Physical Exercise Increases Portal Pressure in Patients With Cirrhosis and Portal Hypertension

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1 GASTROENTEROLOGY 1996;111: Physical Exercise Increases Portal Pressure in Patients With Cirrhosis and Portal Hypertension JOAN CARLES GARCÍA PAGÁN,* CRISTINA SANTOS, JOAN ALBERT BARBERÁ, ANGELO LUCA,* JOSEP ROCA, ROBERTO RODRIGUEZ ROISIN, JAUME BOSCH,* and JOAN RODÉS* *Liver Unit and Pneumology Department, Department of Medicine, Hospital Clinic i Provincial, University of Barcelona, Barcelona, Spain Background & Aims: In healthy subjects, exercise pro- During exercise, an increase in cardiac output and a motes marked hemodynamic and humoral changes redistribution of blood flow from other territories (especharacterized by an increase in cardiac output, a redis- cially the splanchnic area) through an adrenergic-meditribution of blood flow to muscular territories under ac- ated vasoconstriction 6 are the main physiological changes tivity, and an increase in sympathoadrenergic activity. facilitating the increase in blood flow and oxygen supply The aim of this study was to investigate the extent to to the exercising muscles. The present study investigated which hemodynamic and humoral changes caused by whether the hemodynamic changes induced by exercise exercise may influence portal and systemic hemodycan worsen the circulatory disturbances observed in pornamics in patients with cirrhosis. Methods: In 8 patal hypertension. It is conceivable that the increase in tients with liver cirrhosis and portal hypertension, artecardiac output induced by exercise together with an imrial pressure, cardiac output, portal pressure (as hepatic venous pressure gradient [HVPG]), and hepatic paired vasoconstrictive response to norepinephrine in the blood flow were measured before and at two steps of splanchnic territory 4 may increase portal blood flow and cycling exercise equivalent to 30% and 50% of their thus portal pressure. In addition, the increase in norepipeak workload. Results: Exercise (at 30% of peak work- nephrine elicited by exercise may further increase hepatic load) significantly increased arterial pressure and car- vascular resistance and portal pressure. 7,8 diac output and decreased systemic vascular resistance. This was associated with a significant increase Patients and Methods in HVPG (from 16.7 { 1.5 to 19.2 { 1.6 mm Hg; P õ Patients 0.01) and a significant reduction in hepatic blood flow (from 1291 { 216 to 1034 { 152 mlrmin 01 ; P õ The study was performed in patients referred to the 0.05). All of these changes were intensified at 50% of Hepatic Hemodynamic Laboratory for a hemodynamic evaluatarget workload. Conclusions: The present study shows tion and treatment of portal hypertension. Consecutive cirthat moderate exercise increases portal pressure and rhotic patients with preserved liver function that were physi- may therefore increase the risk of variceal bleeding in cally fit (all but one were actively working) were asked to patients with esophageal varices. These findings sugnoninvasive exercise test to determine the workload necessary participate. After obtaining consent, the patients underwent a gest that cirrhotic patients with portal hypertension should be advised of potential risks during exercise. for the study. One week later, the diagnostic invasive hemody- namic study was performed. Ten patients were initially recruited for the protocol, but 2 decided not to participate; ortal hypertension is a frequent clinical syndrome therefore, the complete study was performed in 8 patients. All Passociated with cirrhosis of the liver. 1 Portal hyper- of the patients presented clinical evidence of portal hypertentension is initiated by an increased hepatic vascular resis- sion; all had esophageal varices at endoscopy (without previous tance to portal blood flow 1,2 and aggravated by an in- variceal bleeding), and 2 had mild ascites. Seven patients were creased portal venous inflow caused by splanchnic men, and 1 was a woman; the mean age was 50 { 4 years (mean arteriolar vasodilatation. 