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Physical exercise increases portal pressure in patients with cirrhosis and portal hypertension
GASTROENTEROLOGY 1996;111:1300–1306
Physical Exercise Increases Portal Pressure in Patients With Cirrhosis and Portal Hypertension JOAN CARLES GARCI´A–PAGA´N,* CRISTINA SANTOS,‡ JOAN ALBERT BARBERA´,‡ ANGELO LUCA,* JOSEP ROCA,‡ ROBERTO RODRIGUEZ–ROISIN,‡ JAUME BOSCH,* and JOAN RODE´S* *Liver Unit and ‡Pneumology Department, Department of Medicine, Hospital Clinic i Provincial, University of Barcelona, Barcelona, Spain
Background & Aims: In healthy subjects, exercise promotes marked hemodynamic and humoral changes characterized by an increase in cardiac output, a redistribution of blood flow to muscular territories under activity, and an increase in sympathoadrenergic activity. The aim of this study was to investigate the extent to which hemodynamic and humoral changes caused by exercise may influence portal and systemic hemodynamics in patients with cirrhosis. Methods: In 8 patients with liver cirrhosis and portal hypertension, arterial pressure, cardiac output, portal pressure (as hepatic venous pressure gradient [HVPG]), and hepatic blood flow were measured before and at two steps of cycling exercise equivalent to 30% and 50% of their peak workload. Results: Exercise (at 30% of peak workload) significantly increased arterial pressure and cardiac output and decreased systemic vascular resistance. This was associated with a significant increase in HVPG (from 16.7 { 1.5 to 19.2 { 1.6 mm Hg; P õ 0.01) and a significant reduction in hepatic blood flow (from 1291 { 216 to 1034 { 152 mLrmin01; P õ 0.05). All of these changes were intensified at 50% of target workload. Conclusions: The present study shows that moderate exercise increases portal pressure and may therefore increase the risk of variceal bleeding in patients with esophageal varices. These findings suggest that cirrhotic patients with portal hypertension should be advised of potential risks during exercise.
P
ortal hypertension is a frequent clinical syndrome associated with cirrhosis of the liver.1 Portal hypertension is initiated by an increased hepatic vascular resistance to portal blood flow1,2 and aggravated by an increased portal venous inflow caused by splanchnic arteriolar vasodilatation.1 – 3 Splanchnic vasodilatation is believed to be caused by increased release of vasodilatory mediators.2 Hyposensitivity to endogenous vasoconstrictors1 – 4 may further accentuate vasodilatation, which is not limited to the splanchnic circulation but associated with peripheral vasodilatation and increased blood volume and cardiac output, abnormalities that characterize a hyperkinetic circulatory state.1 – 3,5 / 5e13$$0004
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During exercise, an increase in cardiac output and a redistribution of blood flow from other territories (especially the splanchnic area) through an adrenergic-mediated vasoconstriction6 are the main physiological changes facilitating the increase in blood flow and oxygen supply to the exercising muscles. The present study investigated whether the hemodynamic changes induced by exercise can worsen the circulatory disturbances observed in portal hypertension. It is conceivable that the increase in cardiac output induced by exercise together with an impaired vasoconstrictive response to norepinephrine in the splanchnic territory4 may increase portal blood flow and thus portal pressure. In addition, the increase in norepinephrine elicited by exercise may further increase hepatic vascular resistance and portal pressure.7,8
Patients and Methods Patients The study was performed in patients referred to the Hepatic Hemodynamic Laboratory for a hemodynamic evaluation and treatment of portal hypertension. Consecutive cirrhotic patients with preserved liver function that were physically fit (all but one were actively working) were asked to participate. After obtaining consent, the patients underwent a noninvasive exercise test to determine the workload necessary for the study. One week later, the diagnostic invasive hemodynamic study was performed. Ten patients were initially recruited for the protocol, but 2 decided not to participate; therefore, the complete study was performed in 8 patients. All of the patients presented clinical evidence of portal hypertension; all had esophageal varices at endoscopy (without previous variceal bleeding), and 2 had mild ascites. Seven patients were men, and 1 was a woman; the mean age was 50 { 4 years (mean { SEM). The cause of cirrhosis was alcoholic in 4 patients and after hepatitis C in the remaining 4. The mean Child–Pugh score was 6.9 { 0.7 points. No patient had evidence of intrinsic Abbreviations used in this paper: FHVP, free hepatic venous pressure; HVPG, hepatic venous pressure gradient; WHVP, wedged hepatic venous pressure. q 1996 by the American Gastroenterological Association 0016-5085/96/$3.00
