Liver International ISSN 1478-3223
Editorial DOI:10.1111/liv.12303 Liver Int. 2014: 34: 4–5
Assessment of portal pressure in cirrhosis: how and when can we sedate? Increase in portal venous pressure is pivotal for the development of intestinal varices that can cause lifethreatening bleeding. Furthermore, the degree of portal hypertension is associated with patient prognosis (1–3). Measurement of the portal pressure can only be achieved by direct puncture of the portal vein or one of its branches which requires open surgery or transhepatic puncture of this venous vessel tree. More than 60 years ago, Meyers and Taylor (4) described for the first time that wedging a branch of the hepatic vein and taking the pressure from this position allows fairly accurate determination of the portal pressure (5) since there is little dissipation of blood pressure within the sinusoids because of altered architecture of the cirrhotic liver. In order to minimize fluctuation caused by changes of abdominal pressure the free hepatic venous pressure is taken as reference (3, 6). Thus, the hepatic venous pressure gradient (HVPG) is the best indirect measure of the portal pressure (3). Measurement can be easily achieved via transjugular, transcubital or transfemoral venous access (3). Many studies within the last decades from a limited number of centres showed that HVPG is an independent predictor for survival of patients with cirrhosis (2, 3) and for the risk of first and recurrent bleeding from oesophageal varices (1, 3, 7). Portal hypertension can be graded as mild (HVPG 20 mmHg). Patients with mild portal hypertension have a relatively low risk to develop varices and bleeding (8), while patients with severe portal hypertension and cirrhosis have a high risk of first bleeding, rebleeding and death, especially if the portal pressure cannot be significantly reduced by drugs such as non-selective beta-blockers (9). The average HVPG augments with increasing ChildPugh grade, which reflects the degree of liver decompensation, but there is a rather large overlap between the three Child-grades (2). Multivariate analysis shows that HVPG adds prognostic information to the Child status (2). Medical decompression of portal hypertension by using non-selective beta-blockers, nitrates or vasoactive drugs such as terlipressin is mainly used to treat or prevent variceal bleeding. In this situation, assessment of drug effects by HVPG determination may tailor treatment (7, 10–13). Since changes take place
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in a low pressure system and at that are small (mostly less than 20%), it is important to achieve valid determinations of pressures. Unfortunately, these are prone to many artifacts, thus technical aspects are very important in this context. Correct transducers, adequate calibration, mode of catheter and adequate position in the wedged as well as free position and correct tracing are important variables that may influence the results. Finally, sedation may also influence measurements (3, 6). In this issue, the Barcelona group, which for many years has been a protagonist of HVPG measurement, shows that deep sedation with propofol and remifentanil results in a marked oscillation of the pressure curve induced by respiration (14). While in the awake state, differences between inspiratory and expiratory pressure were not higher than 1–3 mmHg, these pressures fluctuated by up to 10 mmHg when patients were sedated. The authors show that mean end-expiratory pressure in sedated patients correlated best with awake HVPG and that the mean pressure along the respiratory cycle was very similar to awake state HVPG. However, the agreement between the awake and deeply sedated state was rather poor in the individual patients with respect to assessment of the relative pressure reduction after application of propranolol. Furthermore, sedation led to a significant drop of mean arterial pressure, systemic vascular resistance and respiratory rate. This stresses the fact that, even without medical manipulation by using sedatives, interactive systemic hemodynamics may change because of physical activity or time of day (15, 16) and – regarding splanchnic hemodynamics – considerably with meals (16–18). This study convincingly demonstrates the dimension of sedation on HVPG measurement. But does this have clinical implications? Since the mean HVPG along the respiratory cycle remained rather stable, the influence of sedation is probably less crucial if HVPG is assessed to categorize patients for prediction of the bleeding risk or even survival. However, concerning assessment of drug effects, where rather slight changes of 10–20% have been described to separate responders from nonresponders for bleeding prophylaxis, meticulous observation of similar conditions before and after treatment is probably necessary (3, 6), especially if drugs act via change of systemic hemodynamics and change of tributary blood flow. Are we allowed to give these patients Liver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Sauerbruch
Editorial
sedation? Strictly speaking, we do not know since studies with clinical endpoints are lacking. If we use them, low-dose midazolam (19) has been shown to have minor influence. Nevertheless, the mode of the procedure should be kept as similar as possible. Perusing the available publications one has the impression that very experienced groups, where routine measurement of HVPG has been performed for many years, achieve reliable results also with minor sedation because of their routine with this procedure. This may be more of a problem in units where HVPG measurement is not part of the regular repertoire in staging of patients with cirrhosis. In any case, proper execution of the technique is paramount. There are other (20) and new less invasive techniques such as elastography (17, 21, 22) and old techniques such as measurement of portal venous flow (23, 24) that may correlate with HVPG, but they are not sufficiently established as a substitute for HVPG or are not sensitive enough to detect pressure changes (13), and there is no reason why these methods should not be influenced by deep sedation, especially if used for drug monitoring.