1 3 Splanchnic vasodilatation is { SEM). The cause of cirrhosis was alcoholic in 4 patients and believed to be caused by increased release of vasodilatory after hepatitis C in the remaining 4. The mean Child Pugh mediators. 2 Hyposensitivity to endogenous vasoconstrictors score was 6.9 { 0.7 points. No patient had evidence of intrinsic 1 4 may further accentuate vasodilatation, which is not limited to the splanchnic circulation but associated Abbreviations used in this paper: FHVP, free hepatic venous pres- sure; HVPG, hepatic venous pressure gradient; WHVP, wedged hewith peripheral vasodilatation and increased blood volpatic venous pressure. ume and cardiac output, abnormalities that characterize 1996 by the American Gastroenterological Association a hyperkinetic circulatory state. 1 3, /96/$3.00

2 November 1996 PHYSICAL EXERCISE AND PORTAL HYPERTENSION 1301 pulmonary or cardiac disease as confirmed by a normal chest radiograph, electrocardiogram, and forced spirometry. No patient was receiving vasoactive drugs. The protocol was approved by the Ethical Committee of the Hospital Clinic i Provincial of Barcelona. Informed written consent to participate in the study was obtained from all the patients. Procedures At 9 AM, after fasting overnight and under local anesthesia, a catheter introducer (USCI International, Galway, Ire- land) was placed in the right jugular vein by the Seldinger technique and was used to advance a balloon catheter (Medi Tech; Cooper Scientific Corp., Watertown, MA) into the main right hepatic vein for repeated measurements of wedged (occluded) hepatic venous pressure (WHVP) and free hepatic ve- nous pressure (FHVP). A second catheter introducer was placed in the antecubital vein and used to advance a Swan-Ganz catheter (Edwards Laboratory, Los Angeles, CA) into the pul- monary artery for mixed venous sampling and measurement of cardiopulmonary pressures. An arterial cannula (Seldicath; Laboratories Plastimed, Saint Leu La Foret Cedex, France) was inserted under local anesthesia into the radial artery, after ensuring adequate ulnar artery circulation, for arterial blood sampling and monitoring of systemic arterial pressure and heart rate. Intravascular pressures were measured using highly sensitive pressure transducers (model 1280 C; Hewlett-Packard, Andover, MA) calibrated before each measurement. Portal pressure was estimated by the hepatic venous pressure gradient (HVPG), the difference between WHVP and FHVP. Measure- ments were performed in duplicate in each period of the study, and continuous tracings were obtained on a multichannel re- corder (model 7754 B; Hewlett-Packard). Hepatic blood flow was measured using a continuous infusion of indocyanine green (Serb, Paris) prepared in a solution containing 2% human serum albumin infused intravenously at a constant rate of 0.2 mg/min. After an equilibration period of at least 40 minutes, three sets of simultaneous samples of peripheral and hepatic venous blood were obtained for the measurement of hepatic blood flow, hepatic clearance of indocyanine green, and hepatic intrinsic clearance following previously reported methods. 9 The hepatic sinusoidal vascular resistance (dyners 01 rcm 05 ) was estimated as (HVPG/Hepatic Blood Flow) Mixed expired O 2 and CO 2 (mass spectrometer Multi-gas; Medishield, Ohmeda-BOC, England) expiratory flow, mea- sured using a screen pneumotachograph, and electrocardiography (HP7830, Boelingen, Germany) were continuously recorded and digitized. On-line calculations of O 2 consumption (VO 2 ) and CO 2 production (VCO 2 ), minute ventilation, respiratory exchange ratio, heart rate, and respiratory rate were performed, and the data were averaged over sequential 15- second intervals and then displayed on a screen monitor to observe the progress of the test. Simultaneous arterial and femoral venous samples (4 ml each) were collected anaerobi- cally in heparinized syringes for measurement of po 2, pco 2, and ph (IL model 1302, ph/blood gas analyzer and Tonometer model 237; Instrumentation Laboratories, Milan, Italy) and hemoglobin concentration and O 2 saturation (IL 482 co-oxime- ter) in arterial and mixed venous blood. 