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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, Ireland) 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 venous 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 pulmonary 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. Measurements were performed in duplicate in each period of the study, and continuous tracings were obtained on a multichannel recorder (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 (dyners01rcm05) was estimated as (HVPG/Hepatic Blood Flow) 1 80. Mixed expired O2 and CO2 (mass spectrometer Multi-gas; Medishield, Ohmeda-BOC, England) expiratory flow, measured using a screen pneumotachograph, and electrocardiography (HP7830, Boelingen, Germany) were continuously recorded and digitized. On-line calculations of O2 consumption (VO2 ) and CO2 production (VCO2 ), minute ventilation, respiratory exchange ratio, heart rate, and respiratory rate were performed, and the data were averaged over sequential 15second 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 anaerobically in heparinized syringes for measurement of pO2 , pCO2 , and pH (IL model 1302, pH/blood gas analyzer and Tonometer
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model 237; Instrumentation Laboratories, Milan, Italy) and hemoglobin concentration and O2 saturation (IL 482 co-oximeter) 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 (QT ) was determined by the Fick principle using VO2 and arterial to mixed venous O2 content difference (QT Å [VO2 /(CaO2 -CvO2 )] 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, Wu¨rzburg, 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 hemodynamics, whole body O2 uptake and CO2 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 O2 uptake and CO2 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 discomfort. 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 hypertension was accompanied by a hyperdynamic circulation, with high cardiac output, low arterial pressure, and low systemic vascular resistance (Tables 1 and 2). O2 uptake (VO2 ), respiratory exchange ratio, and arterial lactate WBS-Gastro
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Table 1. Effects of Graded Exercise at 30% and 50% of Target Workload on Respiratory Variables and Gas Exchange
O2 consumption (mLrmin01) CO2 (mLrmin01) Respiratory exchange ratio Minute ventilation (Lrmin01; body temperature pressure saturated) Arterial lactate (mmol/L) pH Arterial O2 (mm Hg) Arterial content (mLrmin01) O2 mixed venous content (mLrmin01) System O2 extraction (%)
Baseline
30%
50%
{ { { { { { { { { {
1003 { 88a 846 { 65a 0.86 { 0.06 29.5 { 2a 2.6 { 0.4a 7.42 { 0.2a 86 { 6 17.3 { 1.1 9.8 { 0.6a 41 { 4a
1189 { 80a 1101 { 89a,b 0.94 { 0.08 41 { 3a,b 4.9 { 0.7a,b 7.39 { 0.2a 86 { 6 17.5 { 1.2 9.0 { 0.6a 47 { 4a
284 236 0.84 10 0.98 7.47 91 17.6 14.2 17
21 15 0.03 1 0.1 0.1 6 1.2 0.8 1
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 ventilation was slightly elevated, which was consistent with moderate hypocapnia (29 { 3 mm Hg) and respiratory alkalosis usually observed in these patients.11 Although PaO2 was normal, arterial O2 content (CaO2 ) was moderately low due to anemia (hemoglobin, 12 { 2 grdL01). It should be pointed out that the O2 extraction ratio was low compared with normal because of increased cardiac output.
respiratory exchange ratio (Table 1). This was associated with a slight increase in arterial lactate levels and a slight reduction in arterial pH (Table 1). There were no significant changes in arterial pO2 or in O2 arterial content. However, mixed venous pO2 exhibited a significant reduction attributable to increased systemic O2 extraction (Table 1). All these changes were maintained or even intensified after increasing exercise up to 50% of the peak workload (70 { 10 W; range, 50–140 W) (Table 1). The changes during exercise described in Table 1 were similar to those expected for healthy subjects exercising at a submaximal level. Actually, O2 consumption at 50% of the target workload was 17 mLrkg01rmin01, which is approximately one half of the value expected at peak O2 consumption in healthy sedentary subjects.
Exercise Performance During exercise at 30% of the peak workload (40 { 5 W; range, 30–70 W), minute ventilation, O2 consumption, and CO2 production increased significantly, but no significant changes were observed in the
Table 2. Effects of Graded Exercise at 30% and 50% of Target Workload on Systemic and Hepatic Hemodynamics
Heart rate (bpm) Mean arterial pressure (mm Hg) Cardiac output (Lrmin01) Stroke volume (mL) Systemic vascular resistance (dyners01rcm05) Mean pulmonary arterial pressure (mm Hg) Wedged pulmonary capillary pressure (mm Hg) Right atrial pressure (mm Hg) Pulmonary vascular resistance (dyners01rcm05) WHVP (mm Hg) FHVP (mm Hg) HVPG (mm Hg) Hepatic blood flow (mLrmin01) Estimated hepatic vascular resistance (dyners01rcm05) Indocyanine green extraction (%) Hepatic indocyanine green clearance (mLrmin01) Intrinsic indocyanine green clearance (mLrmin01)
Baseline
30%
50%
83 { 5 97 { 4 8.9 { 1.5 108 { 17 980 { 116 10.5 { 1.7 4.7 { 1.3 0.8 { 0.4 53 { 11 20.5 { 1.8 3.8 { 0.9 16.7 { 1.5 1291 { 216 1159 { 233 30.4 { 6 209 { 37 261 { 49
112 { 6a 123 { 10b 14 { 1.7b 127 { 18 760 { 99a 17.3 { 2.2b 7.0 { 1.4a 3.3 { 1.6 56 { 11 29.1 { 3.3b 9.8 { 3.0a 19.2 { 1.6b 1034 { 152a 1615 { 308b 31.4 { 7 181 { 29a 230 { 42a
126 { 6b,c 131 { 10b 15 { 1.8b 121 { 17 749 { 98a 17.9 { 2.4b 7.1 { 1.3a 3.9 { 1.4a 53 { 9 30.3 { 3.2b 10.4 { 3.0b 19.9 { 1.4b 900 { 121b 1928 { 305b,d 32 { 6 168 { 25b 215 { 39b
NOTE. Results are expressed as mean { SEM. a P õ 0.05 and bP õ 0.01 vs. baseline. c P õ 0.05 and dP õ 0.01 vs. 30%.
