Anemia in cardiac surgery: next target for mortality and morbidity improvement?

Original Article Anemia in cardiac surgery: next target for mortality and morbidity improvement? Asian Cardiovascular & Thoracic Annals 2016, Vol. 24(1) 12 17 ß The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalspermissions.nav DOI: 10.1177/0218492315618032 aan.sagepub.com Hari Padmanabhan 1, Dincer Aktuerk 2, Matthew J Brookes 1,3, Alan M Nevill 3, Alex Ng 4, James Cotton 5 and Heyman Luckraz 2 Abstract Objective: To assess the effects of preoperative anemia on outcomes of cardiac surgery and to explore the trend in mortality over an 8-year period. Methods: During the study period (2005 2012), all 1170 patients undergoing elective or urgent cardiac surgery and classed as anemic were included. A matched group of non-anemic 1170 patients was used as a control group. Postoperative outcomes were compared between the 2 groups. The association between preoperative anemia and postoperative outcomes was analyzed using a logistic regression model. Results: Compared with patients without anemia, the need for airway support (15% vs. 12%, p ¼ 0.05), renal replacement therapy (13% vs. 8%, p < 0.01) and the rate of in-hospital surgical site infection (9% vs. 7%, p ¼ 0.05) were higher in the anemic group. Anemia was associated with greater need for renal replacement therapy (odds ratio ¼ 1.76, confidence interval: 1.21 2.37, p ¼ 0.002) and prolonged (> 7 days) hospital stay (odds ratio ¼ 1.21, confidence interval: 0.97 1.51, p ¼ 0.08). The blood transfusion rate (54% vs. 33%, p < 0.01) and hospital mortality (5.6% vs. 3.5%, p ¼ 0.02) were higher in the anemic group. Over the 8-year period, there was a significant improvement in mortality in the non-anemic group (from 6.5% to 1.6%) but less so in the anemic group (from 6.7% to 4.7%). Conclusion: Anemia impacts significantly on morbidity and mortality after cardiac surgery, with less improvement over time compared to patients without anemia. Preoperative correction of anemia, when feasible, could potentially help to improve cardiac surgery outcomes. Keywords Anemia, Cardiac surgical procedures, Blood transfusion, Hospital mortality, Length of stay Introduction Anemia has been reported to be associated with adverse postoperative outcomes, high cost to the healthcare system, and reduced survival after cardiac surgery. This association originated from observational studies. 1 7 Unfortunately, the available evidence has some limitations in relation to the criteria for anemia and the applicability to complex surgery. In some studies, only patients with severe anemia, with hemoglobin (Hb) < 10 g dl 1 or hematocrit < 30%, were selected, 2,8 whereas in others, patients with any degree of anemia were included. 1,3,5 The threshold for anemia in the latter studies was gender-specific and utilized the definition of the World Health Organization: Hb < 13 g dl 1 in men and <12 g dl 1 in women. 9 It is possible that patients with different degrees of anemia have concomitant variations in comorbidity and blood transfusion requirements, which would 1 Department of Gastroenterology, Heart & Lung Centre, Wolverhampton, UK 2 Department of Cardiothoracic Surgery, Heart & Lung Centre, Wolverhampton, UK 3 Research Institute of Healthcare Sciences, University of Wolverhampton, Wolverhampton, UK 4 Department of Cardiothoracic Anaesthesiology, Heart & Lung Centre, Wolverhampton, UK 5 Department of Cardiology, Heart & Lung Centre, Wolverhampton, UK Corresponding author: Hari Padmanabhan, Department of Gastroenterology, Royal Wolverhampton NHS Trust, Wolverhampton, WV10 0QP, United Kingdom. Email: Hari.Padmanabhan@nhs.net

