http://dx.doi.org/10.1016/S2256-2087(12)40008-6

Review

Henry Oliveros^a*, Édgar Beltrán Linares^b*

^a Associate Professor, Universidad de la Sabana, Specialist in Critical Care, Hospital Militar Central, Bogotá, Colombia
^b Cardiovascular anesthesiologist, Hospital Militar Central, Bogotá, Colombia

Corresponding author at: Trasv 4E No 61-05 Apto. 402 T1, Bogotá, Colombia. Email: henryor@unisabana.edu.co (H. Oliveros); EABELTRAN20010@gmail.com (E. Beltran).

ARTICLE INFO

Article history: Received: March 20, 2011 Accepted: November 17, 2011

Objective: To determine whether preoperative anemia in patients undergoing cardiovascular surgery is associated with higher mortality, renal failure, cerebrovascular accidents and cardiovascular events as compared to patients with normal preoperative levels of hemoglobin.

Methods: A systematic review and a meta-analysis of the cohort observational and of cases and control studies was conducted, exploring the association between the pre-surgical levels of hemoglobin and adverse outcomes in patients undergoing cardiovascular surgery. The MEDLINE, EMBASE, and COCHRANE data-bases up to the 50th week of 2010 were consulted. The studies that complied with the inclusion criteria were independently selected. The sources of heterogeneity among the studies were assessed, including publication bias. Results: Of the total number of studies reviewed, 260 were identified; sufficient data could be extracted from 11 of them to combine the mortality outcome. Out of these studies, 6 were adjusted for severity and comorbidities, while the results of the remaining ones were not adjusted.

Conclusions: Anemic patients undergoing cardiac surgery have a higher risk of postoperative adverse events. There are several factors limiting the interpretation of the data, including a poor standardized definition of anemia, and the lack of studies explicitly designed to quantify the prevalence and the impact of anemia in patients with cardiovascular diseases.

© 2012 Sociedad Colombiana de Anestesiología y Reanimación. Published by Elsevier.

All rights reserved.

Objetivo: Determinar si la anemia preoperatoria en los pacientes que son llevados a cirugía cardiovascular se asocia al aumento de la mortalidad, falla renal, accidentes cerebovasculares y eventos cardiovasculares cuando se comparan sus casos con los de pacientes con niveles de hemoglobina normales en el preoperatorio. Métodos: Se realizó una revisión sistemática y un metaanálisis de los estudios observacionales de cohorte y de casos y controles que exploraron la asociación entre los niveles de hemoglobina prequirúrgica y los desenlaces adversos de los pacientes sometidos a cirugía cardiovascular. Se consultaron las bases de datos MEDLINE, EMBASE, y COCHRANE hasta la semana 50 de 2010; de manera independiente, fueron seleccionados los estudios que cumplieron con los criterios de inclusión. Se evaluaron las fuentes de heterogeneidad entre los estudios, como el sesgo de publicación.

Resultados: De los estudios revisados se identificaron 260; entre dichos estudios, de 11 se pudieron extraer los datos suficientes para combinar el desenlace de mortalidad. De esos estudios, 6 se ajustaron por severidad y comorbilidades, mientras que en los restantes sus resultados no fueron ajustados; aun así se observó un incremento en el riesgo de mortalidad cuando se considera la anemia como variable independiente.

Conclusiones: Los pacientes anémicos sometidos a cirugía cardiaca tienen un mayor riesgo de sufrir eventos adversos postoperatorios. Varios factores más también limitan la interpretación de los datos, incluyendo la falta de una definición uniforme de la anemia y la carencia de estudios expresamente diseñados para cuantificar la prevalencia y el impacto de la anemia en pacientes con enfermedades cardiovasculares.

© 2012 Sociedad Colombiana de Anestesiología y Reanimación. Publicado por Elsevier.

Todos los derechos resevados.

The World Health Organization (WHO) defines anemia as a Hb<13 g/dl for men and Hb<12 g/dL for women. Some observational studies have established the association between preoperative anemia and increased post-surgical complications in patients undergoing non-cardiac surgery. Such increased risk is attributed to the confounding effect of transfusions and the interactions between the comorbidities and low Hb levels.

One of the first studies to report such association was Carson's et al., in 1958, which was conducted on Jehovah's Witnesses patients undergoing non-cardiac surgery.^1,2 The study determined that the low preoperative hemoglobin levels and the intraoperative blood loss, increased the risk of morbidity and mortality; the risk was much higher when the patients had cardiovascular disease.

Hardy et al.³ studied the association between the levels of hemoglobin 24 hours after surgery and morbidity in 2,664 heart surgery patients. These authors found that lower hemoglobin concentrations were associated with higher hemodynamic instability and renal failure, while Nelson et al.⁴ found that a postoperative hematocrit less than 28 was associated with significant myocardial ischemia and a higher number of cardiac events.

