Lack of a Correlation Between Portal Vein Flow and Pressure: Toward a Shared Interpretation of...

ORIGINAL ARTICLE

Lack of a Correlation Between Portal Vein Flowand Pressure: Toward a Shared Interpretation ofHemodynamic Stress Governing InflowModulation in Liver TransplantationMauricio Sainz-Barriga,1 Luigia Scudeller,2 Maria Gabriella Costa,3

Bernard de Hemptinne,1 and Roberto Ivan Troisi11Department of General and Hepatobiliary Surgery, Liver Transplantation Service, Ghent University Hospitaland Medical School, Ghent, Belgium; 2Clinical Epidemiology and Biometric Unit, IRCCS Policlinico SanMatteo, Pavia, Italy; and 3Clinic of Anesthesia and Intensive Care Medicine, Department of Clinical andExperimental 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 prospectivelyassessed to explore their relationships and to better define hyperflow and portal hypertension (PHT) during liver transplanta-tion (LT). Eighty-one LT procedures were analyzed. No correlation between PVF and PVP was observed. Increases in thecentral 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 hemodynamicstress potentially influencing outcomes. An algorithm for graft inflow modulation based on flows, gradients, and systemichemodynamics is provided. In conclusion, the evaluation of PHT severity with PVP could be delusive because of the influ-ence of CVP. PVF and PVP do not correlate and should not be used individually to assess hyperflow and PHT during LT.Liver Transpl 17:836-848, 2011. VC 2011 AASLD.

Received September 16, 2010; accepted February 26, 2011.

The liver has no active role in regulating portal inflow;this function is provided by resistance vessels at thesplanchnic arteriolar level. Hence, the liver is a pas-sive recipient of fluctuating blood flows. The largecapacity of the splanchnic venous system can encom-pass a wide range of portal vein flows (PVFs) withminimal effects on the pressure in the portal system[ie, the portal vein pressure (PVP)].1-4 However, veinshave 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 healthysubjects because of the loss of normal vascular toneand the persistence of abnormal splanchnic hemody-namics.6-9 This increased PVF can reduce the hepaticartery flow (HAF) through an intrahepatic arterialbuffer response.10-12 In fact, in clinical LT, the PVF/HAF ratio increases after reperfusion, and in morethan half of cases, PVF accounts for 93% of the totalliver flow.9 As for partial liver grafts, the blood flow

Abbreviations: AST, aspartate aminotransferase; cPHT, clinical portal hypertension; CVP, central venous pressure; DRI, donor riskindex; Epi, epinephrine; FS, full size; GGT, gamma-glutamyl transpeptidase; GIM, graft inflow modulation; GRWR, graft-to-recipient 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; PGI2, 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: þ32 9332 5519; FAX: þ32 9332 3891;E-mail: [email protected]

DOI 10.1002/lt.22295View 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

LIVER TRANSPLANTATION 17:836–848, 2011

VC 2011 American Association for the Study of Liver Diseases.

that the liver has to accommodate is further increasedbecause the vascular bed of such grafts is reduced.Indeed, higher intraoperative and postoperative PVPshave been significantly correlated with lower graftweights13; likewise, in small partial liver grafts, portalhyperperfusion or high PVPs have been associated withincreased cholestasis and reduced graft survival.14-17

To overcome this hemodynamic stress, the use of PVF orPVP to tailor graft inflowmodulation (GIM) surgical tech-niques in living donor LT has been reported.13,18-21 Thegoal of GIM is to improve the function and outcomethrough a reduction of excessive hyperflow to the liverwithout deterioration of liver function or, in partial livergrafts, without hindering regeneration by excessiveshunting.22-24 By reducing PVF, we can obtain a con-comitant improvement in HAF.19

The PVP threshold for GIM in LT has not been estab-lished yet but seems to be between 15 and 20 mmHg.13,20,25 Additionally, the superior risk flow marginappears to be 4 times the flows measured in healthy sub-jects [�360 mL minute�1 100 g of liver weight (LW)�1].16

Although grafts of different types and qualities may toler-ate higher PVFs, full size (FS) grafts have shown amedianflow of 130 mLminute�1 100 g of LW�1 after reperfusion,whereas the median flow observed in partial liver graftshas been higher at 180 mLminute�1 100 g of LW�1.9

The aims of this study were to explore the relation-ships between PVF, PVP, and hepatic venous pressuregradient (HVPG) values during LT and to better definehyperflow and portal hypertension (PHT) during LT.

PATIENTS AND METHODS

We performed an analysis of 81 LT procedures performedin 77 patients with 65 FS grafts (80.2%) and 16 partialgrafts (19.8%) from September 2007 to September 2009.

After institutional board review (approval number2007/292), informed consent was obtained from alladult LT candidates when their eligibility for transplan-tation was confirmed. In this prospective study, all typesof indications (acute and chronic end-stage liver dis-eases) and grafts (whole and partial) were included.Clinical evidence of PHT [ie, clinical portal hypertension(cPHT)], such as splenomegaly, a transjugular intrahe-patic portosystemic shunt, grade 2 to 3 esophageal vari-ces, and refractory ascites, was assessed before LT.26

The presence of these parameters is in most cases com-patible with clinically significant PHT.27-29

The anesthetic management was standardized. Allrecipients were in a supine position during flow andpressure measurements; the zero reference was at themidaxillary line.

