Splanchnic Hyperemia After LiverTransplantation in Patients With End-StageLiver DiseaseDaniel Alvarez,* Solange Gerona,† Zulema Waisburg,* Miguel Ciardullo,‡Eduardo de Santibanes,‡ and Ricardo Mastai†

Systemic and splanchnic hemodynamic param-eters were evaluated in 12 patients with cirrhosisbefore and 3 and 6 months after liver transplanta-tion. Results were compared with those obtainedin 8 healthy subjects. Three months after livertransplantation recipients had an increase in meanarterial pressure (98 6 7 v 78 6 9 mmHg; P F .05),an insignificant decrease in cardiac index(3.4 6 0.6 v 4.0 6 1.0 L · min 21 · m22), and a markedincrease in peripheral vascular resistance(1,563 6 308 v 800 6 205 dyne · s · cm 25; P F .05)compared with pretransplantation values. Portalblood flow was also significantly increased(1,494 6 200 v 829 6 130 mL/min; P F .05). Thesehemodynamic changes were more pronounced 6months after transplantation (mean arterial pres-sure, 100 6 8 mmHg; cardiac index, 3.0 6 1.0L · min 21 · m22; P F .01; peripheral vascular resis-

tance, 1,680 6 405 dyne · s · cm 25; portal bloodflow, 1,520 6 180 mL/min). Systemic hemodynam-ics 6 months after liver transplantation were simi-lar to those observed in the healthy control group(mean arterial pressure, 95 6 6 mmHg; cardiacindex, 2.9 6 0.9 L · min 21 · m22; peripheral vascu-lar resistance, 1,480 6 380 dyne · s · cm 25). How-ever, portal blood flow was still significantly higherthan in healthy controls at 6 months (1,520 6 180v 910 6 140 mL/min; P F .05). This study showsthat systemic hemodynamics are normalized afterliver transplantation. However, an increase inportal blood flow occurs and persists for at least 6months after liver transplantation. Further studiesare needed to clarify the cause of the abnormallyhigh portal flows.Copyright r 1998 by the American Association forthe Study of Liver Diseases

The circulation of patients with cirrhosis ischaracteristically hyperdynamic, with high

cardiac output and low peripheral vascular resis-tance.1 The splanchnic circulation is also hyperki-netic, with an increase in portal blood flow, whichis an important factor in the development of portalhypertension.2 Although the mechanism for thegenesis of this hyperdynamic state is not wellknown, glucagon-3,4 and endothelial-derived fac-tors5,6 may be involved through their vasodilatoryeffects.

So far, data on the reversal of the circulatoryabnormalities after orthotopic liver transplantation(OLT) are controversial.7-12 Some studies show anincrease in cardiac index,8-10 and others showsignificant decreases after OLT.11 The discrepanciesamong studies could be attributable to several

factors, including clinical and methodologic differ-ences.12 The aim of the present study was toevaluate systemic and splanchnic hemodynamicparameters in 12 patients with cirrhosis before and3 and 6 months after OLT. These results werecompared with those obtained in 8 healthy sub-jects.

Patients and MethodsSystemic and splanchnic hemodynamics were evaluatedin 12 patients (ages 22 to 54 years) before and 3 and 6months after OLT. The cause of chronic liver disease washepatitis C in 6 patients, alcohol in 3, and unknown in 3.The control group consisted of 8 healthy subjects, aged38 to 53 years, with no evidence of liver disease andnormal liver function test results. Liver recipients werestable, and none of them had clinical or histologicevidence of infection or rejection. The patients receivedstandard immunosuppression (cyclosporine A, predni-sone, and azathioprine). None of the patients took anyform of vasoactive drug for treatment of arterial hyperten-sion for at least 30 days before the hemodynamicevaluation. The study was approved by the local clinicalresearch committee, and the patients gave verbal in-formed consent.

Portal blood flow was measured with a Toshiba SSA

From the *Seccion de Ecografıa, †Seccion de Hıgado, Serviciode Clınica Medica, and ‡Servicio de Cirugıa, Hospital Italiano,Buenos Aires, Argentina.

Address reprint request to Ricardo Mastai, MD, Seccion deHıgado, Hospital Italiano, Potosı 4215, Buenos Aires (1199),Argentina.