Other studies were unable to find increased cardiac or non-cardiac related events associated with preoperative anemia in cardiovascular surgical patients,⁵ whilst treatment of anemia with red blood cells transfusion was associated with a 21% increased risk of adverse events per each unit of transfused red blood cells.⁴

The objective of this paper was to review the available evidence with respect to the association between anemia and adverse outcomes in patients undergoing cardiac revascularization surgery or valve replacement, as compared to normal hemoglobin patients.

A systematic literature review was performed by consulting the digital data bases: MEDLINE, EMBASE, COCHRANE up until week 50 of the year 2010 and using the following search strategy:

(((((((((((revascularization)) OR ((cardiac surgery))) OR ((CPB))) OR ((cardiopulmonary bypass))) OR ((Bypass Graft Surgery))) OR ((ischemic heart disease)))) AND (((((Hb) OR ((Hemoglobin))) OR ((Hb concentration))) OR ((Hb))))) AND (((((((Death)) OR ((Mortality))) OR ((kidney failure))) OR ((outcomes))) OR ((Cardiovascular Outcome)))) AND ((Humans[Mesh]) AND (adult[MeSH])))) AND ((((Hemoglobin levels AND ((Humans[Mesh]) AND (adult[MeSH])))) OR ((Hemoglobin levels normal AND ((Humans[Mesh]) AND (adult[MeSH])))) AND ((Humans[Mesh]) AND (adult[MeSH])))) AND ((Humans[Mesh]) AND (adult[MeSH]))

As seen from the flowchart (fig. 1), 260 studies were initially identified; 2 reviewers, HO and EB, independently verified all the abstracts, taking into account the following selection criteria: that the trials were case and control or cohort studies; that they included cardiac revascularization surgery or valve replacement and additionally, that suboptimal Hb levels were compared against normal Hb levels for outcomes of renal failure and ICU stay; the relevant studies were chosen to obtain the information.

Data on the type of population, the categories of comparative hemoglobin levels, the types of outcomes reported, and the levels of hemoglobin deemed normal, were all extracted from every trial. HO and EB completed these processes independently. Any disagreements were solved by consensus.

The analysis of the results of the individual studies was done using the statistical packages, CMA (Biostat, 14 North Dean Street, Englewood, NJ 0763) and STATA 9.0. In order to obtain the summarized measures, the Odds ratios for occurrence of cardiac events and mortality were used when comparing patients with low Hb levels against normal Hb levels. These measures were combined using the fixed and random effects model for binary outcomes.

According to the plan, the subgroup analyses were done within various population categories, such as the different levels of hemoglobin considered for the measurements of the trials reporting mortality. The same approach was used for the studies that reported outcomes of adverse events.

The heterogeneity was assessed using Forest plots and Q and 12 tests, for each of the sub-groups analysis, in order to determine the sources of heterogeneity; likewise, a sensitivity analysis was done of the summary measurement for those trials where the results were adjusted for severity and comorbidity; this analysis was compared against the results of the non-adjusted trials.^1,6-15

As shown in the lowchart (ig. 1), 11 trials met the inclusion criteria; two of them included cardiac revascularization patients; two others did not discriminate the type of cardiac surgery and another included valve replacement patients.⁸

The studies also differed in terms of the variables considered for the adjustment, as well as the cut-off points for hemoglobin to compare anemic versus non-anemic patients (table 1). The study by Kulier's et al¹⁶ makes an adjustment based on the Euroscore <4 and >4, and the number of transfused units; hence, there is an association with cardiac and non-cardiac adverse events and a Hb level below 11 g/dl.

Zindrou⁷ determined patient mortality with Hb<10 g/dl and compared it against patients with Hb>10 g. Also, Cladellas⁸ studied 201 patients undergoing valve replacement with a view to determinining the Hb value that best predicts mortality; he identified a Hb cut-off point of 12 g/dl; thus, Hb<12 g/dl was an independent risk factor for mortality in this group of patients.

Karkouti¹⁰ used a cut-off point of Hb less than 12.5 g/dl; patients with this value were considered anemic and were compared against the non-anemic patients in terms of CVA hospital mortality or acute renal failure, when adjusted for confounding variables such as comorbidity, surgical factors, institution or transfusion.

Finally, Melanie L. Bell¹³ used different Hb categories in the population studied; she found no differences in mortality, but there were differences in morbidity with Hb>10 adjusted for comorbidity.

The above information shows that each trial used different cut-off points to define anemia. Furthermore, each trial included different variables for statistical adjustment; moreover, none of them established the time frame for the occurrence of preoperative anemia, and this could be the result of an acute or a chronic condition.

