A Survey of the Use of Ultrasound During Central Venous Catheterization.[Miscellaneous Article]
Source Anesthesia & Analgesia. 104(3):491-497, March 2007.
Abstract BACKGROUND: Complications during central venous catheterization (CVC) are not rare and can be serious. The use of ultrasound (US) during CVC has been recommended to improve patient safety. We performed a survey to evaluate the frequency of, and factors influencing, US use.
METHODS: We conducted an electronic survey of all members of the Society of Cardiovascular Anesthesiologists. Univariate and multivariate logistic regressions were used to assess the association between the frequency of US use and hospital and physician factors. All tests were two-sided, and a P value <0.05 was considered statistically significant.
RESULTS: Of the 4235 members, 1494 responded (response rate = 35.3%). Two-thirds of the respondents never, or almost never, use US, whereas only 15% always, or almost always, use US. Thirty-three percent of the respondents never, or almost never, have US available, whereas 41% stated that US is always, or almost always, available. Availability of US equipment was strongly associated with US use for CVC (adj OR = 18.9; P value <0.001). The most common reason cited for not using US was "no apparent need for the use of US" (46%). When US was used, rescue or screening approaches were more common (72%) than real-time use (26%).
CONCLUSIONS: The use of US during CVC remains limited and is most strongly associated with the availability of equipment. Screening and rescue use of US are more common than real-time guidance. Our survey suggests that current use of US during CVC differs from existing evidence-based recommendations.
domingo, 15 de julho de 2007
Haesteril e voluven - pros e contras
The Pros and Cons of Hydroxyethyl Starch Solutions
[Editorial]
Vincent, Jean-Louis MD, PhDFrom the Department of Intensive Care, Erasme Hospital, Free University of Brussels, Belgium.
Accepted for publication December 20, 2006.
Address correspondence and reprint requests to Jean-Louis Vincent, Department of Intensive Care, Erasme University Hospital, Route de Lennik 808, B-1070 Brussels, Belgium. Address e-mail to jlvincen@ulb.ac.be.
The optimal type of fluid for intravascular volume resuscitation in critically ill patients remains a matter of debate. With their higher molecular weight, colloids remain in the intravascular space longer, and, therefore, provide more rapid hemodynamic stabilization than crystalloids, which extravasate to a greater degree so that more fluids are required to achieve the same end points. However, colloids are more expensive than crystalloids, in particular albumin, so that other colloids have been developed, including gelatins, dextrans, and hydroxyethyl starch (HES) solutions.
Hydroxyethyl starch solutions have evolved since they were first developed in the Unite States in the 1970s. The first HES solutions included HES molecules of relatively high molecular weight and high degree of substitution, in an attempt to prolong their vascular persistence. These solutions were associated with an increased risk of bleeding (1,2) and renal failure (3–5). Prolonged persistence in the body also raised concern (6), and there are numerous reports of delayed itching in the dermatologic literature (7). Lower molecular weight HES solutions and solutions with lesser degrees of substitution have since been developed that may have an improved pharmacological profile, with fewer negative effects on coagulation and renal function, and more rapid tissue clearance (8,9).
Importantly, in addition to their effects as intravascular volume expanders, HES solutions may have other properties. As early as the 1980s, Zikria et al. (10,11) reported that HES solutions could reduce microvascular permeability, leading to the concept that they could “plug” the leaks created in the endothelium during various disease processes, including sepsis and burns (12). In this issue of Anesthesia & Analgesia, Feng et al. (13) show that, in a model of cecal ligation and perforation, rats that received HES or gelatin solutions had reduced pulmonary capillary leakage compared with those that received normal saline. In addition, HES administration was associated with reduced expression of various proinflammatory mediators, including tumor necrosis factor and interleukin-1, while gelatin administration was not.
In their present study, these authors have extended their previous data in rats, which showed that HES significantly reduced lipopolysaccharide-induced increases in lung capillary permeability, and inhibited lung neutrophil accumulation, cytokine-induced neutrophil chemoattractant protein, and nuclear factor-[kappa] B activation (14). Their results also agree with experimental studies from other groups demonstrating the antiinflammatory effects of HES solutions (15–19). Hydroxyethyl starch has been shown to restore macrophage integrity and prevent the increase in interleukin-6 in mice after trauma-hemorrhage (15), to alter the interaction of neutrophils with activated endothelium (16,17), to decrease the neutrophil respiratory burst induced by Escherichia coli (18), and to attenuate hypoxia-induced increases in vascular leakage and acute inflammation (19). Boldt et al. (20), in patients undergoing major abdominal surgery, reported that the administration of HES was associated with reduced markers of inflammation and endothelial activation compared with crystalloid.
The Feng et al. data (13) thus seem consistent with previous studies, but interpretation remains difficult. An important question is whether the observed effects are due to the solution itself or, rather, due to the effectiveness of the fluid resuscitation. In in vivo studies it is difficult to separate the specific effects of the individual fluids on the vessels from the general effects of fluid resuscitation. These difficulties are well illustrated by Marx et al. (21) in their study in a porcine model, where the early administration of HES solution restored tissue oxygenation better than Ringer’s lactate solution; however, there were no differences in the albumin escape rate, suggesting that the changes observed were due more to hemodynamic than to specific antiinflammatory effects.
Prolonged tissue hypoperfusion with regional tissue hypoxia can increase the inflammatory response. Even in the absence of inflammation, prolonged severe hypoxia results in increased endothelial permeability, believed to be a key factor in the development of organ failure (22); thus, the longer a shock state persists, the greater the likelihood that the patient will develop organ failure. In patients with severe sepsis, we (23) recently showed that the duration of vasopressor requirement was directly related to the risk of subsequent organ failure.
Intravascular fluid resuscitation has been shown to reduce the inflammatory response. For example, improved resuscitation after hemorrhage is associated with reduced pulmonary dysfunction and lung inflammation (24,25), and preemptive intravascular volume administration prevents lipopolysaccharide-induced microcirculatory changes (26). In other septic models, intravascular fluid resuscitation attenuated the release of cytokines or platelet activating factor (27,28). Logically, therefore, rapid reversal of acute circulatory failure should result in a shorter and less intense inflammatory reaction, with fewer permeability alterations and less edema formation.
In the study by Feng et al. (13), the effects of HES were compared with those of an identical amount of gelatin, a colloid with a molecular weight only half that of albumin. Hence, the intravascular volume effects may have been greater in the HES group than in the other group. Arterial blood pressure was similar in the various groups, but this provides only a rough estimate of hemodynamic stability. Even measurements of cardiac output would not be entirely reassuring. Indeed, macrohemodynamic variables can be restored while the microhemodynamic status remains altered (29). Studies in rats, like that by Feng et al. (13), cannot explore these differences reliably, and one would like to see similar experiments in larger animals, or even in humans, and with a more effective colloid (such as albumin) for comparison. In summary, the intensity of the intravascular fluid resuscitation may be more important than the type of fluid itself, and HES solutions have very effective vascular effects.
In the meantime, if the evidence is strong enough to support the antiinflammatory effects of HES, the question then becomes, Do these antiinflammatory properties give HES solutions a definitive advantage over other fluids? Perhaps not. First, a reduced inflammatory response does not necessarily translate into clinical benefit. Decreased capillary leak may be globally beneficial, but decreased neutrophil activation may have unwanted, as well as wanted, consequences. Second, assuming that the antiinflammatory effects are beneficial, other fluids may have similar advantages. Albumin, for example, has been shown to have antiinflammatory and antioxidant effects (30–33). Hydroxyethyl starch solutions may have other drawbacks, including the risk of altered hemostasis and the persistence of HES molecules in the body. In addition, there is new concern about the increased risks of renal failure associated with HES administration. A recent multicenter German study, the Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis study, indicates that HES administration in patients with severe sepsis may be associated with an increased risk of acute renal failure. (Data presented at the 27th International Symposium of Intensive Care and Emergency Medicine, Brussels, March 2006.)
