Nicardipine increases hepatic blood flow and the hepatic clearance of indocyanine green in patients with cirrhosis

CopyrightOJournalofHepatology 1994

Journal of Hepatology 1994; 20:792-796 Printed in Denmark. All rights reserved Munksgaard. Copenhagen

Journal of Hepatology

ISSN 0168-8278

Nicardipine increases hepatic blood flow and the hepatic clearance of indocyanine green in patients with cirrhosis Juan Carlos Garcia-Pagfin, Fausto Feu, Angelo Luca, Mercedes Fernfindez, Pilar Pizcueta, Jaime Bosch and Juan Rod6s Hepatic Hemodynamics Laboratory, Liver Unit, Hospital Clinic i Provincial University of Barcelona, Spain

(Received 26 January 1993)

The present study investigated the hemodynamic effects of nicardipine, a new calcium channel blocker, and placebo in 14 patients with cirrhosis. Sixty minutes after nicardipine administration (20 mg orally; n=8), there was a significant increase in hepatic blood flow (25___21%; p<0.05) and azygos blood flow (33_+40%; p<0.05) but no significant change in the hepatic venous pressure gradient. As a result of the increase in hepatic blood flow and the lack of change in the hepatic venous pressure gradient, nicardipine significantly reduced hepatic sinusoidal resistance (-14___15%; p<0.05). Enhanced liver perfusion was associated with a significant increase in the hepatic clearance of indocyanine green (from 241 -+81 to 265-+92 ml/min, p<0.05). A mild, well-tolerated decrease in mean arterial pressure (-10-+6%, p<0.05), without significant changes in cardiac output, systemic vascular resistance and heart rate, was also observed. Placebo administration (n=6) did not cause significant changes in systemic or hepatic hemodynamics. The results of the present study show that nicardipine, unlike other calcium channel blockers, effectively increases hepatic blood flow and the hepatic clearance of indocyanine green in patients with cirrhosis. The acute beneficial effects of nicardipine should be confirmed in chronic studies. © Journal of Hepatology. Key words: Hemodynamics; Liver; Portal hypertension

Experimental studies in rats with portal hypertension due to carbon tetrachloride-induced cirrhosis have shown that the calcium channel blocker, verapamil, reduces hepatic vascular resistance and portal pressure and improves liver perfusion (1-4). These results suggest that verapamil administration to patients with cirrhosis could also reduce hepatic vascular resistance, increase liver perfusion and improve liver function. However, several studies performed in patients with cirrhosis have failed to show any decrease in the hepatic venous pressure gradient or improvement of liver function with this drug.(5,6). Furthermore, nifedipine, another calcium channel blocker with pronounced systemic effects even had adverse effects and increased portal pressure in patients with cirrhosis (7). This was probably because of the marked arteriolar vasodilatory effect of nifedipine, which caused splanchnic

vasodilation, and an ensuing increase in portal blood flow which overcame any beneficial effect on hepatic resistance. The present study investigated whether nicardipine, a new calcium channel blocker, could improve liver perfusion without increasing portal pressure in patients with cirrhosis and portal hypertension. Patients and Methods

The study was performed in 14 patients with cirrhosis who were referred to the Hepatic Hemodynamics Laboratory at the Liver Unit for evaluation of portal hypertension. All patients gave their informed consent to the investigation after a full explanation of the purpose and nature of the protocol, which was approved by the Clinical In-

Correspondence to: J Bosch, Hepatic HemodynamicsLaboratory,Liver Unit, Hospital Clinic i Provincial,C/. Villaroel 170, 08036 Barcelona, Spain