10,11 Blood lactate concentrations were determined using a YSI 23 L (Yellow Springs Instruments, Yellow Springs, OH) blood lactate analyzer. Cardiac output (Q T ) was determined by the Fick principle using VO 2 and arterial to mixed venous O 2 content difference (Q T Å [VO 2 /(CaO 2 -CvO 2 )] 1 10). In addition, a peripheral venous blood sample was drawn to measure norepinephrine levels as previously described. 12 These measurements were repeated in each period of the study (see later). Study Design All subjects first underwent a preliminary study to exclude patients with clinical, electrocardiogram, or chest radiograph abnormalities. A standard incremental test (20-W increment every 2 minutes, cycloergometer; E. Jaeger, Würz- burg, Germany) was then performed until exhaustion to determine each patient s peak workload, defined as the maximum workload that could be sustained for 2 minutes. 11 On the study day, after the catheterization procedure described above, baseline measurements of systemic and splanchnic hemody- namics, whole body O 2 uptake and CO 2 output, and plasma norepinephrine levels were taken before starting the exercise test. The exercise consisted of two different steps at constant workload equivalent to approximately 30% and approximately 50% of the peak workload. Identical sets of measurements (systemic and splanchnic hemodynamics, whole body O 2 up- take and CO 2 output, and plasma norepinephrine levels) were taken after 3 minutes at each exercise step (30% and 50% of the peak workload). The duration of the measurements required that the patients were cycling for a total period of 8 10 minutes at each workload (30% and 50% of the peak workload). Patients were instructed to stop the exercise if they experienced dizziness, chest pain, or symptoms other than dis- comfort. In 6 patients, the measurements were repeated during the recovery period at 5, 15, and 30 minutes after stopping exercise. All measurements were made in a semirecumbent position. Statistical Analysis The results are reported as mean { SEM. One-way analysis of variance with Scheffe F test for repeated measurements was used in the statistical analysis of the results. Significance was considered at a P value of õ0.05. Results Baseline Data All patients had severe portal hypertension, as manifested by a marked increase in HVPG. Portal hyper- tension was accompanied by a hyperdynamic circulation, with high cardiac output, low arterial pressure, and low systemic vascular resistance (Tables 1 and 2). O 2 uptake (VO 2 ), respiratory exchange ratio, and arterial lactate

3 1302 GARCÍA PAGÁN ET AL. GASTROENTEROLOGY Vol. 111, No. 5 Table 1. Effects of Graded Exercise at 30% and 50% of Target Workload on Respiratory Variables and Gas Exchange Baseline 30% 50% O 2 consumption (mlrmin 01 ) 284 { { 88 a 1189 { 80 a CO 2 (mlrmin 01 ) 236 { { 65 a 1101 { 89 a,b Respiratory exchange ratio 0.84 { { { 0.08 Minute ventilation (Lrmin 01 ; body temperature pressure saturated) 10 { { 2 a 41 { 3 a,b Arterial lactate (mmol/l) 0.98 { { 0.4 a 4.9 { 0.7 a,b ph 7.47 { { 0.2 a 7.39 { 0.2 a Arterial O 2 (mm Hg) 91 { 6 86 { 6 86 { 6 Arterial content (mlrmin 01 ) 17.6 { { { 1.2 O 2 mixed venous content (mlrmin 01 ) 14.2 { { 0.6 a 9.0 { 0.6 a System O 2 extraction (%) 17 { 1 41 { 4 a 47 { 4 a NOTE. Results are expressed as mean { SEM. a P õ 0.05 vs. baseline. b P õ 0.05 vs. 30%. levels were within the reference range. 11 Minute ventila- respiratory exchange ratio (Table 1). This was associated tion was slightly elevated, which was consistent with with a slight increase in arterial lactate levels and a slight moderate hypocapnia (29 { 3 mm Hg) and respiratory reduction in arterial ph (Table 1). There were no significant alkalosis usually observed in these patients. 