Surgical Technique

The caval vein was preserved in all cases. An end-to-side temporary portocaval shunt (PCS) was routinelyapplied to drain splanchnic blood during total hepatec-tomy and was removed during engraftment after the com-pletion of the caval anastomosis. All types of grafts wereimplanted with a broad end-to-side cavocaval anastomo-

sis technique.30-32 An end-to-end arterial reconstructionwas performed in most cases. Other technical variationshave been previously described.19,21,33,34

Intraoperative Hepatic Flow Measurements

The protocol has been previously described in detail.9 Inshort, serial HAF and PVF readings were taken under sta-ble conditions after portal and arterial reperfusion withultrasound transit time flow measurements. We used dif-ferent probe sizes to better fit the vessel diameters, whichranged from 2 to 12 mm. The average flow values (mLminute�1) were determined. At the same time, PVP wasmeasured by direct puncture of the portal vein (PV) with a25-gauge needle after the absence of air in the tubing andthe establishment of the zero level at the height of the PVwere ascertained. Before each measurement, the setwas flushed again, and the zero level was checked fordrifting. HAF, PVF, and PVP were simultaneouslyrecorded (VeriQ 4122, MediStim ASA, Oslo, Norway).We used the central venous pressure (CVP), which wasmeasured at the same time as PVP, to calculate HVPG(HVPG ¼ PVP � CVP). PVP was measured at the originof the recipient PV proximally to the anastomosis.When HVPG was �10 mm Hg, a second measurementwas taken distally to the PV anastomosis to excludethe presence of stenosis if flow or pressure gradientswere absent. Concomitantly, a Doppler ultrasoundassessment of the hepatic venous outflow was per-formed to exclude a compromised outflow (ProSoundSSD-4000, Aloka NV/SA, Mechelen, Belgium).

To avoid the misinterpretation of data and the biasdue to the different sizes and types of grafts, wedefined liver perfusion as the amount of flow normal-ized by LW (mL minute�1 100 g of LW�1). In a previ-ous prospective study,9 we identified the median PVFvalues to be 130 mL minute�1 100 g of LW�1 (range ¼26.5-433.6 mL minute�1 100 g of LW�1) for FS graftsand 180 mL minute�1 100 g of LW�1 (range ¼ 44.6-342.5 mL minute�1 100 g of LW�1) for partial livergrafts. Taking into account the expected better qualityof the grafts used for partial LT and our previous flowresults, we divided the patients into 2 groups: patientswith FS grafts (the FS group) and patients with partialgrafts (the partial graft group). The FS group included59 FS grafts from deceased donors and 6 donation af-ter cardiac death grafts, whereas the partial graftgroup included 12 split liver grafts and 4 living donorgrafts. The donor warm ischemia times for the dona-tion after cardiac death grafts were not included in thewarm ischemia times for the FS grafts.

For the outcome analysis, all patients were catego-rized according to PVF (3 groups: <90, 90 to <270,and �270 mL minute�1 100 g of LW�1), PVP (3groups: <15, 15 to <20, and �20 mm Hg), and HVPGvalues (3 groups: <10, 10 to <15, and �15 mm Hg).

Liver Tests

The peak aspartate aminotransferase (AST) level as amarker of ischemia/reperfusion (I/R) injury and the

LIVER TRANSPLANTATION, Vol. 17, No. 7, 2011 SAINZ-BARRIGA ET AL. 837

serum bilirubin and gamma-glutamyl transpeptidase(GGT) levels as markers of cholestasis were collectedduring the first postoperative month. Thirty-two LTprocedures (39.5%) were excluded solely from the lab-oratory comparative data analysis whenever one ofthe following circumstances arose during the firstmonth after transplantation: early biliary complica-tions (n ¼ 8), acute cellular rejection (n ¼ 7), donationafter cardiac death (n ¼ 6), hepatic artery stenosis orthrombosis (n ¼ 5), graft failure or patient death (n ¼4), and sepsis (n ¼ 2).

Statistical Analysis

Unless otherwise specified, values are expressed asmeans and standard deviations for normally distrib-uted variables and as medians and interquartileranges (IQRs) in other cases. Comparisons of recipi-ent, donor, and operative characteristics betweengroups were made with the Mann-Whitney test forcontinuous variables (the Kruskall-Wallis test wasused for more than 2 groups) and with Fisher’s exacttest for categorical data. The Pearson correlation coef-

ficient (or the Spearman correlation coefficient fornonnormal distributions) was calculated to assesscorrelations of (1) the graft-to-recipient weight ratio(GRWR) with PVP and HVPG, (2) PVF with PVP andHVPG, and (3) CVP with PVP. Graft survival was esti-mated according to the Kaplan-Meier method (fordeaths not due to graft failure, grafts were censoredat patients’ deaths). Linear regression in univariateand multivariate models was used to explore factorsinfluencing flows, pressures, and gradients. Statisticalanalysis was performed with Stata 11 for Windowsand with GraphPad Prism 5.0c for Macintosh.

