Verapamil has no effect on porto-hepatic pressure gradient, hepatic blood flow and elimination function of the liver in patients with liver cirrhosis

302

Verapamil has no effect on porto-hepatic pressure gradient, hepatic blood flow and elimination function of the liver in patients with liver cirrhosis

J.P. Vinel’, J.P. Caocenas’, J.M. Combis’, P. Gales’, J.J. Voigt’ and J.P. Pasta? 2Service d’Anammo-pathologk C. K. U. Porpan, Toulouse Cedex (Fnmce) ‘Service d’Hepar~R~Iro-ent~rologie, (Received 9 August 19BB) (Accepted 14 December 1988)

This study

aimed to assessthe effects of verapamil, a calcium-channelblocker,

on porto-bepatic pressure gm-

and on hepaticfunctionas measuredby the intrinsichepaticclearanceof indocyanine green(ICG) in pahew withbi%psy provenalcoholiccirrhosis.Hepaticvenouspressures and hepaticextractionof KG were measuredbeforeand 5l min after intravenous injection of 10 mg of verapamil in 19 consecutive patients. Hepatic

dient

blood flow and intrinsic bepatic clearance of

ICG were calculated

in the 10 patients whose hepatic extraction

fraction was higher than 10%. No significant difference was observed when comparing portomhepatic pressure gradient (17.72 f 4.79 vs. 17.77 5 4.43 mmHgp), hepatic kg-‘) and intrinsic hepatic clearance of KG

blood flow (13.47 + 4.75 vs. 16.13 f 7.88 mlmin“~

(1.99 f 0.54 VS. 1.97 f 0.45 ml.min-l.kpl)

before and after verapa-

mil injection. We conclude that verapami! has no beneficial effect in patients with alcoholic cirrhosis.

using vasoconstrictors (such as j+blockers

Introduction

pressin) or 10 decrease portal Both increased porrat venous inflow and increased

or VBSO-

venous resistances

osing vasodilators.

portal venous resistance: participate in the pathogen-

Recently,

esis of portal hypertension in patients with cirrhosis

[3,4] wcie

Ul.

their use in the treatment of patients with cirrhosis

Medical

treatment

of portal hypertension

could

therefore aim either to reduce portal venous inflow

Correspondence:

J.P.Vincl. Service d’Hepato.gastro~nterologie,

nitroglycerin

[2] and isosorbide dinitrate

found to decrease portal Pressure and

was considered. Another channel blocker verapamil

vasodilator,

C.H.U. Pwpan. 311359Toulouse Cedex, France

Ott&8278189iS03.M~ 19S9ElsevierSciencePublishersB.V. (BiomedicalDivision)

the calcium-

has been shown to de-

EFFECIS

OF “ERAPAMlL

IN ALCOHOLIC

CIRRHOSIS

cwse intra-hepatic resistances and to mtprove the otetabuiic acuvay of ‘tre irver m perfused cirrhotic rat !Iver [S,S]. :n cirrhotic patients, verapamil was reported in three series [4,7,8] to reduce the porto-hcpatic pressure gradient, calculated as the difference between free and wedged hepatic vein pressurer. In one study, only 6 patients were studied and the etiology of cirrhosis was not stated 141.In the two other series [7,8], patients had post-necrotic cirrhosis, a condition in which wedged hepatic vein pressure is known to be poor!y correlated with portal pressure [S]. Furthermore, the effects of verapamil on hepatic function have not been studied in man, so far. The present study aimed to assess the effects of verdpamil on pno-hepatic pressure gradient and on hepatic function as measured by the intnnsic hepatic clearance of KG in patients with alcoholic cirrhosis.

Patients and Methods Patients 19 consecutive patients (14 males and 5 females) with biopsy proven alcoholic cirrhosis and portal bypertension were studied. Their main clinical and biochemical characteristics are given in Table 1. All the patients gave their informed consent to participate in the study which was approved by the local ethical committee. M&OdS

All the patients were studied after an overnight fast. A 7F Coumand catheter was inserted in the main ri8ht hepatic vein by the tramjugular approach, under fluorowpic control. lndocyanine green (KG) (vert d’indocyanine - Laboratoire SERB, France) was infused through an antecubital vein at a mnstant rate of 0.15 mg-miri’ (0.19~moImin~‘) after a bolus injection of 10 mg. Atier ao equilibration period of 30 min, samples were drawn shnultaneously from a peripheral vein and fmm the hepatic vein at 2 min intervals over a 10 min period. Free and wedged hepatic pressures were measured with an electromapetic maooometer (Honeywell, E.B-200)

