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• W2000963451 abstract "Cardiovascular surgery with cardiopulmonary bypass is associated with postoperative organ injury, which severely affects patient morbidity and mortality. Multiple cardiopulmonary bypass–related mechanisms have been linked to the development of tissue damage, including hypoperfusion, ischemia–reperfusion, and induction of a proinflammatory response. Hemolysis, resulting in increased plasma free hemoglobin concentrations, is generally considered an inevitable but relatively harmless side effect of cardiopulmonary bypass. Recently, however, evidence has been mounting that plasma free hemoglobin scavenges intravascular nitric oxide, thereby attenuating its bioavailability. Any significant reduction in nitric oxide, the most important endogenous vasodilator, impairs tissue perfusion and induces organ injury development. Moreover, urinary free hemoglobin contributes to renal damage, specifically by catalysis of reactive oxygen species formation. In this review, the effects of increased free hemoglobin levels on nitric oxide metabolism are discussed. In addition, we review the role of free hemoglobin in organ injury development, potential sources of free hemoglobin during cardiovascular surgery, and therapeutic options to attenuate the consequences of hemolysis. We propose that hemolysis is more than an innocent bystander effect of cardiopulmonary bypass–assisted surgery. Therapeutic interventions to attenuate the effects of hemolysis seem crucial in the reduction of postoperative morbidity and mortality after cardiovascular surgery. Cardiovascular surgery with extracorporeal circulation is associated with considerable postoperative morbidity and mortality, especially among patients undergoing complex procedures such as combined coronary artery bypass grafting (CABG) and valve surgery, Bentall procedures, and open repair of thoracic and thoracoabdominal aortic aneurysms. These patients are at high risk for development of such major complications as acute kidney injury,1Andersson L.G. Ekroth R. Bratteby L.E. Hallhagen S. Wesslén O. Acute renal failure after coronary surgery—a study of incidence and risk factors in 2009 consecutive patients.Thorac Cardiovasc Surg. 1993; 41: 237-241Crossref PubMed Scopus (137) Google Scholar, 2Conlon P.J. Stafford-Smith M. White W.D. Newman M.F. King S. Winn M.P. et al.Acute renal failure following cardiac surgery.Nephrol Dial Transplant. 1999; 14: 1158-1162Crossref PubMed Scopus (486) Google Scholar, 3Grayson A.D. Khater M. Jackson M. Fox M.A. Valvular heart operation is an independent risk factor for acute renal failure.Ann Thorac Surg. 2003; 75: 1829-1835Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 4Provenchère S. Plantefève G. Hufnagel G. Vicaut E. De Vaumas C. Lecharny J.B. et al.Renal dysfunction after cardiac surgery with normothermic cardiopulmonary bypass: incidence, risk factors, and effect on clinical outcome.Anesth Analg. 2003; 96 (table of contents): 1258-1264Crossref PubMed Google Scholar, 5Achouh P.E. Madsen K. Miller 3rd, C.C. Estrera A.L. Azizzadeh A. Dhareshwar J. et al.Gastrointestinal complications after descending thoracic and thoracoabdominal aortic repairs: a 14-year experience.J Vasc Surg. 2006; 44: 442-446Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 6Jacobs M.J. de Mol B.A. Legemate D.A. Veldman D.J. de Haan P. Kalkman C.J. Retrograde aortic and selective organ perfusion during thoracoabdominal aortic aneurysm repair.Eur J Vasc Endovasc Surg. 1997; 14: 360-366Abstract Full Text PDF PubMed Scopus (42) Google Scholar pulmonary dysfunction,7Coselli J.S. LeMaire S.A. Conklin L.D. Köksoy C. Schmittling Z.C. Morbidity and mortality after extent II thoracoabdominal aortic aneurysm repair.Ann Thorac Surg. 2002; 73: 1107-1116Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar, 8Rectenwald J.E. Huber T.S. Martin T.D. Ozaki C.K. Devidas M. Welborn M.B. et al.Functional outcome after thoracoabdominal aortic aneurysm repair.J Vasc Surg. 2002; 35: 640-647Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar sepsis, and multiple organ failure.9Kieffer E. Chiche L. Godet G. Koskas F. Bahnini A. Bertrand M. et