So, where does this leave us in the big fluid debate? The present results are interesting and add another little piece to the big puzzle, but much more work is needed before we will be able to see the full picture and to better determine where each fluid fits. Although we use these fluids every day, we still know surprisingly little about them.
REFERENCES
1. Symington BE. Hetastarch and bleeding complications. Ann Intern Med 1986;105:627–8. Bibliographic Links [Context Link]
2. Treib J, Haass A, Pindur G. Coagulation disorders caused by hydroxyethyl starch. Thromb Haemost 1997;78:974–83. Bibliographic Links [Context Link]
3. Legendre C, Thervet E, Page B, et al. Hydroxyethylstarch and osmotic-nephrosis-like lesions in kidney transplantation. Lancet 1993;342:248–9. Bibliographic Links [Context Link]
4. Cittanova ML, Leblanc I, Legendre C, et al. Effect of hydroxyethylstarch in brain-dead kidney donors on renal function in kidney-transplant recipients. Lancet 1996;348:1620–2. Bibliographic Links [Context Link]
5. Schortgen F, Lacherade JC, Bruneel F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet 2001;357:911–6. Bibliographic Links [Context Link]
6. Thompson WL, Fukushima T, Rutherford RB, Walton RP. Intravascular persistence, tissue storage, and excretion of hydroxyethyl starch. Surg Gynecol Obstet 1970;131:965–72. Bibliographic Links [Context Link]
7. Bork K. Pruritus precipitated by hydroxyethyl starch: a review. Br J Dermatol 2005;152:3–12. Buy Now Bibliographic Links [Context Link]
8. Treib J, Baron JF, Grauer MT, Strauss RG. An international view of hydroxyethyl starches. Intensive Care Med 1999;25:258–68. Bibliographic Links [Context Link]
9. Treib J, Haass A, Pindur G, et al. All medium starches are not the same: influence of the degree of hydroxyethyl substitution of hydroxyethyl starch on plasma volume, hemorrheologic conditions, and coagulation. Transfusion 1996;36:450–5. Bibliographic Links [Context Link]
10. Zikria BA, Subbarao C, Oz MC, et al. Macromolecules reduce abnormal microvascular permeability in rat limb ischemia-reperfusion injury. Crit Care Med 1989;17:1306–9. Buy Now Bibliographic Links [Context Link]
11. Zikria BA, King TC, Stanford J, Freeman HP. A biophysical approach to capillary permeability. Surgery 1989;105:625–31. Bibliographic Links [Context Link]
12. Vincent JL. Plugging the leaks? New insights into synthetic colloids. Crit Care Med 1991;19:316–8. Buy Now Bibliographic Links [Context Link]
13. Feng X, Liu J, Yu M, et al. Hydroxyethyl starch, but not modified fluid gelatin, affects inflammatory response in a rat model of polymicrobial sepsis with capillary leakage. Anesth Analg 2007;104:624–30. Ovid Full Text Bibliographic Links [Context Link]
14. Tian J, Lin X, Guan R, Xu JG. The effects of hydroxyethyl starch on lung capillary permeability in endotoxic rats and possible mechanisms. Anesth Analg 2004;98:768–74. Ovid Full Text Bibliographic Links [Context Link]
15. Schmand JF, Ayala A, Morrison MH, Chaudry IH. Effects of hydroxyethyl starch after trauma-hemorrhagic shock: restoration of macrophage integrity and prevention of increased circulating IL-6 levels. Crit Care Med 1995;23:806–14. Ovid Full Text Bibliographic Links [Context Link]
16. Handrigan MT, Burns AR, Donnachie EM, Bowden RA. Hydroxyethyl starch inhibits neutrophil adhesion and transendothelial migration. Shock 2005;24:434–9. Buy Now Bibliographic Links [Context Link]
17. Hoffmann JN, Vollmar B, Laschke MW, et al. Hydroxyethyl starch (130 kD), but not crystalloid volume support, improves microcirculation during normotensive endotoxemia. Anesthesiology 2002;97:460–70. Ovid Full Text Bibliographic Links [Context Link]
18. Jaeger K, Heine J, Ruschulte H, et al. Effects of colloidal resuscitation fluids on the neutrophil respiratory burst. Transfusion 2001; 41:1064–8. Bibliographic Links [Context Link]
19. Dieterich HJ, Weissmuller T, Rosenberger P, Eltzschig HK. Effect of hydroxyethyl starch on vascular leak syndrome and neutrophil accumulation during hypoxia. Crit Care Med 2006; 34:1775–82. Ovid Full Text Bibliographic Links [Context Link]
20. Boldt J, Ducke M, Kumle B, et al. Influence of different volume replacement strategies on inflammation and endothelial activation in the elderly undergoing major abdominal surgery. Intensive Care Med 2004;30:416–22. Bibliographic Links [Context Link]
21. Marx G, Pedder S, Smith L, et al. Resuscitation from septic shock with capillary leakage: hydroxyethyl starch (130 kd), but not Ringer’s solution maintains plasma volume and systemic oxygenation. Shock 2004;21:336–41. Buy Now Bibliographic Links [Context Link]
22. Ali MH, Schlidt SA, Hynes KL, et al. Prolonged hypoxia alters endothelial barrier function. Surgery 1998;124:491–7. Bibliographic Links [Context Link]
23. Levy MM, Macias WL, Vincent JL, et al. Early changes in organ function predict eventual survival in severe sepsis. Crit Care Med 2005;33:2194–201. Ovid Full Text Bibliographic Links [Context Link]
24. Claridge JA, Schulman AM, Young JS. Improved resuscitation minimizes respiratory dysfunction and blunts interleukin-6 and nuclear factor-kappa B activation after traumatic hemorrhage. Crit Care Med 2002;30:1815–9. Ovid Full Text Bibliographic Links [Context Link]
25. Kiang JG, Lu X, Tabaku LS, et al. Resuscitation with lactated Ringer solution limits the expression of molecular events associated with lung injury after hemorrhage. J Appl Physiol 2005;98:550–6. Bibliographic Links [Context Link]
26. Anning PB, Finney SJ, Singh S, et al. Fluids reverse the early lipopolysaccharide-induced albumin leakage in rodent mesenteric venules. Intensive Care Med 2004;30:1944–9. Bibliographic Links [Context Link]
27. Wilson MA, Chou MC, Spain DA, et al. Fluid resuscitation attenuates early cytokine mRNA expression after peritonitis. J Trauma 1996; 41:622–7. Buy Now Bibliographic Links [Context Link]
28. Zhang C, Hsueh W, Caplan MS, Kelly A. Platelet activating factor-induced shock and intestinal necrosis in the rat: role of endogenous platelet-activating factor and effect of saline infusion. Crit Care Med 1991;19:1067–72. Buy Now Bibliographic Links [Context Link]
29. Sakr Y, Dubois MJ, De Backer D, et al. Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med 2004;32:1825–31. Ovid Full Text Bibliographic Links [Context Link]
30. Zhang WJ, Frei B. Albumin selectively inhibits TNF alpha-induced expression of vascular cell adhesion molecule-1 in human aortic endothelial cells. Cardiovasc Res 2002;55:820–9. Bibliographic Links [Context Link]
31. Powers KA, Kapus A, Khadaroo RG, et al. Twenty-five percent albumin prevents lung injury following shock/resuscitation. Crit Care Med 2003;31:2355–63. Ovid Full Text Bibliographic Links [Context Link]
32. Simpkins CO, Little D, Brenner A, et al. Heterogeneity in the effect of albumin and other resuscitation fluids on intracellular oxygen free radical production. J Trauma 2004;56:548–58. Buy Now Bibliographic Links [Context Link]
33. Quinlan GJ, Mumby S, Martin GS, et al. Albumin influences total plasma antioxidant capacity favorably in patients with acute lung injury. Crit Care Med 2004;32:755–9. Ovid Full Text Bibliographic Links [Context Link]
[Editorial]
Vincent, Jean-Louis MD, PhDFrom the Department of Intensive Care, Erasme Hospital, Free University of Brussels, Belgium.
