Importance of Erythropoietin in Brain Protection aft er Cardiac Surgery: A Pilot Study
Background: Neurologic complications after cardiac operations present an important medical problem, as well as a financial burden. They increase the morbidity and hospital stays of patients who have otherwise undergone successful heart operations. The current protocols for perioperative brain protection against ischemic events are not optimal. Because of its different pleiotropic mechanisms of action, recombinant human erythropoietin might provide neuroprotection.
Methods: In this study, we included 20 patients who were older than 18 years and required surgical revascularization of the heart with the use of the heart-lung machine. Ten patients received 3 consecutive intravenous doses (24,000 IU) of recombinant human erythropoietin (rHuEpo). Neurologic and magnetic resonance imaging (MRI) examinations were done before and in the first 5 days after surgery.
Results: The erythropoietin-treated and control groups were comparable with respect to study protocol outcomes: number of coronary artery bypass grafts (3.3 and 3.2 grafts/patient, respectively), operative time (4.12 and 4.6 hours), and transfusion volume per patient (708 and 674 mL). The groups were also comparable with respect to blood pressure values at all stages of the operation. MRI scans revealed that 4 of 10 patients from the control group had fresh ischemic brain lesions after open heart surgery. None of the patients in the erythropoietin-treated group had fresh ischemic brain lesions.
Conclusion: Although the number of patients was small, the results regarding brain protection with rHuEpo are encouraging. rHuEpo is a promising neuroprotective agent.
Barber PA, Hach S, Tippett LJ, Ross L, Merry AF, Milsom P. 2008. Cerebral ischemic lesions on diffusion-weighted imaging are associated with neurocognitive decline after cardiac surgery. Stroke 39:1427-33.nCampos JM, Paniagua P. 2008. Hypothermia during cardiac surgery. Best Pract Res Clin Anaesthesiol 22:695-709.nDonato R. 1992. Functional roles of S100 proteins, calcium binding proteins of the EF-hand type. Biochim Biophys Acta 1450:191-231.nEhrenreich H, Hasselblatt M, Dembowski C, et al. 2002. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 8:495-505.nFerguson TB Jr, Hammill BG, Peterson ED, et al. 2002. A decade of change: risk profiles and outcomes for isolated coronary bypass grafting procedures, 1990-1999: a report from the STS National Database Committee and the Duke Clinical Research Institute. Ann Thorac Surg 73:480-9.nFletcher L, Kohli S, Sprague SM, et al. 2009. Intranasal delivery of erythropoietin plus insulin-like growth factor-I for acute neuroprotection in stroke. J Neurosurg 111:164-70.nGibbon JH Jr. 1968. Development of the artificial heart and lung extracorporeal blood circuit. JAMA 206:1983-6.nHerrmann M, Ebert AD, Galazky I, Wunderlich MT, Kunz WS, Huth C. 2000. Neurobehavioral outcome prediction after cardiac surgery: role of neurobiochemical markers of damage to neuronal and glial tissue. Stroke 31:645-50.nInouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. 1990. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med 113:941-8.nJönsson H, Johnsson P, Alling C, Bäckström M, Bergh C, Blomquist S. 1999. S100 after coronary artery surgery: release pattern, source of contamination and relation to neuropsychological outcome. Ann Thorac Surg 68:2202-8.nJunk KA, Mammis A, Savitz SI, et al. 2002. Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury. Proc Natl Acad Sci U S A 99:10659-64.nJuul S. 2002. Erythropoietin in the central nervous system, and its use to prevent hypoxic-ischemic brain damage. Acta Paediatr Suppl 91:36-42.nKidd PM. 2009. Integrated brain restoration after ischemic stroke: medical management, risk factors, nutrients, and other interventions for managing inflammation and enhancing brain plasticity. Altern Med Rev 14:14-35.nKilminster S, Treasure T, McMillan T, Holt DW. 1999. Neuropsychological change and S-100 protein release in 130 unselected patients undergoing cardiac surgery. Stroke 30:1869-74.nKnipp SC, Matatko N, Wilhelm H, et al. 2004. Evaluation of brain injury after coronary artery bypass grafting. A prospective study using neuropsychological assessment and diffusion-weighted magnetic resonance imaging. Eur J Cardiothorac Surg 25:791-800.nMoon C, Krawczyk M, Ahn D, et al. 2003. Erythropoietin reduces myocardial infarction and left ventricular functional decline after coronary artery ligation in rats. Proc Natl Acad Sci U S A 100:11612-7.nNagal A, Nakagawa E, Chol HB, Hatori K, Kobayashi S, Kim SU. 2001. Erythropoietin and erythropoietin receptors in human CNS neurons, astrocytes, microglia, and oligodendrocytes grown in culture. J Neuropathol Exp Neurol 60:386-92.nNewman MF, Kirchner JL, Philips-Bute B, et al. 2001. Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med 344:395-402.nNoguchi CT, Asavaritikrai P, Teng R, Jia Y. 2007. Role of erythropoietin in the brain. Crit Rev Oncol Hematol 64:159-71.nParsa JC, Matsumoto A, Kim J, et al. 2003. A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest 112:999-1007.nRath T, Mactier RA, Weinreich T, Scherhag AW, on behalf of the GAIN investigators. 2009. Effectiveness and safety of recombinant human erythropoietin beta in maintaining common haemoglobin targets in routine clinical practice in Europe: the GAIN study. Curr Med Res Opin 25:961-70.nRoach GW, Kanchuger M, Mora-Mangano C, et al, for the Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators. 1996. Adverse cerebral outcomes after coronary bypass surgery. N Engl J Med 335:1857-63.nSakanaka M, Wen TC, Masuda S, et al. 1998. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci U S A 95:4635-40.nSasaki R. 2003. Pleiotropic function of erythropoietin. Intern Med 42:142-9.nStolz E, Gerriets T, Kluge A, Klövekorn WP, Kaps M, Bachmann G. 2004. Diffusion-weighted magnetic resonance imaging and neurobiochemical markers after aortic valve replacement: implications for future neuroprotective trials? Stroke 35:888-92.nTerrovitis JV, Anastasiou-Nana M, Kaldara E, Drakos SG, Nanas SN, Nanas JN. 2009. Anemia in heart failure: pathophysiologic insights and treatment options. Future Cardiol 5:71-81.nTimmer SA, De Boer K, Knaapen P, Götte MJ, Van Rossum AC. 2009. The potential role of erythropoietin in chronic heart failure: from the correction of anemia to improved perfusion and reduced apoptosis? J Card Fail 15:353-61.nvan der Meer P, Lipscic E, Henning RH, et al. 2005. Erythropoietin induces neovascularization and improves cardiac function in rats with heart failure after myocardial infarction. J Am Coll Cardiol 46:125-33.nvan Diyk D, Keizer AM, Diephuis JC, Durand C, Vos LJ, Hijman R. 2000. Neurocognitive dysfunction after coronary artery bypass surgery: a systematic review. J Thorac Cardiovasc Surg 120:632-9.nWang L, Zhang Z, Wang Y, Zhang R, Chopp M. 2004. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 35:1732-7.nXiong Y, Chopp M, Lee CP. 2009. Erythropoietin improves brain mitochondrial function in rats after traumatic brain injury. Neurol Res 31:496-502.n
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