303 by reference lo a zero point situated at the level of the mid-a?;iila;y line with the patient in the supine position. The same measurements were repeated 60 min after i.v. injection of 10 mgof vcrapamil. Determination of KG plasma concentrations was performed immediately after the investigation by spectrophotometry at 805 nm. Hematocrit was measured by centrifogatioo (Compur M 1100, Compur electronic GmbH, Mitnchen, F.R.G.).

Tiie puiiirhcpiiii

prcbsure grariieni Was calcu-

lated as the difference between wedged hepatic vein pressure and free kepatic vein p:essore. Results were expressed as the mean of at lean three measurements. Hepatic extraction fraction Q was ca:c&ted as C, - C&, where C,, and C, are mean plasma cortceatrations of KG in the peripheral vettow blood and in the hepatlc vein, respectively. Hepatic blood flow and ‘intrinsic’ hepatic clearance of ICG were calculated only when E was higher than 10%. IO patients fulfilled this requirement. Hepatic plasma flow (HPF) was calculated as OC, - C, where 1 is the infusion rate of KG (0.15 mg min-I) [IO]. Hepatic blood flow (HBF) was cZx!ze< as HPE’I- hemam&. The ‘intrinsic’ hepatic clearance (IHC) of ICG was calculated accordi to the sinusoidal model [:I,121 as -HBF.ln(l -E). Whethex a steady-state concentration of ICG was achieved was assessed by &:emdoiog the slopes of the concentrationvenus tirreuuvesduringeachsanlplil8p:rind. TABLE 1 MAIN CLINICAL AND BLOCHEUICAL ISTK3 OF THE PATIENTS

CUARAcTrR-

Patients (n = 19) 57.8 i 13.6 14(74%)/S (26%) 435.3 +92.-l 29.9 + 27.9 9 (47%) 4 (21%) a.2 f 14.7 8.5 + 1.9

304

J.P. VINEL et a,.

TABLE

2

FREE AND WEDGED HEPATIC VElN PRESSURE AND PORTO-HEPATIC PRESSURE GRADIENT BEFORE (A) AND AFI’BR (B) XlWtAVENOUS INJECtTON OF 10 mgVERAPAMlL IN 19 PATIENTS WITH ALCOHOLiCCiRRHOSZi Patient No.

?HVP

wtVP

PHPG (mmHg)

(m&s)

A

B

A

B

A

B

:

2

i.6

13 15

23 15

13 11

3

5

6

4 5

5.3

5

2.6 * 5.6 4 3.3 5

3.6 2 3.5 4 4.3 5.7

23 33 2,

20.7 24.3 26 24 19 15 12.3 24

1E 27.7 18.4 25 15.4 ‘I 10 18.6 18 I8 20.7 20

13 17 14.7 19.3 22.4 22 15.5 1, a 18.3

6 7 8 9 10

:: 15 13.3 23.6

11

12 13 14 15

: 5.3 II i

it 18

11 8 7.3

ii

2

19 Mean + S.D.

:: 27.3 20 21 25 22 29 2.5.8

:: 26 28 2”

4.7, f 2.5,

P

5

25.5 28.7

5.5

22.0

3.98 f 1.68

22.4 + 5.4

:: 24.1 ts

z 14.5 20.7 14.7

21.8 k 4.4

z 15 24 20.3

17.72 f 4.79

N.S.

N.S.

_ FHVP = free hepatic vein pressure; WHVP = wedged hepatic vein pressure; PHPG = pano-hcpatic

Table Results

were expressed

comparisons

as mean

were pctformed

+ S.D.

pressure gradient: N.S. = nor

was observed

when

cornpar-

ing measurements before and after verapamil injec-

Statistical

using the paired

2. No difference

17.77 + 4.43 NS

tion.

r-test.

In the 10 patients hepatic RESUltS

KG

blood were

in whom calculations were made,

flow and intrinsic

not

innuenced

hepatic

by verapamil

clearance

of

(Table

3).

