To the Editor: 

We read with interest Glance et al. 's paper and the related editorial.1,2Several retrospective studies have already reported an association between perioperative blood transfusion and altered outcome.3,,8What is new in the Glance et al.  study is that a similar negative association may exist in preoperative anemic patients having received only one or two units of packed erythrocytes (PRBCs) during the surgical procedure. However, we believe the results of this study should be interpreted with caution for several reasons.

First, as Carson et al.  9wrote, observational studies are subject to uncontrolled confounding. In fact, patients who receive blood transfusions are probably more severely ill than those who do not receive them, and patients who are more severely ill have more adverse clinical outcomes (death, infection, etc .) than less ill patients. Thus, no matter how refined the adjustment is for differences in illness burden, it is never possible to ensure a complete adjustment for differences between patients receiving and not receiving blood transfusion.

Second, the transfusion trigger that was used in the study population was not specified. Was it a hemoglobin-based transfusion trigger or based on objective indices of oxygen delivery deficiency?10,,12PRBC transfusions are administered to increase oxygen transport and restore tissue oxygenation when oxygen demand exceeds supply.13The oxygen extraction ratio reflects the adequacy of the cardiorespiratory response of the patient to anemia. Some authors have explored the utility of oxygen extraction ratio for guiding erythrocyte transfusion.14,15Erythrocyte transfusions can also be based on signs and symptoms of impaired global oxygenation with the use of lactate or mixed venous oxygen saturation. The mixed venous oxygen saturation or its surrogate, the central venous oxygen saturation, integrates the relationship between whole-body oxygen uptake and oxygen transport and has been proposed by Vallet et al.  as a simple physiologic transfusion trigger.16 

Third, the indication for transfusion was not specified in the study. The reason why some anemic patients were transfused with one or two units while other “similar” anemic patients were not was not explained. Reasons could include several factors such as the importance of blood loss, the hemodynamic stability of the patients, and their underlying pathologies that could by themselves influence the postoperative outcome. To minimize the confounding effect of surgical blood loss on patient outcome, the authors have excluded patients who received four or more PRBC units; however, this effort does not completely eliminate the effect of blood loss on the indication for transfusion. They also attempted to take into account the underlying pathologies of their patients but could not evaluate the effect of these pathologies on the transfusion trigger used by the clinician taking care of the patient.

Fourth, another important point that has not been specified is the etiology of anemia in the patient population. Different etiologies may differentially affect the postoperative outcome. Indeed, Kulier et al.  showed that anemic patients have an increased risk of postoperative adverse events, but the extent of preexisting comorbidities substantially affects perioperative anemia tolerance. They recommended that the assessment of blood transfusions should take into account not only the preoperative hemoglobin concentration but also the extent of concomitant risk factors.17 

Finally, the quality of the blood products that were transfused was not described. Were the PRBC units that were transfused leukoreduced? What about the age of the blood transfused? These factors could have affected the known negative association between the transfusion of one or two PRBC units and postoperative morbidity and mortality.

In conclusion, any inappropriate PRBC transfusion should be avoided because the benefit-to-risk ratio of this treatment does not appear favorable for the patient. However, undertransfusion may also be unacceptable because it may expose patients to an increased risk of complications.18Distinguishing the effects of PRBC transfusion on patient postoperative outcome definitely requires well-conducted, prospective randomized studies that account for the multiple confounders associated with transfusion practice.