al.Type IV thoracoabdominal aneurysm repair: predictors of postoperative mortality, spinal cord injury, and acute intestinal ischemia.Ann Vasc Surg. 2008; 22: 822-828Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar The pathophysiologic mechanisms underlying these complications have been studied extensively in an attempt to develop specific prevention and treatment strategies. The cardiopulmonary bypass (CPB) circuit has been associated with the development of tissue damage as a result of insufficient oxygen delivery through hemodilution,10Vermeer H. Teerenstra S. de Sévaux R.G. van Swieten H.A. Weerwind P.W. The effect of hemodilution during normothermic cardiac surgery on renal physiology and function: a review.Perfusion. 2008; 23: 329-338Crossref PubMed Scopus (22) Google Scholar ischemia–reperfusion,11Fink M.P. Thoracoabdominal aortic aneurysm repair: a human model of ischemia/reperfusion-induced cytokine-driven multiple organ dysfunction syndrome.Crit Care Med. 2000; 28: 3356-3357Crossref PubMed Scopus (4) Google Scholar and hypoperfusion.12Leijdekkers V.J. Wirds J.W. Vahl A.C. van Genderingen H.R. Siebenga J. Westerhof N. et al.The visceral perfusion system and distal bypass during thoracoabdominal aneurysm surgery: an alternative for physiological blood flow?.Cardiovasc Surg. 1999; 7: 219-224Crossref PubMed Scopus (17) Google Scholar, 13Kuttila K. Niinikoski J. Haglund U. Visceral and peripheral tissue perfusion after cardiac surgery.Scand J Thorac Cardiovasc Surg. 1991; 25: 57-62Crossref PubMed Scopus (23) Google Scholar Cardiotomy suction during CPB has been shown to be a source of lipid microemboli, which form small vascular occlusions in several tissues, including brain, kidney, spleen, and muscle.14Brooker R.F. Brown W.R. Moody D.M. Hammon Jr., J.W. Reboussin D.M. Deal D.D. et al.Cardiotomy suction: a major source of brain lipid emboli during cardiopulmonary bypass.Ann Thorac Surg. 1998; 65: 1651-1655Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar, 15Brondén B. Dencker M. Allers M. Plaza I. Jönsson H. Differential distribution of lipid microemboli after cardiac surgery.Ann Thorac Surg. 2006; 81: 643-648Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Furthermore, the nonendothelial surface of the CPB system initiates a proinflammatory response that deteriorates cellular function, for instance the function of renal tubular cells.16Hanssen S.J. Derikx J.P. Vermeulen Windsant I.C. Heijmans J.H. Koeppel T.A. Schurink G.W. et al.Visceral injury and systemic inflammation in patients undergoing extracorporeal circulation during aortic surgery.Ann Surg. 2008; 248 (Erratum in: Ann Surg. 2010;251:187): 117-125Crossref PubMed Scopus (65) Google Scholar, 17Rosner M.H. Okusa M.D. Acute kidney injury associated with cardiac surgery.Clin J Am Soc Nephrol. 2006; 1: 19-32Crossref PubMed Scopus (759) Google Scholar Indeed, the use of a mini-CPB system attenuates the release of intestinal and renal tissue damage markers in cardiac surgical patients relative to a normal CPB circuit by reducing both the proinflammatory contact surface area and hemodilution.18Huybregts R.A. Morariu A.M. Rakhorst G. Spiegelenberg S.R. Romijn H.W. de Vroege R. et al.Attenuated renal and intestinal injury after use of a mini-cardiopulmonary bypass system.Ann Thorac Surg. 2007; 83: 1760-1766Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar Similarly, the incidences of liver injury and kidney injury are significantly reduced in patients undergoing CABG without CPB (off-pump CABG) relative to those undergoing on-pump CABG.19Yamada T. Ochiai R. Takeda J. Kikuchi H. Ishibashi M. Watanabe K. Off-pump coronary artery bypass attenuates transient hepatocellular damage after myocardial revascularization.J Cardiothorac Vasc Anesth. 2005; 19: 603-607Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 20Nigwekar S.U. Kandula P. Hix J.K. Thakar C.V. Off-pump coronary artery bypass surgery and acute kidney injury: a meta-analysis of randomized and observational studies.Am J Kidney Dis. 2009; 54: 413-423Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar Nevertheless, although off-pump surgery has gained popularity worldwide, CPB-assisted surgery is still widely used. To reduce CPB-related morbidity and mortality, successful efforts have been made to increase CPB biocompatibility and flow performance. Unfortunately, these improvements have not led to a significantly decreased incidence of organ dysfunction after cardiovascular surgery.21Kelly K.J. Molitoris B.A. Acute renal failure in the new millennium: time to consider combination therapy.Semin Nephrol. 