Variceal wall tension is thought to represent the key

Increasing Intra-abdominal Pressure Increases Pressure, Volume, and Wall Tension in Esophageal Varices Angels Escorsell, 1 Angels Ginès, 2 Josep Llach, 2 Joan C. García-Pagán, 1 Josep M. Bordas, 2 Jaume Bosch, 1 and Joan Rodés 1 Many daily activities cause acute elevations of intra-abdominal pressure (IAP). In portal hypertensive cirrhotic patients, increased IAP increases absolute portal pressure and azygos blood flow, suggesting that it may have detrimental consequences at the esophageal varices. The aim of this study was to investigate the effects of increased IAP on variceal pressure, size, and wall tension. Endosonography and a noninvasive endoscopic pressure gauge were used to measure variceal pressure, radius, wall tension, and volume in baseline conditions and after increasing IAP by 10 mm Hg using an inflatable girdle in 14 patients with cirrhosis and esophageal varices. Increasing IAP markedly increased variceal pressure (from 13.3 4.2 to 17.4 4.6 mm Hg; P.0001) and radius (from 2.9 1.0 to 3.9 1.1 mm; P.0001). Consequently, wall tension dramatically increased (from 38.7 13.6 to 65.9 23.8 mm Hg mm, 78%; P.0001). Variceal volume increased significantly from 1,264 759 to 2,025 1,129 mm 3 (P.0001). In conclusion, in portal hypertensive cirrhotic patients, increases in IAP have deleterious effects on variceal hemodynamics, markedly increasing the volume, pressure, and wall tension of the varices. Increases in IAP may contribute to the progressive dilatation that precedes the rupture of the varices in portal hypertension. (HEPATOLOGY 2002;36:936-940.) Abbreviations: IAP, intra-abdominal pressure; AzBF, azygos blood flow; HVPG, hepatic venous pressure gradient. From the 1 Hepatic Hemodynamics Laboratory, Liver Unit, and 2 Endoscopy Unit, IMD, Hospital Clínic, Institut de Recerca Biomèdica August Pi Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain. Received July 2, 2001; accepted July 10, 2002. Supported in part by grants from the Fondo de Investigación de la Seguridad Social (FIS 99/0362). Address reprint requests to: Jaume Bosch, M.D., Hepatic Hemodynamics Laboratory, Liver Unit, IMD, Hospital Clínic, Villarroel, 170, 08036 Barcelona, Spain. E-mail: jbosch@clinic.ub.es; fax: (34) 93-4515522. Copyright 2002 by the American Association for the Study of Liver Diseases. 0270-9139/02/3604-0019$35.00/0 doi:10.1053/jhep.2002.35817 Variceal wall tension is thought to represent the key factor determining variceal rupture. 1,2 Wall tension is the inwardly directed force that opposes the expanding force that the increased intravascular pressure and blood flow exert on the variceal wall. 1 It is calculated by Frank s modification of Laplace s law, as the transmural pressure at the varices (the difference between intravariceal and esophageal luminal pressures) times the radius of the varix, divided by the thickness of the variceal wall. 1 Several efforts have been made to obtain objective measurements of variceal wall tension. In that regard, we have previously shown that the combination of endosonography and endoscopic measurement of transmural variceal pressure allows a quantitative, objective, and reproducible estimation of variceal wall tension. 3 In addition, endosonography allows for estimation of variceal volume in the distal esophagus. 3 Elevations of intra-abdominal pressure (IAP) in cirrhotic patients have significant effects on both the systemic and the splanchnic circulation. A previous study from our laboratory showed that brief mechanical elevations of IAP increased azygos blood flow (AzBF), an index of gastroesophageal collateral blood flow, and the absolute portal pressure, estimated by the wedged hepatic venous pressure. 4 Therefore, an elevated IAP may be associated with acute increments of both variceal pressure and variceal blood flow. Moreover, Kravetz et al. 5 showed that in cirrhotic patients with ascites releasing an increased IAP by means of total volume paracentesis decreased intravariceal pressure. These effects of total volume paracentesis may be related to a significant decrease in wedged hepatic venous pressure, hepatic venous pressure gradient (HVPG), and AzBF as shown in a previous report from our unit. 6 The present investigation was aimed at assessing the changes in transmural variceal pressure, variceal size, vol- 936