This subgroup of patients with an extraction fraction No systematic concentrations period, carves

devia:ion

in ICG peripheral

was observed.

the

slopes

of

During

did no! differ significantly

Systolic rapamil

arterial

ialection

respectively

pressure (14.3

before

rate was significantly

f

Individual

data and

pmthmmbin group

after ve-

index

which

fraction,

was greater

except

for the

in the former

(70.5 f 14.8% vs. 57.2 + 11.5%. respectively,

P < 0.05).

1.7 mm&, N.S.).

Pulse

by verapamil(76.4

C

P < 0.05).

on free and wedged

porto-hepatic

tients with a lower extraction

time

from zero.

1.6 VS. 14.3 f

decreased

higher than 10% was similar to the subgroup of pa-

sampling

versus

was not changed

and after verapamil,

14.2 vs. 73.0 f 13.8 bpm, pressures

each

concentration

plasma

gradient

hepatic are

vein

listed

in

Pharmacotherapy of portal hypertension so far has relied on vasoconstrictors which reduce portal pres-

EFFECTS OF “ERAPAMIL IN ALCOHOLIC CIRRHOSIS TABLE 3 HEPATfC BLOOD FLOW AND INTRINSIC HEPATIC CLhAMhiE OF KG IN II! PATiENTS WITH ALCOHOLlC CIRRHOSISBEFORE (A) AND AFTER (8) INTRAVENOUSINJECTtONOF !OmgVERAPAUIL Prxtientr corrcrpora 10parien*r L-10 inTable2. Palient Hepaticbloodflow No. (ml.min-‘.kg-‘) A 1 2 3

12.69 20.41 9.83

B

intrinsic hepaticclearance of KG (ml.min?.kg-‘) ~___ B A

19.03

2.39

2.23 1.12 1.56 1.72 1 54 2.09

2.24 2.1, 1.27 1.64 1.67 1 65 2.10

2.26 3.03 1.95

2.17 2.93 1.95

7

16.33

30.62 7.58 8.61 22.89 6.X 12.64

; 10

19.16 14.61 12.64

21 19.16 91 12.64

4

9.19

5 6

12.32 5.53

man f S.D. P

13.47*4 75 16.13+7.88 1.59+0.54 N.S.

,.97+0.45

N.S.

sore by decreasing splanchnic blood flow. However, decreasing perfusion of the liver in patients with eirrhosis could have deleterious effects. Actually, although the clinical relevance of this phenomermn remains to be determined, vx?pressin, posterior pituitary extracts, somatoatatln [U] and propranolol (14.151 were shown to decrease the hepatic elimination function as measured by the clearance technique. Using perfused cirrhotic rat liver, Reichen and Le [S] showed that verapamil, a calcium-channel blocker, reduced portal pressure and intra-hepatic resis. tances, decreased intra-hepatic shunting and increased the extravascular albumin space. This improvement in microvascular exchanges within the liver, was associated with an increase in aotipyrine clearance, a well-known measure of metabolic activityof the liver [la]. As previously stated, the three reports [4,7,8] published on the effects of verapamil on the por-@hep atic pressure gradient in patients with cirrhosis cannot be considered an unequivocal demonstration of the efficacy of this drug ia lowering portal pressure.

Finally, verapamil was shown in cirrhotic patients to mtprove fractional clearance of ICG [17] interpreted as a measwe of apparent liver blood flow. However, this assumption is clearly hazardws since in cirrhosis hepatic extraciion of ICG is decreased so t&t the clearance regime of ICG can no longer be flowdependent [lS]. Fick’s principle must be wad, requiring constant infusion of KG and hepatic venous blood sampling [19]. We therefore undertook the present study to assess the effects of verapandl on both haemodynantica and hepatic function in patients with alcoholic cinhosis. We failed to show any beaefieial effect of this drug either on the pzto-kepatic pressure gradient or on the hepatic elimination function as measured by the intrinsic clearance of KG. These negative restdts could be accounted for by three main methodological prob!cztts owing to: 1. Dosage of the drug and delay between injection and data measurements. 2. Relevance of parameters used to assess tbe effects of the drug. 3. Type 2 error in statisticalanalysfs. As regards dosage, a 10 mg dose was chosen since the same dose was used in the three previously published series [4,7,8j. The delay baweenverapamil injection ano data meawrentent was not stated in the study by

