The rise, fall and future of red blood cell transfusions

Blood transfusion is one of the most frequently employed therapies for hospitalized patients. Transfusion has a long history as the only available lifesaving therapy for patients with exsanguinating hemorrhage and potentially fatal anemia. Over the last decade, however, clinicians have begun to use red cell transfusions much more cautiously. The most publicized reason for this are concerns about viral contamination and cost, but there are two other reasons for this disruptive change in medical practice that have not seen much discussion: red cell transfusions are not nearly as effective as previously  believed, and most importantly, red cell transfusions cause many more serious side effects than had been understood.

Stored red cells do not yield rapid increases in tissue  oxygen consumption nearly as well as has been assumed. This may be due to their decreased levels of biphosphoglycerate (2,3 BPG) and abnormal physical properties, such as an  inability to change shape as they traverse capillaries.¹ In  addition, red cell transfusions cause increases in severe side effects such as healthcare-acquired (nosocomial) infections (HAIs), thrombosis, and mortality.²

Transfusion debate

While there has been debate as to how much of these associations is causal, the scientific facts are now irrefutable. The association of red cell transfusions with post-operative infections has been shown in randomized clinical trials to be partially mitigated by leukoreduction.^3,4 Restricting the transfusion of red cells to much lower levels of hemoglobin than previously thought ideal (< 7g/dl or hematocrit of < 21) also reduces the number of patients who develop HAIs.⁵ It may be that even these guidelines are too liberal, but data are not yet available. Restricting transfusion of red cells to hemoglobins < 7-8g/dl in patients who are hemodynamically stable and not experiencing serious bleeding also appears to reduce  thrombosis and overall mortality.⁶

These issues are critically important because infection is one of the single most common serious complications seen in hospitalized patients, with one percent to two percent of transfused patients developing bacterial, viral, or fungal infections they wouldn’t have developed had they not been transfused.⁷ Infection is also the single most common cause of death in hospitalized patients. About 10 percent of such patients ultimately die as a consequence of their infection.⁸ Nosocomial infection is one of the most common serious complications of red cell transfusion, but it is often not even mentioned in textbooks or reviews on the subject. The transfusion medicine community has been slow and reluctant to accept these scientific data.

The question might be asked: How did we get transfusion of red cells so drastically wrong for so many decades? Some possible explanations are evident. The life-saving capabilities of red cell transfusions first became apparent in the early part of the twentieth century with reference to life-threatening bleeding at the time of childbirth. Then, with the invention of red cell storage solutions and anticoagulants, the utility of red cell transfusion in saving trauma victims seemed miraculous in the first and second thirds of the century. Surgeries such as correction of congenital heart disease and treatment of cancers using drugs toxic to the bone marrow provided evidence for red cell transfusions’ vital role in enabling previously impossible treatments for these fatal diseases.

But when a therapy is so phenomenally successful, something called “indication creep” occurs. In the days before randomized trials, physicians assumed, incorrectly, that restoring near normal hemoglobin/hematocrits would be beneficial. Liberal red cell transfusion practices became established without supporting data. This liberal approach now has been shown to cause net harm in virtually every study performed. Thus, red cell transfusions, which rose to 15 million per year in the United States during the twentieth and early twenty-first century, are now falling. The future no doubt will involve further decreases in transfusion of red cells as their toxicities become more clearly understood.

Tranfustion indicators

There are still important indications for red cell transfusions: 1) life-threatening bleeding and/or anemia; and 2) providing patients with congenital hemoglobin disorders (thalassemia and sickle cell disease) with normal red cells they cannot produce on their own. There will always be a place for red cell transfusion in the management of acute life-threatening anemia or bleeding, and the benefit of red cell transfusions in patients with sickle cell disease at risk of neurologic complications has been proven in randomized trials.^9,10

As healthcare providers, we can minimize the harm and  maximize the benefit of red cell transfusions in the future by  doing three things: transfusing only leukoreduced red cells; using restrictive criteria for transfusion where proven safe; and developing improved preservation and processing methods that minimize the toxicity of red cells that have been stored. It has been shown, for example, that saline-washed, leukoreduced red cell transfusions cause less inflammation than red cells that are only leukoreduced, in children undergoing complex heart  surgeries.¹¹ Similar advances will ensure that when red cell transfusion is needed, it will be much more effective and safer than it is today.

References

1. Marik PE, Corwin HL. Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature. Crit Care Med. 2008;36:2667-2674.
2. Refaai MA, Blumberg N. The transfusion dilemma–weighing the known and newly proposed risks of blood transfusions against the uncertain benefits. Best Pract Res Clin Anaesthesiol. 2013;27:17-35.
3. Fergusson D, Khanna MP, Tinmouth A, Hebert PC. Transfusion of leukoreduced red blood cells may decrease postoperative infections: two meta-analyses of randomized controlled trials. Can J Anaesth. 2004;51:417-424.
4. Blumberg N, Zhao H, Wang H, Messing S, Heal JM, Lyman GH. The intention-to-treat principle in clinical trials and meta-analyses of leukoreduced blood transfusions in surgical patients. Transfusion. 2007;47:573-581.
5. Rohde JM, Dimcheff DE, Blumberg N, et al. Health care-associated infection after red blood cell transfusion: a systematic review and meta-analysis. JAMA. 2014;311:1317-26.
6. Salpeter SR, Buckley JS, Chatterjee S. Impact of more restrictive blood transfusion strategies on clinical outcomes: a meta-analysis and systematic review. Am J Med. 2014;127:124-131 e3.
7. Blumberg N, Rogers MA. Leukoreduction and restrictive red cell (RBC) transfusions minimize healthcare associated infections after orthopedic surgery. Transfusion. 2014;54:abstract in press.
8. Delgado-Rodriguez M, Gomez-Ortega A, Llorca J, Lecuona M, Dierssen T, Sierra A. Nosocomial infection, indices of intrinsic infection risk, and in-hospital mortality in general surgery. J Hosp Infect. 1999;41:203-211.
9. Wang WC, Dwan K. Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease. Cochrane Database Syst Rev. 2013;11:CD003146.
10. Howard J, Malfroy M, Llewelyn C, et al. The transfusion alternatives preoperatively in sickle cell disease (TAPS) study: a randomised, controlled, multicentre clinical trial. Lancet. 2013;381:930-8.
11. Cholette JM, Henrichs KF, Alfieris GM, et al. Washing red blood cells and platelets transfused in cardiac surgery reduces postoperative inflammation and number of transfusions: results of a prospective, randomized, controlled clinical trial. Pediatric critical care medicine: a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2012;13:290-299.