HEPATOLOGY, Vol. 36, No. 4, 2002 ESCORSELL ET AL. 937 ume, and wall tension caused by the mechanical increase of IAP by means of an inflatable girdle. Patients and Methods The study was performed in 15 patients with cirrhosis and esophageal varices referred to the Hepatic Hemodynamic Laboratory for evaluation of pharmacotherapy for portal hypertension. The study was approved by the Ethical Research Committee of the Hospital Clínic in 1997. All patients gave their written informed consent to participate in the study. After an overnight fast, patients were transferred to the endoscopy unit where transmural variceal pressure measurements and endosonography were performed. All measurements were performed in baseline conditions and after increasing IAP (see later). The study was performed under conscious sedation with intravenous midazolam (0.1 mg/kg). 7-9 Heart rate, mean arterial pressure, and arterial saturation of oxygen were measured noninvasively throughout the study (Cardioswiss CM-8; Schiller AG, Basel, Switzerland). Measurement of Transmural Variceal Pressure. During upper endoscopy, and after examination of the esophageal varices, transmural variceal pressure was measured at the largest varix, in the distal 5 cm of the esophagus, after previously described methods. 3,7-10 Briefly, esophageal transmural variceal pressure was assessed by using a miniature pressure-sensitive capsule (measuring surface of 2 mm in diameter) (Varipress; Labotron, Barcelona, Spain) attached to the tip of the fiberscope (Olympus GIF-Q20; Olympus Optical Co., Tokyo, Japan). Variceal pressure is reported as transmural pressure, the difference between the pressure inside the varix and the esophageal luminal pressure (the pressure recorded when the gauge is free in the esophageal lumen). 3,7-10 Before each study, the pressure-sensitive capsule was calibrated with an artificial-varix system. 2 The same investigator performed all measurements. The endoscopist performing the measurement had no access to the data that was being recorded by another member of the team in a physically separated space. He was only told if the pressure tracings were satisfactory (stable intraesophageal pressure, absence of artifacts, and correct placement of the capsule over the varix for at least 12 seconds) or not. 3,7-10 A minimum of 3 satisfactory measurements were required at each period of the study. 3,7-10 Transmural variceal pressure was taken as the mean of the satisfactory measurements obtained. The analysis of transmural variceal pressure tracings was performed by an independent observer under blind conditions (the investigator did not know if the measurement corresponded to baseline or increased IAP, as well as the patient identity). Measurement of the Radius and Volume of the Varices. After successful pressure measurements, the fiberscope was removed and replaced by a radial echoendoscope (Olympus GF-UM2; Olympus Optical Co.) that was advanced up to the gastroesophageal junction to obtain endosonographic images. The images were obtained by using the 12-MHz frequency and a low-pressure water-filled balloon. 3 Five series of 3 frozen endosonographic cross-sectional images were obtained at each 1-cm interval from the gastroesophageal junction to 4 cm above. The images were recorded by a videocassette recorder (U-matic VO-7630; Sony, Tokyo, Japan), and then submitted to a blind morphometric analysis using an automatic computerized image analysis system (Scion Image for Windows; Scion, Frederick, MD). The bigger varix was selected to measure and calculate automatically the cross-sectional area of the varix (square mm) and the equivalent diameter. The mean of the measurements from the 3 images obtained at each 1-cm interval was taken as the variceal diameter. The average of the diameters measured at each 1-cm interval was used in the calculation of variceal wall tension. Variceal volume was calculated from the 3-dimensional reconstruction of a 4-cm variceal column following previously described methods. 