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Figure 1. Effects of graded exercise (30% and 50% of target workload) on (A ) WHVP, (B ) FHVP, and (C ) HVPG. *P õ 0.01 vs. basal. Values are expressed in mm Hg.
Norepinephrine also increased markedly during exercise (from 329 { 151 to 1287 { 445 pgrmL01 at 50% exercise; P õ 0.05). Systemic Hemodynamics at Rest and During Exercise Exercise at 30% of the peak workload significantly increased heart rate, mean arterial pressure, and cardiac output and significantly decreased systemic vascular resistance without significant changes in stroke volume (Table 2). These changes were associated with a significant increase in mean pulmonary artery pressure without concomitant changes in pulmonary vascular resistance (Table 2). At 50% of the peak workload, these changes were maintained (and even intensified) (Table 2). Splanchnic Hemodynamics and Liver Function at Rest and During Exercise During exercise at 30% of the peak workload, there was a marked and significant increase in WHVP (42% { 10%; P õ 0.01) and a significant, albeit less pronounced increase in FHVP (Table 2). Therefore, HVPG increased significantly (16% { 2%; P õ 0.01) (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
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 (Table 2). Recovery After Exercise As indicated in Table 3, CO2 production and minute ventilation were still increased 5 minutes after exercise but returned to baseline levels at 15 minutes. As expected, arterial lactate levels steadily decreased after 5 minutes but still remained above baseline values at 30 minutes. HVPG, hepatic blood flow, and the estimated hepatic vascular resistance were similar to their corresponding resting values from 5 minutes of the recovery period and during all 30 minutes of the observation period (Table 4). Throughout the recovery period, right atrial pressure and stroke volume decreased below baseline resting values (Table 4). During the first 15 minutes of the recovery period, the cardiac output was similar to the baseline values as a result of an increased heart rate. However, the heart rate decreased 30 minutes later, which resulted in a significant reduction of cardiac output and mean arterial pressure. Such a decrease in cardiac output without concomitant changes in O2 consumption is consistent with the slight but significant increase in O2 extraction ratio observed after 15 minutes.
Discussion The present study investigated whether the hemodynamic and neurohumoral changes induced by exercise 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
O2 consumption (mLrmin01) CO2 (mLrmin01) Minute ventilation (Lrmin01; body temperature pressure saturated) Arterial lactate (mmol/L) Systemic O2 extraction
Baseline
5 Minutes
15 Minutes
30 Minutes
273 { 23 230 { 17
309 { 35 319 { 34a
288 { 34 248 { 17
254 { 27 204 { 15
9.1 { 0.6 0.94 { 0.2 0.17 { 0.01
12.7 { 7a 4.5 { 1.2a 0.21 { 0.03
10.6 { 0.5 3.7 { 1.1a 0.23 { 0.02a
9 { 0.6 2.5 { 0.9a 0.26 { 0.03a
NOTE. Results are expressed as mean { SEM; n Å 6. a P õ 0.05 vs. baseline.
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Table 4. Recovery of Splanchnic and Systemic Hemodynamics 5, 15, and 30 Minutes After Exercise
Heart rate (bpm) Mean arterial pressure (mm Hg) Wedged pulmonary capillary pressure (mm Hg) Right atrial pressure (mm Hg) Cardiac output (Lrmin01) Stroke volume (mL) Systemic vascular resistance (dyners01rcm05) HVPG (mm Hg) Hepatic blood flow (mLrmin01) Estimated hepatic vascular resistance (dyners01rcm05)
Baseline
5 Minutes
{ { { { { { { { { {
104 { 5a 98 { 6 00.1 { 1a 01.2 { 0.6a 10.4 { 2 100 { 20 831 { 147 16.9 { 0.7 ND ND
83 97 3.4 0.8 9.9 110 922 16.7 1414 1200
5 4 1.3 0.4 1.9 20 157 1.5 268 240
15 Minutes
30 Minutes
6a 5 1.3a 0.9a 2 20a 236 0.5 220 320
86 { 6 79 { 5a 0.7 { 1a 00.5 { 0.8 7 { 2a 80 { 20a 1127 { 239 15.9 { 0.8 1155 { 221 1440 { 400
95 86 00.4 01 8.3 80 969 17.0 1150 1520
{ { { { { { { { { {
NOTE. Results are expressed as mean { SEM; n Å 6. ND, not done. a P õ 0.05.
