Effects of Systemic Prostaglandin E1 on Splanchnic and Peripheral Haemodynamics in Control Subjects and in Patients with Cirrhosis

Effects of Systemic Prostaglandin E1 onSplanchnic and Peripheral Haemodynamicsin Control Subjects and in Patientswith Cirrhosis

Andrea Fabbri,* Donatella Magalotti,* Giulio Marchesini,1†Mara Brizi,† Giampaolo Bianchi,* and Marco Zoli*

*Dipartimento di Medicina Interna, Cardioangiologia, Epatologia,Universita di Bologna, Policlinico S. Orsola, Bologna, Italy

†Cattedra di Malattie del Metabolismo, Universita di Bologna,Policlinico S. Orsola, Bologna, Italy

Prostaglandins of the E series showed metabolic and clinical effects inpatients with liver disease; changes in splanchnic haemodynamicsmight be involved.

Blood flow in femoral and mesenteric artery and in the portal veinwas measured by echo-Doppler in 10 controls and 14 cirrhotic pa-tients, in response to the systemic infusion of a PGE1 analogue (30mg/h for 2–6 h) or saline, performed in random order. Intraparenchy-mal resistive and pulsatility indices in the liver, spleen and kidneywere also measured.

In both groups PGE1 increased femoral artery flow by 40%, irrespec-tive of infusion time. Heart rate increased slightly, whereas mean arte-rial pressure decreased. There were no changes in mesenteric arteryand portal vein flow, as well as in resistance indices. Saline infusionincreased femoral artery flow by 4%.

PGE1 infusion does not produces significant effects on Doppler-as-sessed splanchnic hemodynamics in controls and in cirrhotic patients,in spite of significant effects on peripheral circulation.

Keywords: Alprostadil-a-ciclodextrin; systemic hemodynamics; splanchnic bloodflow

1Address correspondence to: Giulio Marchesini, Dipartimento di Medicina In-terna, Cardioangiologia, Epatologia, Universita di Bologna Policlinico S. Orsola, 9,Via Massarenti, I-40138 Bologna, Italy; Phone: 139–51-392524; Fax: 139–51-340877.

Prostaglandins & other Lipid Mediators 55:209–218, 1998© 1998 by Elsevier Science Inc. 0090-6980/98/$19.00655 Avenue of the Americas, New York, NY 10010 PII S0090-6980(98)00020-3

Introduction

Several investigations suggested that prostaglandins of the E series mayhave beneficial effects in acute liver damage (1). It has been proposed thatat least part of these effects are mediated by the vasodilator activity ofprostaglandins on smooth muscle, counteracting the vasoconstrictivestimuli leading to ischemia. The mechanism might be amplified by anantiplatelet and fibrinolitic activity, leading to a general cytoprotectiveeffect of prostaglandins on hepatocytes (2). In experimental animals mi-soprostol pretreatment protects the liver from acetaminophen-inducedfailure by preventing microvascular injury (3). In patients with acutehepatitis, systemic prostaglandin infusion leads to reduced hepatocellularnecrosis (4). Also in these conditions reduced liver damage was referred tothe protective effects of prostaglandins, or their synthetic analogs, in theprevention of microvascular hepatic injury.

In subjects submitted to liver transplantation conflicting results werereported on the effects of prostaglandin infusion on primary nonfunction(5–7) and acute rejection (8), but the drug definitely reduced the need ofintensive care support (6) and hospital stay (8). Finally, in patients withliver cirrhosis PGE1 infusion produced significant metabolic effects onamino acid and whole-body nitrogen metabolism (9).

Only a few studies are available on the hemodynamic effects of pros-taglandin infusion on splanchnic circulation (10,11). In patients withliver disease, prostaglandin infusion into the superior mesenteric arteryincreased portal and hepatic vein flow, as well as portal pressure (12),whereas the oral administration of indomethacin, an inhibitor of PGssynthesis, was shown to decrease hepatic blood flow and portal pressure(13). In cirrhosis, the metabolic effects of prostaglandin E were demon-strated in the absence of any change in the splanchnic vessel flow (9), butthe problem has never been studied systematically.

