Anemia and cerebral outcomes: Many questions, fewer answers

Anesthesia and Analgesia

Volumn 107, Issue 4, 2008, Pages 1356-1370

  Hare, Gregory M T ^a,b   Tsui, Albert K Y ^a,b   McLaren, Anya T ^a,b   Ragoonanan, Tenille E ^a,b   Yu, Julie ^a   Mazer, C David ^a,b  

^a ST MICHAEL'S HOSPITAL   (Canada)

^b UNIVERSITY OF TORONTO   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOKINE; DIMER; ENDOTHELIAL NITRIC OXIDE SYNTHASE; ERYTHROPOIETIN; HEMOGLOBIN; HYPOXIA INDUCIBLE FACTOR 1ALPHA; INDUCIBLE NITRIC OXIDE SYNTHASE; NEURONAL NITRIC OXIDE SYNTHASE; NITRIC OXIDE; REACTIVE OXYGEN METABOLITE; TRANSCRIPTION FACTOR; VASCULOTROPIN; HYPOXIA INDUCIBLE FACTOR 1;

ANEMIA; ANGIOGENESIS; APOPTOSIS; BLOOD VESSEL TONE; BRAIN BLOOD FLOW; BRAIN CORTEX; BRAIN EMBOLISM; BRAIN HYPOXIA; BRAIN INJURY; BRAIN OXYGEN CONSUMPTION; BRAIN TISSUE; CARDIOPULMONARY BYPASS; CELL DAMAGE; CELL FUNCTION; CELL NUCLEUS; CELL TYPE; CLINICAL TRIAL; CONCENTRATION (PARAMETERS); CYTOPLASM; ENCEPHALITIS; ENDOTHELIUM; EXCITOTOXICITY; EXPERIMENTAL MODEL; HEMATOCRIT; HEMOGLOBIN BLOOD LEVEL; HOMEOSTASIS; HUMAN; HYPOXEMIA; NEUROPROTECTION; NEUROTOXICITY; NONHUMAN; OXYGEN CONSUMPTION; OXYGEN DELIVERY DEVICE; PERIOPERATIVE PERIOD; PRIORITY JOURNAL; REVIEW; RODENT; TRANSCRIPTION REGULATION; UPREGULATION; VASCULAR SMOOTH MUSCLE; VASCULAR SURGERY; ACUTE DISEASE; ANIMAL; BLOOD; BLOOD TRANSFUSION; BRAIN; CEREBROVASCULAR DISEASE; METABOLISM; PATHOPHYSIOLOGY; PEROPERATIVE COMPLICATION; POSTOPERATIVE COMPLICATION;

ACUTE DISEASE; ANEMIA; ANIMALS; BLOOD TRANSFUSION; BRAIN; CEREBROVASCULAR DISORDERS; HEMATOCRIT; HOMEOSTASIS; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1; INTRAOPERATIVE COMPLICATIONS; OXYGEN CONSUMPTION; POSTOPERATIVE COMPLICATIONS;

EID: 53449097077     PISSN: 00032999     EISSN: None     Source Type: Journal    
DOI: 10.1213/ane.0b013e318184cfe9     Document Type: Review

References (187)

1. Felker GM, Adams KF Jr, Gattis WA, O'Connor CM. Anemia as a risk factor and therapeutic target in heart failure. J Am Coll Cardiol 2004;44:959-66
2. Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Borenstein J. Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure. J Am Coll Cardiol 2002;39:1780-6
3. Karkouti K, Beattie WS, Wijeysundera DN, Rao V, Chan C, Dattilo KM, Djaiani G, Ivanov J, Karski J, David TE. Hemodilution during cardiopulmonary bypass is an independent risk factor for acute renal failure in adult cardiac surgery. J Thorac Cardiovasc Surg 2005;129:391-400
4. Swaminathan M, Phillips-Bute BG, Conlon PJ, Smith PK, Newman MF, Stafford-Smith M. The association of lowest hematocrit during cardiopulmonary bypass with acute renal injury after coronary artery bypass surgery. Ann Thorac Surg 2003;76:784-91
5. Karkouti K, Djaiani G, Borger MA, Beattie WS, Fedorko L, Wijeysundera D, Ivanov J, Karski J. Low hematocrit during cardiopulmonary bypass is associated with increased risk of perioperative stroke in cardiac surgery. Ann Thorac Surg 2005;80:1381-7
6. Kulier A, Levin J, Moser R, Rumpold-Seitlinger G, Tudor IC, Snyder-Ramos SA, Moehnle P, Mangano DT. Impact of preoperative anemia on outcome in patients undergoing coronary artery bypass graft surgery. Circulation 2007;116:471-9
7. Habib RH, Zacharias A, Schwann TA, Riordan CJ, Durham SJ, Shah A. Adverse effects of low hematocrit during cardiopulmonary bypass in the adult: should current practice be changed? J Thorac Cardiovasc Surg 2003;125:1438-50
8. DeFoe GR, Ross CS, Olmstead EM, Surgenor SD, Fillinger MP, Groom RC, Forest RJ, Pieroni JW, Warren CS, Bogosian ME, Krumholz CF, Clark C, Clough RA, Weldner PW, Lahey SJ, Leavitt BJ, Marrin CA, Charlesworth DC, Marshall P, O'Connor GT. Lowest hematocrit on bypass and adverse outcomes associated with coronary artery bypass grafting. Ann Thorac Surg 2001;71:769-76
9. Fang WC, Helm RE, Krieger KH, Rosengart TK, DuBois WJ, Sason C, Lesser ML, Isom OW, Gold JP. Impact of minimum hematocrit during cardiopulmonary bypass on mortality in patients undergoing coronary artery surgery. Circulation 1997;96:194-9
10. Dunne JR, Malone D, Tracy JK, Gannon C, Napolitano LM. Perioperative anemia: an independent risk factor for infection, mortality, and resource utilization in surgery. J Surg Res 2002;102:237-44
11. Carson JL, Duff A, Poses RM, Berlin JA, Spence RK, Trout R, Noveck H, Strom BL. Effect of anaemia and cardiovascular disease on surgical mortality and morbidity. Lancet 1996;348: 1055-60
12. Carson JL, Poses RM, Spence RK, Bonavita G. Severity of anaemia and operative mortality and morbidity. Lancet 1988;1:727-9
13. Karkouti K, Wijeysundera DN, Yau TM, Beattie WS, Abdelnaem E, McCluskey SA, Ghannam M, Yeo E, Djaiani G, Karski J. The independent association of massive blood loss with mortality in cardiac surgery. Transfusion 2004;44:1453-62
14. Carson JL, Duff A, Berlin JA, Lawrence VA, Poses RM, Huber EC, O'Hara DA, Noveck H, Strom BL. Perioperative blood transfusion and postoperative mortality. JAMA 1998;279:199- 205