Freeman er al. [4]; it was 60 min in tbe two other repwts, as in the present study. Verzpamil is metabolized by the liver [Y&21]. Accordiigly, this drug has been shown to have a half-life 3 to 4-times as long in cirrhotic padents as in contmls, and plasma clearance decreased by half [ZZ]so that i.v. dosage should be half the normal dose. Under these mnditions, a 10 mg i.v. dose can be wnsidered a high dose and a 60 min delay should have been adequate. Achtally, the pulse rate was signllicantly decreased in our patients. The absence of any change in arterial pressure was already reported in two studies [6,t?] in which, nevertheless, verapamil was shown to reduce the port”-hepatic gradient. The relevance of the parameters chosen to assess the effects of the drug could also be questioned. Porto-hepatic pressure gradient is a well-established measure of portal venous pressure in alcoholic cir-

J.P. VlNEL et al.

306 rhosiswhere

these two parameters have been shown to be carrelated [23,24]. However, it has been observed that during acute administration of pmpranoloI, the measurement of wedged hepatic venous pressure did not provide a reliable estimation of the magnitude of the changes in portal venous presoure althouph the direction of the changes was the same using both parameters [2S]. Therefore, we cannot role out any effect of verapamii on portal pressure. Should such an effect exist, it would nevertheless be too small to have any therapeutic relevance. Hepatic blood flow was directly calculated using Fick’s principle during constant intravenous ICC? infusion. Calculations

were performed

the hepatic extraction i.e.,

in 10 patients.

only in patients

in whom

fraction was higher than lo%, Since our patients

had severely

liver function, the ICC perfusion rate was lower m this study than in most published serit in order to avoid saturation of ICC elimination krh.etics. impaired

Steady-stare

concentration

being achieved

and hep-

atic extraction being higher than lo%, such a method has been shown to be a suitable test for measuring liver blood flow. However, it measures total liver blood flow, i.e., blood flowing through functioning sinusoids ?s well as through intra-hepatic vascular shunts. In this setting, it is not possible from the results we obtained using this method, to assess whether or not verapamil improved microvascular exchanges within the liver as obwved in vitro [S]. The KG clearance value depends on both the hep atic blood flow and hepatic extraction fraction. The extraction fraction cannot be used as a measure of liver function, since it is partly dependent on flow so that reducing the hepatic blood flow increases hepatic extraction and, conve-W, increasing the blood flow decreases extraction [26]. Intrinsic clearance was conceived as the maximal hepatic clearance that would be obtained, should liver blood flow be infinite (i.e., not rate-limiting) [I6]. In other words, intrinsic clearance provides a flow-independent estimation of the metabolic activity of the liver, which according to

Michaelis Menten kinetics is measured as V,,,,#&,,. One must stress that intrinsic clearance is the net sum of all the processes involved in the elimination of the test substance, including the effects of binding to plasma proteins, hepatocyte uptake, storage, metabolism if any and exaction. Verapamil has been shown to increase antipyrine clearance [5]. aminopyrine and caffeine breath tests [6]. Since this was associated with a reduction in intra-hepatic shunting and an increase in extravascular albumin space, the improvement of hepatic function was ascribed to improved microvascular exchanges within the liver. If verapamil had the same actions in human cirrhotic liver, ICG intrinsic hepatic clearance should have be-_.. .:“---“--A .._._“..1__ Sinci :cc P xii metabolized bv the liver, such a discrepancy, between the effects of verapamil on ICG clearance on one hand and antipyrine, aminopyrine and caffeine clearance on the other hand, could be accounted for by a direct action of verapamil on drugs biottramformation enzymatic processes. An alternative explanation would be that the verapamil doses used in Reichen’s studies were much higher (g-16 mgllCH3ml) than those used in the present study. But using very high doses (100 mg per OS), Navasa et al. [U] failed to observe any beneficial effect of verapamil in patients with cirrhosis. Finally, we cannot rule out a type 2 error in statistical analysis. However, should this be the case, the beneficial (or detrimental) effects of verapamil in patients with cirrhosis would be too small to have any therapeutic relevance.

The beneficial effects of verapamil observed in cirrhotic rat liver could not be reproduced in patients with alcoholic cirrhosis. At a dose within the therapeutic range, verapamil had no action on the portohepatic gradient and metabolic activity of the liver. Therefore, this drug should not be recommended for the treatment of patients with cirrhosis.