RESULTS

Study Population

Recipient, donor, and intraoperative characteristicsare reported in Table 1. FS graft recipients and partialgraft recipients were comparable except for a greaterfrequency of cPHT in the FS group versus the partialgraft group (88% versus 63%, P ¼ 0.027). The donorrisk index (DRI) penalized partial liver grafts; this wasshown by the higher index values for this group (2.13

TABLE 1. Study Population

Overall (n ¼ 81)

FS Grafts

(n ¼ 65)*

Partial Grafts

(n ¼ 16)† P Value

Recipient characteristicsMale gender 57 (70%) 48 (74%) 9 (56%) 0.22Age (years) 60 (51.7-64) 59 (51.6-63.4) 61 (53-65) 0.61cPHT 67 (83%) 57 (88%) 10 (63%) 0.027Indication for LTAlcohol 30 (37%) 26 (40%) 4 (25%) 0.85Cirrhosis 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%) 0Other 7 (9%) 5 (8%) 2 (13%)

Lab Model for End-Stage Liver Disease score 16 (10.4-23.3) 17 (11-24) 13 (9-16.7) 0.096Donor characteristicsMale gender 47 (58%) 38 (58%) 9 (56%) 1Age (years) 45 (29-53) 47 (33-54) 29 (24-42.8) 0.014Intensive care unit stay > 7 days 13 (16%) 10 (15%) 3 (19%) 0.96DRI‡ 1.75 6 0.49 1.66 6 0.45 2.13 6 0.39 0.0012Macrosteatosis (%) 4 (0-6.3) 4 (0-10) 0 (0-5) 0.53Body mass index (kg/m2) 24 (22-26) 24 (22-26.2) 23 (21.5-25) 0.35University of Wisconsin solution 55 (67.9%) 47 (72.3%) 8 (50%) 0.13Histidine tryptophan ketoglutarate solution 26 (32.1%) 18 (27.7%) 8 (50%)

Intraoperative and graft characteristicsCold ischemia time (minutes) 495 (388-603) 490 (388-605) 526 (374-601) 0.49Warm ischemia time (minutes) 45 (35-60) 45 (33-55) 52 (35-75) 0.23Operation time (minutes) 540 (422-630) 510 (422-605) 615 (465-736) 0.007Graft weight (mg) 1451 6 462 1566 6 399 984 6 410 <0.0001GRWR 1.96 6 0.68 2.14 6 0.64 1.37 6 0.48 <0.0001Graft volume to standard liver volume ratio (%) 108 6 35 119 6 31 76 6 28 <0.0001

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.

838 SAINZ-BARRIGA ET AL. LIVER TRANSPLANTATION, July 2011

6 0.39 for the partial graft group versus 1.66 6 0.45for the FS group, P ¼ 0.0012; 4 living donors wereexcluded from the DRI calculation for the partial graftgroup). As expected, the graft weights, GRWRs, andgraft volume to standard liver volume ratios werehigher in the FS group.

Transplant Population Flow, Pressure,

and Gradient Distributions

Hepatic hemodynamics and systemic hemodynamicswere simultaneously measured approximately 90minutes after graft revascularization for the wholedata set. This time was longer for partial grafts (120minutes, IQR ¼ 85-143 minutes) versus FS grafts (81minutes, IQR ¼ 57-103 minutes, P ¼ 0.009). Theresults are reported in Table 2. When PVF wasindexed by the graft weight, significantly higher perfu-sion was observed in partial grafts versus FS grafts(168.5 versus 110.9 mL minute�1 100 g of LW�1, P ¼0.023). Conversely, the median HAF measurement forFS grafts was twice the measurement for partial grafts(249 versus 112 mL minute�1, P ¼ 0.001). The medianHVPG value after reperfusion was 7 mm Hg (IQR ¼ 4-10 mm Hg), and this showed persistent PHT withwhich the newly grafted liver had to comply. No differ-ence between flow and pressure measurements proxi-mal or distal to the PV anastomosis was observed inany high-HVPG cases. Likewise, all Doppler ultrasoundhepatic vein controls showed excellent pulsatility andbackflow (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 thepatients (16/81). Noticeably, 25% of these patients(4/16) had low PVFs (<90 mL minute�1 100 g ofLW�1). The same low PVFs were observed in 27.3% of

the patients (12/44) with PVPs � 15 mm Hg. HighPVFs were observed in 3% of the patients (2/65) withPVPs < 20 mm Hg. In the group with HVPGs � 15mm Hg, only 1 patient had a low PVF (14.3% or 1/7),whereas none of the patients with HVPGs < 15 mmHg had high PVFs (Fig. 1D). The results of linearregression in univariate and multivariate models arepresented in Table 3. In the univariate analysis, theDRI showed an association with higher PVPs (P ¼0.036). CVP increases were transmitted to the PVP(58%, range ¼ 25%-91%, P ¼ 0.001). In the multivari-ate analysis, cPHT showed a significant associationwith higher PVPs (P ¼ 0.009) and a trend towardhigher HVPGs (P ¼ 0.08). Partial grafts were associ-ated only with higher PVF values (P ¼ 0.004) and notwith PVP or HVPG (P ¼ 0.89 and P ¼ 0.9, respec-tively). PVFs � 270 mL minute�1 100 g of LW�1

showed an association with higher HVPGs (P ¼ 0.04).Reciprocally, HVPGs � 15 mm Hg showed an associa-tion with higher PVFs (P ¼ 0.023).

Hyperflow and PHT

No correlation between GRWR and PVP was found (FSgrafts: r ¼ �0.19, P ¼ 0.12; partial grafts: r ¼ �0.109,P ¼ 0.68). Smaller FS grafts showed a correlation withhigher HVPGs (FS grafts: r ¼ �0.303, P ¼ 0.014; par-tial grafts: r ¼ 0.25, P ¼ 0.33). Four patients (4.9%)had high PVFs (�270 mL minute�1 100 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 patientwho underwent transplantation with a partial graftpresented with hyperflow (�360 mL minute�1 100 g ofLW�1). Exceptionally, no GIM was performed in thispatient because we deemed the HAF value to beadequate (>100 mL minute�1) with correct hepatic ve-nous outflow.