15. Engloren MC, Habib RH, Zacharias A, Schwann TA, Riordan CJ, Durham SJ. Effect of blood transfusion on long-term survival after cardiac operation. Ann Thorac Surg 2002;74:1180-6
16. Rao SV, Jollis JG, Harrington RA, Granger CB, Newby LK, Armstrong PW, Moliterno DJ, Lindblad L, Pieper K, Topol EJ, Stamler JS, Califf RM. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004;292:1555-62
17. Hebert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, Yetisir E. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999;340:409-17
18. Lacroix J, Hebert PC, Hutchison JS, Hume HA, Tucci M, Ducruet T, Gauvin F, Collet JP, Toledano BJ, Robillard P, Joffe A, Biarent D, Meert K, Peters MJ. Transfusion strategies for patients in pediatric intensive care units. N Engl J Med 2007;356:1609-19
19. Practice guidelines for blood component therapy: a report by the american society of anesthesiologists task force on blood component therapy. Anesthesiology 1996;84:732-47
20. Ferraris VA, Ferraris SP, Saha SP, Hessel EA, Haan CK, Royston BD, Bridges CR, Higgins RS, Despotis G, Brown JR, Spiess BD, Shore-Lesserson L, Stafford-Smith M, Mazer CD, nett-Guerrero E, Hill SE, Body S. Perioperative blood transfusion and blood conservation in cardiac surgery: the society of thoracic surgeons and the society of cardiovascular anesthesiologists clinical practice guideline. Ann Thorac Surg 2007; 83:S27-86
21. Hebert PC, Yetisir E, Martin C, Blajchman MA, Wells G, Marshall J, Tweeddale M, Pagliarello G, Schweitzer I. Is a low transfusion threshold safe in critically ill patients with cardiovascular diseases? Crit Care Med 2001;29:227-34
22. McIntyre LA, Fergusson DA, Hutchison JS, Pagliarello G, Marshall JC, Yetisir E, Hare GM, Hebert PC. Effect of a liberal versus restrictive transfusion strategy on mortality in patients with moderate to severe head injury. Neurocrit Care 2006;5:4-9
23. Nybo M, Kristensen SR, Mickley H, Jensen JK. The influence of anaemia on stroke prognosis and its relation to N-terminal pro-brain natriuretic peptide. Eur J Neurol 2007;14:477-82
24. Nikolsky E, Aymong ED, Halkin A, Grines CL, Cox DA, Garcia E, Mehran R, Tcheng JE, Griffin JJ, Guagliumi G, Stuckey T, Turco M, Cohen DA, Negoita M, Lansky AJ, Stone GW. Impact of anemia in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention: analysis from the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial. J Am Coll Cardiol 2004;44:547-53
25. Karkouti K, Wijeysundera DN, Beattie WS. Risk associated with preoperative anemia in cardiac surgery: a multicenter cohort study. Circulation 2008;117:478-84
26. Jonas RA, Wypij D, Roth SJ, Bellinger DC, Visconti KJ, du Plessis AJ, Goodkin H, Laussen PC, Farrell DM, Bartlett J, McGrath E, Rappaport LJ, Bacha EA, Forbess JM, del Nido PJ, Mayer JE Jr, Newburger JW. The influence of hemodilution on outcome after hypothermic cardiopulmonary bypass: results of a randomized trial in infants. J Thorac Cardiovasc Surg 2003;126:1765-74
27. Sabatine MS, Morrow DA, Giugliano RP, Burton PB, Murphy SA, McCabe CH, Gibson CM, Braunwald E. Association of hemoglobin levels with clinical outcomes in acute coronary syndromes. Circulation 2005;111:2042-9
28. da Silveira AD, Ribeiro RA, Rossini AP, Stella SF, Ritta HA, Stein R, Polanczyk CA. Association of anemia with clinical outcomes in stable coronary artery disease. Coron Artery Dis 2008;19:21-6
29. Lee MT, Piomelli S, Granger S, Miller ST, Harkness S, Brambilla DJ, Adams RJ. Stroke Prevention Trial in Sickle Cell Anemia (STOP): extended follow-up and final results. Blood 2006;108: 847-52
30. Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, Abboud M, Gallagher D, Kutlar A, Nichols FT, Bonds DR, Brambilla D. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial doppler ultrasonography. N Engl J Med 1998; 339:5-11
31. Meschia JF, Pankratz VS. Defining stroke risks in sickle cell anemia. Nat Genet 2005;37:340-1
32. Raj AB, O'brien LM, Bertolone SJ, Gozal D, EdmondsHLJr. Cerebral oximetry improves detection of sickle cell patients at risk for nocturnal cerebral hypoxia. Pediatr Pulmonol 2006;41: 1088-94
33. Nahavandi M, Tavakkoli F, Hasan SP, Wyche MQ, Castro O. Cerebral oximetry in patients with sickle cell disease. Eur J Clin Invest 2004;34:143-8
34. Maguire JL, deVeber G, Parkin PC. Association between irondeficiency anemia and stroke in young children. Pediatrics 2007;120:1053-7
35. Stolz E, Valdueza JM, Grebe M, Schlachetzki F, Schmitt E, Madlener K, Rahimi A, Kempkes-Matthes B, Blaes F, Gerriets T, Kaps M. Anemia as a risk factor for cerebral venous thrombosis? An old hypothesis revisited. Results of a prospective study. J Neurol 2007;254:729-34
36. Hare GM, Mazer CD, Hutchison JS, McLaren AT, Liu E, Rassouli A, Ai J, Shaye RE, Lockwood JA, Hawkins CE, Sikich N, To K, Baker AJ. Severe hemodilutional anemia increases cerebral tissue injury following acute neurotrauma. J Appl Physiol 2007;103:1021-9
37. Homi HM, Yang H, Pearlstein RD, Grocott HP. Hemodilution during cardiopulmonary bypass increases cerebral infarct volume after middle cerebral artery occlusion in rats. Anesth Analg 2004;99:974-81