NICARDIPINE IN PORTAL HYPERTENSION vestigation Committee of the Hospital Clinic i Provincial of Barcelona (1988). Clinical data of the patients studied are given in Table 1. The investigation was performed during hepatic vein catheterization for the study of portal hypertension. At 9 a.m. after an overnight fffst and under local anesthesia, two venous catheter introducers (USCI International, Galway, Ireland) were placed in the right femoral vein, using the Seldinger technique. One was used to introduce a balloon catheter (Medi Tech, Cooper Scientific Corp. Watertown, Mass) which was then advanced under fluoroscopy and guided into the main right hepatic vein. The other venous introducer was used to advance a SwanGanz catheter (Edwards Laboratory, Los Angeles CA) into the pulmonary artery to measure cardiopulmonary pressures and cardiac output (thermal dilution), and to advance a 7 F coronary sinus continuous thermal dilution catheter (Webster Laboratories, Inc, Baldwin Park 91706 CA) into the azygos vein to measure azygos blood flow (8). Wedged (occluded) and free hepatic venous pressures (WHVP and FHVP, respectively), pulmonary artery pressure, pulmonary capillary wedged pressure, and right atrial pressure were measured using high sensitivity pressure transducers (Hewlett Packard, model 1280 C, Waltham, Mass), calibrated before each measurement (9). Permanent tracings were obtained on a multichannel recorder (Hewlett-Packard, 78309 A). AzBF was measured by continuous thermodilution, according to previously described methods (8). Arterial pressure was measured with an automatic sphygmomanometer (Dinamap, Critikion, Tampa, FI.), and heart rate was derived from the continuous ECG tracings. A solution of indocyanine green (Serb, Paris), containing 2% human serum albumin was infused intravenously, at a constant rate of 0.2 mg/ min. After an equilibration period of at least 45 min, four samples of peripheral and hepatic venous blood were obtained simultaneously at 2-min intervals to measure hepatic blood flow and the systemic and intrinsic clearance of indocyanine green (10). Steady indocyanine green

levels and a hepatic extraction of above 0.1 were required to calculate hepatic blood flow. Plasma indocyanine green concentration was measured by spectrophotometry on the day of the study, using the Nielsen method for correcting the influence of plasma turbidity (10). After obtaining baseline measurements, patients were randomly allocated by sealed envelope to receive nicardipine (20 mg orally; n=8) or placebo (n=6). All measurements were repeated 60 min later. In each period of the study, all measurements were taken at least twice. Portal pressure was estimated from the hepatic venous pressure gradient, the difference between WHVP and FHVP. Systemic vascular resistance (dyn.s.cm -5) was calculated as: (MAP-RAP)/CO × 80 where MAP (mmHg) is the mean arterial pressure, RAP (mmHg) is the right atrial pressure and CO (1/min) is the cardiac output. The hepatic blood flow (l/min) was calculated as: IR/(PV-HV)×(1-Ht) where IR is the indocyanine green infusion rate (mg/min), PV and HV are the plasma indocyanine green concentrations in peripheral venous blood and hepatic venous blood, respectively, and Ht is the hematocrit. The hepatic clearance of indocyanine green was measured as IR/PV. The intrinsic clearance of indocyanine green was calculated according to the sinusoidal model as hepatic blood flow.In (I-E), where E was the extraction ratio of indocyanine green calculated at steady state as PV-HV/PV (10). Since WHVP measured hepatic sinusoidal pressure and hepatic blood flow represents total blood flow perfusing the hepatic sinusoids, the hepatic sinusoidal resistance (dyn.s.cm -5) was estimated as hepatic venous pressure gradient/hepatic blood flowx80. The results are reported as mean_+standard deviation. Statistical analysis of the results was performed using the Wilcoxon signed rank test. Significance was established at p<0.05. Results

TABLE 1 Clinical data of the 14 patients studied Age (years) Sex (male/female) Alcoholic/non-alcoholic Esophageal varices Previous variceal bleeding Presence of ascites Bilirubin (mg/dl) Albumin (mg/dl) Prothrombin ratio Child-Pugh class (A/B/C) Child-Pugh score

793

62--.11 9/5 9/5 14 7 4 1.1-+0.5 40-+6 74-+ 11 12/2/0 5.5-+0.7

Baseline data All patients had severe portal hypertension as shown by a marked increase in the hepatic venous pressure gradient (17.5_+4.3 mmHg, range 10 to 25 mmHg). This was accompanied by an increase in azygos blood flow and by a hyperkinetic systemic circulation, evidenced by a high cardiac output and a decreased mean arterial pressure and systemic vascular resistance (Tables 2 and 3). The hepatic extraction and the hepatic and intrinsic clearance of indocyanine green were low in these patients

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J.C. GARCtA-PAGAN et al.

(Tables 2 and 3). All findings correspond to those observed in other patients with cirrhosis and portal hypertension studied in our laboratory (11).