significant increase in HVPG in such patients during exercise; this increase is 16% and 21% above baseline at 30% and 50% of the peak workload, respectively. It is important to note that modifications of HVPG of similar magnitude, but in opposite direction, promoted by pharmacological agents have been shown to be associated with a marked reduction of the risk of recurrent variceal bleeding,13,14 which suggests that a 20% change in portal pressure could be clinically relevant. Therefore, the increases in HVPG during moderate exercise documented in the present study may be associated with an increased risk of variceal bleeding. Despite the expected marked increase in cardiac output, hepatic blood flow was significantly reduced after exercise, with a reduction of 018% { 5% and 029% { 7% at 30% and 50% of the peak workload, respectively. The magnitude of this reduction was similar to that observed in healthy subjects6,15,16 and suggests that cirrhotic patients have a relative preservation of the splanchnic vasoconstrictive response to exercise. The finding that the HVPG increases significantly during exercise despite a reduction in liver blood flow strongly suggests that the increase in HVPG is due to an increase in hepatic vascular resistance. Actually, the calculated hepatic sinusoidal resistance increased markedly during exercise. How could exercise modify hepatic vascular resistance? There is increasing evidence that the increased hepatic vascular resistance of cirrhosis can be modified by physiological and pharmacological stimuli.7,8,17 – 19 Indeed, studies in isolated perfused cirrhotic livers have shown that norepinephrine, angiotensin II, vasopressin, and endothelin I are able to increase intrahepatic vascular resistance.7,8,17 – 19 Actually, the cirrhotic liver exhibits an exaggerated response to these constrictors, which has been ascribed to endothelial sinusoidal dysfunction.20 In the / 5e13$$0004
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present study, norepinephrine was significantly increased after exercise, reflecting enhanced sympathetic activity. In addition, increased production of angiotensin II and vasopressin after exercise has been shown by other investigators.21 – 27 It is therefore possible than an increase in these endogenous neurohumoral vasoconstrictive factors may produce the observed increase in hepatic vascular resistance. It should be noted that our measurements of hepatic blood flow represent the sum of hepatic arterial blood flow and portal venous blood flow perfusing the liver. However, this measurement does not allow assessment of the portal blood flow escaping through portal-systemic collaterals. Thus, it is possible that a decrease in total hepatic flow is not accompanied by a decrease in collateral blood flow. In that regard, we have previously shown that the reduction in total hepatic blood flow caused by methoxamine (an a-adrenergic agonist) is not accompanied by a decrease in collateral blood flow, assessed by measurements of azygos blood flow.28 Likewise, exercise causes a marked increase in a-adrenergic tone. Therefore, our study cannot absolutely discard that portal-collateral blood flow may increase during exercise and contribute to increase the risk of gastroesophageal variceal bleeding. Previous studies have shown that maximal exercise achieved by cirrhotic patients is lower than that of healthy subjects of similar age and body surface area26,29,30 and that maximal exercise is inversely correlated with the degree of liver failure evaluated by the Child–Pugh score.30 It is important to remark that the significant increase in portal pressure was already present at 30% of the peak workload, which is moderate physical exercise, and may correspond to that required during moderate daily exercise activity such as carrying dishes or walking at 3.5 mph.31 HVPG, hepatic blood flow, and the estimated hepatic WBS-Gastro
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vascular resistance quickly returned to resting values after stopping exercise. However, there was a significant reduction in mean arterial pressure during the recovery period. Postexercise hypotension has been previously described in healthy subjects, especially after bouts of maximal exercise.32,33 However, this reduction in arterial pressure is usually slight and asymptomatic. Either a reduction in systemic vascular resistance with normal or increased cardiac output33 or a reduced cardiac output with normal systemic vascular resistance32 has been described. The postexercise hypotension observed in cirrhotic patients was due to a reduction in cardiac preload that eventually leads to a reduction in cardiac output without significant changes in systemic vascular resistance. Thus, reduction in venous return was the main factor responsible for the decrease in arterial pressure. Venodilatation with increased total vascular compliance has been shown in patients with cirrhosis34,35 and may be responsible for the reduction in cardiac preload and arterial pressure observed in our cirrhotic patients. The present study shows that moderate physical exercise increases portal pressure and may therefore increase the risk for variceal bleeding in patients with esophageal varices. These findings suggest that cirrhotic patients with portal hypertension should be advised of potential risks during moderate to severe exercise.
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28. Mastai R, Bosch J, Navasa M, Kravetz D, Bruix J, Viola C, Rode´s J. Effects of alpha-adrenergic stimulation and beta-adrenergic blockade on azygos blood flow and splanchnic haemodynamics in patients with cirrhosis. J Hepatol 1987;4:71–79. 29. Campillo B, Fouet P, Bonnet JC, Atlan G. Submaximal oxygen consumption in liver cirrhosis. Evidence of severe functional aerobic impairment. J Hepatol 1990;10:163–167. 30. Campillo B, Chapelain C, Bonnet JC, Frisdal E, Devanlay M, Bouissou P, Fouet P, Wirquin E, Atlan G. Hormonal and metabolic changes during exercise in cirrhotic patients. Metabolism 1990; 39:18–24. 31. Jones NL, Makrides L, Hitchcock C, Chypchart T, McCartney N. Normal standards for an incremental progressive cycle ergometer test. Am Rev Resp Dis 1985;131:700–708. 32. Hagberg JM, Montain SJ, Martin WH III. Blood pressure and hemodynamic responses after exercise in older hypertensives. J Appl Physiol 1987;63:270–276. 33. Piepoli M, Coats AJS, Adamopoulos S, Bernardi L, Hong Feng Y, Conway J, Sleight P. Persistent peripheral vasodilatation and
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sympathetic activity in hypotension after maximal exercise. J Appl Physiol 1993;75:1807–1814. 34. Ingles AC, Hernandez I, Garcia-Estan ˜ J, Quesada T, Carbonell LF. Increased total vascular capacity in conscious cirrhotic rats. Gastroenterology 1992;103:275–281. 35. Hadengue A, Moreau R, Gaudin C, Bacq Y, Champigneulle B, Lebrec D. Total effective vascular compliance in patients with cirrhosis: a study of the response to acute blood volume expansion. Hepatology 1992;15:809–815.