38. Karkouti K, Wijeysundera DN, Yau TM, McCluskey SA, van RA, Beattie WS. The influence of baseline hemoglobin concentration on tolerance of anemia in cardiac surgery. Transfusion 2008;48:666-72
39. Weiskopf RB, Kramer JH, DP, Viele M, Neumann M, Feiner JR, Watson JJ, Hopf HW, Toy P. Acute severe isovolemic anemia impairs cognitive function and memory in humans. Anesthesiology 2000;92:1646-52
40. Weiskopf RB, Toy P, Hopf HW, Feiner J, Finlay HE, Takahashi M, Bostrom A, Songster C, Aminoff MJ. Acute isovolemic anemia impairs central processing as determined by P300 latency. Clin Neurophysiol 2005;116:1028-32
41. Semenza GL. Life with oxygen. Science 2007;318:62-4
42. Roy A, Baby SM, Wilson DF, Lahiri S. Rat carotid body chemosensory discharge and glomus cell HIF-1 alpha expression in vitro: regulation by a common oxygen sensor. Am J Physiol 2007;293:R829-36
43. Wilson DF, Mokashi A, Lahiri S, Vinogradov SA. Tissue PO2 and mitochondrial enzymes. Cytochrome C oxidase as O2 sensor. Adv Exp Med Biol 2000;475:259-64
44. Nilsson GE, Lutz PL. Anoxia tolerant brains. J Cereb Blood Flow Metab 2004;24:475-86
45. Hochachka PW. Mechanism and evolution of hypoxiatolerance in humans. J Exp Biol 1998;201:1243-54
46. Hatcher JD, Chiu LK, Jennings DB. Anemia as a stimulus to aortic and carotid chemoreceptors in the cat. J Appl Physiol 1978;44:696-702
47. Meier J, Kemming GI, Kisch-Wedel H, Wolkhammer S, Habler OP. Hyperoxic ventilation reduces 6-hour mortality at the critical hemoglobin concentration. Anesthesiology 2004;100: 70-6
48. Eichelbronner O, D'Almeida M, Sielenkamper A, Sibbald WJ, Chin-Yee IH. Increasing P(50) does not improve DO(2CRIT) or systemic VO(2) in severe anemia. Am J Physiol Heart Circ Physiol 2002;283:H92-101
49. Ickx BE, Rigolet M, Van Der Linden PJ. Cardiovascular and metabolic response to acute normovolemic anemia. Effects of anesthesia. Anesthesiology 2000;93:1011-6
50. van Bommel J, Trouwborst A, Schwarte L, Siegemund M, Ince C, Henny C. Intestinal and cerebral oxygenation during severe isovolemic hemodilution and subsequent hyperoxic ventilation in a pig model. Anesthesiology 2002;97:660-70
51. Crystal GJ, Salem MR. Beta-adrenergic stimulation restores oxygen extraction reserve during acute normovolemic hemodilution. Anesth Analg 2002;95:851-7
52. Matsuoka T, Saiki C, Mortola JP. Metabolic and ventilatory responses to anemic hypoxia in conscious rats. J Appl Physiol 1994;77:1067-72
53. Dunst J, Becker A, Lautenschlager C, Markau S, Becker H, Fischer K, Haensgen G. Anemia and elevated systemic levels of vascular endothelial growth factor (VEGF). Strahlenther Onkol 2002;178:436-41
54. Pichiule P, LaManna JC. Angiopoietin-2 and rat brain capillary remodeling during adaptation and deadaptation to prolonged mild hypoxia. J Appl Physiol 2002;93:1131-9
55. Rakusan K, Cicutti N, Kolar F. Effect of anemia on cardiac function, microvascular structure, and capillary hematocrit in rat hearts. Am J Physiol 2001;280:H1407-14
56. Meisner FG, Kemming GI, Habler OP, Kleen MS, Tillmanns JH, Hutter JW, Bottino DA, Thein E, Meier JM, Wojtczyk CJ, Pape A, Messmer K. Diaspirin crosslinked hemoglobin enables extreme hemodilution beyond the critical hematocrit. Crit Care Med 2001;29:829-38
57. Torres FI, Spiess BD, Pittman RN, Barbee RW, Ward KR. Experimental analysis of critical oxygen delivery. Am J Physiol 2004;288:H1071-9
58. Metry G, Wikstrom B, Valind S, Sandhagen B, Linde T, Beshara S, Langstrom B, Danielson BG. Effect of normalization of hematocrit on brain circulation and metabolism in hemodialysis patients. J Am Soc Nephrol 1999;10:854-63
59. Bruder N, Cohen B, Pellissier D, Francois G. The effect of hemodilution on cerebral blood flow velocity in anesthetized patients. Anesth Analg 1998;86:320-4
60. Brown MM, Wade JP, Marshall J. Fundamental importance of arterial oxygen content in the regulation of cerebral blood flow in man. Brain 1985;108:81-93
61. Muhling J, Dehne MG, Sablotzki A, Hempelmann G. Cerebral blood flow velocity during isovolemic hemodilution and subsequent autologous blood retransfusion. Can J Anesth 1999;46:550-7
62. Sungurtekin H, Cook DJ, Orszulak TA, Daly RC, Mullany CJ. Cerebral response to hemodilution during hypothermic cardiopulmonary bypass in adults. Anesth Analg 1999;89: 1078-83
63. Erzurum SC, Ghosh S, Janocha AJ, Xu W, Bauer S, Bryan NS, Tejero J, Hemann C, Hille R, Stuehr DJ, Feelisch M, Beall CM. Higher blood flow and circulating NO products offset highaltitude hypoxia among Tibetans. Proc Natl Acad Sci USA 2007;104:17593-8
64. Severinghaus JW, Chiodi H, Eger EI, Brandstater B, Hornbein TF. Cerebral blood flow in man at high altitude. Role of cerebrospinal fluid pH in normalization of flow in chronic hypocapnia. Circ Res 1966;19:274-82
65. Johannsson H, Siesjo BK. Blood flow and oxygen consumption in the rat brain in dilutional anemia. Acta Physiol Scand 1974;91:136-8