Padmanabhan et al. 13 confound any association between anemia and postoperative outcome. 2,3 The majority of available data seems to originate from patients who underwent surgical procedures such as coronary artery bypass grafting (CABG) rather than combined complex procedures. 2,3,5,7 In terms of applicability, there is a relative paucity of data regarding complex surgery in which patients are likely to be anemic and require blood transfusion. Furthermore, it seems that some past studies assessing the association between anemia and postoperative outcome, may not have controlled for blood transfusion as a confounding factor. 2,3,8 Despite attempts to compare postoperative outcomes between anemic and non-anemic patients, some selection bias may exist. Moreover, there seems to be a lack of data showing longitudinal trends in mortality between anemic and non-anemic patients. This study assessed the immediate outcomes in patients undergoing any type of cardiac surgery and explored the annual mortality trends over an 8-year period in each exposure group. Patients and methods This was an observational, retrospective, matched casecontrol study of prospectively collected data retrieved from our cardiac surgery database (PATS/Dendrite). Patients undergoing elective and urgent cardiac surgery (isolated CABG, isolated valve surgery, combined valve and CABG as well as other complex cardiac surgery) were included. Patients who had emergency procedures were excluded from the analysis because the mortality and morbidity in this group tend to be related to the pathology giving rise to the emergency rather than anemia. This study was approved by the local research authority, and the need for informed consent from the patients was waived. Patients were classified as anemic based on the WHO criteria (preoperative Hb < 13 g dl 1 for males and <12 g dl 1 for females) and matched with a control non-anemic group using the 17 risk factors of the logistic EuroSCORE. These exposure variables include age, sex, chronic obstructive pulmonary disease, extracardiac arteriopathy, neurological dysfunction, previous cardiac surgery, serum creatinine, active endocarditis, critical preoperative state, unstable angina, left ventricular dysfunction, recent myocardial infarction, pulmonary hypertension, urgency of procedure, major cardiac procedure, surgery on the thoracic aorta, and postinfarction septal rupture. Next-neighbor selection (i.e., with the same/similar EuroSCORE) was used to select non-anemic patients for the control group. During the study period (2005 2012), 7150 patients underwent elective and urgent cardiac surgery. There were 1170 patients identified as anemic in the study group; the incidence of preoperative anemia was 16%. A non-anemic matched group of 1170 patients was created from the data-set, using propensity score matching as described above. The patients demographic data and preoperative characteristics are summarized in Table 1. Hospital mortality was defined as death occurring at any time after surgery during the same hospital admission as for the surgery. Prolonged hospital stay was defined as > 7 days after the operation, and immediate blood transfusion referred to the administration of autologous blood within 48 h of surgery. Complex procedures included combined procedures (CABG þ valve surgery, multiple valve surgery, or valve or CABG þ atrial fibrillation ablation) as well as surgery for type A aortic dissection or ischemic ventricular septal defect closure. Surgery > 24 h after admission was categorized as urgent, and surgery within 24 h was classed as an emergency procedure. Our transfusion trigger was set at a hemoglobin level <8gdL 1. We selected a number of outcome variables that were markers of problems related to anemia: hospital mortality; renal replacement therapy; additional airway support such as continuous positive airway pressure, reintubation, or tracheostomy; duration of stay in the cardiac intensive care unit (CICU); prolonged hospital stay; surgical site infection; atrial fibrillation; and costs accrued as a result of number of units of blood transfused and stay both in the CICU and the hospital. Continuous variables are expressed as mean standard deviation or median and interquartile range for Gaussian and skewed distributed data, respectively. Likewise, group comparison was carried out using Student s t test or the Mann-Whitney U test, accordingly. Data expressed as percentages (categorical variables) were analyzed using the chi-square test with the McNemar correction. A value of p 4 0.05 was considered to be significant in all statistical tests. The association between preoperative anemia and binary postoperative outcomes was analyzed using logistic regression. The following confounding factors were entered in a multivariable logistic model to assess the relationship between preoperative anemia and outcomes: age, sex, preoperative Hb, preoperative creatinine, diabetes status, logistic EuroSCORE, operative priority, cardiac surgical procedure, cardiopulmonary bypass time, infection (sternal site infection and chest infection), and immediate blood transfusion (<48 h). Statistical analyses were performed using SPSS version 15 software (SPSS, Inc., Chicago, IL, USA). Results Postoperative outcome data in patients with anemia and matched controls without anemia are shown in