Tilman Sauerbruch1* 1 Medical Department I, University of Bonn, Bonn, Germany *Present address: Department of Gastroenterology and Endocrinology, Go¨ttingen, Germany
References 1. Vorobioff JD, Groszmann RJ. Hepatic venous pressure gradient measurement in pre-primary and primary prophylaxis of variceal hemorrhage. Ann Hepatol 2013; 12: 22–9. 2. Patch D, Armonis A, Sabin C, et al. Single portal pressure measurement predicts survival in cirrhotic patients with recent bleeding. Gut 1999; 44: 264–9. 3. Bosch J, Abraldes JG, Berzigotti A, Garcı´a-Paga´n JC. The clinical use of HVPG measurements in chronic liver disease. Nat Rev Gastroenterol Hepatol 2009; 6:573–82. 4. Meyers JD, Taylor WJ. An estimation of portal venous pressure by occlusive catheterization of a hepatic vanule. J Clin Invest 1951; 30: 662–3. 5. Perell o A, Escorsell A, Bru C, et al. Wedged hepatic venous pressure adequately reflects portal pressure in hepatitis C virus-related cirrhosis. Hepatology 1999; 30: 1393–7. 6. Groszmann RJ, Wongcharatrawee S. The hepatic venous pressure gradient: anything worth doing should be done right. Hepatology 2004; 39: 280–2. 7. Boyer TD. Changing clinical practice with measurements of portal pressure. Hepatology 2004; 39: 283–5. 8. Groszmann RJ, Garcia-Tsao G, Bosch J et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. Engl J Med 2005; 353: 2254–61.
Liver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
9. D’Amico G, Garcıa-Pagan JC, Luca A, Bosch J. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology 2006; 131: 1611–24. 10. Bureau C, Peron JM, Alric L, et al. ‘A La Carte’ treatment of portal hypertension: adapting medical therapy to hemodynamic response for the prevention of bleeding. Hepatology 2002; 36: 1361–6. 11. Gonzalez A, Augustin S, Perez M, et al. Genesca Hemodynamic response-guided therapy for prevention of variceal rebleeding: an uncontrolled pilot study. Hepatology 2006; 44: 806–12. 12. Abraldes JG, Tarantino I, Turnes J, et al. Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis. Hepatology 2003; 37: 902–8. 13. McCormick PA, Patch D, Greenslade L, et al. Clinical vs haemodynamic response to drugs in portal hypertension. J Hepatol 1998; 28: 1015–9. 14. Reverter E, Blasi A, Abraldes JG, et al. Impact of deep sedation on the accuracy of hepatic and portal venous pressure measurements in patients with cirrhosis. Liver Int 2014; 34: 16–25. 15. Sugano S, Yamamoto K, Sasao K, et al. Daily variation of azygos and portal blood flow and the effect of propranolol administration once an evening in cirrhotics. J Hepatol 2001; 34: 26–31. 16. Schiedermaier P, Koch L, Moj on A, et al. Circadian rhythm of fasting and postprandial portal blood flow in cirrhosis. Scand J Gastroenterol 2006; 41: 826–32. 17. Berzigotti A, De Gottardi A, Vukotic R, et al. Effect of meal ingestion on liver stiffness in patients with cirrhosis and portal hypertension. PLoS One 2013; 8: e58742. 18. Schiedermaier P, Koch L, Stoffel-Wagner B, Layer G, Sauerbruch T. Effect of propranolol and depot lanreotide SR on postprandial and circadian portal haemodynamics in cirrhosis. Aliment Pharmacol Ther 2003; 18: 777–84. 19. Steinlauf AF, Garcia-Tsao G, Zakko MF, et al. Low-dose midazolam sedation: an option for patients undergoing serial hepatic venous pressure measurements. Hepatology 1999; 29: 1070–3. 20. Thabut D, Moreau R, Lebrec D. Noninvasive assessment of portal hypertension in patients with cirrhosis. Hepatology. 2011; 53: 683–94. 21. Castera L, Pinzani M, Bosch J. Non invasive evaluation of portal hypertension using transient elastography. J Hepatol 2012; 56: 696–703. 22. Reiberger T, Ferlitsch A, Payer BA, et al. Non-selective b-blockers improve the correlation of liver stiffness and portal pressure in advanced cirrhosis. J Gastroenterol 2012; 47: 561–8. 23. Schepke M, Raab P, Hoppe A, et al. Comparison of portal vein velocity and the hepatic venous pressure gradient in assessing the acute portal hemodynamic response to propranolol in patients with cirrhosis. Am J Gastroenterol 2000; 95: 2905–9. 24. Berzigotti A, Rinaldi MF, Magalotti D, et al. Primary prophylaxis with nadolol in cirrhotic patients: doppler patterns of splanchnic hemodynamics in good and poor responders. J Hepatol 2006; 44: 310–6.