We measured peripheral and splanchnic haemodynamics by the echo-Doppler technique in control subjects and in patients with cirrhosisduring systemic prostaglandin E1 infusion.

Materials and Methods

Patients

Fourteen patients with cirrhosis (M/F: 12/2, aged 45 to 68 years, median55), without ascites and an optimal echo-Doppler visualisation of thesplanchnic vessels were selected. Their cirrhosis was related to alcoholabuse (6 cases) or hepatitis-C virus (8 cases). Alcoholic patients wereabstaining from alcohol from 6 months or more. Their laboratory datawere as follows: albumin, 3.3 6 0.5 g/dL; prothrombin activity, 58 612%; cholesterol, 139 6 42 mg/dL; bilirubin, 2.9 6 3.3 mg/dL. Threepatients were in Child Pugh class A (14), 8 were in class B, 3 were in class

PGE1 and Hemodynamics: Fabbri et al.

210 Prostaglandins & other Lipid Mediators 1998:55, March

C. The Child-Pugh score ranged from 5 to 13 (median 7.5). Oesophagealvarices were present in 11 patients (small in 6, medium-sized in 2 andlarge in the last 3 cases). Only 1 patient had suffered from episodes ofvariceal bleeding 1 year before the study and had been repeatedly treatedwith endoscopic sclerosis until varices eradication.

No patients had clinically evident ascites at the time of study. In threecases it was detected at ultrasonography before the study. These patientswere treated with diuretics (spironolactone (100–200 mg/day) and/orfurosemide (25 mg/day)), and the protocol was postponed by a few days.In addition, all patients were actively treated with lactulose (15–30 g/day)to prevent hepatic encephalopathy.

Renal function was in the normal range (plasma creatinine , 1.3mg/dL), and there were no evidence of previous or actual endocrinopa-thies or complicating disorders.

Ten healthy subjects were studied as controls (age range 34–70 years,median 52). They had no clinical evidence or routine laboratory dataindicative of renal or hepatic disease.

All subjects gave informed consent to take part in the study and theprotocol was approved by the Senior staff Committee of the Department.

Methods

All studies started at 07:30 a.m., after an overnight fast. After an echo-Doppler measurement of splanchnic and peripheral haemodynamics, per-formed as described below, all subjects received an i.v. infusion of a PGE1analogue (Alprostadil-a-ciclodextrin, Schwarz Pharma AG, Germany) insaline solution, at a constant rate of 30 mg/h. The infusion period was 2 hin the first 8 patients and 6 controls, and 6 h in the following 6 patientsand 4 controls. The infusion rate was calculated to yield plasma concen-trations of 5–6 pg/mL, i.e., approximately 3 times normal values (normalplasma levels: 1.3–1.8 pg/mL) (15). The echo-Doppler measurements wererepeated in the last 20 min. of PGE1 infusion; during the whole period thepatients did not receive any medication.

In all subjects receiving the 6-h infusion, the whole study was per-formed twice, with and without PGE1, in random order at 3–5 dayinterval. The total amount of saline given in each experiment was 250mL/h, with minimum fluid retention during long-term experiments.

The echo-Doppler measurements were performed using an equipmentwhich combines a real time electronic convex scanner and an echo-Doppler unit (AU4-Idea, ESAOTE Ansaldo, Genoa, Italy). We measuredblood velocity and flow in the superior mesenteric artery and in the portalvein. The mesenteric artery flow was measured by positioning the Dopp-ler sample volume in the middle of the artery, just past its origin from theaorta (16). The portal vein was longitudinally scanned and the samplevolume was positioned in the middle of the portal trunk, in the tract justunderneath the hepatic artery, as previously described (17). Care was


211Prostaglandins & other Lipid Mediators 1998:55, March

taken to maintain the u angle (the angle between ultrasonic beam andblood flow direction) at below 55° in each measurement. Hepatic arteryflow was not measured, since it may only be assessed in selected patientswith cirrhosis, due to technical difficulties and frequent anatomic vari-ants (18).