14 Asian Cardiovascular & Thoracic Annals 24(1) Table 1. Preoperative characteristics of anemic and non-anemic patients undergoing cardiac surgery. Variable Anemic (n ¼ 1170) Non-anemic (n ¼ 1170) p value Age (years) 68.7 10.6 69.9 9.4 0.1 Male 868 (74%) 833 (71%) 0.1 Body mass index (kgm 2 ) 27.5 5.1 27.8 4.7 0.02 Caucasian 942 (81%) 1034 (88%) <0.01 Preoperative hemoglobin (gdl 1 ) 11.2 1.0 13.9 1.1 <0.01 Preoperative creatinine (mmoll 1 ) 118 83 98 38 <0.01 Logistic EuroSCORE [range] 6.2 [0.9 75.5] 6.2 [0.9 74.4] 0.99 Diabetes 748 (64%) 886 (76%) <0.01 Kidney disease 61 (5%) 20 (2%) <0.01 Peripheral vascular disease 271 (23%) 300 (26%) 0.2 Nonsmoker 433 (37%) 468 (40%) 0.3 Chronic obstructive pulmonary disease 196 (17%) 208 (18%) 0.5 Impaired left ventricle 481 (41%) 511 (44%) 0.3 Elective surgery 576 (49%) 621 (53%) 0.06 Procedure 0.03 Isolated coronary artery bypass 624 (53%) 665 (57%) Isolated valve surgery 229 (20%) 181 (16%) Complex/combined surgery 317 (27%) 324 (27%) Table 2. Intra- and postoperative data in anemic and non-anemic patients, including complications and survival. Outcome Anemic (n ¼ 1170) Non-anemic (n ¼ 1170) p value Mortality 65 (5.6%) 41 (3.5%) 0.02 Airway support 171 (15%) 142 (12%) 0.05 Peak postoperative creatinine (mmoll 1 ) 166 122 128 81 <0.01 Renal replacement 150 (13%) 94 (8%) <0.01 Prolonged hospital stay (>7 days) 548 (50%) 473 (42%) 0.08 Surgical site infection 105 (9%) 81 (7%) 0.05 Atrial fibrillation 384 (34%) 403 (35%) 0.6 Median blood transfusion units (48 h) [range] 1 [0 27] 0 [0 23] <0.01 Blood transfusion (overall) 672 (58%) 443 (38%) <0.01 Table 2. The anemic group had a higher percentage requiring renal replacement therapy (13% vs. 8%, p < 0.01), increased need for airway support (15% vs. 12%, p ¼ 0.05), and an increased rate of surgical site infection (9% vs. 7%, p ¼ 0.05) compared to the nonanemic group. Overall, the anemic group required an additional 1392 days in CICU (5419 vs. 4027 days, p < 0.01). Likewise, the additional hospital stay was 2275 days (13271 vs. 10996 days, p < 0.01). The proportion of patients needing immediate blood transfusion (within 48 hours) (54% vs. 33.2%, p < 0.01) and the number of units transfused in the anemia group (2314 vs. 1254, p < 0.01) were significantly higher than in the non-anemic group. After controlling for risk factors (age, sex, preoperative Hb, preoperative creatinine, diabetes status, logistic EuroSCORE, operative priority, cardiac surgical procedure, cardiopulmonary bypass time, infection, and immediate blood transfusion), multivariate regression demonstrated that preoperative anemia was independently associated with renal replacement therapy (odds ratio ¼ 1.76, confidence interval: 1.21 2.37, p ¼ 0.002) and prolonged (>7 days) hospital stay (odds ratio ¼ 1.21, confidence interval: 0.97 1.51, p ¼ 0.08). Hospital mortality was higher in anemic patients (5.6% vs. 3.5%, p ¼ 0.02) and over the study period, mortality in the nonanemic group dropped from 6.5% in the year 2005 6 to 1.6% in the year 2011 12 (p < 0.01), without a significant change in the logistic EuroSCORE between these two periods. In the anemic group, the

Padmanabhan et al. 15 Figure 1. Mortality in anemic and non-anemic patient groups in various eras (p < 0.01) Logistic EuroSCORE (mortality risk predictor) and actual mortality in the two groups over the last 8 years showed significant improvement in mortality in the non-anemic group (6.5% in 2005 06 to 1.6% in 2011 12) compared to the anemic group (6.7% in 2005 06 to 4.7% in 2011 12). improvement was much less over the same period, changing from 6.7% in the year 2005 6 to 4.7% in the year 2011 12 (Figure 1). Discussion This study demonstrates that patients with anemia had more adverse outcomes than matched non-anemic patients. The higher hospital mortality seen in the anemic group is consistent with previous reports. 