April 1, 2014
Volume 78, Number 4
What’s New In ... Perioperative Anemia: Is It Still an Innocent Bystander?
Colleen G. Koch, M.D., M.S., M.B.A.
Gregory M.T. Hare, M.D., Ph.D.
Aryeh Shander, M.D., FCCM, FCCP
In multiple clinical settings, anemia has been associated with increased risk for poor outcomes such as lower health-related quality of life, more frequent hospitalizations and higher mortality.1-3 The World Health Organization defines anemia as a hemoglobin value <12 g/dL in women and <13 g/dL in men.4 These definitions of anemia are clinically relevant, as data from the Network of Ontario Transfusion Coordinators (ONTraC) has demonstrated an increased rate of transfusion at preoperative hemoglobin values below 13 g/dL5, and other retrospective data demonstrate an increase in mortality near these thresholds.6,7 Treating anemia with red blood cell transfusions also has associated morbidity risk.8,9 Patients who are admitted to the hospital with normal hemoglobin values and subsequently developed hospital-acquired anemia have an increased risk for in-hospital mortality.10,11 Hence, anemia should not be considered an innocent bystander,12 but rather a negative exposure that contributes to increased risk for worse outcomes.
A Hazard of Hospitalization
The perioperative course is fraught with hazards that place patients at increased morbidity. Risk of developing anemia during hospitalization is high, with estimates that more than 70 percent of medical and surgical inpatients develop hospital-acquired anemia at some point during their stay.11 Multiple factors contribute to the development of anemia: perioperative hemodilution, procedural blood loss and excessive phlebotomy, often compounded by impaired erythropoiesis in chronically ill patients.3,13-15
A recent investigation involving more than 188,000 hospitalizations in a single health system reported 74 percent of patients developed hospital-acquired anemia: 40,828 were mild (11<hgb <12 g/dL in women and 11<hgb <13g/dL in men); 57,184 were moderate (9<hgb <11 g/dL) and 41,795 were severe (hgb <9 g/dL). While patients who developed anemia had more comorbidity, risk-adjusted in-hospital mortality was higher, length of stay longer and total charges associated with the hospitalization were higher in a “dose”-dependent manner. Mortality increased with decreasing levels of hemoglobin (moderate anemia = odds ratio [OR] 1.51, 95 percent confidence limits [CL], 1.33-1.71; severe anemia = OR 3.28, 95 percent CL, 2.90-3.72). If the expected length of stay is four days for a patient without hospital-acquired anemia, and if that patient develops severe anemia, the length of stay would be 7.52 days (1.88-fold higher). For overall charges, if the expected charges were $30,000 for patients without anemia, a patient with severe anemia would have an increase in charges to $54,000 (1.80-fold increase).11 A reduced frequency of diagnostic testing, use of smaller-volume test tubes, appropriate use of hemostatic therapeutics, and meticulous surgical hemostasis are processes-of-care factors that have the potential to alter the prevalence of hospital-acquired anemia.
Anemia in the Perioperative Setting
As with hospital-acquired anemia, preoperative anemia carries its own independent risks and associated increased costs. Anemia is an independent risk for negative outcomes. Allogeneic blood transfusion also has associated adverse effects and both should be avoided whenever possible.16 As suggested above, increased scrutiny of diagnostic tests and reduced volume of phlebotomy may help in curtailing the prevalence of hospital-acquired anemia. Routine incorporation of anemia screening strategies for diagnosis and treatment before a low hemoglobin threshold is reached could invariably result in avoidance of transfusions.
Anemia is by far the number-one reason for transfusion of red blood cells in the perioperative setting.17 Therefore, patients undergoing elective surgery with the potential for large blood volume loss (i.e., those with a Type and Cross) should be screened for anemia as early as possible. A large percentage of patients with anemia will have the opportunity to undergo diagnostic workup and proper treatment prior to surgery, thus reducing or eliminating their exposure to red blood cell transfusions.
Unlike most major medical conditions that might influence surgical outcome, anemia has been “left behind.” Evident today in medical culture, many still ignore mild to moderate anemia and feel that, if “needed,” a transfusion will correct the problem. With large population studies supporting the notion of significant risks of anemia and resultant transfusions,1 a rational, simple and stepwise approach is needed to address screening, diagnosis and treatment of perioperative anemia. As emphasized by “Patient Blood Management,”18,19 a multidisciplinary approach is critical to programmatic success.
Ideally, initial hemoglobin determination should occur as early as 28 days prior to surgery.20 This time interval allows patients and clinicians the opportunity for determining the etiology of anemia, care plan development, early initiation of appropriate treatment and possibly rescheduling the elective procedure if necessary.21 Although algorithms for perioperative anemia exist,20,22 it is important to note they should be thoughtfully incorporated into the culture of the local health care system. Resources for development of “anemia management clinics” are found in the Patient Blood Management Program Standards published by the Society for the Advancement of Blood Management and American Association of Blood Banks.23
How Low Can You Go?
Biomarkers and Hemoglobin Concentrations
Retrospective cohort studies have demonstrated that anemia is associated with adverse clinical events.16 However, no clear universal hemoglobin threshold for anemia-induced morbidity and mortality has been identified. Retrospective trials consistently demonstrate hemoglobin thresholds below which an increase in adverse clinical events are observed. For cardiac and non-cardiac surgery, preoperative hemoglobin values below 12 g/dL have been associated with increased perioperative mortality.6,7,24 In addition, a nadir hematocrit or hemoglobin concentration on cardiopulmonary bypass less than ~20 percent or 7 g/dL has been associated with renal failure, stroke and death.25-28 By contrast, prospective randomized trials favor an opposing outcome, demonstrating that restrictive transfusion strategies are as safe as more liberal therapies29-31 in the absence of an acute coronary syndrome.32 These prospective studies suggest that target hemoglobin thresholds near 8 g/dL and actual Hb levels near 9 g/dL do not increase the risk of major morbidity or mortality.