From the wave-form record of blood flow velocity, the measurement ofpeak systolic, end-diastolic and mean flow velocity, we also calculatedthe intra-parenchymal arterial resistive index (RI) and pulsatility index(PI) in the liver, spleen and kidney, according to the following formulas(19):

RI 5 ~Peak systolic 2 End diastolic velocity!/~Peak systolic velocity!

PI 5 ~Peak systolic 2 End diastolic velocity!/~Mean velocity!

RI and PI of the intra-hepatic artery were obtained from the mean valuesof the left and right branches.

The effects of prostaglandin infusion on peripheral circulatory systemwere also assessed, by measuring femoral artery flow, heart rate andarterial pressure. Blood flow in superficial femoral artery was measured aspreviously described by Katz et al. (20), with the transducer positioned onthe medial portion of the thigh at the inferior border of the femoraltriangle. Great care was taken to visualise the vessel at its largest diameter.

The echo-Doppler examination was always performed by the sameinvestigator, who had more than 5 years experience in Doppler examina-tion of deep abdominal vessels, and who was unaware of the clinicaldiagnosis and of the experimental treatment of subjects.

Patients were examined in the supine position and in the course ofDoppler recording were asked to hold their breath during normal respi-ration. According to previous experiences, the measurements were thenrepeated until three consistent values of blood velocity and flow wereconsecutively obtained (maximum variability: portal velocity, 1 cm/s;mesenteric artery velocity, 5 cm/s), and the mean values were consideredfor statistical purposes (16,17,19). The final intra-observer coefficient ofvariability of blood flow was 6 8%.

During PGE1 infusion two patients showed erythema over the infusedvein, and one subject experienced progressive flushing, but the effectswere well tolerated and the study protocol was completed in all cases.

Statistical Analysis

All data were analyzed by means of a personal computer and StatView IIa

program (Abacus Concepts, Inc., Berkeley, CA). Differences betweenvalues measured in the course of the same experiment were analyzed bypaired t test. A p value , 0.05 (2-tailed analysis) was considered statisti-cally significant. Data in the text and in tables are given as mean [SD].



Results

The effects PGE1 infusion on hemodynamic parameters were not differ-ent when data measured in the 2-h experiment were compared with thoseobtained after 6-h infusion in both control subjects and patients withcirrhosis (e.g., see blood flow in Fig. 1). For this reason the results werepooled in Table 1.

Femoral artery flow at baseline was higher in cirrhosis. In response toPGE1 infusion, it increased by 40% (95% confidence interval, 20–60%) incontrols and by 37% (95% CI, 16–57) in cirrhosis, the increase beinglarger in the presence of lower fasting values. The increase was entirelydue to increased blood velocity (Controls, from 25.1 [9.6] cm/s to 33.4[11.6], p , 0.01; Cirrhosis, from 32.2 [5.1] cm/s to 42.9 [6.4]; p , 0.001),without any change in cross-sectional area. A modest increase in heartrate was observed, whereas mean arterial pressure (which was lower incirrhosis) decreased slightly in response to PGE1 infusion. There were nodetectable differences in mesenteric artery and portal vein flow.

Pre-infusion RI and PI in the liver and spleen were increased in ourpatients with cirrhosis. In both groups they did not change significantlyin the course of the experiment (Table 1).