1,3,4,8 Ranucci and colleagues 8 found that mortality was higher in patients with severe anemia compared to controls (12.7% vs. 7.5%, p ¼ 0.01). van Straten and colleagues 3 found that early (10.3% vs. 3.5%, p < 0.0001) and late mortality (43.8% vs. 18.1%, p < 0.001) was considerably higher in patients with preoperative anemia. Our study also demonstrates that the degree of improvement in mortality seen in the non-anemic group over the last 7 years was not replicated in anemic patients. There was a previous observational study in our unit, analyzing the effect of man-power and team-working on improvement in mortality over the last 10 years. 10 Given that both the anemic and non-anemic groups were managed by the same teams, the difference in degree of mortality improvement between the two groups was most likely due to the presence of anemia. Moreover, our data demonstrating an association between anemia and other outcome measures of resource utilization agree with studies in which there may have been some restriction in patient selection. In our study, multivariate regression showed that preoperative anemia was an independent predictor of acute kidney injury leading to renal replacement therapy (odds ratio ¼ 1.76, confidence interval: 1.21 2.37, p ¼ 0.002) and a prolonged (>7 days) in-hospital duration of stay (odds ratio ¼ 1.21, confidence interval: 0.97 1.51, p ¼ 0.08). De Santo and colleagues 6 found that preoperative anemia (based on the WHO definition) was independently associated with acute kidney injury and hospital stay > 7 days. In a study by Kulier and colleagues, 5 patients with a hematocrit < 36% had a longer intensive care unit stay compared to nonanemic patients. A significant association between anemia and prolonged intensive care unit stay was also reported by Hung and colleagues. 1 Our study also showed that patients with and without anemia differ in the need for airway support (15% vs. 12%, p ¼ 0.05). Anemic patients were found to have a higher incidence of infection, particularly surgical site infection (9% vs. 7%, p ¼ 0.05) compared to the nonanemic group. Likewise, in a recent study by Ranucci and colleagues, 8 the duration of mechanical ventilation was longer and the incidence of blood stream infection was higher in severely anemic patients (hematocrit < 30%). The cause of the deleterious effect of preoperative anemia on outcomes is multifactorial. First, anemic patients consume a substantially higher amount of blood products. Although blood transfusion is given in an effort to enhance oxygen delivery and improve outcomes, yet in susceptible patients, it may impair tissue oxygen delivery, leading to organ dysfunction. Blood transfusion can generate a systemic inflammatory response secondary to an altered host-immune response. 11 Depletion of 2,3-diphosphoglycerate levels and morphological changes in red cells due to depletion of adenosine triphosphate can severely limit oxygen delivery to the tissues. 11 14 Second, anemic patients have a much high prevalence of comorbidities such as diabetes and kidney disease, which can put them at higher risk. Third, there is evidence linking

16 Asian Cardiovascular & Thoracic Annals 24(1) preoperative anemia and hemodilution during cardiopulmonary bypass with adverse outcomes. This can lead to tissue hypoxia and an increased likelihood of postoperative renal injury. 15 17 Given this evidence of the detrimental effects of preoperative anemia, its correction before surgery is vital. Our current strategy of restoring normal Hb levels with allogeneic blood transfusion in the immediate perioperative period is not only associated with adverse outcomes but also an economic and resource burden on transfusion services. 