Eighty-three percent of the patients (67/81) had adiagnosis of cPHT. The mean spleen diameter of thecPHT patients indicated splenomegaly (>13 cm) and

TABLE 2. Systemic and Hepatic Hemodynamics During LT

Overall (n ¼ 81)

FS Grafts

(n ¼ 65)

Partial Grafts

(n ¼ 16) P Value

Systemic hemodynamicsCVP (mm Hg) 8 (6-10) 8 (6-10) 8.5 (6.8-10) 0.8MAP (mm Hg) 70 (62-77) 68 (61.7-77) 77 (65.3-84.2) 0.049

Hepatic hemodynamicsHAF (mL minute�1) 205 (112-373) 249 (133.5-385) 112 (82-140.6) 0.001HAF (mL minute�1 100 g of LW�1) 15.6 (8.2-22.3) 16 (8.2-23) 14.1 (8.5-19) 0.5PVF (mL minute�1) 1621 (1229-2409) 1690 (1324-2409) 1618 (785.5-2228) 0.3PVF (mL minute�1 100 g of LW�1) 122 (77-171) 110.9 (75-145.6) 168.5 (113.5-223) 0.023PVP (mm Hg) 15 (12-18) 15 (12.2-18) 15.5 (11-19.5) 0.9HVPG (mm Hg)* 7 (4-10) 7 (4-9.6) 6.9 (5-10.3) 0.69Portal blood flow to arterialblood flow ratio

7.7 (3.9-15.8) 6.6 (3.7-14.1) 15.4 (7-20.6) 0.055

NOTE: The results are expressed as medians and IQRs.*HVPG ¼ PVP � CVP.


was significantly larger than the mean diameter of thenon-cPHT patients (14.7 6 3 versus 11.4 6 1.4 cm, P ¼0.0002). After revascularization, the proportion ofpatients with HVPGs � 10 mm Hg was 26% (21/81).Thus, 46 of the 67 patients with cPHT before LT no longershowed it after LT, and this represented an improvementin PHT immediately after revascularization in 68.6% ofthe patients (46/67). The distributions of patients withHVPGs � 10 mm Hg were similar for the partial graftgroup (31.2% or 5/16) and the FS group (24.6% or 16/65, P ¼ 0.75). Severe PHT (HVPG � 15 mm Hg) wasobserved in 33% of these patients (7/21) and was 3 timesmore frequent in patients with partial grafts (18.7% or 3/16) versus patients with FS grafts (6% or 4/65, P¼ 0.27).

GIM

Three LT patients (2 partial grafts and 1 FS graft)underwent splenic artery ligation (SAL) because of lowHAF (<100 mL minute�1). A successful 60% reductionof PVF was obtained, and this was followed by a57.2% improvement in HAF. In 1 partial graft, theHVPG value was reduced from 13 to 5 mm Hg. In theother 2 grafts, our previous experience35 was con-firmed: little or no effect of SAL on PVP or HVPG (astable gradient of 9 mm Hg and a reduction from 7 to6 mm Hg) was observed.

Liver Tests in the PVF, PVP, and HVPG Groups

The I/R damage (the peak AST level divided by thegraft 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 thelow-PVF group (<90 mL minute�1 100 g of LW�1),whereas the higher PVF groups displayed lower peakswith both FS and partial grafts (P ¼ 0.045 and P ¼0.21, respectively). This suggests either that greater I/R damage was responsible for the lower PVFs or, con-versely and more likely, that lower flows predisposedthe patients to greater I/R damage. Similar resultshave been observed by others.36 In Fig. 3, we can seethe curves for the total bilirubin levels. A trend towardnormalization at the end of the first month after LTwas observed in all groups. In the severe PHT group,we observed nonsignificantly higher AST and GGTpeaks in the patients with FS grafts (Figs. 2 and 4).This may suggest a combined effect of I/R and HVPGon cholestasis. The evolution of total bilirubin andGGT levels in partial liver grafts paradoxically showedlower cholestasis with high flows and high gradients.Although the beneficial effect of higher flows withinsafe limits has been previously described,22,37 thepositive effect of higher gradients might resemble theeffect of I/R on partial grafts because the groups withhigher AST peaks had higher levels of cholestasis(Figs. 2-4).

Graft Survival

With a median follow-up of 25 months (range ¼ 0.03-36 months), the overall 1-year graft survival rate was93.5%. No significant differences were observed

Figure 1. Relationship between PVP, PVF and HVPG (HVPG ¼ PVP � CVP). No correlation was found (A) between the portal pressureand 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 portalperfusion (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 portalflow (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 portalperfusion (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 circlesrepresent FS grafts. The lines reflect currently applied threshold levels with clinical relevance for PHT.