Identification of real-time, patient-specific biomarkers of tissue hypoxia may help clinicians to resolve this paradox and identify the hemoglobin threshold at which inadequate organ perfusion and tissue hypoxia occurs. Utilizing such biomarkers, we may be able to identify the optimal threshold hemoglobin concentration at which to treat acute anemia in surgical patients who experience surgical blood loss. Traditional systemic biomarkers of inadequate organ perfusion, including serum lactate and creatinine, are not adequate as they are not sensitive and respond slowly. Therefore novel, real-time biomarkers, which accurately detect anemia-induced tissue hypoxia, would be of great value to help guide optimal management of the acutely anemic patient.
Translational animal models of acute anemia have identified several tissue-specific biomarkers of anemia-induced hypoxia in the brain, kidney and liver.33-35 These include neuronal nitric oxide synthase (nNOS) and hypoxia-inducible factor (HIF). Animal studies have identified that tissue hypoxia and increased HIF expression increase earlier and at higher hemoglobin concentrations (7 to 9 g/dL) in the kidney and liver than in the heart or brain (5 g/dL).35-37
In the kidney, anemia-induced increases in HIF levels result in increased erythropoietin expression, while in the liver, increased HIF results in reduced hepcidin expression, (personal communication, Tsui AKY and Hare GMT). Preliminary data suggest that an early increase in serum erythropoietin, and reduced hepcidin, may reflect renal and hepatic hypoxia in acutely anemic patients at a hemoglobin threshold near 9 to 10 g/L. In addition, the increase in nNOS-derived nitric oxide may lead to rapid oxidation of hemoglobin to methemoglobin in animal models and human subjects.38,39 Thus, anemia-induced tissue hypoxia may result in extremely rapid increases in methemoglobin levels, which may help direct treatment. The hemoglobin threshold for these events appears to be near 9 g/dL in humans.39
Prospective clinical trials are required to determine whether these novel biomarkers of anemia-induced tissue hypoxia are associated with adverse clinical outcomes and whether they can be used to detect tissue hypoxia and guide treatment. One primary goal of this research would be to determine if these biomarkers can be utilized to identify the appropriate hemoglobin threshold for transfusion of red blood cells to augment tissue oxygen delivery and reduce adverse clinical events.
Anemia should no longer be considered an innocent bystander in the perioperative care of our patients. Whether the patient presents with anemia on admission or develops it during the course of hospitalization, it portends a negative outcome. Recent advances in basic science have provided us with a potential future means of biomarker identification of patient-specific thresholds for tolerance of anemia.
Colleen G. Koch, M.D., M.S., M.B.A. is Professor of Anesthesiology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Department of Cardiothoracic Anesthesia, and Quality and Patient Safety Institute, Cleveland Clinic, Cleveland, Ohio.
Gregory M.T. Hare, M.D., Ph.D. is Associate Professor, Departments of Anesthesia and Physiology, Associate Member, Institute of Medical Science, University of Toronto and Scientist, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto.
Aryeh Shander, M.D., FCCM, FCCP is Chief, Department of Anesthesiology, Critical Care and Hyperbaric Medicine, Englewood Hospital and Medical Center, and Clinical Professor of Anesthesiology, Medicine and Surgery, Icahn School of Medicine at Mount Sinai, New York, New York.
1. Zakai NA, Katz R, Hirsch C, et al. A prospective study of anemia status, hemoglobin concentration, and mortality in an elderly cohort: the Cardiovascular Health Study. Arch Intern Med. 2005;165:2214-20.
2. Lucca U, Tettamanti M, Mosconi P, et al. Association of mild anemia with cognitive, functional, mood and quality of life outcomes in the elderly: the “Health and Anemia” study. PLoS One. 2008;3(4):e1920.
3. Shander A. Anemia in the critically ill. Crit Care Clin. 2004;20(2):159-178.
4. World Health Organization. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. WHO Vitamin and Mineral Nutrition Information System website. http://www.who.int/vmnis/indicators/haemoglobin.pdf. Published 2011. Accessed February 10, 2014.
5. Hare GM, Freedman J, Mazer CD. Review article: risks of anemia and related management strategies: can perioperative blood management improve patient safety? Can J Anaesth. 2013;60(2):168-175.
6. Karkouti K, Wijeysundera DN, Beattie WS; Reducing Bleeding in Cardiac Surgery (RBC) Investigators. Risk associated with preoperative anemia in cardiac surgery: a multicenter cohort study. Circulation. 2008;117(4):478-484.
7. Kulier A, Levin J, Moser R, et al.; Investigators of the Multicenter Study of Perioperative Ischemia Research Group; Ischemia Research and Education Foundation. Impact of preoperative anemia on outcome in patients undergoing coronary artery bypass graft surgery. Circulation. 2007;116(5):471-479.
8. Koch CG, Li L, Duncan AI, et al. Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting. Crit Care Med. 2006;34(6):1608-1616.
9. Koch CG, Li L, Duncan AI, et al. Transfusion in coronary artery bypass grafting is associated with reduced long-term survival. Ann Thorac Surg. 2006;81(5):1650-1657.
10. Salisbury AC, Amin AP, Reid KJ, et al. Hospital-acquired anemia and in-hospital mortality in patients with acute myocardial infarction. Am Heart J. 2011;162(2):300-309 e3.
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