11 Although changes in arterial po 2 or in O 2 arterial content. PaO 2 was normal, arterial O 2 content (CaO 2 ) was moder- However, mixed venous po 2 exhibited a significant reduction ately low due to anemia (hemoglobin, 12 { 2grdL 01 ). attributable to increased systemic O 2 extraction It should be pointed out that the O 2 extraction ratio was (Table 1). All these changes were maintained or even low compared with normal because of increased cardiac intensified after increasing exercise up to 50% of the output. peak workload (70 { 10 W; range, W) (Table Exercise Performance 1). The changes during exercise described in Table 1 were similar to those expected for healthy subjects exer- During exercise at 30% of the peak workload cising at a submaximal level. Actually, O 2 consumption (40 { 5 W; range, W), minute ventilation, O 2 at 50% of the target workload was 17 mlrkg 01 rmin 01, consumption, and CO 2 production increased signifi- which is approximately one half of the value expected at cantly, but no significant changes were observed in the peak O 2 consumption in healthy sedentary subjects. Table 2. Effects of Graded Exercise at 30% and 50% of Target Workload on Systemic and Hepatic Hemodynamics Baseline 30% 50% Heart rate (bpm) 83 { { 6 a 126 { 6 b,c Mean arterial pressure (mm Hg) 97 { { 10 b 131 { 10 b Cardiac output (Lrmin 01 ) 8.9 { { 1.7 b 15 { 1.8 b Stroke volume (ml) 108 { { { 17 Systemic vascular resistance (dyners 01 rcm 05 ) 980 { { 99 a 749 { 98 a Mean pulmonary arterial pressure (mm Hg) 10.5 { { 2.2 b 17.9 { 2.4 b Wedged pulmonary capillary pressure (mm Hg) 4.7 { { 1.4 a 7.1 { 1.3 a Right atrial pressure (mm Hg) 0.8 { { { 1.4 a Pulmonary vascular resistance (dyners 01 rcm 05 ) 53 { { { 9 WHVP (mm Hg) 20.5 { { 3.3 b 30.3 { 3.2 b FHVP (mm Hg) 3.8 { { 3.0 a 10.4 { 3.0 b HVPG (mm Hg) 16.7 { { 1.6 b 19.9 { 1.4 b Hepatic blood flo (mlrmin 01 ) 1291 { { 152 a 900 { 121 b Estimated hepatic vascular resistance (dyners 01 rcm 05 ) 1159 { { 308 b 1928 { 305 b,d Indocyanine green extraction (%) 30.4 { { 7 32 { 6 Hepatic indocyanine green clearance (mlrmin 01 ) 209 { { 29 a 168 { 25 b Intrinsic indocyanine green clearance (mlrmin 01 ) 261 { { 42 a 215 { 39 b NOTE. Results are expressed as mean { SEM. a P õ 0.05 and b P õ 0.01 vs. baseline. c P õ 0.05 and d P õ 0.01 vs. 30%.

4 November 1996 PHYSICAL EXERCISE AND PORTAL HYPERTENSION 1303 blood flow decreased significantly (018% { 5%; P õ 0.05) (Table 2). As a consequence of the decrease in hepatic blood flow together with the increase in HVPG, the estimated hepatic vascular resistance increased markedly (/48% { 16%; P õ 0.01). All these changes were even more pronounced at 50% of the peak workload (Table 2). There was a significant and progressive reduction in the hepatic and intrinsic clearance of indocyanine green Figure 1. Effects of graded exercise (30% and 50% of target workload) (Table 2). on (A) WHVP, (B) FHVP, and (C ) HVPG. *P õ 0.01 vs. basal. Values are expressed in mm Hg. Recovery After Exercise As indicated in Table 3, CO 2 production and minute ventilation were still increased 5 minutes after exer- Norepinephrine also increased markedly during exercise but returned to baseline levels at 15 minutes. As cise (from 329 { 151 to 1287 { 445 pgrml 01 at 50% expected, arterial lactate levels steadily decreased after 5 exercise; P õ 0.05). minutes but still remained above baseline values at 30 Systemic Hemodynamics at Rest and minutes. HVPG, hepatic blood flow, and the estimated During Exercise hepatic vascular resistance were similar to their corresponding resting values from 5 minutes of the recovery Exercise at 30% of the peak workload significantly period and during all 30 minutes of the observation increased heart rate, mean arterial pressure, and cardiac period (Table 4). output and significantly decreased systemic vascular re- Throughout the recovery period, right atrial pressure sistance without significant changes in stroke volume and stroke volume decreased below baseline resting val- (Table 2). These changes were associated with a signifi- ues (Table 4). During the first 15 minutes of the recovery cant increase in mean pulmonary artery pressure without period, the cardiac output was similar to the baseline concomitant changes in pulmonary vascular resistance values as a result of an increased heart rate. However, (Table 2). At 50% of the peak workload, these changes the heart rate decreased 30 minutes later, which resulted were maintained (and even