TABLE

3.LinearRegressionAnalysis

ofth

eVariablesInfluencingPVF,PVP,andHVPG

PVF(m

LMinute

�1100gofLW

�1)

PVP(m

mHg)

HVPG

(mm

Hg)*

Coefficien

t

95%

Confiden

ce

Interval

PValue

Coefficien

t

95%

Confiden

ce

Interval

PValue

Coefficien

t

95%

Confiden

ce

Interval

PValue

Univariate

analysis

cPHT(yes

versusno)

20.5

�22.06to

63.1

0.34

3.02

0.24to

5.79

0.033

2.21

�0.52to

4.95

0.11

DRI

29.7

�3.55to

62.98

0.079

2.27

0.15to

4.38

0.036

1.31

�0.84to

3.47

0.23

Partialgra

ftve

rsus

FSgra

ft55.8

17.1

to94.5

0.005

0.3

�2.4

to3

0.82

0.57

�2.06to

3.21

0.67

LabModel

forEnd-S

tage

Liver

Disea

sesc

ore

�0.11

�1.88to

1.66

0.9

�0.02

�0.13to

0.1

0.76

�0.58

�0.17to

0.57

0.31

Cold

isch

emia

time(m

inutes)

�0.04

�0.14to

0.06

0.42

�0.004

�0.01to

0.0026

0.23

0.0008

�0.005to

0.0073

0.79

Warm

isch

emia

time(m

inutes)

�0.65

�1.71to

0.4

0.22

0.006

�0.065to

0.077

0.86

0.02

�0.05to

0.09

0.57

CVP(m

mHg)

1.14

�4.18to

6.45

0.67

0.58

0.25to

0.91

0.001

Notapplica

ble

HAF(m

Lminute

�1)

�0.09

�0.18to

0.0004

0.051

0.00005

�0.062to

0.0063

0.98

�0.0023

�0.008to

0.004

0.44

PVF(m

Lminute

�1

100gofLW

�1)

<90

�1.08

�3.38to

1.22

0.351

�0.51

�2.76to

1.74

0.65

90to

<270

Notapplica

ble

Referen

cegroup

Referen

cegroup

�270

4.68

�0.23to

9.59

0.061

4.93

0.13to

9.72

0.04

PVP(m

mHg)

<15

Referen

cegroup

15to

<20

15.87

�19.9

to51.67

0.38

Notapplica

ble

Notapplica

ble

�20

43.87

1.11to

86.64

0.04

HVPG

(mm

Hg)

<10

Referen

cegroup

10to

<15

�18.23

�59.3

to22.7

0.37

Notapplica

ble

Notapplica

ble

�15

83.2

28.1-1

38.3

0.004

Multivariate

analysis

cPHT(yes

versusno)

31.8

�12.2

to75.9

0.15

4.1

1.04to

7.18

0.009

2.71

�0.36to

5.78

0.08

Partialgra

ftve

rsusFSgra

ft59.5

20to

98.8

0.004

0.19

�2.63to

3.02

0.89

0.16

�2.67to

2.99

0.9

Cold

isch

emia

time(m

inutes)

�0.042

�0.14to

0.57

0.39

�0.005

�0.012to

0.012

0.11

0.0005

�0.0063to

0.0073

0.87

Warm

isch

emia

time(m

inutes)

�0.65

�1.74to

0.43

0.23

0.046

�0.03to

0.12

0.23

0.063

�0.013to

0.14

0.1

PVF(m

Lminute

�1

100gofLW

�1)

<90

Notapplica

ble

�0.85

�3.2

to1.5

0.47

�0.69

�3.05to

1.67

0.56

90to

<270

Referen

cegroup

Referen

cegroup

�270

4.57

�0.4

to9.55

0.071

5.25

0.26-1

0.23

0.04

HVPG

(mm

Hg)*

<10

Referen

cegroup

10to

<15

�10.8

�51.3

to29.6

0.59

Notapplica

ble

Notapplica

ble

�15

63.7

9.02-1

18.3

0.023

*HVPG

¼PVP�

CVP.


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 graftweight are compared for the flow, pressure, and gradient groups according to the graft type. A significantly higher AST peak was foundonly in the low-PVF group (<90 mL minute�1 100 g of LW�1) within FS grafts. Boxes represent IQRs, and whiskers represent minimumand maximum values. The number of patients in each group is presented in parentheses. *P ¼ 0.045.

Figure 3. Cholestasis according to the type of graft. The median bilirubin values during the first month after LT are compared for theflow, pressure, and gradient groups according to the graft type. Gray bands represent the normal range of bilirubin values. Circlesrepresent PVF groups (white, <90 mL minute�1 100 g of LW�1; gray, 90 to <270 mL minute�1 100 g of LW�1; black, �270 mLminute�1 100 g of LW�1). Squares represent PVP groups (white, <15 mm Hg, gray, 15 to <20 mm Hg; black, �20 mm Hg). Trianglesrepresent HVPG groups (white, <10 mm Hg; gray, 10 to <15 mm Hg; black, �15 mm Hg).


between the PVF, PVP, and HVPG groups. Although atrend toward lower graft survival in the severe PHTgroup (HVPG � 15 mm Hg) could be hypothesized(Fig. 5), we experienced 6 graft losses; 2 were lategraft losses and were, therefore, unlikely related tohepatic hemodynamics. Graft failure was recordedonly in the FS group; details of the 6 graft losses arepresented in Table 4.