3 Endosonographic images were read under code later on by an experienced, independent observer, blinded for the patient name, date, and conditions of the measurement. Calculation of Variceal Wall Tension. Variceal wall tension was estimated as the product of the transmural variceal pressure times the mean radius of the varix. Wall tension is expressed in mg mm 1 : Wall tension (mg mm 1 ) transmural variceal pressure(mg mm 2 ) variceal radius (mm) Conversion factor for pressure measurements: 1 mm Hg 13.59 mg mm 2. Variceal wall thickness, although being included in the calculation of variceal wall tension, was not taken into account because it cannot be measured accurately enough with the 12-MHz endosonographic equipment, and it is unlikely to be significantly modified by an acute and brief increase in IAP. Increase of IAP. All measurements were performed in baseline conditions and 10 minutes after increasing IAP by 10 mm Hg. This was performed by using an inflatable girdle. A sphigmomanometer pad placed between the abdominal wall and the girdle (over the anterior abdominal wall, above the umbilicus) was used to verify the pressure exerted by the girdle on the abdomen. Preliminary studies in 5 patients undergoing an invasive hemodynamic study

938 ESCORSELL ET AL. HEPATOLOGY, October 2002 Table 1. Effects of Increasing IAP on Systemic and Variceal Hemodynamics Variable Baseline Increase in IAP P Mean arterial pressure (mm Hg) 81 10 83 12.48 Heart rate (bpm) 106 15 105 16.86 Variceal pressure (mm Hg) 13.3 4.2 17.3 4.6.0001 Variceal radius (mm) 2.99 0.97 3.87 1.1.0001 Variceal volume (mm 3 ) 1,264 759 2,025 1,129.0001 Wall tension (mg/mm) 526 184 895 323.0001 Data are expressed as mean SD. showed that the inferior vena cava pressure increased by 9 1.7 mm Hg after increasing the external abdominal pressure by 10 mm Hg using the inflatable girdle. Data Analysis. The results are reported as mean SD. The effects of increasing IAP were evaluated by using Student s t test for paired data. Correlations were performed by using the Pearson correlation test. Significance was established at P.05. Results Finally, the study included 14 assessable patients (in one patient, correct variceal pressure tracings could not be obtained). Seven patients were men and 7 were women; the mean age was 57 12 years (mean SD; range, 34-72 years). Only one patient had previously bled from the esophageal varices. Ascites were present in 8 patients. Cirrhosis was alcohol-induced in 5 cases, hepatitis C virus related in 6, and from both causes in 3 cases. The mean Child-Pugh score was 7.9 2.0. Endoscopy disclosed the presence of big esophageal varices in all patients (F3 varices in 9 patients and F4 in the remaining 5 patients; mean North Italian Endoscopic Club [NIEC] index: 31 7). Additional hemodynamic data are shown in Table 1. Systemic Hemodynamics. No significant changes were observed either in mean arterial pressure or heart rate after the increase in IAP (Table 1). Transmural Variceal Pressure. A marked and significant increase in transmural variceal pressure was observed after increasing IAP in all the patients studied (Table 1). Individual changes are shown in Fig. 1A. The mean increase was 34% 26% (P.0001) (Fig. 2). In one patient having repeated measurements before, during, and after increasing IAP, transmural variceal pressure returned to baseline values after releasing the increased IAP (11.7 mm Hg; increased IAP, 21.5 mm Hg; after deflating the girdle, 11.2 mm Hg). Radius and Volume of Esophageal Varices. Increasing IAP resulted in a significant increase in variceal radius (32% 21%; P.0001; Fig. 2 and Table 1) and volume (76% 62%; P.0001; Fig. 1B and Table 1). These Fig. 1. Individual changes in (A) variceal pressure and (B) variceal volume after the acute increase in IAP. changes were observed in every patient. The individual responses of variceal radius and volume were rather homogeneous. Variceal Wall Tension. As a result of the increase in transmural variceal pressure and radius, all patients showed an increase in variceal wall tension with the increased IAP (Table 1). Overall, the mean increase was of 78% 49% (P.0001) (Fig. 2 and Table 1). The increase in variceal wall tension was significantly greater than the increases observed in variceal pressure (P.006) and radius (P.003) (Fig. 2). Changes in variceal wall tension were not significantly related either to baseline variceal pressure, radius, or volume. However, there was a significant correlation between changes in variceal wall tension and changes in variceal volume (r 0.71; P.01). Discussion The present study was designed to verify the effects of elevations in IAP on variceal hemodynamics, assessed by Fig. 2. Summary of the changes caused by the acute increase of IAP on variceal pressure, radius, and wall tension. *P.0001 vs. baseline; # P.01 vs. changes in variceal pressure and radius.