Copyright r 1998 by the American Association for the Study ofLiver Diseases

1074-3022/98/0404-0009$3.00/0

Liver Transplantation and Surgery, Vol 4, No 4 ( July), 1998: pp 300-303300

270A (Tokyo, Japan) duplex scanner, consisting of areal-time, two-dimensional ultrasonic device and anattached 3.5-MHz pulse Doppler flowmeter. After asampling marker had been set in the middle of the lumenof the portal vein along the beam axis, a second markerwas positioned parallel to the direction of blood flow.Care was taken to maintain the angle u (the angle formedby the ultrasonic beam and the direction of blood flow)below 60° because the accuracy of the measurementsdecreases as angles increase. Measurements were carriedout during expiration because it can be standardizedeasily and allows better visualization of the portal veinfor Doppler as the angle u is reduced to a minimum.

Blood flow was measured by multiplication of theblood velocity by the cross-sectional area of the vessel,calculated on the basis of the inner diameter andassuming circular geometry. Doppler assessment of theleft ventricular ejection velocity was obtained by position-ing of the sample marker in the aorta just distal to theaortic valve on a B-mode, four-chamber image plus aortaimage with the transducer placed on the apical zone.This position makes the angle between the ultrasoundbeam and the direction of blood stream near zero.Doppler evaluation was always carried out by the samespecialized examiner (D.A.).

Arterial pressure was measured with a sphygmoma-nometer and expressed as mean arterial pressure accord-ing to the following formula:

(Systolic Pressure 1 Diastolic Pressure 3 2)/3

Systemic vascular resistance was calculated as

Mean Arterial Pressure/Cardiac Output 3 80

Results are expressed as means 6 SD. Comparisonsbetween values from normal subjects and those frompatients evaluated before and after OLT were made withone-way analysis of variance (ANOVA) and Turkey-Kramer multiple-comparison tests. Differences were con-sidered significant when P was less than .05.

Results

Systemic Hemodynamics

Compared with normal subjects, patients withcirrhosis had hyperdynamic circulation character-ized by decreased mean arterial pressure and periph-eral vascular resistance and increased cardiac index(Table 1).

A significant increase in mean arterial pressureand peripheral vascular resistance was seen 3months after OLT (Fig. 1). Six months after OLT,further increases in both hemodynamic parameterswere observed (Fig. 1). A reduction in cardiacindex was observed after transplantation andreached statistical significance 6 months after OLT(Fig. 1). Values of systemic hemodynamic param-eters 3 and 6 months after OLT were similar tothose observed in healthy subjects (Table 1).

Splanchnic Hemodynamics

Measurements of portal blood flow before and afterOLT are shown in Figure 2. Portal blood flow wasmarkedly increased at 3 and 6 months after OLT(Table 1) and was significantly higher than inhealthy subjects (Fig. 2).

Discussion

Our study shows that despite the normalization ofsystemic hemodynamic parameters, portal bloodflow increases after OLT and remains elevated forat least 6 months.

Splanchnic hyperemia in liver-transplant recipi-ents, manifested by a significant increase in hepaticand azygos venous blood flow, has been shownrecently by other authors,7-11 suggesting that it is aconsistent hemodynamic finding in liver-trans-

Table 1. Systemic and Splanchnic Hemodynamic Parameters in Healthy Subjects and Cirrhotic PatientsBefore and After Liver Transplantation

Healthy Controls Before OLT

After OLT

3 mo 6 mo

Mean arterial pressure (mmHg) 95 6 6 78 6 9* 98 6 7† 100 6 8†Cardiac index (L · min21 · m22) 2.9 6 0.9 4.0 6 1.0* 3.4 6 0.6 3.0 6 1.0†Peripheral vascular resistance (dyne · s · cm25) 1,480 6 380 800 6 205* 1,563 6 308† 1,680 6 405†Portal blood flow (mL/min) 910 6 140 829 6 130 1,494 6 200*† 1,520 6 180*†

*P , .05 compared with healthy controls.†P , .05 compared with values before OLT.

Portal Blood Flow and OLT 301

plant recipients. However, the effect of OLT onsystemic hemodynamic parameters is more contro-versial. Some studies show an increase in cardiacindex,7-10 and others show a significant decreaseafter OLT.11 The conflicting results could be attrib-utable in part to methodologic differences or to thedifferent basal conditions in which recipients wereevaluated. In this regard, in the present study,hemodynamic measurements were obtained understable conditions, without evidence of hepatocellu-lar dysfunction (e.g., rejection), infection, or ane-mia. In addition, none of the patients were takingany form of vasoactive drug as treatment forarterial hypertension when they were studied. Withrespect to this latter point, in two previous studies,an important number of patients received antihyper-tensive drugs, and in one of them treatment wasdiscontinued only 2 days before hemodynamic

evaluation.9,11 Drugs such as nicardipine or hydrala-zine may increase cardiac output both in normalsubjects and in patients with hypertension.13,14

Thus, use of either drug could contribute to thepersistent hyperkinetic state after OLT.