Accepted for publication December 20, 2006.
Address correspondence and reprint requests to Jean-Louis Vincent, Department of Intensive Care, Erasme University Hospital, Route de Lennik 808, B-1070 Brussels, Belgium. Address e-mail to jlvincen@ulb.ac.be.
The optimal type of fluid for intravascular volume resuscitation in critically ill patients remains a matter of debate. With their higher molecular weight, colloids remain in the intravascular space longer, and, therefore, provide more rapid hemodynamic stabilization than crystalloids, which extravasate to a greater degree so that more fluids are required to achieve the same end points. However, colloids are more expensive than crystalloids, in particular albumin, so that other colloids have been developed, including gelatins, dextrans, and hydroxyethyl starch (HES) solutions.
Hydroxyethyl starch solutions have evolved since they were first developed in the Unite States in the 1970s. The first HES solutions included HES molecules of relatively high molecular weight and high degree of substitution, in an attempt to prolong their vascular persistence. These solutions were associated with an increased risk of bleeding (1,2) and renal failure (3–5). Prolonged persistence in the body also raised concern (6), and there are numerous reports of delayed itching in the dermatologic literature (7). Lower molecular weight HES solutions and solutions with lesser degrees of substitution have since been developed that may have an improved pharmacological profile, with fewer negative effects on coagulation and renal function, and more rapid tissue clearance (8,9).
Importantly, in addition to their effects as intravascular volume expanders, HES solutions may have other properties. As early as the 1980s, Zikria et al. (10,11) reported that HES solutions could reduce microvascular permeability, leading to the concept that they could “plug” the leaks created in the endothelium during various disease processes, including sepsis and burns (12). In this issue of Anesthesia & Analgesia, Feng et al. (13) show that, in a model of cecal ligation and perforation, rats that received HES or gelatin solutions had reduced pulmonary capillary leakage compared with those that received normal saline. In addition, HES administration was associated with reduced expression of various proinflammatory mediators, including tumor necrosis factor and interleukin-1, while gelatin administration was not.
In their present study, these authors have extended their previous data in rats, which showed that HES significantly reduced lipopolysaccharide-induced increases in lung capillary permeability, and inhibited lung neutrophil accumulation, cytokine-induced neutrophil chemoattractant protein, and nuclear factor-[kappa] B activation (14). Their results also agree with experimental studies from other groups demonstrating the antiinflammatory effects of HES solutions (15–19). Hydroxyethyl starch has been shown to restore macrophage integrity and prevent the increase in interleukin-6 in mice after trauma-hemorrhage (15), to alter the interaction of neutrophils with activated endothelium (16,17), to decrease the neutrophil respiratory burst induced by Escherichia coli (18), and to attenuate hypoxia-induced increases in vascular leakage and acute inflammation (19). Boldt et al. (20), in patients undergoing major abdominal surgery, reported that the administration of HES was associated with reduced markers of inflammation and endothelial activation compared with crystalloid.
The Feng et al. data (13) thus seem consistent with previous studies, but interpretation remains difficult. An important question is whether the observed effects are due to the solution itself or, rather, due to the effectiveness of the fluid resuscitation. In in vivo studies it is difficult to separate the specific effects of the individual fluids on the vessels from the general effects of fluid resuscitation. These difficulties are well illustrated by Marx et al. (21) in their study in a porcine model, where the early administration of HES solution restored tissue oxygenation better than Ringer’s lactate solution; however, there were no differences in the albumin escape rate, suggesting that the changes observed were due more to hemodynamic than to specific antiinflammatory effects.
Prolonged tissue hypoperfusion with regional tissue hypoxia can increase the inflammatory response. Even in the absence of inflammation, prolonged severe hypoxia results in increased endothelial permeability, believed to be a key factor in the development of organ failure (22); thus, the longer a shock state persists, the greater the likelihood that the patient will develop organ failure. In patients with severe sepsis, we (23) recently showed that the duration of vasopressor requirement was directly related to the risk of subsequent organ failure.
Intravascular fluid resuscitation has been shown to reduce the inflammatory response. For example, improved resuscitation after hemorrhage is associated with reduced pulmonary dysfunction and lung inflammation (24,25), and preemptive intravascular volume administration prevents lipopolysaccharide-induced microcirculatory changes (26). In other septic models, intravascular fluid resuscitation attenuated the release of cytokines or platelet activating factor (27,28). Logically, therefore, rapid reversal of acute circulatory failure should result in a shorter and less intense inflammatory reaction, with fewer permeability alterations and less edema formation.
In the study by Feng et al. (13), the effects of HES were compared with those of an identical amount of gelatin, a colloid with a molecular weight only half that of albumin. Hence, the intravascular volume effects may have been greater in the HES group than in the other group. Arterial blood pressure was similar in the various groups, but this provides only a rough estimate of hemodynamic stability. Even measurements of cardiac output would not be entirely reassuring. Indeed, macrohemodynamic variables can be restored while the microhemodynamic status remains altered (29). Studies in rats, like that by Feng et al. (13), cannot explore these differences reliably, and one would like to see similar experiments in larger animals, or even in humans, and with a more effective colloid (such as albumin) for comparison. In summary, the intensity of the intravascular fluid resuscitation may be more important than the type of fluid itself, and HES solutions have very effective vascular effects.
In the meantime, if the evidence is strong enough to support the antiinflammatory effects of HES, the question then becomes, Do these antiinflammatory properties give HES solutions a definitive advantage over other fluids? Perhaps not. First, a reduced inflammatory response does not necessarily translate into clinical benefit. Decreased capillary leak may be globally beneficial, but decreased neutrophil activation may have unwanted, as well as wanted, consequences. Second, assuming that the antiinflammatory effects are beneficial, other fluids may have similar advantages. Albumin, for example, has been shown to have antiinflammatory and antioxidant effects (30–33). Hydroxyethyl starch solutions may have other drawbacks, including the risk of altered hemostasis and the persistence of HES molecules in the body. In addition, there is new concern about the increased risks of renal failure associated with HES administration. A recent multicenter German study, the Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis study, indicates that HES administration in patients with severe sepsis may be associated with an increased risk of acute renal failure. (Data presented at the 27th International Symposium of Intensive Care and Emergency Medicine, Brussels, March 2006.)
So, where does this leave us in the big fluid debate? The present results are interesting and add another little piece to the big puzzle, but much more work is needed before we will be able to see the full picture and to better determine where each fluid fits. Although we use these fluids every day, we still know surprisingly little about them.