Effects of placebo administration As shown in Table 2, placebo administration did not cause significant modifications in systemic or hepatic hemodynamics.

Effects of nicardipine on hepatic and systemic hemodynamics Nicardipine caused a mild, well-tolerated decrease in mean arterial pressure (-10___3 mmHg, p<0.05). Cardiac output, systemic vascular resistance and heart rate did not change significantly (Table 3).

TABLE 2 Effects of placebo on splanchnic and systemic hemodynamics in the six patients studied Baseline Heart rate (bpm) Mean arterial pressure (mmHg) Cardiac output (1/min) SVR (dyn.s.cm -5) HVPG (mmHg) Azygos blood flow (1/min) Hepatic blood flow (l/min) CLH oflCG (ml/min) CLI oflCG (ml/min) Hepatic extraction of indocyanine green

71 _+13 82+-14

Placebo

p

76+-8 83+-15

NS NS

8.2-+2.0 8.7+- 1.7 822+-310 780+-329 16.7+-4.6 16.7_+4.8 0.50+-0.19 0.62+-0.39 1.8-+0.8 1.7+-0.5 224+-134 203+-122 254+-175 231_+156 0.23_+0.11 0.22+-0.10

NS NS NS NS NS NS NS NS

SVR=Systemic vascular resistance; HVPG=Hepatic venous pressure gradient; CLH and CLI of ICG=hepatic and intrinsic clearance of indocyanine green.

Nicardipine caused a significant increase in total hepatic blood flow (+25+_21%; p<0.05) and in portal-collateral blood flow, estimated by measurement of azygos blood flow (+33---40%; p<0.05) (Table 3). However, W H V P , F H V P and the hepatic venous pressure gradient did not change significantly (Table 3). As a result of the increase in hepatic blood flow and the lack of change in hepatic venous pressure gradient, nicardipine significantly reduced the hepatic sinusoidal resistance (from 1258+__755 to 1014+424 dyn.s.cm -5, p<0.05). The effect of nicardipine on the hepatic venous pressure gradient of individual patients was heterogeneous (hepatic venous pressure gradient decreased in two patients, increased in three and remained equal in the remaining three patients) (Fig. 1). However, hepatic blood flow increased in all but one patient (Fig. 2).

Effects of nicardip&e on the hepatic extraction, clearance and intrinsic clearance of indocyanine green The enhanced liver perfusion following nicardipine was associated with a significant increase in the hepatic clearance of indocyanine green (+9___ 10%; p<0.05). As shown in Fig. 3, this increase did not occur in three o f the eight patients in the study. Two of these patients had the lowest baseline hepatic clearance o f indocyanine green. The in-

HVPG

mmHg 30

N$ 25,

TABLE 3 Effects of nicardipine on splanchnic and systemic hemodynamics in the eight patients studied Baseline Heart rate (bpm) Mean arterial pressure (mmHg) Cardiac output (I/rain) SVR (dyn.s.em -5) WHVP (mmHg) FHVP (mmHg) HVPG (mmHg) Azygos blood flow (l/rain) Hepatic blood flow (l/min) CLH ofICG (ml/min) CLI ofICG (ml/min) Hepatic extraction of indocyanine green

Nicardipine

82+-10 81---9 100+-17 9 0 + - I 1 7.3 +-1.4 7.0+-1.0 1087+-268 997_+171 23.7+-5.0 24.7-+5.1 5.9+-2.5 6.3+-2.7 17.8+-4.2 18.4+-4.2 0.44-+0.190.59+-0.41 1.3+-0.4 1.6+-0.4 241+-81 265+-92 290+-103 313+-123 0.30+-0.11 0.26+-0.10

20

p NS <0.01 NS NS NS NS NS <0.05 <0.05 <0.05 NS NS

SVR=Systemic vascular resistance; HVPG=Hepatic venous pressure gradient; CLH and CLI of ICG=hepatic and intrinsic clearance of indocyanine green.

15-

Baseline

Nicardipine

Fig. I. Individual response of the hepatic venous pressure gradient (HVPG) 60 min after the oral administration of 20 mg of nicardipine.