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Editorial DOI:10.1111/liv.12303 Liver Int. 2014: 34: 4–5
Assessment of portal pressure in cirrhosis: how and when can we sedate? Increase in portal venous pressure is pivotal for the development of intestinal varices that can cause lifethreatening bleeding. Furthermore, the degree of portal hypertension is associated with patient prognosis (1–3). Measurement of the portal pressure can only be achieved by direct puncture of the portal vein or one of its branches which requires open surgery or transhepatic puncture of this venous vessel tree. More than 60 years ago, Meyers and Taylor (4) described for the first time that wedging a branch of the hepatic vein and taking the pressure from this position allows fairly accurate determination of the portal pressure (5) since there is little dissipation of blood pressure within the sinusoids because of altered architecture of the cirrhotic liver. In order to minimize fluctuation caused by changes of abdominal pressure the free hepatic venous pressure is taken as reference (3, 6). Thus, the hepatic venous pressure gradient (HVPG) is the best indirect measure of the portal pressure (3). Measurement can be easily achieved via transjugular, transcubital or transfemoral venous access (3). Many studies within the last decades from a limited number of centres showed that HVPG is an independent predictor for survival of patients with cirrhosis (2, 3) and for the risk of first and recurrent bleeding from oesophageal varices (1, 3, 7). Portal hypertension can be graded as mild (HVPG 20 mmHg). Patients with mild portal hypertension have a relatively low risk to develop varices and bleeding (8), while patients with severe portal hypertension and cirrhosis have a high risk of first bleeding, rebleeding and death, especially if the portal pressure cannot be significantly reduced by drugs such as non-selective beta-blockers (9). The average HVPG augments with increasing ChildPugh grade, which reflects the degree of liver decompensation, but there is a rather large overlap between the three Child-grades (2). Multivariate analysis shows that HVPG adds prognostic information to the Child status (2). Medical decompression of portal hypertension by using non-selective beta-blockers, nitrates or vasoactive drugs such as terlipressin is mainly used to treat or prevent variceal bleeding. In this situation, assessment of drug effects by HVPG determination may tailor treatment (7, 10–13). Since changes take place
4
in a low pressure system and at that are small (mostly less than 20%), it is important to achieve valid determinations of pressures. Unfortunately, these are prone to many artifacts, thus technical aspects are very important in this context. Correct transducers, adequate calibration, mode of catheter and adequate position in the wedged as well as free position and correct tracing are important variables that may influence the results. Finally, sedation may also influence measurements (3, 6). In this issue, the Barcelona group, which for many years has been a protagonist of HVPG measurement, shows that deep sedation with propofol and remifentanil results in a marked oscillation of the pressure curve induced by respiration (14). While in the awake state, differences between inspiratory and expiratory pressure were not higher than 1–3 mmHg, these pressures fluctuated by up to 10 mmHg when patients were sedated. The authors show that mean end-expiratory pressure in sedated patients correlated best with awake HVPG and that the mean pressure along the respiratory cycle was very similar to awake state