REFERENCES
1. Symington BE. Hetastarch and bleeding complications. Ann Intern Med 1986;105:627–8. Bibliographic Links [Context Link]
2. Treib J, Haass A, Pindur G. Coagulation disorders caused by hydroxyethyl starch. Thromb Haemost 1997;78:974–83. Bibliographic Links [Context Link]
3. Legendre C, Thervet E, Page B, et al. Hydroxyethylstarch and osmotic-nephrosis-like lesions in kidney transplantation. Lancet 1993;342:248–9. Bibliographic Links [Context Link]
4. Cittanova ML, Leblanc I, Legendre C, et al. Effect of hydroxyethylstarch in brain-dead kidney donors on renal function in kidney-transplant recipients. Lancet 1996;348:1620–2. Bibliographic Links [Context Link]
5. Schortgen F, Lacherade JC, Bruneel F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet 2001;357:911–6. Bibliographic Links [Context Link]
6. Thompson WL, Fukushima T, Rutherford RB, Walton RP. Intravascular persistence, tissue storage, and excretion of hydroxyethyl starch. Surg Gynecol Obstet 1970;131:965–72. Bibliographic Links [Context Link]
7. Bork K. Pruritus precipitated by hydroxyethyl starch: a review. Br J Dermatol 2005;152:3–12. Buy Now Bibliographic Links [Context Link]
8. Treib J, Baron JF, Grauer MT, Strauss RG. An international view of hydroxyethyl starches. Intensive Care Med 1999;25:258–68. Bibliographic Links [Context Link]
9. Treib J, Haass A, Pindur G, et al. All medium starches are not the same: influence of the degree of hydroxyethyl substitution of hydroxyethyl starch on plasma volume, hemorrheologic conditions, and coagulation. Transfusion 1996;36:450–5. Bibliographic Links [Context Link]
10. Zikria BA, Subbarao C, Oz MC, et al. Macromolecules reduce abnormal microvascular permeability in rat limb ischemia-reperfusion injury. Crit Care Med 1989;17:1306–9. Buy Now Bibliographic Links [Context Link]
11. Zikria BA, King TC, Stanford J, Freeman HP. A biophysical approach to capillary permeability. Surgery 1989;105:625–31. Bibliographic Links [Context Link]
12. Vincent JL. Plugging the leaks? New insights into synthetic colloids. Crit Care Med 1991;19:316–8. Buy Now Bibliographic Links [Context Link]
13. Feng X, Liu J, Yu M, et al. Hydroxyethyl starch, but not modified fluid gelatin, affects inflammatory response in a rat model of polymicrobial sepsis with capillary leakage. Anesth Analg 2007;104:624–30. Ovid Full Text Bibliographic Links [Context Link]
14. Tian J, Lin X, Guan R, Xu JG. The effects of hydroxyethyl starch on lung capillary permeability in endotoxic rats and possible mechanisms. Anesth Analg 2004;98:768–74. Ovid Full Text Bibliographic Links [Context Link]
15. Schmand JF, Ayala A, Morrison MH, Chaudry IH. Effects of hydroxyethyl starch after trauma-hemorrhagic shock: restoration of macrophage integrity and prevention of increased circulating IL-6 levels. Crit Care Med 1995;23:806–14. Ovid Full Text Bibliographic Links [Context Link]
16. Handrigan MT, Burns AR, Donnachie EM, Bowden RA. Hydroxyethyl starch inhibits neutrophil adhesion and transendothelial migration. Shock 2005;24:434–9. Buy Now Bibliographic Links [Context Link]
17. Hoffmann JN, Vollmar B, Laschke MW, et al. Hydroxyethyl starch (130 kD), but not crystalloid volume support, improves microcirculation during normotensive endotoxemia. Anesthesiology 2002;97:460–70. Ovid Full Text Bibliographic Links [Context Link]
18. Jaeger K, Heine J, Ruschulte H, et al. Effects of colloidal resuscitation fluids on the neutrophil respiratory burst. Transfusion 2001; 41:1064–8. Bibliographic Links [Context Link]
19. Dieterich HJ, Weissmuller T, Rosenberger P, Eltzschig HK. Effect of hydroxyethyl starch on vascular leak syndrome and neutrophil accumulation during hypoxia. Crit Care Med 2006; 34:1775–82. Ovid Full Text Bibliographic Links [Context Link]
20. Boldt J, Ducke M, Kumle B, et al. Influence of different volume replacement strategies on inflammation and endothelial activation in the elderly undergoing major abdominal surgery. Intensive Care Med 2004;30:416–22. Bibliographic Links [Context Link]
21. Marx G, Pedder S, Smith L, et al. Resuscitation from septic shock with capillary leakage: hydroxyethyl starch (130 kd), but not Ringer’s solution maintains plasma volume and systemic oxygenation. Shock 2004;21:336–41. Buy Now Bibliographic Links [Context Link]
22. Ali MH, Schlidt SA, Hynes KL, et al. Prolonged hypoxia alters endothelial barrier function. Surgery 1998;124:491–7. Bibliographic Links [Context Link]
23. Levy MM, Macias WL, Vincent JL, et al. Early changes in organ function predict eventual survival in severe sepsis. Crit Care Med 2005;33:2194–201. Ovid Full Text Bibliographic Links [Context Link]
24. Claridge JA, Schulman AM, Young JS. Improved resuscitation minimizes respiratory dysfunction and blunts interleukin-6 and nuclear factor-kappa B activation after traumatic hemorrhage. Crit Care Med 2002;30:1815–9. Ovid Full Text Bibliographic Links [Context Link]
25. Kiang JG, Lu X, Tabaku LS, et al. Resuscitation with lactated Ringer solution limits the expression of molecular events associated with lung injury after hemorrhage. J Appl Physiol 2005;98:550–6. Bibliographic Links [Context Link]
26. Anning PB, Finney SJ, Singh S, et al. Fluids reverse the early lipopolysaccharide-induced albumin leakage in rodent mesenteric venules. Intensive Care Med 2004;30:1944–9. Bibliographic Links [Context Link]
27. Wilson MA, Chou MC, Spain DA, et al. Fluid resuscitation attenuates early cytokine mRNA expression after peritonitis. J Trauma 1996; 41:622–7. Buy Now Bibliographic Links [Context Link]
28. Zhang C, Hsueh W, Caplan MS, Kelly A. Platelet activating factor-induced shock and intestinal necrosis in the rat: role of endogenous platelet-activating factor and effect of saline infusion. Crit Care Med 1991;19:1067–72. Buy Now Bibliographic Links [Context Link]
29. Sakr Y, Dubois MJ, De Backer D, et al. Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med 2004;32:1825–31. Ovid Full Text Bibliographic Links [Context Link]
30. Zhang WJ, Frei B. Albumin selectively inhibits TNF alpha-induced expression of vascular cell adhesion molecule-1 in human aortic endothelial cells. Cardiovasc Res 2002;55:820–9. Bibliographic Links [Context Link]
31. Powers KA, Kapus A, Khadaroo RG, et al. Twenty-five percent albumin prevents lung injury following shock/resuscitation. Crit Care Med 2003;31:2355–63. Ovid Full Text Bibliographic Links [Context Link]
32. Simpkins CO, Little D, Brenner A, et al. Heterogeneity in the effect of albumin and other resuscitation fluids on intracellular oxygen free radical production. J Trauma 2004;56:548–58. Buy Now Bibliographic Links [Context Link]
33. Quinlan GJ, Mumby S, Martin GS, et al. Albumin influences total plasma antioxidant capacity favorably in patients with acute lung injury. Crit Care Med 2004;32:755–9. Ovid Full Text Bibliographic Links [Context Link]
Levosimedan-Artigo
The Effects of Levosimendan in Cardiac Surgery Patients with Poor Left Ventricular Function.[Report]
Source Anesthesia & Analgesia. 104(4):766-773, April 2007.
Abstract BACKGROUND: Patients with poor left ventricular function often require inotropic drug support immediately after cardiopulmonary bypass. Levosimendan improves cardiac function by a novel mechanism of action compared to currently available drugs. We hypothesized that, in patients with severely compromised ventricular function, the use of levosimendan would be associated with better postoperative cardiac function than with inotropic drugs that increase myocardial oxygen consumption.