18 21 The cost to the National Health Service for blood transfusion is 110 GBP for one unit of blood. However, the cumulative service cost for providing blood transfusion is considerably higher than this single unit. Patients with preoperative anemia had increased CICU and hospital stays of 1392 days and 2275 days, respectively, compared to the nonanemic group. The cost of one day in the CICU is 1200 GBP, and one day in the ward is 385 GBP. One can extrapolate that there is significant additional cost associated with managing an anemic patient compared to a non-anemic one. Without taking into account the cost of treating infections, renal replacement therapy, reexplorations, and additional airway support, the additional cost for treating the anemic group was at least 2.3 million GBP. Alternative strategies to treat anemia include erythropoietin supplementation and oral or intravenous iron before surgery. Two randomized trials of anemic patients undergoing cardiac surgery have demonstrated the efficacy of preoperative recombinant human erythropoietin administration to decrease blood transfusions. 22,23 A recent study has shown that administration of intravenous iron for preoperative anemia in patients with colorectal cancer was associated with an increase in Hb and a reduction in allogenic blood transfusions. Cladellas and colleagues 24 have shown that combined therapy with intravenous recombinant human erythropoietin and intravenous iron administered before cardiac valve replacement in anemic patients was associated with an improvement in postoperative outcomes and a decrease in blood transfusions. Although these treatment options appear attractive, further studies are required to evaluate their usage in the context of cardiac surgery. This study had some limitations. First, it was a retrospective study that relied on the completeness or accuracy of recorded information. Second, despite the utility of our findings and applicability to a broad patient group with even mild anemia, our data were observational and may still be prone to confounding factors. Owing to the limitations of our study design, it is possible that there was a selection bias and unknown confounding factors for which there were insufficient statistical adjustments. Random allocation of treatment would eliminate selection bias and confounding factors. To determine the benefit of preoperative treatment options (oral iron, intravenous iron, or erythropoietin) for correcting preoperative anemia, randomized controlled trials would be desirable. If intravenous iron therapy is proven to improve the preoperative Hb level, then the need for blood transfusion is likely to be reduced. Additional effects such as preoperative optimization will be in line with the government strategy to enhance recovery after surgery. Our results agree with previous studies, but we have integrated the gaps in the literature by using wider selection criteria to include mildly anemic patients, based on the WHO definition, including patients undergoing isolated CABG or complex valve surgery with or without CABG, and adjusting for a greater number of confounding factors including blood transfusion. Over all, anemic patients experience worse outcomes and potentially consume significantly more resources during their cardiac surgical stay. Although mortality has improved significantly over the last decade, the degree is less in anemic patients, and further improvements are likely to be possible by treating the underlying condition and implementing preoperative therapies. Presented at FACTS-Care 2013, 10th Annual CVT Critical Care Conference, Washington, USA, October 10 12, 2013. Declaration of conflicting interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The authors received no financial support for the research, authorship, and/or publication of this article. References 1. Hung M, Besser M, Sharples LD, Nair SK and Klein AA. The prevalence and association with transfusion, intensive care unit stay and mortality of pre-operative anaemia in a cohort of cardiac surgery patients. Anaesthesia 2011; 66: 812 818. 2. Zindrou D, Taylor KM and Bagger JP. Preoperative haemoglobin concentration and mortality rate after coronary artery bypass surgery. Lancet 2002; 359: 1747 1748. 3. van Straten AH, Hamad MA, van Zundert AJ, Martens EJ, Schonberger JP and de Wolf AM. Preoperative hemoglobin level as a predictor of survival after coronary artery bypass grafting: a comparison with the matched general population. Circulation 2009; 120: 118 125. 4. Karkouti K, Wijeysundera DN and Beattie WS Reducing Bleeding in Cardiac Surgery (RBC) Investigators. Risk associated with preoperative anemia in cardiac surgery: a multicenter cohort study. Circulation 2008; 117: 478 484.