66. Hudak ML, Jones MD Jr, Popel AS, Koehler RC, Traystman RJ, Zeger SL. Hemodilution causes size-dependent constriction of pial arterioles in the cat. Am J Physiol 1989;257:H912-7
67. Todd MM, Wu B, Maktabi M, Hindman BJ, Warner DS. Cerebral blood flow and oxygen delivery during hypoxemia and hemodilution: role of arterial oxygen content. Am J Physiol 1994;267:H2025-31
68. Cook DJ, Orszulak TA, Daly RC. Minimum hematocrit at differing cardiopulmonary bypass temperatures in dogs. Circulation 1998;98:II170-4
69. Plochl W, Liam BL, Cook DJ, Orszulak TA. Cerebral response to haemodilution during cardiopulmonary bypass in dogs: the role of nitric oxide synthase. Br J Anaesth 1999;82:237-43
70. Detti L, Oz U, Guney I, Ferguson JE, Bahado-Singh RO, Mari G; Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. Doppler ultrasound velocimetry for timing the second intrauterine transfusion in fetuses with anemia from red cell alloimmunization. Am J Obstet Gynecol 2001;185:1048-51
71. Mari G, Rahman F, Olofsson P, Ozcan T, Copel JA. Increase of fetal hematocrit decreases the middle cerebral artery peak systolic velocity in pregnancies complicated by rhesus alloimmunization. J Matern Fetal Med 1997;6:206-8
72. Hare GM, Worrall JM, Baker AJ, Liu E, Sikich N, Mazer CD. Beta2 adrenergic antagonist inhibits cerebral cortical oxygen delivery after severe haemodilution in rats. Br J Anaesth 2006;97:617-23
73. Hudetz AG, Wood JD, Kampine JP. 7-Nitroindazole impedes erythrocyte flow response to isovolemic hemodilution in the cerebral capillary circulation. J Cereb Blood Flow Metab 2000;20:220-4
74. Hare GMT, Mazer CD, Mak W, Gorczynski RM, Hum KM, Kim SY, Wyard L, Barr A, Qu R, Baker AJ. Hemodilutional anemia is associated with increased cerebral neuronal nitric oxide synthase gene expression. J Appl Physiol 2003;94:2058-67
75. McLaren AT, Marsden PA, Mazer CD, Baker AJ, Stewart DJ, Tsui AK, Li X, Yucel Y, Robb M, Boyd SR, Liu E, Yu J, Hare GM. Increased expression of HIF-1{alpha}, nNOS, and VEGF in the cerebral cortex of anemic rats. Am J Physiol 2007;292: R403-14
76. Tsai AG, Acero C, Nance PR, Cabrales P, Frangos JA, Buerk DG, Intaglietta M. Elevated plasma viscosity in extreme hemodilution increases perivascular nitric oxide concentration and microvascular perfusion. Am J Physiol 2005;288:H1730-9
77. Toda N, Okamura T. The pharmacology of nitric oxide in the peripheral nervous system of blood vessels. Pharmacol Rev 2003;55:271-324
78. Iadecola C, Niwa K. Nitric oxide. In: Edvinsson L, Kraus DN, eds. Cerebral blood flow and metabolism. Philidelphia: Lipincott Williams & Wilkins, 2002:295-310
79. Hudetz AG, Shen H, Kampine JP. Nitric oxide from neuronal NOS plays critical role in cerebral capillary flow response to hypoxia. Am J Physiol 1998;274:H982-9
80. Toda N, Okamura T. Neurogenic nitric oxide (NO) in the regulation of cerebroarterial tone. J Chem Neuroanat 1996;10:
81. Ayajiki K, Fujioka H, Okamura T, Toda N. Relatively selective neuronal nitric oxide synthase inhibition by 7-nitroindazole in monkey isolated cerebral arteries. Eur J Pharmacol 2001;423: 179-83
82. Lindauer U, Kunz A, Schuh-Hofer S, Vogt J, Dreier JP, Dirnagl U. Nitric oxide from perivascular nerves modulates cerebral arterial pH reactivity. Am J Physiol 2001;281:H1353-63
83. Lee TJ, Zhang W, Sarwinski S. Presynaptic beta(2)-adrenoceptors mediate nicotine-induced NO ergic neurogenic dilation in porcine basilar arteries. Am J Physiol 2000;279:H808-16
84. Si ML, Lee TJ. Alpha7-nicotinic acetylcholine receptors on cerebral perivascular sympathetic nerves mediate cholineinduced nitrergic neurogenic vasodilation. Circ Res 2002;91: 62-9
85. Toda N, Tanaka T, Ayajiki K, Okamura T. Cerebral vasodilatation induced by stimulation of the pterygopalatine ganglion and greater petrosal nerve in anesthetized monkeys. Neuroscience 2000;96:393-8
86. Joshi S, Young WL, Duong DH, Ostapkovich ND, Aagaard BD, Hashimoto T, Pile-Spellman J. Intracarotid infusion of the nitric oxide synthase inhibitor, l-NMMA, modestly decreases cerebral blood flow in human subjects. Anesthesiology 2000;93:699-707
87. Kelly PA, Ritchie IM, Arbuthnott GW. Inhibition of neuronal nitric oxide synthase by 7-nitroindazole: effects upon local cerebral blood flow and glucose use in the rat. J Cereb Blood Flow Metab 1995;15:766-73
88. Preckel MP, Leftheriotis G, Ferber C, Degoute CS, Banssillon V, Saumet JL. Effect of nitric oxide blockade on the lower limit of the cortical cerebral autoregulation in pentobarbitalanaesthetized rats. Int J Microcirc Clin Exp 1996;16:277-83
89. Karabiyikoglu M, Han HS, Yenari MA, Steinberg GK. Attenuation of nitric oxide synthase isoform expression by mild hypothermia after focal cerebral ischemia: variations depending on timing of cooling. J Neurosurg 2003;98:1271-6
90. Niwa M, Inao S, Takayasu M, Kawai T, Kajita Y, Nihashi T, Kabeya R, Sugimoto T, Yoshida J. Time course of expression of three nitric oxide synthase isoforms after transient middle cerebral artery occlusion in rats. Neurol Med Chir 2001; 41:63-72