Glance LG, Dick AW, Mukamel DB, Fleming FJ, Zollo RA, Wissler R, Salloum R, Meredith UW, Osler TM: Association between intraoperative blood transfusion and mortality and morbidity in patients undergoing noncardiac surgery. ANESTHESIOLOGY 2011; 114:283–92
Spahn DR, Shander A, Hofmann A, Berman MF: More on transfusion and adverse outcome: It's time to change. ANESTHESIOLOGY 2011; 114:234–6
Koch CG, Li L, Duncan AI, Mihaljevic T, Cosgrove DM, Loop FD, Starr NJ, Blackstone EH: Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting. Crit Care Med 2006; 34:1608–16
Corwin HL, Gettinger A, Pearl RG, Fink MP, Levy MM, Abraham E, MacIntyre NR, Shabot MM, Duh MS, Shapiro MJ: The CRIT Study: Anemia and blood transfusion in the critically ill–current clinical practice in the United States. Crit Care Med 2004; 32:39–52
Sakr Y, Lobo S, Knuepfer S, Esser E, Bauer M, Settmacher U, Barz D, Reinhart K: Anemia and blood transfusion in a surgical intensive care unit. Crit Care 2010; 14:R92
Kipps AK, Wypij D, Thiagarajan RR, Bacha EA, Newburger JW: Blood transfusion is associated with prolonged duration of mechanical ventilation in infants undergoing reparative cardiac surgery. Pediatr Crit Care Med 2011; 12:52–6
Church GD, Matthay MA, Liu K, Milet M, Flori HR: Blood product transfusions and clinical outcomes in pediatric patients with acute lung injury. Pediatr Crit Care Med 2009; 10:297–302
Székely A, Cserép Z, Sápi E, Breuer T, Nagy CA, Vargha P, Hartyánszky I, Szatmári A, Treszl A: Risks and predictors of blood transfusion in pediatric patients undergoing open heart operations. Ann Thorac Surg 2009; 87:187–97
Carson JL, Terrin ML, Magaziner J, Chaitman BR, Apple FS, Heck DA, Sanders D, FOCUS Investigators: Transfusion trigger trial for functional outcomes in cardiovascular patients undergoing surgical hip fracture repair (FOCUS). Transfusion 2006; 46:2192–206
Hébert 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: Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999; 340:409–17
Hajjar LA, Vincent JL, Galas FR, Nakamura RE, Silva CM, Santos MH, Fukushima J, Kalil Filho R, Sierra DB, Lopes NH, Mauad T, Roquim AC, Sundin MR, Leo WC, Almeida JP, Pomerantzeff PM, Dallan LO, Jatene FB, Stolf NA, Auler JO Jr: Transfusion requirements after cardiac surgery: The TRACS randomized controlled trial. JAMA 2010; 304:1559–67
Cholette JM, Rubenstein JS, Alfieris GM, Powers KS, Eaton M, Lerner NB: Children with single-ventricle physiology do not benefit from higher hemoglobin levels post cavopulmonary connection: Results of a prospective, randomized, controlled trial of a restrictive versus  liberal red-cell transfusion strategy. Pediatr Crit Care Med 2011; 12:39–45
Wang JK, Klein HG: Red blood cell transfusion in the treatment and management of anaemia: The search for the elusive transfusion trigger. Vox Sang 2010; 98:2–11
Orlov D, O'Farrell R, McCluskey SA, Carroll J, Poonawala H, Hozhabri S, Karkouti K: The clinical utility of an index of global oxygenation for guiding red blood cell transfusion in cardiac surgery. Transfusion 2009; 49:682–8
Sehgal LR, Zebala LP, Takagi I, Curran RD, Votapka TV, Caprini JA: Evaluation of oxygen extraction ratio as a physiologic transfusion trigger in coronary artery bypass graft surgery patients. Transfusion 2001; 41:591–5
Vallet B, Adamczyk S, Barreau O, Lebuffe G: Physiologic transfusion triggers. Best Pract Res Clin Anaesthesiol 2007; 21:173–81
Kulier A, Levin J, Moser R, Rumpold-Seitlinger G, Tudor IC, Snyder-Ramos SA, Moehnle P, Mangano DT, 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; 116:471–9
Lienhart A, Auroy Y, Péquignot F, Benhamou D, Warszawski J, Bovet M, Jougla E: Survey of anesthesia-related mortality in France. ANESTHESIOLOGY 2006; 105:1087–97