Received December 4, 1995. Accepted June 3, 1996. Address requests for reprints to: Jaume Bosch, M.D., Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic i Provincial, Villarroel 170, 08036 Barcelona, Spain. Supported in part by grants 94/0757, 94/1106, and 95/1016 from Fondo de Investigacio´n Sanitaria. The authors thank Diana Bird for her secretarial support and Angeles Baringo and Laura Rocabert for expert technical assistance.
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Physical Exercise Increases Portal Pressure in Patients With Cirrhosis and Portal Hypertension JOAN CARLES GARCI´A–PAGA´N,* CRISTINA SANTOS,‡ JOAN ALBERT BARBERA´,‡ ANGELO LUCA,* JOSEP ROCA,‡ ROBERTO RODRIGUEZ–ROISIN,‡ JAUME BOSCH,* and JOAN RODE´S* *Liver Unit and ‡Pneumology Department, Department of Medicine, Hospital Clinic i Provincial, University of Barcelona, Barcelona, Spain
Background & Aims: In healthy subjects, exercise promotes marked hemodynamic and humoral changes characterized by an increase in cardiac output, a redistribution of blood flow to muscular territories under activity, and an increase in sympathoadrenergic activity. The aim of this study was to investigate the extent to which hemodynamic and humoral changes caused by exercise may influence portal and systemic hemodynamics in patients with cirrhosis. Methods: In 8 patients with liver cirrhosis and portal hypertension, arterial pressure, cardiac output, portal pressure (as hepatic venous pressure gradient [HVPG]), and hepatic blood flow were measured before and at two steps of cycling exercise equivalent to 30% and 50% of their peak workload. Results: Exercise (at 30% of peak workload) significantly increased arterial pressure and cardiac output and decreased systemic vascular resistance. This was associated with a significant increase in HVPG (from 16.7 { 1.5 to 19.2 { 1.6 mm Hg; P õ 0.01) and a significant reduction in hepatic blood flow (from 1291 { 216 to 1034 { 152 mLrmin01; P õ 0.05). All of these changes were intensified at 50% of target workload. Conclusions: The present study shows that moderate exercise increases portal pressure and may therefore increase the risk of variceal bleeding in patients with esophageal varices. These findings suggest that cirrhotic patients with portal hypertension should be advised of potential risks during exercise.
P
ortal hypertension is a frequent clinical syndrome associated with cirrhosis of the liver.1 Portal hypertension is initiated by an increased hepatic vascular resistance to portal blood flow1,2 and aggravated by an increased portal venous inflow caused by splanchnic arteriolar vasodilatation.1 – 3 Splanchnic vasodilatation is believed to be caused by increased release of vasodilatory mediators.2 Hyposensitivity to endogenous vasoconstrictors1 – 4 may further accentuate vasodilatation, which is not limited to the splanchnic circulation but associated with peripheral vasodilatation and increased blood volume and cardiac output, abnormalities that characterize a hyperkinetic circulatory state.1 – 3,5 / 5e13$$0004
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During exercise, an increase in cardiac output and a redistribution of blood flow from other territories (especially the splanchnic area) through an adrenergic-mediated vasoconstriction6 are the main physiological changes facilitating the increase in blood flow and oxygen supply to the exercising muscles. The present study investigated whether the hemodynamic changes induced by exercise can worsen the circulatory disturbances observed in portal hypertension. It is conceivable that the increase in cardiac output induced by exercise together with an impaired vasoconstrictive response to norepinephrine in the splanchnic territory4 may increase portal blood flow and thus portal pressure. In addition, the increase in norepinephrine elicited by exercise may further increase hepatic vascular resistance and portal pressure.7,8
Patients and Methods Patients The study was performed in patients referred to the Hepatic Hemodynamic Laboratory for a hemodynamic evaluation and treatment of portal hypertension. Consecutive cirrhotic patients with preserved liver function that were physically fit (all but one were actively working) were asked to participate. After obtaining consent, the patients underwent a noninvasive exercise test to determine the workload necessary for the study. One week later, the diagnostic invasive hemodynamic study was performed. Ten patients were initially recruited for the protocol, but 2 decided not to participate; therefore, the complete study was performed in 8 patients. All of the patients presented clinical evidence of portal hypertension; all had esophageal varices at endoscopy (without previous variceal bleeding), and 2 had mild ascites. Seven patients were men, and 1 was a woman; the mean age was 50 { 4 years (mean { SEM). The cause of cirrhosis was alcoholic in 4 patients and after hepatitis C in the remaining 4. The mean Child–Pugh score was 6.9 { 0.7 points. No patient had evidence of intrinsic Abbreviations used in this paper: FHVP, free hepatic venous pressure; HVPG, hepatic venous pressure gradient; WHVP, wedged hepatic venous pressure. q 1996 by the American Gastroenterological Association 0016-5085/96/$3.00