DISCUSSION

One of the main findings of our study is the lack of acorrelation between PVF and PVP. High PVPs (�20mm Hg) were distributed throughout the entire spec-trum of flows and perfusions in our study population(Fig. 1A,B). Our results confirm in a prospective waythe absence of a correlation between direct PVF meas-urements and PVP, which has also been observed byothers.37,38 In our view, the lack of a correlationbetween PVF and PVP raises the question whetherany decision regarding the need for modulating graftinflow should require an evaluation of both. Becausethe SAL and PCS techniques have direct effects onPVF reduction, this also raises the question of grafthypoperfusion. In our study, 25% of the patients withPVPs � 20 mm Hg presented low PVF values (<90 mLminute�1 100 g of LW�1) that were inferior than PVFmeasurements in healthy living donors.9 In suchpatients, a decision to decrease PVF could potentiallyfurther reduce the portal inflow to the liver and riskhypoperfusion of the graft and, consequently, inferioroutcomes.37,39,40 If we were to apply the PVP thresh-

old of �15 mm Hg, even more patients would be atrisk for hypoperfusion. Also, contrary to the experi-ence of Ito et al.,13 no correlation between GRWR andPVP was found. A similar lack of a correlationbetween the graft weight and PVP in living donorrecipients has been observed by other groups.25,37

The literature for GIM in partial LT abounds withreports on adequate levels of PVP for avoiding damage

Figure 5. Estimated graft survival according to HVPG groups. Ashorter survival can be hypothesized for those with HVPG levels �15 mm Hg (overall P value ¼ 0.042). The number of patients atrisk at time 0, 3 and 6 months are provided.

Figure 4. Cholestasis according to the type of graft. The median GGT values during the first month after LT are compared for theflow, pressure, and gradient groups according to the graft type. Gray bands represent the normal range of GGT values. Circlesrepresent PVF groups (white, <90 mL minute�1 100 g of LW�1; gray, 90 to <270 mL minute�1 100 g of LW�1; black, �270 mLminute�1 100 g of LW�1). Squares represent PVP groups (white, <15 mm Hg, gray, 15 to <20 mm Hg; black, �20 mm Hg). Trianglesrepresent HVPG groups (white, <10 mm Hg; gray, 10 to <15 mm Hg; black, �15 mm Hg).


to liver grafts. An arbitrary PVP threshold of 20 mmHg was initially proposed for applying GIM accordingto the higher PVPs observed in the recipients of smallliving donor grafts (GRWR < 0.8) and their negativeinfluence on patient survival.13 This threshold hasrecently been challenged because of failures observedunder this cutoff level; after single-center reports,41

the Kyoto group described the first retrospective seriesand 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 couldexplain the graft failures reported in the literaturewith PVPs < 20 mm Hg. Such patients may benefitfrom GIM and will remain unknown if pressures aloneare used to make a decision. The relationship betweenPVF and PVP could be better clarified by Ohm’s law,which states that the current equals the voltage dif-ference divided by the resistance. When we relateOhm’s law to fluid flow, the current is the blood flow,the voltage difference is the pressure difference orpressure gradient (HVPG), and the resistance is theresistance to flow offered by the blood vessel and itsinteractions with the flowing blood (PVF ¼ PVP �CVP/resistance). This indicates a linear and propor-tionate relationship between PVF and PVP that ismodulated by CVP. We have observed a significantassociation between CVP and PVP (Table 3). Similarlyto our results, in experimental in vivo studies, 60% ofthe CVP increase was transmitted to the PVP.42 Whenthe CVP was markedly elevated, 90% was transmittedto the PVP, and 64% was transmitted to the cap-sule43; this suggests that the compliance of the capac-itance vessels may also be related to the distensibilityof the liver tissue because the capacitance vesselscannot enlarge without expansion of the surroundingliver tissue. In this respect, the association betweenthe DRI (a representative marker of graft quality) andPVP is interesting (Table 3). A higher DRI, represent-ing an inferior quality graft, may also identify a higherresistance graft. At any given PVF, an increase in re-sistance increases the pressure gradient. Partial graftsdid not show any association with PVP in this study,and the higher DRI values observed in this particulargroup (Table 1) should not bring this finding intoquestion. Because of the CVP and graft quality associ-ation, the diagnosis of PHT on the basis of PVP couldbe delusive.

Another important finding of our study is the poten-tial role of HVPG in assessing PHT during LT. HVPGtakes into account both the upward and downwardpressures acting on liver grafts. Furthermore, HVPG iswidely used to determine PHT and the risk associatedwith variceal bleeding in patients with cirrhosis.28,44,45

In fact, an HVPG value � 10 mm Hg characterizes thedevelopment of collateral circulation aiming for decom-pression of the portal system. Above this gradient,splanchnic circulation becomes markedly vasodilatedand contributes to the maintenance of increased portalpressure.28 In our study, 26% of the patients pre-sented this value after revascularization of the liver

TABLE

4.SpecificsofGraft

Failure

Gra

ftNumber

Disea

seType

Card

iac

Index

(L/minute/m

2)

cPHT

Donor

Age

(Yea

rs)

DRI

GRWR

Cold

Isch

emia

Tim

e(M

inutes)

Warm

Isch

emia

Tim

e(M

inutes)

PVF(m

LMinute

�1)

PVF(m

LMinute

�1

100g

ofLW

�1)

HAF(m

LMinute

�1)

HAF(m

LMinute

�1

100g

ofLW

�1)

PVP

(mm

Hg)

HVPG

(mm

Hg)*

Gra

ftSurvival

(Days)

Cause

of

Gra

ftLoss

1Cirrh

osis

FS

4.1

No

68

2.84

2.1

367

38

446

35.6

167

13.4

13

31

PV

thrombosis

andhep

atic

artery

thrombosis

2Acu

tehep

atic

failure

FS

5.4

No

59

2.04

2.5

508

62

1245

76.4

554

33.9

12

411

I/R

and

cholestasis

3Primary

sclerosing

cholangitis

FS

6.7

Yes

52

1.67

1.5

391

27

2719

217.5

205

16.4

13

633

Hep

aticartery

thrombosis†

4Alcoholic

cirrhosis

FS

5.6

Yes

60

2.84

1.5

343

56

3277

243.4

125

9.2

27

20

48

Isch

emic-type

biliary

lesions

5Alcoholic

cirrhosis

FS

4.5

Yes

55

1.8

1.9

831

50

1466

112.7

49

3.7

16

10

318

PHTand

chronic

rejection

6Hep

atitis

Ccirrhosis

FS

5.6

Yes

59

1.75

2.2

850

35

2875

184.3

96

6.1

15

8551

Sec

ondary

biliary

cirrhosis

*HVPG

¼PVP�

CVP.