795

N I C A R D I P I N E IN P O R T A L H Y P E R T E N S I O N

L/min

HBF

CLH

ml/min 450

2.5

p
p O.05

400 2

._.....@

350

1.5

300

250 e-

200

j J

J

0.,5

150 I00

Baseline

Nicardipine

Baseline

Nicardipine

Fig. 2. Individual response of the hepatic blood flow (HBF) 60 min after the oral administration of 20 mg of nicardipine.

Fig. 3. Individual response of the hepatic clearance of indocyanine green (CLH) 60 min after the oral administration of 20 mg of nicardipine.

trinsic clearance of indocyanine green also increased, although this change did not reach statistical significance (+6___12%; NS).

the clinical relevance of this effect remains to be established. The increase in liver blood flow caused by nicardipine may be due to an increase in the portal blood flow, in the hepatic artery blood flow or in both. Although both components of liver blood flow cannot be accurately measured separately in humans, the increase in azygos blood flow following nicardipine suggests an increase in the portal component of the liver blood flow. This increase in portal blood flow may be due to splanchnic vasodilation, because of arterial smooth muscle relaxation induced by the calcium channel blocking effect of nicardipine. The effect of this drug was not associated with adverse effects, or with significant changes in portal pressure, which did not change significantly. Unchanged portal pressure, despite increased liver blood indicates decreased hepatic resistance. In fact, the increase in flow and the reduction in resistance may explain the improvement in liver perfusion and in the hepatic clearance of indocyanine green. This study was not double-blind, but this does not detract from the validity of our findings. Other agents have been shown to increase hepatic blood flow in patients with cirrhosis (12). However, increased perfusion was not associated with an improve-

Discussion

The results of the present study show that, unlike other calcium channel blockers, nicardipine effectively increases hepatic blood flow and the hepatic clearance of indocyanine green in patients with cirrhosis and portal hypertension. This supports the initial observation by Reichen & Le in rats with carbon tetrachloride-induced cirrhosis treated with verapamil (I). Although this has not yet been confirmed in human studies (5,6), and adverse effects on portal hypertensive patients with cirrhosis have been noted with nifedipine (7), these results clearly indicate that the hepatic clearance of indocyanine green may be increased in cirrhosis by pharmacologically enhancing liver perfusion. Although it is difficult tO extrapolate an improvement in liver function from changes in the clearance of a prototype compound (indocyanine green), these findings suggest that nicardipine may favourably influence liver function in patients with cirrhosis. However,

796 ment in the intrinsic and hepatic clearance o f indocyanine green, thus suggesting that the increased flow circulates through anatomic or functional intrahepatic shunts, without improving the effective liver blood flow (13). In contrast, the results o f the present study show that nicardipine not only reduces sinusoidal resistance and increases liver blood flow, but also enhances the hepatic and intrinsic clearance o f indocyanine green. Thus, these d a t a suggest that the increase in the hepatic clearance o f indocyanine green by nicardipine is due to increased blood flow to functional areas o f the liver. In that regard, it should be noted that, despite an increase in liver blood flow, there was no increase in the hepatic clearance of indocyanine green in the two patients with the lowest baseline hepatic clearance of this substance. A possible explanation might be that in patients with worse baseline hepatic function, more advanced architectural liver distortion may prevent a hypothetical recruitment o f functioning sinusoids when increasing hepatic blood flow (2). In any case, the results o f this study indicate that nicardipine would be more useful in patients with relatively preserved liver function. The beneficial effects o f nicardipine, which have also been suggested by other recent observations (14), should be confirmed in chronic studies. However, since this drug also increases azygos blood flow, studies aimed at assessing its long-term effects should be restricted to Child's class A patients without esophageal varices or previous hepatic encephalopathy.

Acknowledgements We are indebted to Ms Angels Baringo for her expert assistance in these studies and to Ms Encarna Gutierrez for secretarial support. Supported in part by grants from the F u n d a c i 6 Catalana per a l'Estudi de les Malalties del Fetge and F o n d o de Investigaci6n de la Seguridad Social (FISS) no. 91/ 0374. Dr J. C. Garcia-PagS.n had a postdoctoral grant from FISS (89/1516) and Dr. F Feu had a postdoctoral grant from Generalitat de Catalunya.

J.C. GARdA-PAGAN et al.

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