2000; 20: 4-19PubMed Google Scholar This relative failure underscores the need for further clarification of underlying pathophysiologic mechanisms of tissue damage and dysfunction in this setting.21Kelly K.J. Molitoris B.A. Acute renal failure in the new millennium: time to consider combination therapy.Semin Nephrol. 2000; 20: 4-19PubMed Google Scholar A common consequence of CPB is hemolysis, which is generally considered an inevitable but relatively harmless phenomenon. Hemolysis is principally caused by mechanical shear stress within the perfusion circuit and results in the release of hemoglobin into the circulation.22Fransen E.J. Ganushchak Y.M. Vijay V. de Jong D.S. Buurman W.A. Maessen J.G. Evaluation of a new condensed extra-corporeal circuit for cardiac surgery: a prospective randomized clinical pilot study.Perfusion. 2005; 20: 91-99Crossref PubMed Scopus (9) Google Scholar, 23Vercaemst L. Hemolysis in cardiac surgery patients undergoing cardiopulmonary bypass: a review in search of a treatment algorithm.J Extra Corpor Technol. 2008; 40: 257-267PubMed Google Scholar The role of this cell-free plasma hemoglobin (fHb) in the development of organ injury has gained increasing interest ever since a direct relationship of hemolysis, impaired vascular function, decreased organ perfusion, and organ dysfunction was reproducibly shown in experimental animal models and in chronic hemolytic diseases in human beings.24Reiter C.D. Wang X. Tanus-Santos J.E. Hogg N. Cannon 3rd, R.O. Schechter A.N. et al.Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease.Nat Med. 2002; 8: 1383-1389Crossref PubMed Scopus (938) Google Scholar, 25Minneci P.C. Deans K.J. Zhi H. Yuen P.S. Star R.A. Banks S.M. et al.Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin.J Clin Invest. 2005; 115: 3409-3417Crossref PubMed Scopus (222) Google Scholar Most recently, Meyer and colleagues26Meyer C. Heiss C. Drexhage C. Kehmeier E.S. Balzer J. Mühlfeld A. et al.Hemodialysis-induced release of hemoglobin limits nitric oxide bioavailability and impairs vascular function.J Am Coll Cardiol. 2010; 55: 454-459Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar showed that fHb arising from hemodialysis-induced hemolysis impairs vascular function in patients, leading to speculation regarding a role for fHb in the development of microcirculatory dysfunction during acute and transient hemolysis.27Donadee C.L. Gladwin M.T. Hemodialysis hyperhemolysis. A novel mechanism of endothelial dysfunction and cardiovascular risk?.J Am Coll Cardiol. 2010; 55: 460-462Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Moreover, the results of Meyer and colleagues26Meyer C. Heiss C. Drexhage C. Kehmeier E.S. Balzer J. Mühlfeld A. et al.Hemodialysis-induced release of hemoglobin limits nitric oxide bioavailability and impairs vascular function.J Am Coll Cardiol. 2010; 55: 454-459Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar substantiate our own recent findings28Vermeulen Windsant I.C. Snoeijs M.G. Hanssen S.J. Altintas S. Heijmans J.H. Koeppel T.A. et al.Hemolysis is associated with acute kidney injury during major aortic surgery.Kidney Int. 2010; 77: 913-920Crossref PubMed Scopus (104) Google Scholar that acute hemolysis during major aortic surgery is independently associated with proximal renal tubular damage and postoperative acute kidney injury. We therefore propose that hemolysis is an important but as yet generally unrecognized contributor to the development of organ injury during surgical procedures associated with hemolysis, such as cardiovascular surgery. The interfering role of fHb in intravascular nitric oxide (NO) metabolism is believed to play a critical role in the development of microcirculatory impairment, organ damage, and organ dysfunction.24Reiter C.D. Wang X. Tanus-Santos J.E. Hogg N. Cannon 3rd, R.O. Schechter A.N. et al.Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease.Nat Med. 2002; 8: 1383-1389Crossref PubMed Scopus (938) Google Scholar In this review we will therefore discuss (1) the effects of fHb on intravascular NO bioavailability, (2) the role of fHb in the induction of microcirculatory dysfunction and organ damage, (3) the potential sources of fHb during cardiovascular surgery, and (4) therapeutic options to attenuate the consequences of hemolysis during CPB-assisted surgery. On the intravascular destruction of red blood cells (RBCs), fHb enters the circulation. This fHb either gets bound to haptoglobin or is oxidized to methemoglobin. The hemoglobin–haptoglobin complex is rapidly cleared from the circulation through endocytosis by the surface scavenger receptor CD163, which is expressed on monocytes and tissue macrophages. In this way haptoglobin prevents accumulation of plasma fHb under physiologic circumstances.29Rother R.P. Bell L. Hillmen P. Gladwin M.T. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease.JAMA. 2005; 293: 1653-1662Crossref PubMed Scopus (1050) Google Scholar This effect was illustrated in patients undergoing cardiac surgery in whom intravenous administration of haptoglobin significantly reduced circulating fHb levels.30Tanaka K. Kanamori Y. Sato T. Kondo C. Katayama Y. Yada I. et al.Administration of haptoglobin during cardiopulmonary bypass surgery.ASAIO Trans. 1991; 37: M482-M483PubMed Google Scholar Free heme, another byproduct of hemolysis, is released during oxidation of free hemoglobin and is scavenged by circulating hemopexin. Subsequently, heme oxygenase (HO)-1, activated as a result of reduced microcirculation, degrades heme to carbon monoxide (CO), biliverdin, and iron, mainly in the liver and spleen.31Maines M.D. The heme oxygenase system: a regulator of second messenger gases.Annu Rev Pharmacol Toxicol. 1997; 37: 517-554Crossref PubMed Scopus (2133) Google Scholar This cytoprotective induction of HO-1 by the microvasculature has been shown to modulate inflammation in patients after cardiac surgery with CPB, which may benefit patient recovery postoperatively32Philippidis P. Mason J.C. Evans B.J. Nadra I. Taylor K.M. Haskard D.O. et al.Hemoglobin scavenger receptor CD163 mediates interleukin-10 release and heme oxygenase-1 synthesis: antiinflammatory monocyte-macrophage responses in vitro, in resolving skin blisters in vivo, and after cardiopulmonary bypass surgery.Circ Res. 2004; 94: 119-126Crossref PubMed Scopus (374) Google Scholar; furthermore, the induction of HO-1 inhibits vascular inflammation and vasoocclusion in transgenic sickle cell mice.32Philippidis P. Mason J.C. Evans B.J. Nadra I. Taylor K.M. Haskard D.O. et al.Hemoglobin scavenger receptor CD163 mediates interleukin-10 release and heme oxygenase-1 synthesis: antiinflammatory monocyte-macrophage responses in vitro, in resolving skin blisters in vivo, and after cardiopulmonary bypass surgery.Circ Res. 2004; 94: 119-126Crossref PubMed Scopus (374) Google Scholar, 33Belcher J.D. Mahaseth H. Welch T.E. Otterbein L.E. Hebbel R.P. Vercellotti G.M. Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice.J Clin Invest. 2006; 116: 808-816Crossref PubMed Scopus (182) Google Scholar Because both haptoglobin and hemopexin are not recycled after clearance of hemoglobin–haptoglobin or heme–hemopexin complexes, excessive RBC lysis rapidly exhausts their storage pools. This results in enhanced levels of fHb and free heme, both harmful products. First of all, free heme is able to react with endogenous hydrogen peroxide, thereby forming toxic free radicals that are involved in the induction of prooxidant damage.34Kristiansen M. Graversen J.H. Jacobsen C. Sonne O. Hoffman H.J. Law S.K. et al.Identification of the haemoglobin scavenger receptor.Nature. 2001; 409: 198-201Crossref PubMed Scopus (1165) Google Scholar Second, oxygenated fHb has been shown to be a potent scavenger of NO, the most important endogenous vasodilator. The fast (6–8 × 107 mol/[L · s]) and irreversible reaction of oxygenated fHb with NO results in conversion of fHb to methemoglobin and conversion of NO to nitrate. Circulating fHb is also present in a deoxygenated form. Such deoxygenated fHb also scavenges NO, forming nitrosyl hemoglobin, but this reaction is both slower (107 mol/[L · s]) and reversible.24Reiter C.D. Wang X. Tanus-Santos J.E. Hogg N. Cannon 3rd, R.O. Schechter A.N. et al.Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease.Nat Med. 2002; 8: 1383-1389Crossref PubMed Scopus (938) Google Scholar, 29Rother R.P. Bell L. Hillmen P. Gladwin M.T. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease.JAMA. 2005; 293: 1653-1662Crossref PubMed Scopus (1050) Google Scholar As a result, hemolysis significantly impairs NO bioavailability, potentially inducing microcirculatory dysfunction.35Liao J.C. Hein T.W. Vaughn M.W. Huang K.T. Kuo L. Intravascular flow decreases erythrocyte consumption of nitric oxide.Proc Natl Acad Sci U S A. 1999; 96: 8757-8761Crossref PubMed Scopus (255) Google Scholar, 36Vaughn M.W. Huang K.T. Kuo L. Liao J.C. Erythrocytes possess an intrinsic barrier to nitric oxide consumption.J Biol Chem. 2000; 275: 2342-2348Crossref PubMed Scopus (191) Google Scholar In an in vivo canine hemolysis model, fHb-associated NO scavenging has been found to be correlated with systemic vasoconstriction and a reduction in renal function.25Minneci P.C. Deans K.J. Zhi H. Yuen P.S. Star R.A. Banks S.M. et al.Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin.J Clin Invest. 2005; 115: 3409-3417Crossref PubMed Scopus (222) Google Scholar In patients with chronic high fHb levels as a result of sickle cell disease, forearm blood flow responses were reduced by 80% after infusion of the NO donor sodium nitroprusside relative to patients with below average fHb levels.24Reiter C.D. Wang X. Tanus-Santos J.E. Hogg N. Cannon 3rd, R.O. Schechter A.N. et al.Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease.Nat Med. 2002; 8: 1383-1389Crossref PubMed Scopus (938) Google Scholar Third, hemolysis also results in release of arginase 1, an enzyme that converts l-arginine, the substrate for NO synthesis, to ornithine.37Morris C.R. Kato G.J. Poljakovic M. Wang X. Blackwelder W.C. Sachdev V. et al.Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease.JAMA. 2005; 294: 81-90Crossref PubMed Scopus (509) Google Scholar In this way, hemolysis not only causes scavenging of NO but also theoretically prevents new NO formation. In practice, however, we have shown that arginase 1 release during surgery with CPB does not affect the arginine to ornithine ratio (unpublished data). This implies that arginase levels during this type of surgery are not high enough to affect arginine levels and thus attenuate NO synthesis.38van de Poll M.C. Hanssen S.J. Berbée M. Deutz N.E. Monbaliu D. Buurman W.A. et al.Elevated plasma arginase-1 does not affect plasma arginine in patients undergoing liver resection.Clin Sci (Lond). 2008; 114: 231-241Crossref PubMed Scopus (15) Google Scholar The role of hemolysis in organ damage development had already been described in the mid 1970s.24Reiter C.D. Wang X. Tanus-Santos J.E. Hogg N. Cannon 3rd, R.O. Schechter A.N. et al.Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease.Nat Med. 2002; 8: 1383-1389Crossref PubMed Scopus (938) Google Scholar, 39Burck H.C. Diekman M.A. Sedlaczek T. [Acute renal failure after the infusion of hemoglobin solutions with or without red cell ghosts in rabbits].Res Exp Med. 1975; 166 (German): 79-84Crossref PubMed Scopus (1) Google Scholar These studies focused on acute kidney injury because glomerularly filtered urinary fHb, rather than plasma fHb, was considered the culprit in organ injury induction. At that time, only the kidney was believed to be at risk for fHb-induced damage. Two mechanisms were proposed to underlie the association between hemolysis and renal tissue damage development. First, urinary fHb–derived free iron and heme catalyze the generation of reactive oxygen species, which damage the renal tubular epithelium.40Zager R.A. Gamelin L.M. Pathogenetic mechanisms in experimental hemoglobinuric acute renal failure.Am J Physiol. 