91. Zhang F, White JG, Iadecola C. Nitric oxide donors increase blood flow and reduce brain damage in focal ischemia: evidence that nitric oxide is beneficial in the early stages of cerebral ischemia. J Cereb Blood Flow Metab 1994;14:217-26
92. Hunter CJ, Blood AB, White CR, Pearce WJ, Power GG. Role of nitric oxide in hypoxic cerebral vasodilatation in the ovine fetus. J Physiol 2003;549:625-33
93. Fabricius M, Rubin I, Bundgaard M, Lauritzen M. NOS activity in brain and endothelium: relation to hypercapnic rise of cerebral blood flow in rats. Am J Physiol 1996;271:H2035-44
94. Harada M, Fuse A, Tanaka Y. Measurement of nitric oxide in the rat cerebral cortex during hypercapnoea. Neuroreport 1997;8:999-1002
95. Iadecola C, Zhang F. Nitric oxide-dependent and -independent components of cerebrovasodilation elicited by hypercapnia. Am J Physiol 1994;266:R546-52
96. Yang G, Zhang Y, Ross ME, Iadecola C. Attenuation of activity-induced increases in cerebellar blood flow in mice lacking neuronal nitric oxide synthase. Am J Physiol 2003;285:H298-304
97. Uchida S, Kawashima K, Lee TJ. Nicotine-induced NOmediated increase in cortical cerebral blood flow is blocked by beta2-adrenoceptor antagonists in the anesthetized rats. Auton Neurosci 2002;96:126-30
98. Castro-Blanco S, Encinas JM, Serrano J, Alonso D, Gomez MB, Sanchez J, Rios-Tejada F, Fernandez-Vizarra P, Fernandez AP, Martinez-Murillo R, Rodrigo J. Expression of nitrergic system and protein nitration in adult rat brains submitted to acute hypobaric hypoxia. Nitric Oxide 2003;8:182-201
99. Ward ME, Toporsian M, Scott JA, Teoh H, Govindaraju V, Quan A, Wener AD, Wang G, Bevan SC, Newton DC, Marsden PA. Hypoxia induces a functionally significant and translationally efficient neuronal NO synthase mRNA variant. J Clin Invest 2005;115:3128-39
100. Hill MA, Davis MJ, Meininger GA, Potocnik SJ, Murphy TV. Arteriolar myogenic signalling mechanisms: implications for local vascular function. Clin Hemorheol Microcirc 2006; 34:67-79
101. Tomiyama Y, Brian JE Jr, Todd MM. Cerebral blood flow during hemodilution and hypoxia in rats: role of ATP-sensitive potassium channels. Stroke 1999;30:1942-7
102. Jones SC, Easley KA, Radinsky CR, Chyatte D, Furlan AJ, Perez-Trepichio AD. Nitric oxide synthase inhibition depresses the height of the cerebral blood flow-pressure autoregulation curve during moderate hypotension. J Cereb Blood Flow Metab 2003;23:1085-95
103. Kusano E, Akimoto T, Umino T, Yanagiba S, Inoue M, Ito C, Ando Y, Asano Y. Modulation of endothelin-1-induced cytosolic free calcium mobilization and mitogen-activated protein kinase activation by erythropoietin in vascular smooth muscle cells. Kidney Blood Press Res 2001;24:192-200
104. Barrett JD, Zhang Z, Zhu JH, Lee DB, Ward HJ, Jamgotchian N, Hu MS, Fredal A, Giordani M, Eggena P. Erythropoietin upregulates angiotensin receptors in cultured rat vascular smooth muscle cells. J Hypertens 1998;16:1749-57
105. Ito C, Kusano E, Furukawa Y, Yamamoto H, Takeda S, Akimoto T, Iimura O, Ando Y, Asano Y. Modulation of the erythropoietin-induced proliferative pathway by cAMP in vascular smooth muscle cells. Am J Physiol 2002;283:C1715-21
106. Lindenblatt N, Menger MD, Klar E, Vollmar B. Darbepoetinalpha does not promote microvascular thrombus formation in mice: role of eNOS-dependent protection through platelet and endothelial cell deactivation. Arterioscler Thromb Vasc Biol 2007;27:1191-8
107. Huang Z, Huang PL, Ma J, Meng W, Ayata C, Fishman MC, Moskowitz MA. Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine. J Cereb Blood Flow Metab 1996;16:981-7
108. Zhang ZG, Chopp M, Zaloga C, Pollock JS, Forstermann U. Cerebral endothelial nitric oxide synthase expression after focal cerebral ischemia in rats. Stroke 1993;24:2016-21
109. Endres M, Gertz K, Lindauer U, Katchanov J, Schultze J, Schrock H, Nickenig G, Kuschinsky W, Dirnagl U, Laufs U. Mechanisms of stroke protection by physical activity. Ann Neurol 2003;54:582-90
110. Chen J, Zacharek A, Zhang C, Jiang H, Li Y, Roberts C, Lu M, Kapke A, Chopp M. Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice. J Neurosci 2005;25:2366-75
111. Morariu AM, Maathuis MH, Asgeirsdottir SA, Leuvenink HG, Boonstra PW, VAN OW, Ploeg RJ, Molema I, Rakhorst G. Acute isovolemic hemodilution triggers proinflammatory and procoagulatory endothelial activation in vital organs: role of erythrocyte aggregation. Microcirculation 2006;13:397-409
112. Mazer CD, Briet F, Blight KR, Stewart DJ, Robb M, Wang Z, Harrington AM, Mak W, Li X, Hare GM. Increased cerebral and renal endothelial nitric oxide synthase gene expression after cardiopulmonary bypass in the rat. J Thorac Cardiovasc Surg 2007;133:13-20
113. Gladwin MT, Lancaster JR Jr, Freeman BA, Schechter AN. Nitric oxide's reactions with hemoglobin: a view through the SNO-storm. Nat Med 2003;9:496-500
114. Singel DJ, Stamler JS. Chemical physiology of blood flow regulation by red blood cells: the role of nitric oxide and S-nitrosohemoglobin. Annu Rev Physiol 2005;67:99 -145.