intensified) (Table 2). in a significant reduction of cardiac output and mean Splanchnic Hemodynamics and Liver arterial pressure. Such a decrease in cardiac output with- Function at Rest and During Exercise out concomitant changes in O 2 consumption is consistent with the slight but significant increase in O 2 extraction During exercise at 30% of the peak workload, ratio observed after 15 minutes. there was a marked and significant increase in WHVP (42% { 10%; P õ 0.01) and a significant, albeit less Discussion pronounced increase in FHVP (Table 2). Therefore, The present study investigated whether the hemodynamic and neurohumoral changes induced by HVPG increased significantly (16% { 2%; P õ 0.01) exercise (Table 2 and Figure 1). The increase in HVPG was observed in all patients studied and was unrelated to baseline HVPG or other hemodynamic parameters. Hepatic can influence the circulatory disturbances observed in patients with liver cirrhosis and portal hypertension. The main finding of the study is that there is a highly Table 3. Recovery of Respiratory Variables and Gas Exchange 5, 15, and 30 Minutes After Exercise Baseline 5 Minutes 15 Minutes 30 Minutes O 2 consumption (mlrmin 01 ) 273 { { { { 27 CO 2 (mlrmin 01 ) 230 { { 34 a 248 { { 15 Minute ventilation (Lrmin 01 ; body temperature pressure saturated) 9.1 { { 7 a 10.6 { { 0.6 Arterial lactate (mmol/l) 0.94 { { 1.2 a 3.7 { 1.1 a 2.5 { 0.9 a Systemic O 2 extraction 0.17 { { { 0.02 a 0.26 { 0.03 a NOTE. Results are expressed as mean { SEM; n Å 6. a P õ 0.05 vs. baseline.

5 1304 GARCÍA PAGÁN ET AL. GASTROENTEROLOGY Vol. 111, No. 5 Table 4. Recovery of Splanchnic and Systemic Hemodynamics 5, 15, and 30 Minutes After Exercise Baseline 5 Minutes 15 Minutes 30 Minutes Heart rate (bpm) 83 { { 5 a 95 { 6 a 86 { 6 Mean arterial pressure (mm Hg) 97 { 4 98 { 6 86 { 5 79 { 5 a Wedged pulmonary capillary pressure (mm Hg) 3.4 { { 1 a 00.4 { 1.3 a 0.7 { 1 a Right atrial pressure (mm Hg) 0.8 { { 0.6 a 01 { 0.9 a 00.5 { 0.8 Cardiac output (Lrmin 01 ) 9.9 { { { 2 7 { 2 a Stroke volume (ml) 110 { { { 20 a 80 { 20 a Systemic vascular resistance (dyners 01 rcm 05 ) 922 { { { { 239 HVPG (mm Hg) 16.7 { { { { 0.8 Hepatic blood flo (mlrmin 01 ) 1414 { 268 ND 1150 { { 221 Estimated hepatic vascular resistance (dyners 01 rcm 05 ) 1200 { 240 ND 1520 { { 400 NOTE. Results are expressed as mean { SEM; n Å 6. ND, not done. a P õ significant increase in HVPG in such patients during present study, norepinephrine was significantly increased exercise; this increase is 16% and 21% above baseline at after exercise, reflecting enhanced sympathetic activity. 30% and 50% of the peak workload, respectively. It is In addition, increased production of angiotensin II and important to note that modifications of HVPG of similar vasopressin after exercise has been shown by other inves- magnitude, but in opposite direction, promoted by phar- tigators It is therefore possible than an increase in macological agents have been shown to be associated these endogenous neurohumoral vasoconstrictive factors with a marked reduction of the risk of recurrent variceal may produce the observed increase in hepatic vascular bleeding, 13,14 which suggests that a 20% change in portal resistance. pressure could be clinically relevant. Therefore, the in- It should be noted that our measurements of hepatic creases in HVPG during moderate exercise documented blood flow represent the sum of hepatic arterial blood in the present study may be associated with an increased flow and portal venous blood flow perfusing the liver. risk of variceal bleeding. However, this measurement does not allow assessment Despite the expected marked increase in cardiac out- of the portal blood flow escaping through portal-systemic put, hepatic blood flow was significantly reduced after collaterals. Thus, it is possible that a decrease in total exercise, with a reduction of 018% { 5% and 029% hepatic flow is not accompanied by a decrease in collateral { 7% at 30% and 50% of the peak workload, respectively. blood flow. In that regard, we have previously shown The magnitude of this reduction was similar to