METHODS: Thirty patients with a preoperative ejection fraction <=30% scheduled for elective cardiac surgery with cardiopulmonary bypass were randomized to two different inotropic protocols: milrinone 0.5 mg [middle dot] kg-1 [middle dot] min-1 or levosimendan 0.1 mg [middle dot] kg-1 [middle dot] min-1, started immediately after the release of the aortic crossclamp. The treatment was masked to the observers. All patients received dobutamine 5 mg [middle dot] kg-1 [middle dot] min-1.
RESULTS: Stroke volume was similar between groups initially after surgery, but it declined 12 h after surgery in the milrinone group but not in the levosimendan group (P < 0.05 between groups) despite similar filling pressures. Total dose, duration of inotropic drug administration and norepinephrine dose were lower in the levosimendan group than in the milrinone group (P < 0.05). The duration of tracheal intubation was shorter in the former group compared with the milrinone group (P = 0008). Three patients in the milrinone group but none in the levosimendan group died within 30 days of surgery.
CONCLUSION: In cardiac surgery patients with a low preoperative ejection fraction, stroke volume was better maintained with the combination of dobutamine with levosimendan than with the combination of dobutamine with milrinone.
Source Anesthesia & Analgesia. 104(4):766-773, April 2007.
Abstract BACKGROUND: Patients with poor left ventricular function often require inotropic drug support immediately after cardiopulmonary bypass. Levosimendan improves cardiac function by a novel mechanism of action compared to currently available drugs. We hypothesized that, in patients with severely compromised ventricular function, the use of levosimendan would be associated with better postoperative cardiac function than with inotropic drugs that increase myocardial oxygen consumption.
METHODS: Thirty patients with a preoperative ejection fraction <=30% scheduled for elective cardiac surgery with cardiopulmonary bypass were randomized to two different inotropic protocols: milrinone 0.5 mg [middle dot] kg-1 [middle dot] min-1 or levosimendan 0.1 mg [middle dot] kg-1 [middle dot] min-1, started immediately after the release of the aortic crossclamp. The treatment was masked to the observers. All patients received dobutamine 5 mg [middle dot] kg-1 [middle dot] min-1.
RESULTS: Stroke volume was similar between groups initially after surgery, but it declined 12 h after surgery in the milrinone group but not in the levosimendan group (P < 0.05 between groups) despite similar filling pressures. Total dose, duration of inotropic drug administration and norepinephrine dose were lower in the levosimendan group than in the milrinone group (P < 0.05). The duration of tracheal intubation was shorter in the former group compared with the milrinone group (P = 0008). Three patients in the milrinone group but none in the levosimendan group died within 30 days of surgery.
CONCLUSION: In cardiac surgery patients with a low preoperative ejection fraction, stroke volume was better maintained with the combination of dobutamine with levosimendan than with the combination of dobutamine with milrinone.
Levosimedan-Artigo
The Effects of Levosimendan in Cardiac Surgery Patients with Poor Left Ventricular Function.[Report]
Source Anesthesia & Analgesia. 104(4):766-773, April 2007.
Abstract BACKGROUND: Patients with poor left ventricular function often require inotropic drug support immediately after cardiopulmonary bypass. Levosimendan improves cardiac function by a novel mechanism of action compared to currently available drugs. We hypothesized that, in patients with severely compromised ventricular function, the use of levosimendan would be associated with better postoperative cardiac function than with inotropic drugs that increase myocardial oxygen consumption.
METHODS: Thirty patients with a preoperative ejection fraction <=30% scheduled for elective cardiac surgery with cardiopulmonary bypass were randomized to two different inotropic protocols: milrinone 0.5 mg [middle dot] kg-1 [middle dot] min-1 or levosimendan 0.1 mg [middle dot] kg-1 [middle dot] min-1, started immediately after the release of the aortic crossclamp. The treatment was masked to the observers. All patients received dobutamine 5 mg [middle dot] kg-1 [middle dot] min-1.
RESULTS: Stroke volume was similar between groups initially after surgery, but it declined 12 h after surgery in the milrinone group but not in the levosimendan group (P < 0.05 between groups) despite similar filling pressures. Total dose, duration of inotropic drug administration and norepinephrine dose were lower in the levosimendan group than in the milrinone group (P < 0.05). The duration of tracheal intubation was shorter in the former group compared with the milrinone group (P = 0008). Three patients in the milrinone group but none in the levosimendan group died within 30 days of surgery.
CONCLUSION: In cardiac surgery patients with a low preoperative ejection fraction, stroke volume was better maintained with the combination of dobutamine with levosimendan than with the combination of dobutamine with milrinone.
Source Anesthesia & Analgesia. 104(4):766-773, April 2007.
Abstract BACKGROUND: Patients with poor left ventricular function often require inotropic drug support immediately after cardiopulmonary bypass. Levosimendan improves cardiac function by a novel mechanism of action compared to currently available drugs. We hypothesized that, in patients with severely compromised ventricular function, the use of levosimendan would be associated with better postoperative cardiac function than with inotropic drugs that increase myocardial oxygen consumption.
METHODS: Thirty patients with a preoperative ejection fraction <=30% scheduled for elective cardiac surgery with cardiopulmonary bypass were randomized to two different inotropic protocols: milrinone 0.5 mg [middle dot] kg-1 [middle dot] min-1 or levosimendan 0.1 mg [middle dot] kg-1 [middle dot] min-1, started immediately after the release of the aortic crossclamp. The treatment was masked to the observers. All patients received dobutamine 5 mg [middle dot] kg-1 [middle dot] min-1.
RESULTS: Stroke volume was similar between groups initially after surgery, but it declined 12 h after surgery in the milrinone group but not in the levosimendan group (P < 0.05 between groups) despite similar filling pressures. Total dose, duration of inotropic drug administration and norepinephrine dose were lower in the levosimendan group than in the milrinone group (P < 0.05). The duration of tracheal intubation was shorter in the former group compared with the milrinone group (P = 0008). Three patients in the milrinone group but none in the levosimendan group died within 30 days of surgery.
CONCLUSION: In cardiac surgery patients with a low preoperative ejection fraction, stroke volume was better maintained with the combination of dobutamine with levosimendan than with the combination of dobutamine with milrinone.
An Economic Analysis of Costs Associated with Development of a Cell Salvage Program.[Miscellaneous Article]
Source Anesthesia & Analgesia. 104(4):869-875, April 2007.
Abstract BACKGROUND: The increasing cost of blood products and associated risks of transfusion have lead to a heightened interest in techniques which reduce or replace allogeneic blood transfusion. The use of cell salvage is being explored in a number of institutions. We present financial information which may be useful to institutions that are considering the addition of a cell salvage service.
METHODS: A review of the cell salvage data from 2328 patients was used to estimate the average cost of a packed red blood cell unit equivalent processed by cell salvage equipment. In addition, an analysis was performed to assess the break-even point of establishing a cell salvage service.
RESULTS: Initial capital outlay to establish a cell salvage service at this institution was $103,551. The annual fixed operating cost was $250,943. The average cost of transfusion of an allogeneic packed red blood cell unit was $200. For an equivalent cell salvage unit, the cost was $89.46. The payback period was 1.9 mo.
CONCLUSION: This analysis suggests that cell salvage can be significantly less expensive than allogeneic blood. The cost of cell salvage in other institutions will vary depending upon case volume, expected levels of blood loss per case, and initial investment costs. A step-by-step formula is provided to assist in the evaluation of a cell salvage service in hospitals of various sizes.
Source Anesthesia & Analgesia. 104(4):869-875, April 2007.