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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, Ireland) 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 venous 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 pulmonary 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. Measurements were performed in duplicate in each period of the study, and continuous tracings were obtained on a multichannel recorder (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 (dyners01rcm05) was estimated as (HVPG/Hepatic Blood Flow) 1 80. Mixed expired O2 and CO2 (mass spectrometer Multi-gas; Medishield, Ohmeda-BOC, England) expiratory flow, measured using a screen pneumotachograph, and electrocardiography (HP7830, Boelingen, Germany) were continuously recorded and digitized. On-line calculations of O2 consumption (VO2 ) and CO2 production (VCO2 ), minute ventilation, respiratory exchange ratio, heart rate, and respiratory rate were performed, and the data were averaged over sequential 15second 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 anaerobically in heparinized syringes for measurement of pO2 , pCO2 , and pH (IL model 1302, pH/blood gas analyzer and Tonometer
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model 237; Instrumentation Laboratories, Milan, Italy) and hemoglobin concentration and O2 saturation (IL 482 co-oximeter) 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 (QT ) was determined by the Fick principle using VO2 and arterial to mixed venous O2 content difference (QT Å [VO2 /(CaO2 -CvO2 )] 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, Wu¨rzburg, 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 hemodynamics, whole body O2 uptake and CO2 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 O2 uptake and CO2 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 discomfort. 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 hypertension was accompanied by a hyperdynamic circulation, with high cardiac output, low arterial pressure, and low systemic vascular resistance (Tables 1 and 2). O2 uptake (VO2 ), respiratory exchange ratio, and arterial lactate WBS-Gastro
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Table 1. Effects of Graded Exercise at 30% and 50% of Target Workload on Respiratory Variables and Gas Exchange
O2 consumption (mLrmin01) CO2 (mLrmin01) Respiratory exchange ratio Minute ventilation (Lrmin01; body temperature pressure saturated) Arterial lactate (mmol/L) pH Arterial O2 (mm Hg) Arterial content (mLrmin01) O2 mixed venous content (mLrmin01) System O2 extraction (%)
Baseline
30%
50%
{ { { { { { { { { {
1003 { 88a 846 { 65a 0.86 { 0.06 29.5 { 2a 2.6 { 0.4a 7.42 { 0.2a 86 { 6 17.3 { 1.1 9.8 { 0.6a 41 { 4a
1189 { 80a 1101 { 89a,b 0.94 { 0.08 41 { 3a,b 4.9 { 0.7a,b 7.39 { 0.2a 86 { 6 17.5 { 1.2 9.0 { 0.6a 47 { 4a
284 236 0.84 10 0.98 7.47 91 17.6 14.2 17
21 15 0.03 1 0.1 0.1 6 1.2 0.8 1
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 ventilation was slightly elevated, which was consistent with moderate hypocapnia (29 { 3 mm Hg) and respiratory alkalosis usually observed in these patients.11 Although PaO2 was normal, arterial O2 content (CaO2 ) was moderately low due to anemia (hemoglobin, 12 { 2 grdL01). It should be pointed out that the O2 extraction ratio was low compared with normal because of increased cardiac output.
respiratory exchange ratio (Table 1). This was associated with a slight increase in arterial lactate levels and a slight reduction in arterial pH (Table 1). There were no significant changes in arterial pO2 or in O2 arterial content. However, mixed venous pO2 exhibited a significant reduction attributable to increased systemic O2 extraction (Table 1). All these changes were maintained or even intensified after increasing exercise up to 50% of the peak workload (70 { 10 W; range, 50–140 W) (Table 1). The changes during exercise described in Table 1 were similar to those expected for healthy subjects exercising at a submaximal level. Actually, O2 consumption at 50% of the target workload was 17 mLrkg01rmin01, which is approximately one half of the value expected at peak O2 consumption in healthy sedentary subjects.