In subjects restudied during matched saline infusion, baseline Dopplermeasurements of peripheral and splanchnic hemodynamics differed fromvalues measured before PGE1 infusion by less than 10% (not reported indetail). At the end of the 6-h saline infusion no remarkable changes insplanchnic flow and resistance indexes were measured. Only femoral

FIGURE 1. Percent change in blood flow in peripheral and splanchnic vessels following a 2-hand a 6-h PGE1 infusion in control subjects (open columns) and in patients with liver cirrhosis(closed columns) (mean [2 SE]).



artery flow increased by nearly 4% in controls (from 570 [337] mL/min. to591 [356]; p , 0.05) and by 5% in cirrhosis (from 809 [227] mL/min. to 852[210]; p , 0.05), possibly due to increased blood volume.

Discussion

Our study shows that the peripheral infusion of PGE1, at a rate to elicitan effect on the systemic circulation, does not produce Doppler-detect-able effects on splanchnic hemodynamics both in control subjects and inpatients with cirrhosis and portal hypertension. The data do not supportthe hypothesis that the beneficial effects of PGE1 in patients with liverdisease are mediated by their vasoregulatory activity.

The present study was planned to test the hemodynamic effects ofperipheral PGE1 infusion. Since plasma concentrations of infused PGE1rapidly reach steady-state levels (15), a 2-h experiment was programmed.No effects on splanchnic hemodynamics were measured by this experi-mental design; therefore in additional patients the infusion was pro-longed to 6 h and experiments were controlled with saline to cope withpossible volume expansion. Data were not different, and the results wereconsequently pooled.

The study was carried out by means of the Doppler technique, using astrictly standardized procedure to minimize the errors intrinsic to Dopp-ler measurements in large vessels (16,17). Accordingly, interobservervariability can be kept below 10% for most parameters. The same tech-

TABLE 1. Effects of systemically-infused prostaglandin E1 on splanchnic and peripheral haemo-dynamics in control subjects and in patients with cirrhosis (means [SD]). Data measured in thecourse of short-term (2-h) and long-term (6-h) experiments were pooled, since no differenceswere demonstrated in relation to infusion time.

Controls (n 5 10) Cirrhosis (n 5 14)

Baseline Prostaglandin Basline Prostaglandin

Femoral blood flow (mL/min.) 543 [131] 738 [169]a 728 [212]b 953 [189]a,b

Heart rate (beats/min.) 67 [17] 71 [17]a 70 [14] 74 [13]Mean arterial pressure (mm Hg) 101 [4] 98 [8] 90 [5]b 86 [4]a,b

Portal flow (mL/min.) 968 [432] 961 [384] 1147 [509] 1087 [491]Mesenteric artery flow (mL/min.) 648 [151] 619 [148] 589 [132] 616 [173]Resistive Index Liver 0.58 [0.06] 0.60 [0.04] 0.65 [0.09]b 0.66 [0.06]b

Spleen 0.52 [0.06] 0.54 [0.05] 0.60 [0.07]b 0.62 [0.09]b

Kidney 0.58 [0.06] 0.60 [0.04] 0.62 [0.07] 0.62 [0.07]Pulsatility Index Liver 0.90 [0.17] 0.92 [0.14] 1.16 [0.28]b 1.18 [0.20]b

Spleen 0.75 [0.11] 0.78 [0.12] 0.94 [0.16]b 0.99 [0.21]b

Kidney 0.91 [0.12] 0.94 [0.09] 1.05 [0.22] 1.04 [0.24]

aSignificantly different from the corresponding value at baseline; p , 0.05.bSignificantly different from the corresponding control value; p , 0.05.



nique also allows the measurement of intraparenchymal resistance indi-ces in splanchnic organs (19), representing the downstream arterial resis-tance. A correlation was previously reported between the resistive indexand organ perfusion (19), and the pulsatility index may be considered aeven better index of resistance. They both give clues to microcirculationand add significant information to blood flow measurement in largevessels. Any increase in organ perfusion would be expected to carry out areduction in resistance indices.