†LupusAntico

agulans:risk

factorforhep

aticarteryth

rombosis.

graft. Patients with cPHT showed a trend toward higherHVPGs, and the group with severe PHT showed a re-ciprocal association with high PVFs in the multivariatelinear regression analysis (Table 3). In light of thesepremises, HVPG could be useful in understanding therisks of hyperflow and PHT during LT.

Although HVPGs � 10 mmHg were found to be equallydistributed between the FS grafts and the partial grafts,severe PHT was found in 18.7% of the partial graft recipi-ents (ie, 3 times more frequently in comparison withrecipients of FS grafts). Indeed, HVPG showed a negativecorrelation with GRWR. Comparing small partial graftswith FS grafts in a large-animal LT model, Fondevilaet al.46 described significantly higher HVPGs in the par-tial graft group even in the absence of the hyperdynamicstatus of cirrhosis. More recently, Botha et al.47 describedthe first US multicenter series studying the intentionaluse of left liver lobes and PCS. A median HVPG value of17.5 mm Hg (range ¼ 10-25 mm Hg) was observed afterPCS clamping; this pressure was reduced to 5 mm Hg(range ¼ 1-15 mmHg) after the clamp was released, andthe values were similar to our observations. Likewise,with available published data, an HVPG value of 9 mmHg (IQR ¼ 6-10.2 mm Hg) can be calculated in a similarsetting.48 We could hypothesize a trend toward lowergraft survival in patients with severe PHT (Fig. 5),although the available evidence of an influence of HVPGon outcomes is still circumstantial. Successful trans-plantation of small grafts (GRWR < 0.8) with GIM tech-niques has been reported with HVPGs < 15 mmHg.47,48

The single graft lost because of small-for-size syndromein the aforementioned series had been transplanted intoa patient with persistent severe PHT despite the PCS.47

We have assumed CVP to be comparable to the he-patic vein pressure, although this may not always betrue. An underestimation of HVPG due to a high CVPcan occur if there is a mechanical obstruction or ahigh positive end expiratory pressure.5,49,50 In ourstudy, all measurements were taken in a supine posi-tion and under stable systemic hemodynamic condi-tions, and the positive end expiratory pressure, when-ever it was applied, was not greater than 5 mm Hg;this reduced the risk of a pressure gradient betweenthe hepatic veins and the superior vena cava. More-over, the absence of a pressure gradient in PVPsmeasured proximally and distally to the PV anastomo-sis and the triphasic Doppler findings for hepaticveins with high gradients indicated that anastomotictechnical problems or outflow insufficiencies wereunlikely. Taking all this into account, we believe thatthe HVPG measurements of our study should providea real estimate of the pressure gradient that takesplace at the sinusoidal level. The lack of a correlationbetween HVPG and PVF could be a result of flow re-sistance due to variations in the graft quality, as pre-viously discussed. This resistance is also determinedby the sizes of individual vessels (length and diameter)and the organization of the vascular network (seriesand parallel arrangements), which vary from graft tograft. The reported flows cannot identify variations atthe microvascular level. Areas of relative hypoperfu-

sion may lead to turbulent flow, which could explainhigh HVPGs with low PVFs.

Nowadays, the decision to perform GIM relies onthe clinical judgment of the surgeon, which is basedon subjective parameters such as the coloration andconsistency of the graft at reperfusion and is aided byobjective measurements of PVF or HVPG. The idealtarget PVF for partial grafts has been interpreted to betwice the perfusion observed in the FS graft (260 mLminute�1 100 g of LW�1)51-53 and as twice the baselineflows observed in the healthy donor (180 mL minute�1

100 g of LW�1).9,21 The risk of sinusoidal damage andgraft failure rises as we depart further from this idealvalue. In a previous report,16 we identified a superiorthreshold of 4 times the flows observed in healthydonors (360 mL minute�1 100 g of LW�1) as a riskfactor for graft failure; also, flows below the target of180 mL minute�1 100 g of LW�1 led to lower survivalrates. Recently, the Barcelona group confirmed ourprevious clinical observations in an experimentalmodel: a PVF value that is twice the baseline value pre-vents 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 flowsis an interesting concept that needs to be confirmedand refined.