1989; 256: F446-F455PubMed Google Scholar Indeed, administration of the iron scavenger deferoxamine did attenuate glomerular and tubular dysfunction induced by intravenous fHb administration in rats.41Paller M.S. Hemoglobin- and myoglobin-induced acute renal failure in rats: role of iron in nephrotoxicity.Am J Physiol. 1988; 255: F539-F544PubMed Google Scholar Similarly, a reduced intravascular iron scavenging capacity—reflected by low plasma ferritin concentrations—was associated with acute kidney injury after human cardiovascular surgery.42Davis C.L. Kausz A.T. Zager R.A. Kharasch E.D. Cochran R.P. Acute renal failure after cardiopulmonary bypass in related to decreased serum ferritin levels.J Am Soc Nephrol. 1999; 10: 2396-2402PubMed Google Scholar Second, intratubular fHb precipitation and heme cast formation in the acidic ultrafiltrate were considered to obstruct the tubular lumen, reducing glomerular filtration.40Zager R.A. Gamelin L.M. Pathogenetic mechanisms in experimental hemoglobinuric acute renal failure.Am J Physiol. 1989; 256: F446-F455PubMed Google Scholar, 43Everse J. Hsia N. The toxicities of native and modified hemoglobins.Free Radic Biol Med. 1997; 22: 1075-1099Crossref PubMed Scopus (293) Google Scholar Subsequent prevention of cast formation by urinary alkalanization was found to reduce tubular injury and glomerular dysfunction after intravenous fHb infusion in rats.40Zager R.A. Gamelin L.M. Pathogenetic mechanisms in experimental hemoglobinuric acute renal failure.Am J Physiol. 1989; 256: F446-F455PubMed Google Scholar The discovery of the NO-scavenging properties of circulating plasma fHb by Reiter and coworkers24Reiter C.D. Wang X. Tanus-Santos J.E. Hogg N. Cannon 3rd, R.O. Schechter A.N. et al.Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease.Nat Med. 2002; 8: 1383-1389Crossref PubMed Scopus (938) Google Scholar in 2002 provided a complementary explanation for hemolysis-induced organ injury. For the first time, circulating fHb was recognized as a key player in the pathophysiologic mechanisms of complications in patients with chronic hemolytic disorders, such as sickle cell disease and malaria infection.24Reiter C.D. Wang X. Tanus-Santos J.E. Hogg N. Cannon 3rd, R.O. Schechter A.N. et al.Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease.Nat Med. 2002; 8: 1383-1389Crossref PubMed Scopus (938) Google Scholar Furthermore, the reported adverse effects associated with administration of a hemoglobin-based oxygen carrier—which basically consisted of fHb—could be explained by intravascular NO scavenging through fHb.44Natanson C. Kern S.J. Lurie P. Banks S.M. Wolfe S.M. Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: a meta-analysis.JAMA. 2008; 299 (Erratum in: JAMA. 2008;300:1300): 2304-2312Crossref PubMed Scopus (450) Google Scholar The negative effects of increased plasma fHb have been confirmed by many studies since 2002 in both animals and patients. For example, hemolysis induced by water infusion or direct intravascular fHb administration in dogs was associated with a significant increase in plasma NO consumption and with simultaneous enhanced systemic vascular resistance. These effects were attenuated by NO inhalation (which causes conversion of plasma fHb into the less bioactive molecule methemoglobin in the pulmonary circulation), supporting a causal role for NO scavenging by fHb.25Minneci P.C. Deans K.J. Zhi H. Yuen P.S. Star R.A. Banks S.M. et al.Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin.J Clin Invest. 2005; 115: 3409-3417Crossref PubMed Scopus (222) Google Scholar In human beings, forearm blood flow responses to intra-arterial infusion of sodium nitroprusside, a NO donor, were found to be negatively correlated with plasma fHb levels in patients with sickle cell disease.24Reiter C.D. Wang X. Tanus-Santos J.E. Hogg N. Cannon 3rd, R.O. Schechter A.N. et al.Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease.Nat Med. 2002; 8: 1383-1389Crossref PubMed Scopus (938) Google Scholar, 25Minneci P.C. Deans K.J. Zhi H. Yuen P.S. Star R.A. Banks S.M. et al.Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin.J Clin Invest. 