that the reduction in total hepatic blood flow caused by that observed in healthy subjects 6,15,16 and suggests that methoxamine (an a-adrenergic agonist) is not accompa- cirrhotic patients have a relative preservation of the nied by a decrease in collateral blood flow, assessed by splanchnic vasoconstrictive response to exercise. The measurements of azygos blood flow. 28 Likewise, exercise finding that the HVPG increases significantly during causes a marked increase in a-adrenergic tone. Therefore, exercise despite a reduction in liver blood flow strongly our study cannot absolutely discard that portal-collateral suggests that the increase in HVPG is due to an increase blood flow may increase during exercise and contribute in hepatic vascular resistance. Actually, the calculated to increase the risk of gastroesophageal variceal bleeding. hepatic sinusoidal resistance increased markedly during Previous studies have shown that maximal exercise exercise. achieved by cirrhotic patients is lower than that of How could exercise modify hepatic vascular resistance? healthy subjects of similar age and body surface area 26,29,30 There is increasing evidence that the increased hepatic and that maximal exercise is inversely correlated with vascular resistance of cirrhosis can be modified by physio- the degree of liver failure evaluated by the Child Pugh logical and pharmacological stimuli. 7,8,17 19 Indeed, studies score. 30 It is important to remark that the significant in isolated perfused cirrhotic livers have shown that increase in portal pressure was already present at 30% norepinephrine, angiotensin II, vasopressin, and endothelin of the peak workload, which is moderate physical exertance. I are able to increase intrahepatic vascular resis- cise, and may correspond to that required during moder- 7,8,17 19 Actually, the cirrhotic liver exhibits an exaggerated ate daily exercise activity such as carrying dishes or walk- response to these constrictors, which has been ing at 3.5 mph. 31 ascribed to endothelial sinusoidal dysfunction. 20 In the HVPG, hepatic blood flow, and the estimated hepatic

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7 1306 GARCÍA PAGÁN ET AL. GASTROENTEROLOGY Vol. 111, No Mastai R, Bosch J, Navasa M, Kravetz D, Bruix J, Viola C, Rodés sympathetic activity in hypotension after maximal exercise. J Appl J. Effects of alpha-adrenergic stimulation and beta-adrenergic Physiol 1993; 75: blockade on azygos blood flo and splanchnic haemodynamics 34. Ingles AC, Hernandez I, Garcia-Estañ J, Quesada T, Carbonell in patients with cirrhosis. J Hepatol 1987; 4: LF. Increased total vascular capacity in conscious cirrhotic rats. 29. Campillo B, Fouet P, Bonnet JC, Atlan G. Submaximal oxygen Gastroenterology 1992; 103: consumption in liver cirrhosis. Evidence of severe functional aerobic 35. Hadengue A, Moreau R, Gaudin C, Bacq Y, Champigneulle B, impairment. J Hepatol 1990; 10: Lebrec D. Total effective vascular compliance in patients with 30. Campillo B, Chapelain C, Bonnet JC, Frisdal E, Devanlay M, Bouissou cirrhosis: a study of the response to acute blood volume expanchanges P, Fouet P, Wirquin E, Atlan G. Hormonal and metabolic sion. Hepatology 1992; 15: during exercise in cirrhotic patients. Metabolism 1990; 39: Jones NL, Makrides L, Hitchcock C, Chypchart T, McCartney N. Received December 4, Accepted June 3, Normal standards for an incremental progressive cycle ergometer Address requests for reprints to: Jaume Bosch, M.D., Hepatic Hetest. Am Rev Resp Dis 1985; 131: modynamic Laboratory, Liver Unit, Hospital Clinic i Provincial, Vil- 32. Hagberg JM, Montain SJ, Martin WH III. Blood pressure and he- larroel 170, Barcelona, Spain. modynamic responses after exercise in older hypertensives. J Supported in part by grants 94/0757, 94/1106, and 95/1016 Appl Physiol 1987; 63: from Fondo de Investigación Sanitaria. 33. Piepoli M, Coats AJS, Adamopoulos S, Bernardi L, Hong Feng Y, The authors thank Diana Bird for her secretarial support and Conway J, Sleight P. Persistent peripheral vasodilatation and Angeles Baringo and Laura Rocabert for expert technical assistance.