In contrast to previous reports (12,13), we failed to demonstrate anyincrease in splanchnic vessel flow in response to PGE1 infusion. Bloodflow in mesenteric artery and in portal vein was normal and did notchange. In this series, due to difficulties in the measurement of hepaticartery flow, this value was not recorded and total hepatic flow cannot becalculated. However, there is no rationale to suggest a selective effect ofsystemic PGE1 infusion on hepatic artery flow, different from the resultsobtained in mesenteric artery flow. Similarly, resistance indices did notchange. They both were increased in the liver and in the spleen ofpatients with cirrhosis, as previously reported in relation to portal hyper-tension (19), but did not decrease in response to PGE1 infusion, indirectlysuggesting that hepatic artery blood flow was not affected.

The negative results of PGE1 infusion on splanchnic hemodynamicswere accompanied by significant effects on systemic circulation, in keep-ing with a previous study (21). PGE1 infusion definitely produces a hy-perdynamic circulation, characterised by increased heart rate and cardiacoutput, and decreased peripheral vascular resistances (22). The dose weused (30 mg/h, approximately equal to 7 ng/kg per min.) is the doseusually recommended to elicit a systemic effect, minimizing side effects,and is expected to raise plasma PGE1 by 100–200% (15). In the pharma-ceutical preparation we used, the binding of PGE1 to a-ciclodextrin in-creases the systemic bioavailabilty of the compound (15). Our patientswith cirrhosis were characterized by the well-known hyperdynamic stateof advanced liver disease (23,24), and PGE1 infusion further increasedfemoral artery blood flow, had minor effects on heart rate and meanarterial pressure. The cardiac index was not measured in the presentexperiments, but only in patients with cardiac disease an increase instroke volume and cardiac index is expected with doses as low as 10–30ng/kg per min (25). In conclusion, the lack of effects on splanchnichemodynamics during PGE1 infusion was observed in the presence of adefinite effect on systemic hemodynamics and only minor effects on theheart.

The actual concentration of PGE1 in the splanchnic vein bed duringPGE1 infusion was not measured. Nishida et al. (12) showed that portalpressure and flow increases significantly in patients with a variety of liverdisease after an intraarterial infusion of PGE1 at a rate of 1 mg/min.,approximately twice as much the dose we used. A possibility remains



that splanchnic vein flow may be increased by a higher PGE1 infusionrate, but such treatment is likely to produce systemic side effects (25,26),and the ensuing increase in portal pressure is potentially dangerous incirrhosis.

We studied both control subjects, with normal liver function andnormal portal pressure, and patients with cirrhosis, in a wide range ofhepatocellular dysfunction and portal hypertension. In clinical hepatol-ogy PGE1 treatment has been proposed both in acute liver failure (1,4),characterized by hepatocellular failure and normal or elevated portalpressure, and in primary non-function (5) and acute rejection followingliver transplantation (8). The last two conditions are characterized by anormal liver and normal portal pressure. In these patients PGE1 infusionproved effective in ameliorating prognosis, reducing intensive care sup-port and hospital charges (6,27). On the basis of the present data theputative beneficial effect of PGE1 is more likely dependent on its meta-bolic effects on amino acid and whole body nitrogen metabolism, leadingto nitrogen sparing (9), than on their ability to counteract the vasocon-strictive mechanism of ischemia-induced toxins on intrahepatic sinu-soids (1). Further studies are needed to clarify this topic.

Acknowledgments

The authors are indebted to Schwarz Pharma AG, Monheim, Germany,for kindly providing the alprostadil-a-ciclodextrin preparations (Prostava-sin®) used in the study. Supported by Funds from Ministerodell’Universita e della Ricerca Scientifica (MURST), Fondi ex 60%,Rome, Italy.

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Editor: Dr. P. Ramwell Received: 12-31-97 Accepted: 02-20-98



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Effects of Systemic Prostaglandin E1 on Splanchnic and Peripheral Haemodynamics in Control Subjects and in Patients with Cirrhosis