In the present study, hemodynamic measure-ments were performed by use of the Dopplertechnique. During the last few years, duplex ultra-sound has become a reliable, noninvasive methodof assessing systemic and splanchnic blood flow.Several reports from our laboratory and othersshow the reliability of this technique in evaluationof hemodynamic changes under physiologic andpharmacologic stimuli in portal hypertensive pa-tients.15-19

Splanchnic hyperemia after OLT could be re-lated to several factors. Navasa et al11 showed apersistent increase in azygos blood flow, an indexof gastroesophageal collateral blood flow in liver-transplant patients. Their findings suggest thatalthough portal pressure returns to normal,20 porto-collateral vessels remain open after OLT. Passage ofvasoactive hormones from the gastrointestinal tractinto the systemic circulation via portal systemicshunting could be responsible for the increasedportal blood flow after OLT. This explanation ischallenged by the normalization of levels of gluca-gon, an important mediator in the splanchnichyperemia in cirrhotic patients, after OLT.11 Recentstudies have demonstrated that vasodilation inportal hypertension is influenced by increasedproduction of nitric oxide (NO).5,6 Therefore, it isreasonable to hypothesize that NO also contributesto the splanchnic hyperemia associated with OLT.The increase of NO release in the latter group couldbe related with an increase in shear stress second-

Figure 1. Systemic hemodynamic parameters in patients with cirrhosis before and 3 and 6 months afterOLT. (*) indicates significant difference from pre-OLT values.

Figure 2. Portal blood flow in patients with cirrho-sis before and 3 and 6 months after OLT. Thisfigure also shows data for portal blood flow inhealthy controls. (*) indicates significant differencefrom values obtained before OLT and healthycontrols.

Alvarez et al302

ary to persistent hyperdynamic splanchnic circula-tion.21 In addition, an accumulation of vasodilatorysubstances of splanchnic origin, such as substanceP and vasoactive intestinal polypeptide, mightcontribute to the release of NO.22 Further studiesare needed to evaluate the role of endothelial-independent and -dependent factors in the hemody-namic changes after OLT. Persistent collaterals maybe responsible for the increase in cardiac output, asis observed after portacaval shunting.20 In ourstudy, cardiac output returned to nearly normalvalues, and no angiographic or duplex ultrasoundevidence of abnormal vascular collaterals was ob-served. This finding suggests that other mecha-nisms are responsible for the increase in portalblood flow after OLT.

Finally, another factor that could be involved inthe increased portal blood flow is the effect ofsympathetic denervation of transplanted liver. How-ever, portal venous flow is under the influence ofthe vasomotor tone in the superior mesentericarteries, which should be undisturbed after OLT.Therefore, the denervation of the liver should nothave a major influence on the hemodynamic pat-tern observed in transplant recipients.

In conclusion, our data show normalization ofsystemic hemodynamics after OLT. However,splanchnic hyperemia manifested by an increase inportal blood flow develops after OLT and persistsfor at least 6 months. Further studies are needed toclarify the mechanisms involved in the splanchnichyperemia seen after OLT.

References

1. Bosch J, Navasa M, Garcıa-Pagan JC, De Lacy AM,Rodes J. Portal hypertension. Med Clin North Am1989;73:931-953.

2. Vorobioff J, Bredfeldt JE, Groszmann R. Increasedblood flow through portal system in cirrhotic rats. Gastro-enterology 1984;87:1120-1126.

3. Benoit JN, Zimmerman B, Premen AJ, Go VLW, GrangerDN. Role of glucagon in splanchnic hyperemia ofchronic portal hypertension. Am J Physiol 1986;251:6674-6677.

4. Silva G, Navasa M, Bosch J, Chesta J, Pizcueta MP,Casamitjana R, et al. Hemodynamic effects of glucagonin portal hypertension. Hepatology 1990;11:668-673.