115. Pawloski JR, Hess DT, Stamler JS. Export by red blood cells of nitric oxide bioactivity. Nature 2001;409:622-6
116. Stamler JS, Jia L, Eu JP, McMahon TJ, Demchenko IT, Bonaventura J, Gernert K, Piantadosi CA. Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient. Science 1997;276:2034-7
117. Lipton AJ, Johnson MA, MacDonald T, Lieberman MW, Gozal D, Gaston B. S-nitrosothiols signal the ventilatory response to hypoxia. Nature 2001;413:171-4
118. Reynolds JD, Ahearn GS, Angelo M, Zhang J, Cobb F, Stamler JS. S-nitrosohemoglobin deficiency: a mechanism for loss of physiological activity in banked blood. Proc Natl Acad Sci USA 2007;104:17058-62
119. Gustavsson M, Mallard C, Vannucci SJ, Wilson MA, Johnston MV, Hagberg H. Vascular response to hypoxic preconditioning in the immature brain. J Cereb Blood Flow Metab 2007;27:928-38
120. Kadyrov M, Kosanke G, Kingdom J, Kaufmann P. Increased fetoplacental angiogenesis during first trimester in anaemic women. Lancet 1998;352:1747-9
121. Miura T, Sakamoto T, Kobayashi M, Shin'oka T, Kurosawa H. Hemodilutional anemia impairs neurologic outcome after cardiopulmonary bypass in a piglet model. J Thorac Cardiovasc Surg 2007;133:29-36
122. Shin'oka T, Shum-Tim D, Jonas RA, Lidov HG, Laussen PC, Miura T, du PA. Higher hematocrit improves cerebral outcome after deep hypothermic circulatory arrest. J Thorac Cardiovasc Surg 1996;112:1610-20
123. Borgstrom L, Johannsson H, Siesjo BK. The influence of acute normovolemic anemia on cerebral blood flow and oxygen consumption of anesthetized rats. Acta Physiol Scand 1975;93:505-14
124. Djaiani G, Fedorko L, Borger MA, Green R, Carroll J, Marcon M, Karski J. Continuous-flow cell saver reduces cognitive decline in elderly patients after coronary bypass surgery. Circulation 2007;116:1888-95
125. Liebold A, Khosravi A, Westphal B, Skrabal C, Choi YH, Stamm C, Kaminski A, Alms A, Birken T, Zurakowski D, Steinhoff G. Effect of closed minimized cardiopulmonary bypass on cerebral tissue oxygenation and microembolization. J Thorac Cardiovasc Surg 2006;131:268-76
126. Murkin JM, Adams SJ, Novick RJ, Quantz M, Bainbridge D, Iglesias I, Cleland A, Schaefer B, Irwin B, Fox S. Monitoring brain oxygen saturation during coronary bypass surgery: a randomized, prospective study. Anesth Analg 2007;104:51-8
127. Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 1994;265:1883-5
128. Dawson VL, Kizushi VM, Huang PL, Snyder SH, Dawson TM. Resistance to neurotoxicity in cortical cultures from neuronal nitric oxide synthase-deficient mice. J Neurosci 1996;16:2479-87
129. Dawson VL, Dawson TM. Nitric oxide neurotoxicity. J Chem Neuroanat 1996;10:179-90
130. Schulz JB, Matthews RT, Klockgether T, Dichgans J, Beal MF. The role of mitochondrial dysfunction and neuronal nitric oxide in animal models of neurodegenerative diseases. Mol Cell Biochem 1997;174:193-7
131. Hyman BT, Marzloff K, Wenniger JJ, Dawson TM, Bredt DS, Snyder SH. Relative sparing of nitric oxide synthasecontaining neurons in the hippocampal formation in Alzheimer's disease. Ann Neurol 1992;32:818-20
132. Brown GC, Bal-Price A. Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol Neurobiol 2003;27:325-55
133. Gursoy-Ozdemir Y, Bolay H, Saribas O, Dalkara T. Role of endothelial nitric oxide generation and peroxynitrite formation in reperfusion injury after focal cerebral ischemia. Stroke 2000;31:1974-80
134. Atochin DN, Clark J, Demchenko IT, Moskowitz MA, Huang PL. Rapid cerebral ischemic preconditioning in mice deficient in endothelial and neuronal nitric oxide synthases. Stroke 2003;34:1299-303
135. McCullough LD, Zeng Z, Blizzard KK, Debchoudhury I, Hurn PD. Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J Cereb Blood Flow Metab 2005;25:502-12
136. Duebener LF, Sakamoto T, Hatsuoka S, Stamm C, Zurakowski D, Vollmar B, Menger MD, Schafers HJ, Jonas RA. Effects of hematocrit on cerebral microcirculation and tissue oxygenation during deep hypothermic bypass. Circulation 2001;104:I260-4
137. Roth-Isigkeit A, Borstel TV, Seyfarth M, Schmucker P. Perioperative serum levels of tumour-necrosis-factor alpha (TNFalpha), IL-1 beta, IL-6, IL-10 and soluble IL-2 receptor in patients undergoing cardiac surgery with cardiopulmonary bypass without and with correction for haemodilution. Clin Exp Immunol 1999;118:242-6
138. Morganti-Kossmann MC, Rancan M, Stahel PF, Kossmann T. Inflammatory response in acute traumatic brain injury: a double-edged sword. Curr Opin Crit Care 2002;8:101-5