Padmanabhan et al. 17 5. Kulier A, Levin J, Moser R, et al. Impact of preoperative anemia on outcome in patients undergoing coronary artery bypass graft surgery. Circulation 2007; 116: 471 479. 6. De Santo L, Romano G, Della Corte A, et al. Preoperative anemia in patients undergoing coronary artery bypass grafting predicts acute kidney injury. J Thorac Cardiovasc Surg 2009; 138: 965 970. 7. Boening A, Boedeker RH, Scheibelhut C, Rietzschel J, Roth P and Schonburg M. Anemia before coronary artery bypass surgery as additional risk factor increases the perioperative risk. Ann Thorac Surg 2011; 92: 805 810. 8. Ranucci M, Di Dedda U, Castelvecchio S, Menicanti L, Frigiola A and Pelissero G. Impact of preoperative anemia on outcome in adult cardiac surgery: a propensity-matched analysis. Ann Thorac Surg 2012; 94: 1134 1141. 9. Nutritional anaemia. Report of a WHO Scientific Group. World Health Organization Technical Report Series 1968; 405: 5 37. 10. Southey D, Mishra PK, Nevill A, Aktuerk D and Luckraz H. Continuity of care by cardiothoracic nurse practitioners: Impact on outcome. Asian Cardiovasc Thorac Ann 2014; 22: 944 947. 11. Tinmouth A, Fergusson D, Yee IC and Hebert PC. Clinical consequences of red cell storage in the critically ill. Transfusion 2006; 46: 2014 2027. 12. Valtis DJ. Defective gas-transport function of stored red blood-cells. Lancet 1954; 266: 119 124. 13. Valeri CR and Hirsch NM. Restoration in vivo of erythrocyte adenosine triphosphate, 2,3-diphosphoglycerate, potassium ion, and sodium ion concentrations following the transfusion of acid-citrate-dextrose-stored human red blood cells. J Lab Clin Med 1969; 73: 722 733. 14. Dern RJ, Brewer GJ and Wiorkowski JJ. Studies on the preservation of human blood. II. The relationship of erythrocyte adenosine triphosphate levels and other in vitro measures to red cell storageability. J Lab Clin Med 1967; 69: 968 978. 15. DeFoe GR, Ross CS, Olmstead EM, et al. Lowest hematocrit on bypass and adverse outcomes associated with coronary artery bypass grafting. Northern New England Cardiovascular Disease Study Group. Ann Thorac Surg 2001; 71: 769 776. 16. Swaminathan M, Phillips-Bute BG, Conlon PJ, Smith PK, Newman MF and 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: 784 791. 17. Karkouti K, Beattie WS, Wijeysundera DN, et al. 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. 18. Surgenor SD, Kramer RS, Olmstead EM, et al. The association of perioperative red blood cell transfusions and decreased long-term survival after cardiac surgery. Anesth Analg 2009; 108: 1741 1746. 19. Ranucci M, Baryshnikova E, Castelvecchio S and Pelissero G. Major bleeding, transfusions, and anemia: the deadly triad of cardiac surgery. Ann Thorac Surg 2013; 96: 478 485. 20. Koch CG, Li L, Duncan AI, et al. Morbidity and mortality risk associated with red blood cell and bloodcomponent transfusion in isolated coronary artery bypass grafting. Crit Care Med 2006; 34: 1608 1616. 21. van Straten AH, Bekker MW, Soliman Hamad MA, et al. Transfusion of red blood cells: the impact on short-term and long-term survival after coronary artery bypass grafting, a ten-year follow-up. Interact Cardiovasc Thorac Surg 2010; 10: 37 42. 22. Sowade O, Warnke H, Scigalla P, et al. Avoidance of allogeneic blood transfusions by treatment with epoetin beta (recombinant human erythropoietin) in patients undergoing open-heart surgery. Blood 1997; 89: 411 418. 23. Kiyama H, Ohshima N, Imazeki T and Yamada T. Autologous blood donation with recombinant human erythropoietin in anemic patients. Ann Thorac Surg 1999; 68: 1652 1656. 24. Cladellas M, Farre N, Comin-Colet J, et al. Effects of preoperative intravenous erythropoietin plus iron on outcome in anemic patients after cardiac valve replacement. Am J Cardiol 2012; 110: 1021 1026.