A graft with homogeneous revascularization thatfeels soft on palpation (which indicates a compliantgraft) and presents with adequate HAF (�100 mLminute�1) and PVF values (90 to <270 mL minute�1

100 g of LW�1 according to the graft type) with anHVPG less than 15 mm Hg represents the best casescenario, and a consideration of GIM will not beexpected. Likewise, a patient presenting with hyper-perfusion (PVF � 360 mL minute�1 100 g of LW�1)and severe PHT (HVPG � 15 mm Hg) with low HAF(<100 mL minute�1) represents the worst case sce-nario, and there will be a consensus to apply a GIMtechnique. Controversy will arise when severe PHTwith a normal PVF or hyperflow with a normal HVPGoccurs. In the case of hyperflow and a normal HVPG,the decision will differ according to the measuredHAF. If a correct HAF value is registered, a secondreading (eg, after the completion of the biliary anasto-mosis) will be performed. In most cases, the PVFvalue will change (�360 mL minute�1 100 g of LW�1).If a low HAF value is associated with hyperflow with anormal gradient, after the exclusion of anastomoticproblems or hepatic artery spasms, a PV test clampshould be performed. If a progressive increase in theHAF value is observed, the new readings will be stablein all cases within 30 to 60 seconds, and the clampshould be released. In such cases, we will consider aSAL. In Fig. 6, the algorithm currently used in our centerto decide whether GIM is needed is presented, and it isbased on flows, gradients, and systemic hemodynamics.Flow tailoring implies the measurement of flows andgradients to determine whether a patient may benefitfrom GIM. If a splenic artery clamping test results inhyperflow or severe PHT relief, SAL can be considered toreduce the original PVF or HVPG. When greater GIM is


needed, the construction of a PCS will allow for a higherreduction of the initial PVF or HVPG. Furthermore, themeasurement of the flows through the shunt and to theliver will allow for calibration through the application ofbanding to the shunt or to the donor PV.21 In all thesecases, PVF measurements will be required to adequatelycustomize the degree of flow diversion because graft is-chemia due to excessive shunting has been reportedwhen PVP alone has been used.39

It can be argued that normalization of the blood flow toLW may be somewhat misleading. On the contrary, webelieve that in order to understand the stress that hyper-flow exerts on the liver tissue, perfusion values shouldbe evaluated. Besides their statistical significance, theresults have strong clinical significance. Hepatic flows inpatients with cirrhosis are increased and are twice thebaseline flows observed in healthy subjects. Even normalhepatic blood flows passing through half of a liver (eg, inpartial LT) exert greater stress on the liver tissue.Whether such stress is doubled can be debated. Weacknowledge that as experience is gained, the proposedhigh limit of 4 times the baseline flows of healthy donorswill be better defined and validated or even deemed notuseful. However, the graft weight is only one of the fac-tors to consider. The clinical status of the recipient canincrease the hepatic flows,9 and we have observed inthis study a reciprocal correlation between high PVFand severe PHT. Also, the quality of the graft plays a fun-damental role in the tolerance of hemodynamic stress,as previously discussed, and this quality is influencedby many variables such as donor characteristics, ische-mic times, and I/R.36,54 One limitation of our study is

the small number of partial grafts: the detrimentaleffects of portal hyperperfusion and hypertension havebeen extensively studied in partial grafts, and little in-formation is available about their effects on FS grafts.Portal hyperperfusion and hypertension are generallynot issues in FS grafts when an optimal outflow is war-ranted. Nevertheless, when hyperperfusion values(�360 mL minute�1 100 g of LW�1) have been present,we have observed histological damage similar to thedamage observed in small partial grafts with reducedgraft survival.16 Because of these results, in select FScases, we consider and perform GIM according to thealgorithm described in Fig. 6. According to our experi-ence, flow and gradient measurements during LT areuseful and reproducible tools for checking the quality ofanastomoses. Concomitantly, we can modify the hemo-dynamic stress related to portal hyperperfusion andhypertension and improve systemic hemodynamics,especially in patients presenting with established cPHTand receiving marginal or partial grafts.

The identification of a window of adequate flowsand pressures according to graft quality still remainsan open question. The recognition of the risk of hemo-dynamic damage and the tailoring of a solution when-ever possible are important.

With this study, we have prospectively confirmedthe absence of a correlation between PVP and PVF af-ter graft reperfusion. The use of PVP to judge the se-verity of PHT could be delusive because it is influ-enced by CVP. Also, relying on PVP alone to determinewhether or not GIM is needed does not seem advisa-ble because of the possibility of hypoperfusion or

Figure 6. Algorithm for GIM according to flows, gradients and systemic hemodynamics. The measurements should be performedunder stable hemodynamic conditions in the absence of active bleeding. The interpretation of flows and gradients is meaningful if anoptimal outflow (represented by a triphasic waveform on duplex ultrasound) can be confirmed. When GIM is being considered, a PVFvalue < 90 mL minute�1 100 g of LW�1 should be avoided. Technical failures of the arterial anastomosis, kinking, or arterial spasmsshould be ruled out before the evaluation of HAF (mL minute�1). PVF � 4 indicates a PVF value (mL minute�1 100 g of LW�1) greaterthan 4 times the baseline normal value (�360 mL minute�1 100 g of LW�1). The MAP and HVPG values are presented as millimeters ofmercury (HVPG ¼ PVP � CVP). The LDC (ie, Ne/Epi) dose is �0.05 g kg�1 minute�1.


unrecognized hyperflow. On the basis of our results,we affirm that both PVF and PVP (the latter as HVPG)should be measured. HVPG is nowadays the bestavailable means for measuring PHT, and available evi-dence seems to support its use during LT. Based onthis initial experience, our current policy is to applyGIM not only in cases of hyperflow but also wheneversevere PHT is found during LT. The HVPG thresholdof �15 mm Hg has been proved to be promising forthe evaluation of hemodynamic stress potentiallyinfluencing outcomes.

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