E D I T O R I A L

Too much, too little, too soon, too late? Transfusion andlong-term survival in children

How blood transfusions impact patientoutcome is of interest to health economists,insurers, transfusion medicine specialists,prescribing physicians, families, and most

importantly, vulnerable patients. There are two differentapproaches to evaluating impact within the health caresystem: micro and macro. At the micro level, attention isfocused on a single patient or group of patients, one pro-vider at a time. Population-based clinical trials, clinicaleffectiveness studies, meta-analyses, and clinical experi-ence are used to inform physician decision making on amicro level. Discussion of risks and benefits are implicit inthe consent process and occur at the bedside with thephysician, parent, and child (if age appropriate) reviewinghow transfusion can alleviate symptoms and/or support achild’s hematopoietic system. In these cases, the physi-cian’s allegiance to the patient is measured as an “n of 1”study, and there is no role for the discussion of cost impli-cations, resource limitations, or societal burden.

At the macro level, care is provided to populations ofpatients. In this setting, care that benefits the greatestnumber of patients while minimizing risks, complica-tions, and costs in the aggregate is the focus. Measure-ment strategies like mortality and complication rates,proportions, incidence, and prevalence become impor-tant tools that help to inform health care policy decisionsaffecting access, cost, and quality. Those technologies andtreatments, be they mechanical or biologic, that result inbetter outcomes at lower costs will have the greatest valueto populations of patients. Admittedly, there is consider-able interplay between the two care systems just defined.In reality, they are not discrete, but rather porous to effectsin both directions and have important implications fortransfusion medicine.

In this issue of TRANSFUSION, Gauvin and col-leagues1 describe a single institution’s experience with thelong-term follow-up of patients who received blood trans-fusions between 1990 and 1992. Their demographic find-ings provide some insight regarding practice patterns inthe early 1990s. From a diagnostic perspective, cardiacdisease, malignancies, and operative procedures, specifi-cally cardiac and orthopedic procedures, were the diag-noses most frequently requiring transfusion. Age was animportant consideration for transfusion; nearly a third of

patients were neonates and half were less than a year ofage. The most frequently transfused product was redblood cells (RBCs) and 42.5 percent of patients receivedone to two transfusions.

There are several important findings from this studywhen evaluated from the micro and macro level. At themicro level, the study provides an opportunity to contrasthistorical transfusion practices in children to those cur-rently in use. The study also advances our understandingof some of the potential ill effects of transfusion and spe-cifically focuses on the impact of transfusion on mortality.From a methodologic perspective, two specific concernsare raised on a macro level. A single-institution databaseto inform practices raises questions as to the generaliz-ability of the findings at the intersection of the micro andmacro levels. In addition, the ability of a small data set toreliably predict outcomes that are distinct in time or loca-tion raises analytical concerns.

Historical perspectives are useful in providing contextin caring for patients, which is why long-term follow-upstudies are so valuable.2,3 The patient profiles of trans-fused pediatric patients have not changed dramatically. Arecently published, multi-institutional analysis of transfu-sion practices in pediatric teaching hospitals4 found strik-ingly similar results to the study by Gauvin and colleagues.RBCs are the most frequent product transfused and age,race, disease severity score, and discharge disposition areall important demographic considerations for those whoreceived transfusions. Are these similarities in findings intwo studies of very different design and time periods goodor bad news? At the micro level, progress in clinical trans-fusion medicine and provider prescribing behavior hasnot changed dramatically. To improve prescriber transfu-sion practices and outcomes, data regarding patterns andoutcome need to be made available to that prescriber in“real time.” It is clear that transfusions provide benefit forspecific subsets of patients with different disorders acrossa diverse range of conditions. No one would argue with thevalue of transfusion for acute bleeding, trauma, and spe-cific disorders like sickle cell disease and symptomaticanemia. However, there is increasing attention in theliterature to the potential adverse effects of transfusion,especially noninfectious risks, like transfusion-relatedacute lung injury (TRALI) and fatal or near-miss clericaland administration errors. Published data on transfusioncomplications in hospitalized children are rare,3-5 reflecta tendency to publish single-institution studies, useTRANSFUSION 2008;48:796-798.

796 TRANSFUSION Volume 48, May 2008

inadequate counting methods, and suffer from underre-porting. When an individual physician views his or herpractice in terms of serial “n of 1” studies, there is neverthe opportunity to learn about transfusion risks, compli-cations, marginal benefits, and excessive costs. Compli-ance with clinical transfusion guidelines provides anotheropportunity to improve provider prescribing behavior buthas limited effect.6-10 Only through carefully constructedhemovigilance systems will there be an opportunity toimprove individual clinical practices at the micro level andthe ability to capture data at the macro level.

Clinical outcomes need to be important, clear, rel-evant, easy to define, and measurable. Mortality, as a vari-able, fulfills all of these criteria, which makes it especiallyappealing as a clinical outcome measure. While mortalityis clear and objective, its use as an outcome measure inclinical studies may be difficult and, if improperly used,can be misleading. Gauvin and colleagues1 should beapplauded for tackling this important and difficult issue,particularly the detailed “sourcing” of death certificates.Their findings related to the effects of transfusion on long-term survival are both interesting and important. In mul-tivariate models, they found that age, malignancy, a largenumber of transfusions (n > 20), and transfusion of morethan one type of blood component were all associatedwith mortality.1 While they found important micro-leveleffects on mortality in their study, we have reservationsconcerning the application and generalizability to macro-level clinical practices because of methodologic issues.