Abstract BACKGROUND: The increasing cost of blood products and associated risks of transfusion have lead to a heightened interest in techniques which reduce or replace allogeneic blood transfusion. The use of cell salvage is being explored in a number of institutions. We present financial information which may be useful to institutions that are considering the addition of a cell salvage service.
METHODS: A review of the cell salvage data from 2328 patients was used to estimate the average cost of a packed red blood cell unit equivalent processed by cell salvage equipment. In addition, an analysis was performed to assess the break-even point of establishing a cell salvage service.
RESULTS: Initial capital outlay to establish a cell salvage service at this institution was $103,551. The annual fixed operating cost was $250,943. The average cost of transfusion of an allogeneic packed red blood cell unit was $200. For an equivalent cell salvage unit, the cost was $89.46. The payback period was 1.9 mo.
CONCLUSION: This analysis suggests that cell salvage can be significantly less expensive than allogeneic blood. The cost of cell salvage in other institutions will vary depending upon case volume, expected levels of blood loss per case, and initial investment costs. A step-by-step formula is provided to assist in the evaluation of a cell salvage service in hospitals of various sizes.
Fator 7 - relato de 2 casos
Coagulopathy After Cardiopulmonary Bypass in Jehovah's Witness Patients: Management of Two Cases Using Fractionated Components and Factor VIIa.[Report]
Source
Anesthesia & Analgesia. 104(4):763-765, April 2007.
Abstract
BACKGROUND: Changes in the Jehovah's Witness (JW) blood refusal policy now give members the personal choice to accept certain processed fractions of blood, such as factor concentrates and cryoprecipitate.METHODS: Two JW patients undergoing complex aortic surgery who developed severe microvascular bleeding after prolonged use of cardiopulmonary bypass were treated with recombinant activated factor VII, cryoprecipitate, and antithrombin concentrate.RESULTS: Cardiopulmonary bypass-induced coagulopathy was successfully treated, allowing chest closure without evidence of thrombotic complications.CONCLUSIONS: Processed blood fractions can be a valuable adjuvant to drugs when treating bleeding in JW patients.
Source
Anesthesia & Analgesia. 104(4):763-765, April 2007.
Abstract
BACKGROUND: Changes in the Jehovah's Witness (JW) blood refusal policy now give members the personal choice to accept certain processed fractions of blood, such as factor concentrates and cryoprecipitate.METHODS: Two JW patients undergoing complex aortic surgery who developed severe microvascular bleeding after prolonged use of cardiopulmonary bypass were treated with recombinant activated factor VII, cryoprecipitate, and antithrombin concentrate.RESULTS: Cardiopulmonary bypass-induced coagulopathy was successfully treated, allowing chest closure without evidence of thrombotic complications.CONCLUSIONS: Processed blood fractions can be a valuable adjuvant to drugs when treating bleeding in JW patients.
Levosimedan-Editorial
Levosimendan in Cardiac Surgery: A
Unique Drug for the Treatment of
Perioperative Left Ventricular
Dysfunction or Just Another Inodilator
Searching for a Clinical Application?
Paul S. Pagel, MD, PhD The myofilament calcium (Ca2) sensitizers are a class of positive inotropic,
vasodilating drugs ("inodilators") that augment myocardial contractility by
increasing the Ca2 sensitivity of the contractile apparatus without altering
intracellular Ca2 concentration (1). Ca2 sensitizers (including levosimendan,
pimobendan, sulmazole, EMD 57033, and MCI-154) have received
considerable attention for the treatment of acute and chronic congestive heart
failure because, unlike 1-adrenoceptor agonists or cardiac phosphodiesterase
(PDE) III inhibitors that stimulate cyclic adenosine monophosphate (cAMP)-
mediated signaling and increase intracellular Ca2 concentration, these drugs
do not adversely affect myocardial oxygen supply-demand relations (2),
produce cardiotoxicity, or predispose to the development of arrhythmias (3).
Levosimendan was developed over a decade ago, and based on a large body
of accumulated experimental and clinical evidence, appears to be the most
promising of these drugs. Levosimendan has already been approved for the
treatment of acute exacerbation of chronic heart failure in several European
countries following European Society of Cardiology guidelines (4,5). The
drug is currently undergoing Phase III clinical trials in the United States
(REVIVE study) to evaluate its utility for the acute or chronic management
of heart failure, and has received "fast-track" status from the Food and
Drug Administration.
The mechanisms by which levosimendan enhances the inotropic state and
produces vasodilation have been extensively studied (1). Briefly, levosimendan
binds to the regulatory protein troponin C (TnC) (6) and stabilizes the
Ca2-bound conformation of TnC, thereby allowing unopposed interaction
between actin and myosin filaments and enhancing the rate and extent of
myocyte contraction (7). A unique feature of levosimendan-TnC binding is its
dependence on intracellular Ca2 concentration that facilitates the interaction
between TnC and Ca2 during systole, while simultaneously allowing Ca2 to
dissociate from the protein during diastole (8). This Ca2-dependence of TnC
binding prevents deleterious abnormalities in relaxation that would otherwise
be expected to occur (9). Preservation of lusitropic function is also facilitated
by the PDE-inhibiting properties of levosimendan that occur at higher doses
of the drug (10). Levosimendan-induced systemic, pulmonary, and coronary
vasodilation occurs as a result of at least three distinct mechanisms. Levosimendan
opens several types of potassium (K) channels (including voltagedependent,
ATP-sensitive, and Ca2-activated forms) in conductance and
resistance vessels, actions that reduce intracellular Ca2 concentration in
vascular smooth muscle (11). Levosimendan induces Ca2 desensitization of
the contractile apparatus in vascular smooth muscle that does not contain TnC
independent of intracellular Ca2 concentration (12). PDE inhibition may also
play a role in vasodilation produced by higher doses of the drug.
Unlike other inotropic drugs, levosimendan may exert important antiischemic
effects by virtue of its actions as a KATP channel opener. Levosimendan
From the Anesthesia Service, the Clement
J. Zablocki Veterans Affairs Medical Center,
Milwaukee, Wisconsin.
Accepted for publication December 7,
2006.
Address correspondence to Paul S. Pagel,
MD, PhD, Clement J. Zablocki Veterans Affairs
Medical Center, Anesthesia Service, 5000
W. National Ave., Milwaukee, WI 53295. Address
e-mail to paul.pagel@med.va.gov.
Copyright © 2007 International Anesthesia
Research Society
DOI: 10.1213/01.ane.0000256864.75206.6d
Vol. 104, No. 4, April 2007 759
activates sarcolemmal (13) and mitochondrial (14) KATP
channels in vitro, and these channels play a critical role in
myocardial protection against reversible and irreversible
ischemic injury (15). Levosimendan reduced myocardial
infarct size in a canine model of ischemia and reperfusion
in vivo, independent of alterations in systemic
hemodynamics or coronary collateral blood flow, and
this beneficial action was abolished by the nonselective
KATP channel antagonist glyburide (16). Levosimendan
enhanced the functional recovery of stunned myocardium
after percutaneous transluminal coronary angioplasty
in patients with acute myocardial ischemia (17)
and was also beneficial for the treatment of cardiogenic
shock resulting from stunning of border zone myocardium
during infarction (18). Brief administration of levosimendan
to patients undergoing coronary artery bypass graft
surgery before cardiopulmonary bypass was associated
with lower postoperative troponin I concentrations (19).
These latter data suggested that levosimendan may be
capable of producing pharmacological preconditioning in
humans, presumably as a consequence of its actions on the
KATP channel.