EFFECTS OF VERAPAMIL

IN ALCOHOLIC

ClRRHOSlS

1 Benoit IN, Granyer DN. Spknebnic hemodynamin in chronic portal hypertension. Sem Liv Dir ,986; 6: 287-298. 2 Blei AT, O’Rendy DJ. Gottstein J. Portal systemic rhoming and hemodynamic effects of nitroglycerin in the rat. Garrw”tero,o8y x98-%86: 1428-1436. 3 Blei AT, Gottstein 1. Irosorbidc diritate in expximental portal hypertenston: a study of factora tbar mu;.:nte tha hemodynamic response. Hepatology 1986; 6: 107-111. 4 Freeman JG, Batton JG. Record CO. Effect of isosotbide dioitmte. verapamil and labetato, on portal pressure in cirthesis. Br MedJ ,985;29,: 561-562. 5 Reichen J and Le M. Vetapatnif favorably iti~~encen hep atic mictovassttlar exchange and function in rats with cirrhosis of the liver. J Clin lnvcst ,986: ‘78:448-455. 6 Rcichenl, Hfrlinpr A, HaHRandSlgerxr S. Chronicverapemil administration lowers portal pressure and improves hepatic function in rats with liver cirrhosis. J Hepato, ,986; 3: 49-58. 7 Kon8 CW, Lay CS, Tsaf YT, et a,. The hemodynamic effect of verapamil on portal hypettension in patients with port necmtic cirrhosis. Heoatolopv ,986: 6: 423-426. 8 ‘.a)_ CS, Tsai YT. Kong CW, et a,. Effectsof nifedipine, verapamd on hepatic and systemic hemwtynamics in patients with HBsAg positive cirrhosis: comparison with propranolo,. Chinese J Gastmenterol1986: 3: 74-80. 9 Ponder-Laytatgttes G, Kwietewia D, Willems B, et al. Presinusoidd portal hyprtension in non-atcoholic cinbusib Hepatology 198% 291: S61-‘%Z. 10 Caesar I. Sheldon S, Chiandussi L, et d. The ure of indacyanine 8rcen in the tnrarorcmcnt of hcpatic blood flow andasatatofhepaticfunctiott. ClinSzf ,96,:21: 43-51. 1, Bass L, Keidin8 S, Winkler K. Tysstrop NJ. Enzymatic elimination of substances tbwing through the intact liver. J Theor Biol19’16: 6:: 393-410. 12 Keidktg S. Hepatic clearance and livct blood flow. I Hepato1 1987; J: 393-398. 13 Batbare JC. Pouwn R. Jailloo P, et al. The i~Zun,ce of vasoactive agents on metabolic activity of the liver in cit. rhosis: a study of the effects of p+szerfor pituitary enract, vasoptesrin, andsomatostatin. Hepatology ,984; 4: 59-02. 14 Braillon A, Jiron MI. Valla D. et al. Effect of pmpranofol on hepztic Ilwd ilow III patients with cirrhosis. Oin PharI,

307 maco, Tber 1% 37: 376-f90. IS Vine1 JP, Caucanas m, C&s P. et al. Effect of pmpmnolo, on metabolic activity of the liver in patients with alcoholic eirrbosis. J “epat0, ,988: 7: ,86-w!. 16 Brench RA. Drug BSindieaton of hepatfc function. Hep ntology 1982; 2: w-105. 17 Miotti T md Rcichcn I. Ver~pamif iotpracr fractiona, clearance of indqanine 8xen io patfettts aith bver cftrbo. sir. J Hepatol1985; Sttpnt2: S291. 18 Cohn JN, Khstty IM. Groszmamt RJ, et al. Hepab blood flow in alcohottc tiwr dixare measured by an indicator dilution technique. AC., Pled 1972.53: 704-714. 19 Gruszmaon RJ. E:.E measmetnent of blood fbw using clearance techtdqoe. Hepatobp,y ,983; 3: 1039-1040. 20 Shorneros M, Spicgelhalder B. Stieren Band Eichelbaum M. Pbysio,o$eat disposition of wtapamfl io man. CstdiovascRcs ,?7& :o. 60(-612. 21 Hamann SR, Blo& RA and McAllister RG. Cffnifpl pharmacokmetics ot ~erapwtti,. C&n Pharmacokinet ,984, 9: 26-41. WoodcoFk BG, Ri
liver

22