When considering the potential effects of blood trans-fusion on mortality in children, one must consider timing.One would expect (from the perspective of face validity)that the adverse effects of a transfusion would decreaseover time. At what point in time do the effects of the trans-fusion become unimportant? Is it 1 month, 1 year, 5 years,or 10 years? The second concern is related to clinical plau-sibility. Except for transfusion-transmitted infections, canone really expect that mortality 10 years after a transfu-sion is related to the transfusion alone or is it more amanifestation of another factor that was associated withthe indication for transfusion in the first place? Further-more, the life expectancy of children is longer than that ofadults2,3 imparting additional “lead time” for adverseoccurrences related to the transfusion to occur, but alsofor other life events to occur.

The authors have attempted to improve their abilityto link transfusions with survival through their analysis.The issue of controlling for other unmeasured variablesthat may also be associated with mortality, however, isimportant and underappreciated in the current study. Themost critical variable is severity of illness. Hospitalizedchildren who are more severely ill require more medicaland surgical interventions and have comorbid conditionsrequiring more transfusions. The more severely ill andtransfused patients may die from their transfusion, from

the severe nature of their disease, or from some unmea-sured variable associated with their condition. In thissingle-institution study with small numbers of recipients,it becomes difficult to disentangle whether transfusionis related to mortality or another unmeasured variablewithout a severity scoring system.

While overgeneralizing from this study could lead tomisinterpretation and be questioned at the micro level,we congratulate the authors for incrementally movingforward our knowledge related to evidence-based transfu-sion practices in children and use this as an opportunityfor reflection on how we can build robust data reportingsystems to inform physician practices at both the patientand the population level. In 2026, perhaps we can lookback on the work of Gauvin and colleagues to see just howfar we have advanced our knowledge, improved the prac-tices of our colleagues, and most critically, the outcomesof our patients.

Anthony D. Slonim, MD, DrPHCarilion Clinic and Carilion Clinic Children’s Hospital

Medical Affairs, Carilion Medical CenterRoanoke, VA

Medicine, Pediatrics and Public HealthUniversity of Virginia, School of Medicine

Charlottesville, VANaomi L.C. Luban, MD

Laboratory Medicine & PathologyTransfusion Medicine/The Edward J. Miller Donor Center

Pediatric Clinical Research CenterChildren’s National Medical Center

Pediatrics and PathologyThe George Washington University Medical Center

Washington, DCe-mail: nluban@cnmc.org

REFERENCES

1. Gauvin F, Champagne MA, Robillard P, Le Cruguel JP,

Lapointe H, Hume H. Long-term survival rate of pediatric

patients after blood transfusion. Transfusion 2008;48:

801-8.

2. Kleinman S, Marshall D, Aubuchon J, Patton M. Survival

after transfusion as assessed in a large multi-state US

cohort. Transfusion 2004;44:386-90.

3. Luban NL, Colvin C, Mohan P, Alter HJ. The epidemiology

of transfusion-associated hepatitis C in a children’s hospi-

tal. Transfusion 2007;47:615-20.

4. Slonim AD, Joseph JG, Turenne WM, Sharangpani A, Luban

NL. Blood transfusions in children: a multi-institutional

analysis of practices and complications. Transfusion 2008;

48:73-80.

5. Kneyber MC, Hersi MI, Twisk JW, Markhorst DG, Plotz FB.

Red blood cell transfusion in critically ill children is inde-

pendently associated with increased mortality. Intensive

Care Med 2007;33:1414-22.

EDITORIAL

Volume 48, May 2008 TRANSFUSION 797

6. Wong CJ, Vandervoort MK, Vandervoort SL, Donner A, Zou

G, MacDonald JK, Freedman J, Karkouti K, MacDonald SJ,

Feagan BG. A cluster-randomized controlled trial of a

blood conservation algorithm in patients undergoing total

hip joint arthroplasty. Transfusion 2007;47:832-41.

7. Society of Thoracic Surgeons Blood Conservation Guide-

line Task Force and Society of Cardiovascular Anesthesiolo-

gists Special Task Force on Blood Transfusion.

Perioperative blood transfusion and blood conservation in

cardiac surgery: the Society of Thoracic Surgeons and the

Society of Cardiovascular Anesthesiologists clinical prac-

tice guideline. Ann Thorac Surg 2007;83:S27-86.

8. Weldon BC. Blood conservation in pediatric anesthesia.

Anesthesiol Clin North Am 2005;23:347-61.

9. Lacroix J, Hébert PC, Hutchison JS, Hume HA, Tucci M,

Ducruet T, Gauvin F, Collet JP, Toledano BJ, Robillard P,

Joffe A, Biarent D, Meert K, Peters MJ; TRIPICU

Investigators; Canadian Critical Care Trials Group; Pediat-

ric Acute Lung Injury and Sepsis Investigators Network.

Transfusion strategies for patients in pediatric intensive

care units. N Engl J Med 2007;356:1609-19.

10. Dzik S. Use of a computer-assisted system for blood utili-

zation review. Transfusion 2007;47:125S-29S.

EDITORIAL

798 TRANSFUSION Volume 48, May 2008