The clinical efficacy of levosimendan in patients with
heart failure resulting from ischemic heart disease
(20,21), dilated cardiomyopathy (21), and acute myocardial
infarction (22) has been well documented. Levosimendan
causes dose-dependent improvements in
systemic and pulmonary hemodynamics in patients
with heart failure concomitant with a reduction in clinical
symptoms (21); but the myofilament Ca2 sensitizer
does not produce hypotension, exacerbate ongoing ischemia,
or contribute to mortality by increasing the incidence
of arrhythmias (22). In contrast, a major clinical
trial of the PDE III inhibitor, milrinone, in patients
admitted for an acute exacerbation of chronic heart
failure demonstrated that milrinone did not alter inhospital
or 60-day mortality when compared with placebo,
caused more frequent episodes of hypotension
requiring intervention, and increased the incidence of
arrhythmias as compared to placebo (23). When compared
with the -adrenoceptor agonist, dobutamine,
levosimendan also produced more favorable alterations
in hemodynamics and reduced mortality in patients
with low-output heart failure (24) and in those with
cardiogenic shock after percutaneous coronary intervention
(25). The relative superiority of levosimendan when
compared with dobutamine described in these studies
(24,25) may be related to the antiinflammatory and
antiapoptotic effects of the myofilament Ca2 sensitizer
(26). Similar to the findings in the setting of heart failure,
levosimendan has also been shown to increase cardiac
performance concomitant with reductions in pulmonary
capillary occlusion pressure and systemic vascular resistance
in patients with normal (27) and depressed (28,29)
left ventricular (LV) function undergoing cardiac surgery
with or without (30) cardiopulmonary bypass.
In the current issue of Anesthesia & Analgesia, De
Hert et al. (31) provide further evidence that levosimendan
produces beneficial hemodynamic effects in
patients with preoperative LV dysfunction (ejection
fraction 30%) undergoing cardiac surgery who required
inotropic support after cardiopulmonary bypass.
Despite the inherent problems associated with a
strict comparison between drugs of differing pharmacological
action and relative potency, the authors
demonstrate that the combination of IV infusions of
levosimendan (0.1 g kg1 min1) and dobutamine (5
g kg1 min1) produces very similar cardiovascular
effects to those observed with the combination of milrinone
(0.5 g kg1 min1) and dobutamine during the
first 24 h after cardiopulmonary bypass. The data
further suggest that levosimendan-dobutamine may
augment stroke volume index to a greater degree than
milrinone-dobutamine 12 and 24 h after bypass, although
these results may most likely be attributed to
the greater reductions in systemic vascular resistance
observed in patients receiving the combination of
levosimendan and dobutamine. Loading doses of levosimendan
or milrinone were not administered, but
infusions of these drugs were initiated upon removal
of the aortic cross-clamp preceding a prolonged reperfusion
before separation from bypass. Thus, steadystate
plasma concentrations of levosimendan and
milrinone were probably established before bypass
was discontinued. Perhaps of more importance, the
results indicate that the total doses of dobutamine and
norepinephrine (used to treat mean arterial blood
pressure 60 mm Hg) required during the first 48 h
after cardiopulmonary bypass, the total duration of
inotropic drug treatment, the duration of mechanical
circulatory support (intraaortic balloon counterpulsation
was required in four of 15 patients per group),
and time to tracheal extubation were significantly less in
patients receiving levosimendan-dobutamine when compared
with those treated with milrinone-dobutamine. The
beneficial hemodynamic effects of levosimendan have been
shown to persist for at least 24 h after discontinuation of
a continuous infusion as a result of a biologically active
metabolite (OR-1896) (32), and it is likely that the accumulation
and prolonged effect of this metabolite may, at
least partially, account for these dramatic differences
between levosimendan- and milrinone-treated patients.
PDE III inhibitors such as milrinone have been a
mainstay in the pharmacological management of LV
dysfunction after cardiopulmonary bypass for many
years. These drugs are commonly used in combination
with 1-adrenoceptor agonists to provide a synergistic
positive inotropic effect in the presence of bypassinduced
down regulation of the 1-adrenoceptor and
dysfunctional adenylyl cyclase-mediated signal transduction
(33). Because the mechanism of action of levosimendan
is not dependent on this signaling pathway, the
drug may have the distinct advantage of enhancing
myocardial contractility by acting directly at the level of
the contractile apparatus. In addition, levosimendan
may reduce the development of arrhythmias and the
incidence of cardiotoxicity that often occur with other
clinically used inotropic drugs, because increases in
760 Editorial ANESTHESIA & ANALGESIA
intracellular Ca2 concentration do not occur with the
myofilament Ca2 sensitizer at typical therapeutic doses.
KATP channel-mediated antiischemic effects and prolonged
drug action resulting from an active metabolite
also represent potentially important benefits of levosimendan
in patients with LV dysfunction after cardiac
surgery. Thus, the recent findings of De Hert et al. (31)
are certainly promising, and support the work of
previous investigations (28,29). Nevertheless, PDE III
inhibitors and 1-adrenoceptor agonists have a wellestablished
record of clinical efficacy in the treatment of
perioperative LV dysfunction. Given the success of these
drugs in this setting, a fundamental question remains: Is
another positive inotropic drug with vasodilating properties
truly required to successfully treat these patients?
Thus, whether the theoretical advantages of levosimendan
will ultimately translate into improved outcome in
cardiac surgical patients with LV dysfunction is
unknown and will require additional investigation to
define.
Unique Drug for the Treatment of
Perioperative Left Ventricular
Dysfunction or Just Another Inodilator
Searching for a Clinical Application?
Paul S. Pagel, MD, PhD The myofilament calcium (Ca2) sensitizers are a class of positive inotropic,
vasodilating drugs ("inodilators") that augment myocardial contractility by
increasing the Ca2 sensitivity of the contractile apparatus without altering
intracellular Ca2 concentration (1). Ca2 sensitizers (including levosimendan,
pimobendan, sulmazole, EMD 57033, and MCI-154) have received
considerable attention for the treatment of acute and chronic congestive heart
failure because, unlike 1-adrenoceptor agonists or cardiac phosphodiesterase
(PDE) III inhibitors that stimulate cyclic adenosine monophosphate (cAMP)-
mediated signaling and increase intracellular Ca2 concentration, these drugs
do not adversely affect myocardial oxygen supply-demand relations (2),
produce cardiotoxicity, or predispose to the development of arrhythmias (3).
Levosimendan was developed over a decade ago, and based on a large body
of accumulated experimental and clinical evidence, appears to be the most
promising of these drugs. Levosimendan has already been approved for the
treatment of acute exacerbation of chronic heart failure in several European
countries following European Society of Cardiology guidelines (4,5). The
drug is currently undergoing Phase III clinical trials in the United States
(REVIVE study) to evaluate its utility for the acute or chronic management
of heart failure, and has received "fast-track" status from the Food and
Drug Administration.
The mechanisms by which levosimendan enhances the inotropic state and
produces vasodilation have been extensively studied (1). Briefly, levosimendan
binds to the regulatory protein troponin C (TnC) (6) and stabilizes the
Ca2-bound conformation of TnC, thereby allowing unopposed interaction
between actin and myosin filaments and enhancing the rate and extent of
myocyte contraction (7). A unique feature of levosimendan-TnC binding is its
dependence on intracellular Ca2 concentration that facilitates the interaction
between TnC and Ca2 during systole, while simultaneously allowing Ca2 to
dissociate from the protein during diastole (8). This Ca2-dependence of TnC
binding prevents deleterious abnormalities in relaxation that would otherwise
be expected to occur (9). Preservation of lusitropic function is also facilitated
by the PDE-inhibiting properties of levosimendan that occur at higher doses
of the drug (10). Levosimendan-induced systemic, pulmonary, and coronary
vasodilation occurs as a result of at least three distinct mechanisms. Levosimendan
opens several types of potassium (K) channels (including voltagedependent,
ATP-sensitive, and Ca2-activated forms) in conductance and
resistance vessels, actions that reduce intracellular Ca2 concentration in
vascular smooth muscle (11). Levosimendan induces Ca2 desensitization of
the contractile apparatus in vascular smooth muscle that does not contain TnC
independent of intracellular Ca2 concentration (12). PDE inhibition may also
play a role in vasodilation produced by higher doses of the drug.