Exercise Performance During exercise at 30% of the peak workload (40 { 5 W; range, 30–70 W), minute ventilation, O2 consumption, and CO2 production increased significantly, but no significant changes were observed in the
Table 2. Effects of Graded Exercise at 30% and 50% of Target Workload on Systemic and Hepatic Hemodynamics
Heart rate (bpm) Mean arterial pressure (mm Hg) Cardiac output (Lrmin01) Stroke volume (mL) Systemic vascular resistance (dyners01rcm05) Mean pulmonary arterial pressure (mm Hg) Wedged pulmonary capillary pressure (mm Hg) Right atrial pressure (mm Hg) Pulmonary vascular resistance (dyners01rcm05) WHVP (mm Hg) FHVP (mm Hg) HVPG (mm Hg) Hepatic blood flow (mLrmin01) Estimated hepatic vascular resistance (dyners01rcm05) Indocyanine green extraction (%) Hepatic indocyanine green clearance (mLrmin01) Intrinsic indocyanine green clearance (mLrmin01)
Baseline
30%
50%
83 { 5 97 { 4 8.9 { 1.5 108 { 17 980 { 116 10.5 { 1.7 4.7 { 1.3 0.8 { 0.4 53 { 11 20.5 { 1.8 3.8 { 0.9 16.7 { 1.5 1291 { 216 1159 { 233 30.4 { 6 209 { 37 261 { 49
112 { 6a 123 { 10b 14 { 1.7b 127 { 18 760 { 99a 17.3 { 2.2b 7.0 { 1.4a 3.3 { 1.6 56 { 11 29.1 { 3.3b 9.8 { 3.0a 19.2 { 1.6b 1034 { 152a 1615 { 308b 31.4 { 7 181 { 29a 230 { 42a
126 { 6b,c 131 { 10b 15 { 1.8b 121 { 17 749 { 98a 17.9 { 2.4b 7.1 { 1.3a 3.9 { 1.4a 53 { 9 30.3 { 3.2b 10.4 { 3.0b 19.9 { 1.4b 900 { 121b 1928 { 305b,d 32 { 6 168 { 25b 215 { 39b
NOTE. Results are expressed as mean { SEM. a P õ 0.05 and bP õ 0.01 vs. baseline. c P õ 0.05 and dP õ 0.01 vs. 30%.
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Figure 1. Effects of graded exercise (30% and 50% of target workload) on (A ) WHVP, (B ) FHVP, and (C ) HVPG. *P õ 0.01 vs. basal. Values are expressed in mm Hg.
Norepinephrine also increased markedly during exercise (from 329 { 151 to 1287 { 445 pgrmL01 at 50% exercise; P õ 0.05). Systemic Hemodynamics at Rest and During Exercise Exercise at 30% of the peak workload significantly increased heart rate, mean arterial pressure, and cardiac output and significantly decreased systemic vascular resistance without significant changes in stroke volume (Table 2). These changes were associated with a significant increase in mean pulmonary artery pressure without concomitant changes in pulmonary vascular resistance (Table 2). At 50% of the peak workload, these changes were maintained (and even intensified) (Table 2). Splanchnic Hemodynamics and Liver Function at Rest and During Exercise During exercise at 30% of the peak workload, there was a marked and significant increase in WHVP (42% { 10%; P õ 0.01) and a significant, albeit less pronounced increase in FHVP (Table 2). Therefore, HVPG increased significantly (16% { 2%; P õ 0.01) (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
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 (Table 2). Recovery After Exercise As indicated in Table 3, CO2 production and minute ventilation were still increased 5 minutes after exercise but returned to baseline levels at 15 minutes. As expected, arterial lactate levels steadily decreased after 5 minutes but still remained above baseline values at 30 minutes. HVPG, hepatic blood flow, and the estimated hepatic vascular resistance were similar to their corresponding resting values from 5 minutes of the recovery period and during all 30 minutes of the observation period (Table 4). Throughout the recovery period, right atrial pressure and stroke volume decreased below baseline resting values (Table 4). During the first 15 minutes of the recovery period, the cardiac output was similar to the baseline values as a result of an increased heart rate. However, the heart rate decreased 30 minutes later, which resulted in a significant reduction of cardiac output and mean arterial pressure. Such a decrease in cardiac output without concomitant changes in O2 consumption is consistent with the slight but significant increase in O2 extraction ratio observed after 15 minutes.
Discussion The present study investigated whether the hemodynamic and neurohumoral changes induced by exercise 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
O2 consumption (mLrmin01) CO2 (mLrmin01) Minute ventilation (Lrmin01; body temperature pressure saturated) Arterial lactate (mmol/L) Systemic O2 extraction
Baseline
5 Minutes
15 Minutes
30 Minutes
273 { 23 230 { 17
309 { 35 319 { 34a
288 { 34 248 { 17
254 { 27 204 { 15
9.1 { 0.6 0.94 { 0.2 0.17 { 0.01
12.7 { 7a 4.5 { 1.2a 0.21 { 0.03
10.6 { 0.5 3.7 { 1.1a 0.23 { 0.02a
9 { 0.6 2.5 { 0.9a 0.26 { 0.03a
NOTE. Results are expressed as mean { SEM; n Å 6. a P õ 0.05 vs. baseline.
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Table 4. Recovery of Splanchnic and Systemic Hemodynamics 5, 15, and 30 Minutes After Exercise
Heart rate (bpm) Mean arterial pressure (mm Hg) Wedged pulmonary capillary pressure (mm Hg) Right atrial pressure (mm Hg) Cardiac output (Lrmin01) Stroke volume (mL) Systemic vascular resistance (dyners01rcm05) HVPG (mm Hg) Hepatic blood flow (mLrmin01) Estimated hepatic vascular resistance (dyners01rcm05)
Baseline
5 Minutes
{ { { { { { { { { {
104 { 5a 98 { 6 00.1 { 1a 01.2 { 0.6a 10.4 { 2 100 { 20 831 { 147 16.9 { 0.7 ND ND
83 97 3.4 0.8 9.9 110 922 16.7 1414 1200
5 4 1.3 0.4 1.9 20 157 1.5 268 240
15 Minutes
30 Minutes
6a 5 1.3a 0.9a 2 20a 236 0.5 220 320
86 { 6 79 { 5a 0.7 { 1a 00.5 { 0.8 7 { 2a 80 { 20a 1127 { 239 15.9 { 0.8 1155 { 221 1440 { 400
95 86 00.4 01 8.3 80 969 17.0 1150 1520
{ { { { { { { { { {
NOTE. Results are expressed as mean { SEM; n Å 6. ND, not done. a P õ 0.05.