HEPATOLOGY, Vol. 36, No. 4, 2002 ESCORSELL ET AL. 939 measuring changes in variceal pressure, variceal volume, and variceal wall tension. Changes in variceal pressure were measured by using a noninvasive pressure-sensitive gauge developed in our laboratory that allowed reliable, reproducible measurements of variceal pressure. 2,3,7-9 Changes in variceal volume were derived from a 3-dimensional reconstruction of the varices from a sequence of cross-sectional endosonographic images. 3 Variceal wall tension was estimated from measurements of variceal pressure and radius. 3 Three previous studies suggested that physiologic increases in IAP (of approximately 10 mm Hg) may markedly influence variceal hemodynamics. 4-6 The first study showed that the mechanical increase of IAP markedly increased gastroesophageal collateral blood flow, assessed by measurements of AzBF, although it did not change the HVPG, suggesting an increase in variceal volume. 4 The second and third studies evaluated the changes in HVPG, AzBF, 6 and variceal pressure 5 caused by total volume paracentesis, a maneuver that decreases IAP. These studies showed a significant reduction in HVPG, AzBF, and variceal pressure after total volume paracentesis. 5,6 These observations are compatible with the concept that releasing a high IAP may have a beneficial effect on variceal bleeding. In addition, a study performed by Staritz et al. 10 showed that transient increases in IAP, such as those caused by the Valsalva maneuver, significantly increased intravascular esophageal variceal pressure. The present study showed that increasing IAP results in a highly significant increase in variceal pressure and size. As a result, variceal wall tension increased markedly, which is of relevance because variceal wall tension is thought to be the key parameter defining the risk for bleeding. 1,2 It is important to emphasize that we used a very moderate increase in IAP, lower than that caused by many daily activities such as stretching, defecating, raising moderate weights, and so forth, which caused a dramatic effect on variceal wall tension that increased by 78%. The change in variceal pressure after increasing IAP was quite variable (Fig. 1A). This difference may reflect, in part, the variability of the method. However, this is unlikely because the difference in the observed changes exceeds the variation after placebo administration or sham increases in variceal pressure. 3,8,9 Another possibility is that variations in the response might be related to different stiffness of the abdominal wall. Alternatively, because variceal volume varied similarly in both groups, it can be postulated that variceal compliance was lower in the patients with more pronounced increases in variceal pressure than in those with minor increases in variceal pressure (i.e., a greater increase in variceal pressure will be needed to cause the same increase in variceal volume in a patient with less compliant varices). In the light of our results, we can hypothesize that other physiologic situations known to transiently increase portal pressure and/or AzBF, such as moderate physical exercise 11,12 or meals, 13-20 may cause significant increases in variceal pressure. It is of interest to note that propranolol therapy has been shown to prevent the changes in HVPG associated with moderate exercise. 12 All the splanchnic and variceal hemodynamic parameters aggravated by increasing IAP reverse after releasing the high IAP. 4 Although in our study we assessed these changes over relatively short periods, it is likely that the reiteration of even transient increases in variceal pressure, size, and wall tension may contribute to the progressive dilatation of the esophageal varices that precedes its rupture when the elastic limit of variceal wall is exceeded. 1 These findings suggest that it may be wise to advise patients with cirrhosis and portal hypertension to avoid, whenever possible, activities that cause marked increases in IAP such as lifting heavy objects. In addition, constipation and recurrence of ascites should be prevented. In summary, the present study shows that in cirrhotic patients with portal hypertension, brief increases in IAP have deleterious effects increasing variceal pressure, radius, volume, and wall tension. Thus, increasing IAP may increase the risk for variceal rupture in these patients. Because daily activities include many occasions in which IAP is increased, this may represent another mechanism to explain the progressive dilatation that precedes the rupture of the varices in portal hypertension. Acknowledgment: The authors thank Angels Baringo, Laura Rocabert, Rosa Sáez, and the nursing staff of the Endoscopy Unit for their expert assistance; and Diana Bird for secretarial support. References 1. Polio J, Groszmann RJ. Hemodynamic factors involved in the development and rupture of esophageal varices: a pathophysiologic approach to treatment. Semin Liver Dis 1986;6:318-331. 2. Rigau J, Bosch J, Bordas JM, Navasa M, Mastai R, Kravetz D, Bruix J, et al. 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