cannot enlarge without expansion of the surrounding liver tissue. In this respect, the association between the DRI (a representative marker of graft quality) and PVP is interesting (Table 3). A higher DRI, representing an inferior quality graft, may also identify a higher resistance graft. At any given PVF, an increase in resistance increases the pressure gradient. Partial grafts did not show any association with PVP in this study, and the higher DRI values observed in this particular group (Table 1) should not bring this finding into question. Because of the CVP and graft quality association, the diagnosis of PHT on the basis of PVP could be delusive. Another important finding of our study is the potential role of HVPG in assessing PHT during LT. HVPG takes into account both the upward and downward pressures acting on liver grafts. Furthermore, HVPG is widely used to determine PHT and the risk associated with variceal bleeding in patients with cirrhosis. 28,44,45 In fact, an HVPG value 10 mm Hg characterizes the development of collateral circulation aiming for decompression of the portal system. Above this gradient, splanchnic circulation becomes markedly vasodilated and contributes to the maintenance of increased portal pressure. 28 In our study, 26% of the patients presented this value after revascularization of the liver

10 LIVER TRANSPLANTATION, Vol. 17, No. 7, 2011 SAINZ-BARRIGA ET AL. 845 graft. Patients with cpht showed a trend toward higher HVPGs, and the group with severe PHT showed a reciprocal association with high PVFs in the multivariate linear regression analysis (Table 3). In light of these premises, HVPG could be useful in understanding the risks of hyperflow and PHT during LT. Although HVPGs 10 mm Hg were found to be equally distributed between the FS grafts and the partial grafts, severe PHT was found in 18.7% of the partial graft recipients (ie, 3 times more frequently in comparison with recipients of FS grafts). Indeed, HVPG showed a negative correlation with GRWR. Comparing small partial grafts with FS grafts in a large-animal LT model, Fondevila et al. 46 described significantly higher HVPGs in the partial graft group even in the absence of the hyperdynamic status of cirrhosis. More recently, Botha et al. 47 described the first US multicenter series studying the intentional use of left liver lobes and PCS. A median HVPG value of 17.5 mm Hg (range ¼ mm Hg) was observed after PCS clamping; this pressure was reduced to 5 mm Hg (range ¼ 1-15 mm Hg) after the clamp was released, and the values were similar to our observations. Likewise, with available published data, an HVPG value of 9 mm Hg (IQR ¼ mm Hg) can be calculated in a similar setting. 48 We could hypothesize a trend toward lower graft survival in patients with severe PHT (Fig. 5), although the available evidence of an influence of HVPG on outcomes is still circumstantial. Successful transplantation of small grafts (GRWR < 0.8) with GIM techniques has been reported with HVPGs < 15 mm Hg. 47,48 The single graft lost because of small-for-size syndrome in the aforementioned series had been transplanted into a patient with persistent severe PHT despite the PCS. 47 We have assumed CVP to be comparable to the hepatic vein pressure, although this may not always be true. An underestimation of HVPG due to a high CVP can occur if there is a mechanical obstruction or a high positive end expiratory pressure. 5,49,50 In our study, all measurements were taken in a supine position and under stable systemic hemodynamic conditions, and the positive end expiratory pressure, whenever it was applied, was not greater than 5 mm Hg; this reduced the risk of a pressure gradient between the hepatic veins and the superior vena cava. Moreover, the absence of a pressure gradient in PVPs measured proximally and distally to the PV anastomosis and the triphasic Doppler findings for hepatic veins with high gradients indicated that anastomotic technical problems or outflow insufficiencies were unlikely. Taking all this into account, we believe that the HVPG measurements of our study should provide a real estimate of the pressure gradient that takes place at the sinusoidal level. The lack of a correlation between HVPG and PVF could be a result of flow resistance due to variations in the graft quality, as previously discussed. This resistance is also determined by the sizes of individual vessels (length and diameter) and the organization of the vascular network (series and parallel arrangements), which vary from graft to graft. The reported flows cannot identify variations at the microvascular level. Areas of relative hypoperfusion may lead to turbulent flow, which could explain high HVPGs with low PVFs. Nowadays, the decision to perform GIM relies on the clinical judgment of the surgeon, which is based on subjective parameters such as the coloration and consistency of the graft at reperfusion and is aided by objective measurements of PVF or HVPG. The ideal target PVF for partial grafts has been interpreted to be twice the perfusion observed in the FS graft (260 ml minute g of LW 1 ) and as twice the baseline flows observed in the healthy donor (180 ml minute g of LW 1 ). 9,21 The risk of sinusoidal damage and graft failure rises as we depart further from this ideal value. In a previous report, 16 we identified a superior threshold of 4 times the flows observed in healthy donors (360 ml minute g of LW 1 ) as a risk factor for graft failure; also, flows below the target of 180 ml minute g of LW 1 led to lower survival rates. Recently, the Barcelona group confirmed our previous clinical observations in an experimental model: a PVF value that is twice the baseline value prevents graft dysfunction and the failure of partial grafts, and flows below this target level, as well as hyperflows, lead to lower survival rates. 24 A window of ideal flows is an interesting concept that needs to be confirmed and refined. A graft with homogeneous revascularization that feels soft on palpation (which indicates a compliant graft) and presents with adequate HAF (100 ml minute 1 ) and PVF values (90 to <270 ml minute g of LW 1 according to the graft type) with an HVPG less than 15 mm Hg represents the best case scenario, and a consideration of GIM will not be expected. Likewise, a patient presenting with hyperperfusion (PVF 360 ml minute g of LW 1 ) and severe PHT (HVPG 15 mm Hg) with low HAF (<100 ml minute 1 ) represents the worst case scenario, and there will be a consensus to apply a GIM technique. Controversy will arise when severe PHT with a normal PVF or hyperflow with a normal HVPG occurs. In the case of hyperflow and a normal HVPG, the decision will differ according to the measured HAF. If a correct HAF value is registered, a second reading (eg, after the completion of the biliary anastomosis) will be performed. In most cases, the PVF value will change (360 ml minute g of LW 1 ). If a low HAF value is associated with hyperflow with a normal gradient, after the exclusion of anastomotic problems or hepatic artery spasms, a PV test clamp should be performed. If a progressive increase in the HAF value is observed, the new readings will be stable in all cases within 30 to 60 seconds, and the clamp should be released. In such cases, we will consider a SAL. In Fig. 6, the algorithm currently used in our center to decide whether GIM is needed is presented, and it is based on flows, gradients, and systemic hemodynamics. Flow tailoring implies the measurement of flows and gradients to determine whether a patient may benefit from GIM. If a splenic artery clamping test results in hyperflow or severe PHT relief, SAL can be considered to reduce the original PVF or HVPG. When greater GIM is