significant increase in HVPG in such patients during exercise; this increase is 16% and 21% above baseline at 30% and 50% of the peak workload, respectively. It is important to note that modifications of HVPG of similar magnitude, but in opposite direction, promoted by pharmacological agents have been shown to be associated with a marked reduction of the risk of recurrent variceal bleeding,13,14 which suggests that a 20% change in portal pressure could be clinically relevant. Therefore, the increases in HVPG during moderate exercise documented in the present study may be associated with an increased risk of variceal bleeding. Despite the expected marked increase in cardiac output, hepatic blood flow was significantly reduced after exercise, with a reduction of 018% { 5% and 029% { 7% at 30% and 50% of the peak workload, respectively. The magnitude of this reduction was similar to that observed in healthy subjects6,15,16 and suggests that cirrhotic patients have a relative preservation of the splanchnic vasoconstrictive response to exercise. The finding that the HVPG increases significantly during exercise despite a reduction in liver blood flow strongly suggests that the increase in HVPG is due to an increase in hepatic vascular resistance. Actually, the calculated hepatic sinusoidal resistance increased markedly during exercise. How could exercise modify hepatic vascular resistance? There is increasing evidence that the increased hepatic vascular resistance of cirrhosis can be modified by physiological and pharmacological stimuli.7,8,17 – 19 Indeed, studies in isolated perfused cirrhotic livers have shown that norepinephrine, angiotensin II, vasopressin, and endothelin I are able to increase intrahepatic vascular resistance.7,8,17 – 19 Actually, the cirrhotic liver exhibits an exaggerated response to these constrictors, which has been ascribed to endothelial sinusoidal dysfunction.20 In the / 5e13$$0004
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present study, norepinephrine was significantly increased after exercise, reflecting enhanced sympathetic activity. In addition, increased production of angiotensin II and vasopressin after exercise has been shown by other investigators.21 – 27 It is therefore possible than an increase in these endogenous neurohumoral vasoconstrictive factors may produce the observed increase in hepatic vascular resistance. It should be noted that our measurements of hepatic blood flow represent the sum of hepatic arterial blood flow and portal venous blood flow perfusing the liver. However, this measurement does not allow assessment of the portal blood flow escaping through portal-systemic collaterals. Thus, it is possible that a decrease in total hepatic flow is not accompanied by a decrease in collateral blood flow. In that regard, we have previously shown that the reduction in total hepatic blood flow caused by methoxamine (an a-adrenergic agonist) is not accompanied by a decrease in collateral blood flow, assessed by measurements of azygos blood flow.28 Likewise, exercise causes a marked increase in a-adrenergic tone. Therefore, our study cannot absolutely discard that portal-collateral blood flow may increase during exercise and contribute to increase the risk of gastroesophageal variceal bleeding. Previous studies have shown that maximal exercise achieved by cirrhotic patients is lower than that of healthy subjects of similar age and body surface area26,29,30 and that maximal exercise is inversely correlated with the degree of liver failure evaluated by the Child–Pugh score.30 It is important to remark that the significant increase in portal pressure was already present at 30% of the peak workload, which is moderate physical exercise, and may correspond to that required during moderate daily exercise activity such as carrying dishes or walking at 3.5 mph.31 HVPG, hepatic blood flow, and the estimated hepatic WBS-Gastro
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vascular resistance quickly returned to resting values after stopping exercise. However, there was a significant reduction in mean arterial pressure during the recovery period. Postexercise hypotension has been previously described in healthy subjects, especially after bouts of maximal exercise.32,33 However, this reduction in arterial pressure is usually slight and asymptomatic. Either a reduction in systemic vascular resistance with normal or increased cardiac output33 or a reduced cardiac output with normal systemic vascular resistance32 has been described. The postexercise hypotension observed in cirrhotic patients was due to a reduction in cardiac preload that eventually leads to a reduction in cardiac output without significant changes in systemic vascular resistance. Thus, reduction in venous return was the main factor responsible for the decrease in arterial pressure. Venodilatation with increased total vascular compliance has been shown in patients with cirrhosis34,35 and may be responsible for the reduction in cardiac preload and arterial pressure observed in our cirrhotic patients. The present study shows that moderate physical exercise increases portal pressure and may therefore increase the risk for variceal bleeding in patients with esophageal varices. These findings suggest that cirrhotic patients with portal hypertension should be advised of potential risks during moderate to severe exercise.
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Received December 4, 1995. Accepted June 3, 1996. Address requests for reprints to: Jaume Bosch, M.D., Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic i Provincial, Villarroel 170, 08036 Barcelona, Spain. Supported in part by grants 94/0757, 94/1106, and 95/1016 from Fondo de Investigacio´n Sanitaria. The authors thank Diana Bird for her secretarial support and Angeles Baringo and Laura Rocabert for expert technical assistance.
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