Unlike other inotropic drugs, levosimendan may exert important antiischemic
effects by virtue of its actions as a KATP channel opener. Levosimendan
From the Anesthesia Service, the Clement
J. Zablocki Veterans Affairs Medical Center,
Milwaukee, Wisconsin.
Accepted for publication December 7,
2006.
Address correspondence to Paul S. Pagel,
MD, PhD, Clement J. Zablocki Veterans Affairs
Medical Center, Anesthesia Service, 5000
W. National Ave., Milwaukee, WI 53295. Address
e-mail to paul.pagel@med.va.gov.
Copyright © 2007 International Anesthesia
Research Society
DOI: 10.1213/01.ane.0000256864.75206.6d
Vol. 104, No. 4, April 2007 759
activates sarcolemmal (13) and mitochondrial (14) KATP
channels in vitro, and these channels play a critical role in
myocardial protection against reversible and irreversible
ischemic injury (15). Levosimendan reduced myocardial
infarct size in a canine model of ischemia and reperfusion
in vivo, independent of alterations in systemic
hemodynamics or coronary collateral blood flow, and
this beneficial action was abolished by the nonselective
KATP channel antagonist glyburide (16). Levosimendan
enhanced the functional recovery of stunned myocardium
after percutaneous transluminal coronary angioplasty
in patients with acute myocardial ischemia (17)
and was also beneficial for the treatment of cardiogenic
shock resulting from stunning of border zone myocardium
during infarction (18). Brief administration of levosimendan
to patients undergoing coronary artery bypass graft
surgery before cardiopulmonary bypass was associated
with lower postoperative troponin I concentrations (19).
These latter data suggested that levosimendan may be
capable of producing pharmacological preconditioning in
humans, presumably as a consequence of its actions on the
KATP channel.
The clinical efficacy of levosimendan in patients with
heart failure resulting from ischemic heart disease
(20,21), dilated cardiomyopathy (21), and acute myocardial
infarction (22) has been well documented. Levosimendan
causes dose-dependent improvements in
systemic and pulmonary hemodynamics in patients
with heart failure concomitant with a reduction in clinical
symptoms (21); but the myofilament Ca2 sensitizer
does not produce hypotension, exacerbate ongoing ischemia,
or contribute to mortality by increasing the incidence
of arrhythmias (22). In contrast, a major clinical
trial of the PDE III inhibitor, milrinone, in patients
admitted for an acute exacerbation of chronic heart
failure demonstrated that milrinone did not alter inhospital
or 60-day mortality when compared with placebo,
caused more frequent episodes of hypotension
requiring intervention, and increased the incidence of
arrhythmias as compared to placebo (23). When compared
with the -adrenoceptor agonist, dobutamine,
levosimendan also produced more favorable alterations
in hemodynamics and reduced mortality in patients
with low-output heart failure (24) and in those with
cardiogenic shock after percutaneous coronary intervention
(25). The relative superiority of levosimendan when
compared with dobutamine described in these studies
(24,25) may be related to the antiinflammatory and
antiapoptotic effects of the myofilament Ca2 sensitizer
(26). Similar to the findings in the setting of heart failure,
levosimendan has also been shown to increase cardiac
performance concomitant with reductions in pulmonary
capillary occlusion pressure and systemic vascular resistance
in patients with normal (27) and depressed (28,29)
left ventricular (LV) function undergoing cardiac surgery
with or without (30) cardiopulmonary bypass.
In the current issue of Anesthesia & Analgesia, De
Hert et al. (31) provide further evidence that levosimendan
produces beneficial hemodynamic effects in
patients with preoperative LV dysfunction (ejection
fraction 30%) undergoing cardiac surgery who required
inotropic support after cardiopulmonary bypass.
Despite the inherent problems associated with a
strict comparison between drugs of differing pharmacological
action and relative potency, the authors
demonstrate that the combination of IV infusions of
levosimendan (0.1 g kg1 min1) and dobutamine (5
g kg1 min1) produces very similar cardiovascular
effects to those observed with the combination of milrinone
(0.5 g kg1 min1) and dobutamine during the
first 24 h after cardiopulmonary bypass. The data
further suggest that levosimendan-dobutamine may
augment stroke volume index to a greater degree than
milrinone-dobutamine 12 and 24 h after bypass, although
these results may most likely be attributed to
the greater reductions in systemic vascular resistance
observed in patients receiving the combination of
levosimendan and dobutamine. Loading doses of levosimendan
or milrinone were not administered, but
infusions of these drugs were initiated upon removal
of the aortic cross-clamp preceding a prolonged reperfusion
before separation from bypass. Thus, steadystate
plasma concentrations of levosimendan and
milrinone were probably established before bypass
was discontinued. Perhaps of more importance, the
results indicate that the total doses of dobutamine and
norepinephrine (used to treat mean arterial blood
pressure 60 mm Hg) required during the first 48 h
after cardiopulmonary bypass, the total duration of
inotropic drug treatment, the duration of mechanical
circulatory support (intraaortic balloon counterpulsation
was required in four of 15 patients per group),
and time to tracheal extubation were significantly less in
patients receiving levosimendan-dobutamine when compared
with those treated with milrinone-dobutamine. The
beneficial hemodynamic effects of levosimendan have been
shown to persist for at least 24 h after discontinuation of
a continuous infusion as a result of a biologically active
metabolite (OR-1896) (32), and it is likely that the accumulation
and prolonged effect of this metabolite may, at
least partially, account for these dramatic differences
between levosimendan- and milrinone-treated patients.
PDE III inhibitors such as milrinone have been a
mainstay in the pharmacological management of LV
dysfunction after cardiopulmonary bypass for many
years. These drugs are commonly used in combination
with 1-adrenoceptor agonists to provide a synergistic
positive inotropic effect in the presence of bypassinduced
down regulation of the 1-adrenoceptor and
dysfunctional adenylyl cyclase-mediated signal transduction
(33). Because the mechanism of action of levosimendan
is not dependent on this signaling pathway, the
drug may have the distinct advantage of enhancing
myocardial contractility by acting directly at the level of
the contractile apparatus. In addition, levosimendan
may reduce the development of arrhythmias and the
incidence of cardiotoxicity that often occur with other
clinically used inotropic drugs, because increases in
760 Editorial ANESTHESIA & ANALGESIA
intracellular Ca2 concentration do not occur with the
myofilament Ca2 sensitizer at typical therapeutic doses.
KATP channel-mediated antiischemic effects and prolonged
drug action resulting from an active metabolite
also represent potentially important benefits of levosimendan
in patients with LV dysfunction after cardiac
surgery. Thus, the recent findings of De Hert et al. (31)
are certainly promising, and support the work of
previous investigations (28,29). Nevertheless, PDE III
inhibitors and 1-adrenoceptor agonists have a wellestablished
record of clinical efficacy in the treatment of
perioperative LV dysfunction. Given the success of these
drugs in this setting, a fundamental question remains: Is
another positive inotropic drug with vasodilating properties
truly required to successfully treat these patients?
Thus, whether the theoretical advantages of levosimendan
will ultimately translate into improved outcome in
cardiac surgical patients with LV dysfunction is
unknown and will require additional investigation to
define.
Assinar:
Postagens (Atom)
Postagens