5. Pizcueta P, Pique JM, Fernandez M, Bosch J, Rodes J,Whittle BJR, Moncada S. Modulation of the hyperdy-namic circulation of cirrhotic rats by nitric oxide inhibi-tion. Gastroenterology 1992;103:1909-1915.

6. Lee FE, Albillos A, Colombato LA, Groszmann RJ. Therole of nitric oxide in the vascular hyporesponsivenessto methoxamine in portal hypertensive rats. Hepatology1992;16:1043-1048.

7. Henderson JM, Millikan WJ, Hooks MH, Noe B, KutnerMH, Warnen WD. Increased galactose clearance afterliver transplantation: A measure of increased blood flowthrough the denervate liver? Hepatology 1989;10:288-291.

8. Hadengue A, Lebrec D, Moreau R, Sogni P, Durand F,Gaudin C, et al. Persistance of systemic and splanchnichyperkinetic circulation in liver transplant patients. Hepa-tology 1993;17:175-178.

9. GadanoA, HadengueA, Widmann J, Vachiery F, MoreauR, Yang S, et al. Hemodynamics after orthotopic livertransplantation: Study of associated factors and long-term effects. Hepatology 1995;22:458-465.

10. Henderson JM, Mackay GJ, Hooks MH, Chezman JL,Galloway JR, Dodson JF, et al. High cardiac output ofadvanced liver disease persists after orthotopic livertransplantation. Hepatology 1992;15:258-262.

11. Navasa M, Feu F, Garcıa-Pagan JC, Jimenez W, LlachJ, Rimola A, et al. Hemodynamic and humoral changesafter liver transplantation in patients with cirrhosis.Hepatology 1993;17:355-360.

12. Henderson JM. Abnormal splanchnic and systemichemodynamics of end-stage liver disease: What hap-pens after liver transplantation? Hepatology 1993;17:514-516.

13. Burlew BS, Gheorghiade M, Jafri SM, Goldberg AD,Goldstein S. Acute and chronic hemodynamic effects ofnicardipine hydrochloride in patients with heart failure.Am Heart J 1987;114:793-804.

14. Rubin S, Chatterjee K, Ports T, Gelberg H, Brundage B,Parmely W. Influence of short-term oral hydralazinetherapy on exercise hemodynamics in patients with severechronic heart failure.Am J Cardiol 1979;44:1183-1189.

15. Alvarez D, Mastai R, Lennie A, Soifer G, Levi D, Terg R.Noninvasive measurement of portal venous blood flowin patients with cirrhosis: Effects of physiological andpharmacological stimuli. Dig Dis Sci 1991;36:82-86.

16. Alvarez D, Golombek D, Lopez P, de las Heras M, ViolaL, Sanchez S, et al. Diurnal fluctuations of portal andsystemic hemodynamic parameters in patients withcirrhosis. Hepatology 1994;20:1198-1203.

17. Rojter S, Tessler J, Alvarez D, Persico R, Lopez P, BandiJC, et al. Vasodilatory effects of propyilthiouracil inpatients with cirrhosis. J Hepatol 1995;22:184-188.

18. Sabba C, Weetin G, Cichetti DV, Fernaioli G, Taylor K,Nakamura T, et al. Observer variability in echo-Dopplermeasurements of portal blood flow in cirrhotic patients andnormal volunteers. Gastroenterology 1990;96:1603-1611.

19. Zoli M, Marchesini G, Brunoni A, Cordaini R, Pisi E.Portal venous blood flow in response to acute betablockers and vasodilatory treatment in patients withcirrhosis. Hepatology 1986;6:1248-1251.

20. Bosch J, Mastai R, Kravetz D, Bruix J, Rigau J, Rodes J.Measurement of azygos venous blood flow in theevaluation of portal hypertension in patients with cirrho-sis: Clinical and hemodynamic correlations in 100 pa-tients. J Hepatol 1985;1:125-139.

21. Bernardich C, Fernandez M, Bandi JC, Bosch J, RodesJ. Mechanical pumping of portal blood to the liver:Hemodynamic effects of a new experimental treatmentfor portal hypertension. J Hepatol 1996;25:98-105.

22. Gray DW, Marshall I. Human alpha-calcitonin gene-related peptide stimulates adenilate cyclase and guanyl-ate cyclase and relaxes rat thoracic aorta by releasingnitric oxide. Br J Pharmacol 1992;107:691-696.

Portal Blood Flow and OLT 303