HVPG. However, the agreement between the awake and deeply sedated state was rather poor in the individual patients with respect to assessment of the relative pressure reduction after application of propranolol. Furthermore, sedation led to a significant drop of mean arterial pressure, systemic vascular resistance and respiratory rate. This stresses the fact that, even without medical manipulation by using sedatives, interactive systemic hemodynamics may change because of physical activity or time of day (15, 16) and – regarding splanchnic hemodynamics – considerably with meals (16–18). This study convincingly demonstrates the dimension of sedation on HVPG measurement. But does this have clinical implications? Since the mean HVPG along the respiratory cycle remained rather stable, the influence of sedation is probably less crucial if HVPG is assessed to categorize patients for prediction of the bleeding risk or even survival. However, concerning assessment of drug effects, where rather slight changes of 10–20% have been described to separate responders from nonresponders for bleeding prophylaxis, meticulous observation of similar conditions before and after treatment is probably necessary (3, 6), especially if drugs act via change of systemic hemodynamics and change of tributary blood flow. Are we allowed to give these patients Liver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Sauerbruch
Editorial
sedation? Strictly speaking, we do not know since studies with clinical endpoints are lacking. If we use them, low-dose midazolam (19) has been shown to have minor influence. Nevertheless, the mode of the procedure should be kept as similar as possible. Perusing the available publications one has the impression that very experienced groups, where routine measurement of HVPG has been performed for many years, achieve reliable results also with minor sedation because of their routine with this procedure. This may be more of a problem in units where HVPG measurement is not part of the regular repertoire in staging of patients with cirrhosis. In any case, proper execution of the technique is paramount. There are other (20) and new less invasive techniques such as elastography (17, 21, 22) and old techniques such as measurement of portal venous flow (23, 24) that may correlate with HVPG, but they are not sufficiently established as a substitute for HVPG or are not sensitive enough to detect pressure changes (13), and there is no reason why these methods should not be influenced by deep sedation, especially if used for drug monitoring.
Tilman Sauerbruch1* 1 Medical Department I, University of Bonn, Bonn, Germany *Present address: Department of Gastroenterology and Endocrinology, Go¨ttingen, Germany
References 1. Vorobioff JD, Groszmann RJ. Hepatic venous pressure gradient measurement in pre-primary and primary prophylaxis of variceal hemorrhage. Ann Hepatol 2013; 12: 22–9. 2. Patch D, Armonis A, Sabin C, et al. Single portal pressure measurement predicts survival in cirrhotic patients with recent bleeding. Gut 1999; 44: 264–9. 3. Bosch J, Abraldes JG, Berzigotti A, Garcı´a-Paga´n JC. The clinical use of HVPG measurements in chronic liver disease. Nat Rev Gastroenterol Hepatol 2009; 6:573–82. 4. Meyers JD, Taylor WJ. An estimation of portal venous pressure by occlusive catheterization of a hepatic vanule. J Clin Invest 1951; 30: 662–3. 5. Perell o A, Escorsell A, Bru C, et al. Wedged hepatic venous pressure adequately reflects portal pressure in hepatitis C virus-related cirrhosis. Hepatology 1999; 30: 1393–7. 6. Groszmann RJ, Wongcharatrawee S. The hepatic venous pressure gradient: anything worth doing should be done right. Hepatology 2004; 39: 280–2. 7. Boyer TD. Changing clinical practice with measurements of portal pressure. Hepatology 2004; 39: 283–5. 8. Groszmann RJ, Garcia-Tsao G, Bosch J et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. Engl J Med 2005; 353: 2254–61.