2005; 115: 3409-3417Crossref PubMed Scopus (222) Google Scholar The potential role of plasma fHb in the development of organ injury is further supported by our observation that plasma fHb levels are significantly associated with renal proximal tubular damage during CPB-assisted major aortic surgery.26Meyer C. Heiss C. Drexhage C. Kehmeier E.S. Balzer J. Mühlfeld A. et al.Hemodialysis-induced release of hemoglobin limits nitric oxide bioavailability and impairs vascular function.J Am Coll Cardiol. 2010; 55: 454-459Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Moreover, peak plasma fHb levels significantly predict postoperative acute kidney injury. We could not detect fHb in urinary samples during the perioperative period, indicating that urinary fHb is not a major contributor to renal tubular injury development in this setting.26Meyer C. Heiss C. Drexhage C. Kehmeier E.S. Balzer J. Mühlfeld A. et al.Hemodialysis-induced release of hemoglobin limits nitric oxide bioavailability and impairs vascular function.J Am Coll Cardiol. 2010; 55: 454-459Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Also, forearm blood flow responses after infusion of sodium nitroprusside at the time of peak plasma fHb concentrations are significantly reduced relative to the response measured when fHb-levels are normalized. This observation further underscores a potential causal role of fHb-induced tissue perfusion impairment during surgery (unpublished data). In addition, we have shown that fHb induces intestinal microcirculatory dysfunction and tissue integrity loss in a rat hemolysis model.45Hanssen S.J. Lubbers T. Hodin C.M. Prinzen F.W. Buurman W.A. Jacobs M.J. Hemolysis results in impaired intestinal microcirculation and intestinal epithelial cell injury.World J Gastroenterol. 2011; 17: 213-218Crossref PubMed Scopus (5) Google Scholar Hemolysis can principally be attributed to 3 sources during cardiovascular surgery: the CPB, the cell salvage system, and (massive) RBC transfusion. CPB inflicts sublethal to lethal RBC damage through turbulence and shear stress within the pump, tubes, connectors, cannula, reservoirs, and oxygenator.23Vercaemst L. Hemolysis in cardiac surgery patients undergoing cardiopulmonary bypass: a review in search of a treatment algorithm.J Extra Corpor Technol. 2008; 40: 257-267PubMed Google Scholar Blood–air contact, blood–nonendothelial surface contact, wall impact forces, the use of positive and negative pressures to assist venous drainage, and the use of an integrated cardiotomy suction reservoir all contribute to intraoperative hemolysis.23Vercaemst L. Hemolysis in cardiac surgery patients undergoing cardiopulmonary bypass: a review in search of a treatment algorithm.J Extra Corpor Technol. 2008; 40: 257-267PubMed Google Scholar, 46Fabre O. Vincentelli A. Corseaux D. Juthier F. Susen S. Bauters A. et al.Comparison of blood activation in the wound, active vent, and cardiopulmonary bypass circuit.Ann Thorac Surg. 2008; 86: 537-541Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 47Mulholland J.W. Massey W. Shelton J.C. Investigation and quantification of the blood trauma caused by the combined dynamic forces experienced during cardiopulmonary bypass.Perfusion. 2000; 15: 485-494Crossref PubMed Scopus (56) Google Scholar In addition to CPB composition, CPB duration is considered to influence the degree of hemolysis, with longer CPB times resulting in increased lysis of RBCs.48Cheung A.T. Cruz-Shiavone G.E. Meng Q.C. Pochettino A. Augoustides J.A. Bavaria J.E. et al.Cardiopulmonary bypass, hemolysis, and nitroprusside-induced cyanide production.Anesth Analg. 2007; 105: 29-33Crossref PubMed Scopus (25) Google Scholar As evidence of this phenomenon, we found a positive and statistically significant correlation between total fHb release in the perioperative period and the duration of CPB in a group of 54 patients undergoing CPB-assisted major aortic surgery (unpublished data; Figure 1). In addition to direct RBC lysis, the CPB system induces sublethal RBC injury.49Kameneva M.V. Undar A. An" @default.
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• W2000963451 title "Cardiovascular surgery and organ damage: Time to reconsider the role of hemolysis" @default.
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• W2000963451 doi "https://doi.org/10.1016/j.jtcvs.2011.02.012" @default.
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