11 846 SAINZ-BARRIGA ET AL. LIVER TRANSPLANTATION, July 2011 Figure 6. Algorithm for GIM according to flows, gradients and systemic hemodynamics. The measurements should be performed under stable hemodynamic conditions in the absence of active bleeding. The interpretation of flows and gradients is meaningful if an optimal outflow (represented by a triphasic waveform on duplex ultrasound) can be confirmed. When GIM is being considered, a PVF value < 90 ml minute g of LW 1 should be avoided. Technical failures of the arterial anastomosis, kinking, or arterial spasms should be ruled out before the evaluation of HAF (ml minute 1 ). PVF 4 indicates a PVF value (ml minute g of LW 1 ) greater than 4 times the baseline normal value (360 ml minute g of LW 1 ). The MAP and HVPG values are presented as millimeters of mercury (HVPG ¼ PVP CVP). The LDC (ie, Ne/Epi) dose is 0.05 g kg 1 minute 1. needed, the construction of a PCS will allow for a higher reduction of the initial PVF or HVPG. Furthermore, the measurement of the flows through the shunt and to the liver will allow for calibration through the application of banding to the shunt or to the donor PV. 21 In all these cases, PVF measurements will be required to adequately customize the degree of flow diversion because graft ischemia due to excessive shunting has been reported when PVP alone has been used. 39 It can be argued that normalization of the blood flow to LW may be somewhat misleading. On the contrary, we believe that in order to understand the stress that hyperflow exerts on the liver tissue, perfusion values should be evaluated. Besides their statistical significance, the results have strong clinical significance. Hepatic flows in patients with cirrhosis are increased and are twice the baseline flows observed in healthy subjects. Even normal hepatic blood flows passing through half of a liver (eg, in partial LT) exert greater stress on the liver tissue. Whether such stress is doubled can be debated. We acknowledge that as experience is gained, the proposed high limit of 4 times the baseline flows of healthy donors will be better defined and validated or even deemed not useful. However, the graft weight is only one of the factors to consider. The clinical status of the recipient can increase the hepatic flows, 9 and we have observed in this study a reciprocal correlation between high PVF and severe PHT. Also, the quality of the graft plays a fundamental role in the tolerance of hemodynamic stress, as previously discussed, and this quality is influenced by many variables such as donor characteristics, ischemic times, and I/R. 36,54 One limitation of our study is the small number of partial grafts: the detrimental effects of portal hyperperfusion and hypertension have been extensively studied in partial grafts, and little information is available about their effects on FS grafts. Portal hyperperfusion and hypertension are generally not issues in FS grafts when an optimal outflow is warranted. Nevertheless, when hyperperfusion values (360 ml minute g of LW 1 ) have been present, we have observed histological damage similar to the damage observed in small partial grafts with reduced graft survival. 16 Because of these results, in select FS cases, we consider and perform GIM according to the algorithm described in Fig. 6. According to our experience, flow and gradient measurements during LT are useful and reproducible tools for checking the quality of anastomoses. Concomitantly, we can modify the hemodynamic stress related to portal hyperperfusion and hypertension and improve systemic hemodynamics, especially in patients presenting with established cpht and receiving marginal or partial grafts. The identification of a window of adequate flows and pressures according to graft quality still remains an open question. The recognition of the risk of hemodynamic damage and the tailoring of a solution whenever possible are important. With this study, we have prospectively confirmed the absence of a correlation between PVP and PVF after graft reperfusion. The use of PVP to judge the severity of PHT could be delusive because it is influenced by CVP. Also, relying on PVP alone to determine whether or not GIM is needed does not seem advisable because of the possibility of hypoperfusion or

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