Liver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
9. D’Amico G, Garcıa-Pagan JC, Luca A, Bosch J. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology 2006; 131: 1611–24. 10. Bureau C, Peron JM, Alric L, et al. ‘A La Carte’ treatment of portal hypertension: adapting medical therapy to hemodynamic response for the prevention of bleeding. Hepatology 2002; 36: 1361–6. 11. Gonzalez A, Augustin S, Perez M, et al. Genesca Hemodynamic response-guided therapy for prevention of variceal rebleeding: an uncontrolled pilot study. Hepatology 2006; 44: 806–12. 12. Abraldes JG, Tarantino I, Turnes J, et al. Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis. Hepatology 2003; 37: 902–8. 13. McCormick PA, Patch D, Greenslade L, et al. Clinical vs haemodynamic response to drugs in portal hypertension. J Hepatol 1998; 28: 1015–9. 14. Reverter E, Blasi A, Abraldes JG, et al. Impact of deep sedation on the accuracy of hepatic and portal venous pressure measurements in patients with cirrhosis. Liver Int 2014; 34: 16–25. 15. Sugano S, Yamamoto K, Sasao K, et al. Daily variation of azygos and portal blood flow and the effect of propranolol administration once an evening in cirrhotics. J Hepatol 2001; 34: 26–31. 16. Schiedermaier P, Koch L, Moj on A, et al. Circadian rhythm of fasting and postprandial portal blood flow in cirrhosis. Scand J Gastroenterol 2006; 41: 826–32. 17. Berzigotti A, De Gottardi A, Vukotic R, et al. Effect of meal ingestion on liver stiffness in patients with cirrhosis and portal hypertension. PLoS One 2013; 8: e58742. 18. Schiedermaier P, Koch L, Stoffel-Wagner B, Layer G, Sauerbruch T. Effect of propranolol and depot lanreotide SR on postprandial and circadian portal haemodynamics in cirrhosis. Aliment Pharmacol Ther 2003; 18: 777–84. 19. Steinlauf AF, Garcia-Tsao G, Zakko MF, et al. Low-dose midazolam sedation: an option for patients undergoing serial hepatic venous pressure measurements. Hepatology 1999; 29: 1070–3. 20. Thabut D, Moreau R, Lebrec D. Noninvasive assessment of portal hypertension in patients with cirrhosis. Hepatology. 2011; 53: 683–94. 21. Castera L, Pinzani M, Bosch J. Non invasive evaluation of portal hypertension using transient elastography. J Hepatol 2012; 56: 696–703. 22. Reiberger T, Ferlitsch A, Payer BA, et al. Non-selective b-blockers improve the correlation of liver stiffness and portal pressure in advanced cirrhosis. J Gastroenterol 2012; 47: 561–8. 23. Schepke M, Raab P, Hoppe A, et al. Comparison of portal vein velocity and the hepatic venous pressure gradient in assessing the acute portal hemodynamic response to propranolol in patients with cirrhosis. Am J Gastroenterol 2000; 95: 2905–9. 24. Berzigotti A, Rinaldi MF, Magalotti D, et al. Primary prophylaxis with nadolol in cirrhotic patients: doppler patterns of splanchnic hemodynamics in good and poor responders. J Hepatol 2006; 44: 310–6.
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