139. Felszeghy K, Banisadr G, Rostene W, Nyakas C, Haour F. Dexamethasone downregulates chemokine receptor CXCR4 and exerts neuroprotection against hypoxia/ischemia-induced brain injury in neonatal rats. Neuroimmunomodulation 2004;11:404-13
140. Moro MA, Cardenas A, Hurtado O, Leza JC, Lizasoain I. Role of nitric oxide after brain ischaemia. Cell Calcium 2004;36:265-75
141. Kaur C, Sivakumar V, Ang LS, Sundaresan A. Hypoxic damage to the periventricular white matter in neonatal brain: role of vascular endothelial growth factor, nitric oxide and excitotoxicity. J Neurochem 2006;98:1200-16
142. Fischer S, Wobben M, Marti HH, Renz D, Schaper W. Hypoxiainduced hyperpermeability in brain microvessel endothelial cells involves VEGF-mediated changes in the expression of zonula occludens-1. Microvasc Res 2002;63:70-80
143. Schoch HJ, Fischer S, Marti HH. Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain. Brain 2002;125:2549-57
144. Mayhan WG. VEGF increases permeability of the blood-brain barrier via a nitric oxide synthase/cGMP-dependent pathway. Am J Physiol 1999;276:C1148-53
145. Schmidt-Kastner R, guirre-Chen C, Kietzmann T, Saul I, Busto R, Ginsberg MD. Nuclear localization of the hypoxia-regulated pro-apoptotic protein BNIP3 after global brain ischemia in the rat hippocampus. Brain Res 2004;1001:133-42
146. Bergeron M, Gidday JM, Yu AY, Semenza GL, Ferriero DM, Sharp FR. Role of hypoxia-inducible factor-1 in hypoxiainduced ischemic tolerance in neonatal rat brain. Ann Neurol 2000;48:285-96
147. Clarkson AN. Anesthetic-mediated protection/preconditioning during cerebral ischemia. Life Sci 2007;80:1157-75
148. Gidday JM. Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci 2006;7:437-48
149. Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 1999;15:551-78
150. Sharp FR, Bernaudin M. HIF1 and oxygen sensing in the brain. Nat Rev Neurosci 2004;5:437-48
151. Richard DE, Berra E, Pouyssegur J. Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1alpha in vascular smooth muscle cells. J Biol Chem 2000;275:26765-71
152. Marsden PA. Low-molecular-weight S-nitrosothiols and blood vessel injury. J Clin Invest 2007;117:2377-80
153. Metzen E, Zhou J, Jelkmann W, Fandrey J, Brune B. Nitric oxide impairs normoxic degradation of HIF-1alpha by inhibition of prolyl hydroxylases. Mol Biol Cell 2003;14:3470-81
154. Palmer LA, Gaston B, Johns RA. Normoxic stabilization of hypoxia-inducible factor-1 expression and activity: redoxdependent effect of nitrogen oxides. Mol Pharmacol 2000;58:1197-203
155. Kitano H, Kirsch JR, Hurn PD, Murphy SJ. Inhalational anesthetics as neuroprotectants or chemical preconditioning agents in ischemic brain. J Cereb Blood Flow Metab 2007;27:1108-28
156. Zhang CP, Zhu LL, Zhao T, Zhao H, Huang X, Ma X, Wang H, Fan M. Characteristics of neural stem cells expanded in lowered oxygen and the potential role of hypoxia-inducible factor- 1alpha. Neurosignals 2007;15:259-65
157. Chen HL, Pistollato F, Hoeppner DJ, Ni HT, McKay RD, Panchision DM. Oxygen tension regulates survival and fate of mouse CNS precursors at multiple levels. Stem Cells 2007;25:2291-301
158. Semenza GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 2000;88: 1474-80
159. Bernaudin M, Nedelec AS, Divoux D, Mackenzie ET, Petit E, Schumann-Bard P. Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia-inducible factor-1 and its target genes, erythropoietin and VEGF, in the adult mouse brain. J Cereb Blood Flow Metab 2002;22:393-403
160. Baranova O, Miranda LF, Pichiule P, Dragatsis I, Johnson RS, Chavez JC. Neuron-specific inactivation of the hypoxia inducible factor 1 alpha increases brain injury in a mouse model of transient focal cerebral ischemia. J Neurosci 2007;27:6320-32
161. Vangeison G, Carr D, Federoff HJ, Rempe DA. The good, the bad, and the cell type-specific roles of hypoxia inducible factor-1 alpha in neurons and astrocytes. J Neurosci 2008; 28:1988-93
162. Brune B, Zhou J. The role of nitric oxide (NO) in stability regulation of hypoxia inducible factor-1alpha (HIF-1alpha). Curr Med Chem 2003;10:845-55
163. Dery MA, Michaud MD, Richard DE. Hypoxia-inducible factor 1: regulation by hypoxic and non-hypoxic activators. Int J Biochem Cell Biol 2005;37:535-40
164. Agani FH, Puchowicz M, Chavez JC, Pichiule P, LaManna J. Role of nitric oxide in the regulation of HIF-1alpha expression during hypoxia. Am J Physiol 2002;283:C178-86
165. Huang LE, Willmore WG, Gu J, Goldberg MA, Bunn HF. Inhibition of hypoxia-inducible factor 1 activation by carbon monoxide and nitric oxide. Implications for oxygen sensing and signaling. J Biol Chem 1999;274:9038-44