This can also be explained in terms of the heterogeneity of the results, which differ widely among the various trials, as shown in figure. 2 and table 2, using the Forest plot,⁸ the summary measurements for the various trials that reported mortality independently, adjusted and non-adjusted results for severity and comorbidity, in addition to the estimated values obtained with the fixed and random effect models.

Finally, the publication bias was explored with a graphic representation of the scatter of the trials, taking into account the distance with regards to the summary measurement in accordance with its accuracy, as shown in figure 3.

Several trials with cardiovascular patients support the finding that preoperative anemia is associated with an increased number of adverse events; however, such results may be confounded by the pump effect and the comorbidities present in these patients.^1,4,7,17-20

The results of the combined studies are also derived from studies that evaluated the preoperative hemoglobin and adjusted based on the various comorbidities. The specific risk estimate is conclusive, in that the low levels of preoperative hemoglobin represent a risk factor for mortality and morbidity in patients undergoing cardiovascular surgery.

The benefit of correcting preoperative anemia has been shown in cancer patients and in orthopedic surgery; the rate of postoperative complications has been lowered with erythropoietin treatment.²¹ However, the Hb level to determine the need for transfusion has not been clearly established; as has been thoroughly documented, transfusion increases the risk of developing adverse events.²² The overall recommendation is to transfuse whenever the Hb level is below 7-8 g/dl.

Moreover, in a study with 179 surgical cardiovascular patients, Karkouti¹⁰ found no differences in terms of the risk of adverse outcomes with these levels of preoperative Hb; however, there were differences when the Hb level dropped 50% from its baseline level.²³

The risk of mortality in anemic patients decreases when adjusted for confounding variables such as age, peripheral vascular disease, renal failure and a history of myocardial infarction or chronic obstructive pulmonary disease (COPD).¹³ Even though it is not easy to control the bias associated with the indication in the studies that report an association between anemia and adverse events in patients who need to be transfused, it is important to highlight the number of studies in which transfusion is associated with adverse events, such as: pneumonia, mediastinitis, renal dysfunction, mortality and decreased survival.

No disclosures

Financing Source: the author's own resources

1. Carson JL, Duff A, Poses RM, et al. Effect of anaemia and cardiovascular disease on surgical mortality and morbidity. Lancet. 1996;348:1055-60.

2. Groenveld HF, Januzzi JL, Damman K, et al. Anemia and mortality in heart failure patients a systematic review and meta-analysis. J Am Coll Cardiol. 2008;52:818-27.

3. Hardy JF, Martineau R, Couturier A, et al. Influence of haemoglobin concentration after extracorporeal circulation on mortality and morbidity in patients undergoing cardiac surgery. Br J Anaesth. 1998;81 Suppl 1:S38-45.

4. Nelson AH, Fleisher LA, Rosenbaum SH. Relationship between postoperative anemia and cardiac morbidity in high-risk vascular patients in the intensive care unit. Crit Care Med. 1993;21:860-6.

5. McKechnie RS, Smith D, Montoye C, et al. Prognostic implication of anemia on in-hospital outcomes after percutaneous coronary intervention. Circulation. 2004;110:271-7.

6. Magovern JA, Sakert T, Magovern GJ, et al. A model that predicts morbidity and mortality after coronary artery bypass graft surgery. J Am Coll Cardiol. 1996;28:1147-53.

7. Zindrou D, Taylor KM, Bagger JP. Preoperative haemoglobin concentration and mortality rate after coronary artery bypass surgery. Lancet. 2002;359:1747-8.

8. Cladellas M, Bruguera J, Comin J, et al. Is pre-operative anaemia a risk marker for in-hospital mortality and morbidity after valve replacement? Eur Heart J. 2006;27:1093-9.

9. Kulier A. Anemia and morbidity and mortality in coronary bypass surgery. Curr Opin Anaesthesiol. 2007;20:57-64.

10. Karkouti K, Wijeysundera DN, Beattie WS. Risk associated with preoperative anemia in cardiac surgery: a multicenter cohort study. Circulation. 2008;117:478-84.

11. van Straten AH, Hamad MA, van Zundert AJ, et al. Preoperative hemoglobin level as a predictor of survival after coronary artery bypass grafting: a comparison with the matched general population. Circulation. 2009;120:118-25.

12. Carrascal Y, Maroto L, Rey J, et al. Impact of preoperative anemia on cardiac surgery in octogenarians. Interact Cardiovasc Thorac Surg. 2010;10:249-55.

13. Bell ML, Grunwald GK, Baltz JH, et al. Does preoperative hemoglobin independently predict short-term outcomes after coronary artery bypass graft surgery? Ann Thorac Surg. 2008;86:1415-23.

14. 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;138:965-70.

15. Riera M, Ibáñez J, Molina M, et al. Anemia preoperatoria en la cirugía coronaria: ¿un factor de riesgo? Med Intensiva. 2009;33:370-6.