166. Sogawa K, Numayama-Tsuruta K, Ema M, Abe M, Abe H, Fujii-Kuriyama Y. Inhibition of hypoxia-inducible factor 1 activity by nitric oxide donors in hypoxia. Proc Natl Acad Sci USA 1998;95:7368-73
167. Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C, Itri LM, Cerami A. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 2000;97:10526-31
168. Chong ZZ, Kang JQ, Maiese K. Erythropoietin: cytoprotection in vascular and neuronal cells. Curr Drug Targets Cardiovasc Haematol Disord 2003;3:141-54
169. Noguchi CT, Asavaritikrai P, Teng R, Jia Y. Role of erythropoietin in the brain. Crit Rev Oncol Hematol 2007;64:159-71
170. Digicaylioglu M, Lipton SA. Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signaling cascades. Nature 2001;412:641-7
171. Beleslin-Cokic BB, Cokic VP, Yu X, Weksler BB, Schechter AN, Noguchi CT. Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells. Blood 2004;104:2073-80
172. Nakano M, Satoh K, Fukumoto Y, Ito Y, Kagaya Y, Ishii N, Sugamura K, Shimokawa H. Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice. Circ Res 2007;100:662-9
173. Kanagy NL, Perrine MF, Cheung DK, Walker BR. Erythropoietin administration in vivo increases vascular nitric oxide synthase expression. J Cardiovasc Pharmacol 2003;42:527-33
174. Martinez-Estrada OM, Rodriguez-Millan E, Gonzalez-De Vicente E, Reina M, Vilaro S, Fabre M. Erythropoietin protects the in vitro blood-brain barrier against VEGF-induced permeability. Eur J Neurosci 2003;18:2538-44
175. Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P, Stiefel M, Rustenbeck HH, Breiter N, Jacob S, Knerlich F, Bohn M, Poser W, Ruther E, Kochen M, Gefeller O, Gleiter C, Wessel TC, De RM, Itri L, Prange H, Cerami A, Brines M, Siren AL. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 2002;8:495-505
176. Corwin HL, Gettinger A, Fabian TC, May A, Pearl RG, Heard S, An R, Bowers PJ, Burton P, Klausner MA, Corwin MJ. Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med 2007;357:965-76
177. Feagan BG, Wong CJ, Kirkley A, Johnston DW, Smith FC, Whitsitt P, Wheeler SL, Lau CY. Erythropoietin with iron supplementation to prevent allogeneic blood transfusion in total hip joint arthroplasty. A randomized, controlled trial. Ann Intern Med 2000;133:845-54
178. Safran M, Kim WY, O'Connell F, Flippin L, Gunzler V, Horner JW, Depinho RA, Kaelin WG Jr. Mouse model for noninvasive imaging of HIF prolyl hydroxylase activity: assessment of an oral agent that stimulates erythropoietin production. Proc Natl Acad Sci USA 2006;103:105-10
179. Siddiq A, Ayoub IA, Chavez JC, Aminova L, Shah S, LaManna JC, Patton SM, Connor JR, Cherny RA, Volitakis I, Bush AI, Langsetmo I, Seeley T, Gunzler V, Ratan RR. Hypoxiainducible factor prolyl 4-hydroxylase inhibition. A target for neuroprotection in the central nervous system. J Biol Chem 2005;280:41732-43
180. Urao N, Okigaki M, Yamada H, Aadachi Y, Matsuno K, Matsui A, Matsunaga S, Tateishi K, Nomura T, Takahashi T, Tatsumi T, Matsubara H. Erythropoietin- mobilized endothelial progenitors enhance reendothelialization via Akt-endothelial nitric oxide synthase activation and prevent neointimal hyperplasia. Circ Res 2006;98:1405-13
181. Ogunshola OO, Stewart WB, Mihalcik V, Solli T, Madri JA, Ment LR. Neuronal VEGF expression correlates with angiogenesis in postnatal developing rat brain. Brain Res Dev Brain Res 2000;119:139-53
182. Cao L, Jiao X, Zuzga DS, Liu Y, Fong DM, Young D, During MJ. VEGF links hippocampal activity with neurogenesis, learning and memory. Nat Genet 2004;36:827-35
183. Wick A, Wick W, Waltenberger J, Weller M, Dichgans J, Schulz JB. Neuroprotection by hypoxic preconditioning requires sequential activation of vascular endothelial growth factor receptor and Akt. J Neurosci 2002;22:6401-7
184. Cho S, Park EM, Zhou P, Frys K, Ross ME, Iadecola C. Obligatory role of inducible nitric oxide synthase in ischemic preconditioning. J Cereb Blood Flow Metab 2005;25:493-501
185. Kawano T, Kunz A, Abe T, Girouard H, Anrather J, Zhou P, Iadecola C. iNOS-derived NO and nox2-derived superoxide confer tolerance to excitotoxic brain injury through peroxynitrite. J Cereb Blood Flow Metab 2007;27:1453-62
186. Kunz A, Park L, Abe T, Gallo EF, Anrather J, Zhou P, Iadecola C. Neurovascular protection by ischemic tolerance: role of nitric oxide and reactive oxygen species. J Neurosci 2007;27: 7083-93
187. Kapinya KJ, Lowl D, Futterer C, Maurer M, Waschke KF, Isaev NK, Dirnagl U. Tolerance against ischemic neuronal injury can be induced by volatile anesthetics and is inducible NO synthase dependent. Stroke 2002;33:1889-98