16. Kulier A, Levin J, Moser R, et al. Impact of preoperative anemia on outcome in patients undergoing coronary artery bypass graft surgery. Circulation. 2007;116:471-9.

17. Fang WC, Helm RE, Krieger KH, et al. Impact of minimum hematocrit during cardiopulmonary bypass on mortality in patients undergoing coronary artery surgery. Circulation. 1997;96 SupplII:194-9.

18. Ferraris VA, Ferraris SP. Risk factors for postoperative morbidity. J Thorac Cardiovasc Surg. 1996;111:731-8.

19. Rady MY, Ryan T, Starr NJ. Perioperative determinants of morbidity and mortality in elderly patients undergoing cardiac surgery. Crit Care Med. 1998;26:225-35.

20. Habib RH, Zacharias A, Schwann TA, et al. Adverse effects of low hematocrit during cardiopulmonary bypass in the adult: should current practice be changed? J Thorac Cardiovasc Surg.2003;125:1438-50.

21. Drueke TBE, Eckardt KU, Frei U, et al. Does early anemia correction prevent complications of chronic renal failure? Clin Nephrol. 1999;51:1-11.

22. Hebert PC, Yetisir E, Martin C, et al. Is a low transfusion threshold safe in critically ill patients with cardiovascular diseases?Crit Care Med. 2001;29:227-34.

23. Karkouti K, Wijeysundera DN, Yau TM, et al. The influence of baseline hemoglobin concentration on tolerance of anemia in cardiac surgery. Transfusion. 2008;48:666-72.

24. Bracey AW, Radovancevic R, Riggs SA, et al. Lowering the hemoglobin threshold for transfusion in coronary artery bypass procedures: effect on patient outcome. Transfusion. 1999;39: 1070-7.

25. Mohnle P, Snyder-Ramos SA, Miao Y, et al. Postoperative red blood cell transfusion and morbid outcome in uncomplicated cardiac surgery patients. Intensive Care Med 2011;37:97-109.

26. Dardashti A, Ederoth P, Algotsson L, Bronden B, Luhrs C, Bjursten H. Blood transfusion after cardiac surgery: is it the patient or the transfusion that carries the risk? Acta Anaesthesiol Scand. 2011;55:952-61.

27. Scott BH, Seifert FC, Grimson R. Blood transfusion is associated with increased resource utilisation, morbidity and mortality in cardiac surgery. Ann Card Anaesth. 2008;11:15-9.

28. Paone G, Brewer R, Theurer PF, Bell GF, Cogan CM, Prager RL. Preoperative predicted risk does not fully explain the association between red blood cell transfusion and mortality in coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2012;143:178-85.

29. Dorneles CC, Bodanese LC, Guaragna JC, et al. The impact of blood transfusion on morbidity and mortality after cardiac surgery. Rev Bras Cir Cardiovasc. 2011;26:222-9.

30. van Straten AH, Kats S, Bekker MW, et al. Risk factors for red blood cell transfusion after coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth. 2010;24:413-7.

31. van Straten AH, Bekker MW, Soliman Hamad MA, et al. Transfusion of red blood cells: the impact on short-term and longterm survival after coronary artery bypass grafting, a ten-year follow-up. Interact Cardiovasc Thorac Surg. 2010;10:37-42.

32. Roth JV. Blood transfusion and survival in cardiac surgery. Anesthesiology. 2010;112:761-2.

33. Gross I, Shander A, Waters JH. The evidence shows that allogeneic transfusion is associated with reduced survival after coronary artery bypass surgery. Anesthesiology. 2010;112:760-1.

34. Koch C, Li L, Figueroa P, Mihaljevic T, Svensson L, Blackstone EH. Transfusion and pulmonary morbidity after cardiac surgery. Ann Thorac Surg. 2009;88:1410-8.

35. Rogers MA, Blumberg N, Saint SK, Kim C, Nallamothu BK, Langa KM. Allogeneic blood transfusions explain increased mortality in women after coronary artery bypass graft surgery. Am Heart J. 2006;152:1028-34.

36. 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;108:1741-6.

37. Whitson BA, Huddleston SJ, Savik K, Shumway SJ. Risk of adverse outcomes associated with blood transfusion after cardiac surgery depends on the amount of transfusion. J Surg Res.2010;158:20-7.

38. Gardner TJ. To transfuse or not to transfuse. Circulation. 2007;116:458-60.

39. Yap CH, Lau L, Krishnaswamy M, Gaskell M, Yii M. Age of trans-fused red cells and early outcomes after cardiac surgery. Ann Thorac Surg. 2008;86:554-9.

40. Engoren M, Habib RH, Hadaway J, et al. The effect on long-term survival of erythrocyte transfusion given for cardiac valve operations. Ann Thorac Surg. 2009;88:95-100.