E D I T O R I A L

Tolerating anemia: taking aim at the right target before pullingthe transfusion trigger

At the heart of the discussion about blood trans-fusion is how one strikes a balance between twopotentially morbid perioperative exposures:anemia and red blood cell (RBC) transfusion.

Which combination of patient demographics,comorbidities, physiologic variables, or laboratory valuesmight favor exposure to one over the other? In an indi-vidual patient, in the real-time setting of the fast-pacedsurgical arena, this decision can be tough. Those of us whopractice in this space do not always know if we have madethe right decision—uncertainty persists. What we do knowis there is a point when hemoglobin (Hb) values reach athreshold below which RBC transfusion is indicated andbeneficial—but where is this decision point for an indi-vidual patient? At present, lack of specific methods tomeasure tissue hypoxia directly means reliance on indi-rect feedback to support decision making regardinganemia and RBC transfusion.

With the exception of ongoing hemorrhage, the tradi-tional approach to transfusion has usually involved a spe-cific Hb threshold beneath which one begins to consider aRBC transfusion. This decision point, often referred to as a“transfusion trigger,” varies with practitioner, health careinstitution, and guideline recommendation. A widelyapplied Hb transfusion trigger of 7 g/dL seems a simplesolution to the question of when to transfuse.1 However, toparaphrase H.L. Mencken, “For every complex problemthere is an answer that is clear, simple, and wrong.” Thereis an underlying complexity to this issue; that is, physiol-ogy is geared to adapt to a degree of stress more than it isset to react to a certain trigger. Those who provide care forcardiac surgical patients recognize the complexity of thedecision-making process beyond that of a laboratorycutoff value. The individual patient’s Hb values andtrends, ongoing microvascular bleeding, degree of vaso-pressor support, and patient comorbidity are among anumber of important variables factored into our real-timemental models triggering transfusion decisions.

The study by Hogervorst and colleagues2 stands tobroadly inform our decision-making capability regardingthe choice of RBC transfusion versus tolerating anemia atthe point of care for an individual patient. They report thata “relative” reduction in the patient’s baseline Hb value ofmore than 50% is an important factor associated with

poor postoperative outcomes, even when specific Hbvalues may not have reached a traditional “trigger.” Thefact that there is an intolerance to a relative reduction inHb versus an absolute threshold trigger suggests thatthere is a patient-specific response in terms of ability toadapt to the onset of an acute anemic episode. The inge-nuity of the current study goes beyond a new tool fordeciding when to give blood; it is the realization that thereis a dynamic underlying the decision that reflects theability of the system to adapt.

ADAPTATION TO ACUTE ANEMIA

There is biologic and clinical plausibility to the authors’findings, supported by a number of investigations charac-terizing risk associated with acute anemia. These investi-gations suggest that there is an adaptive response toanemia up to a point after which one witnesses organdamage, presumably related to hypoxia.3-7 In the presentstudy setting, cardiac patients are often treated withperioperative beta blockade, have substantialcomorbidity, or may experience the potential for post–cardiopulmonary bypass ischemic reperfusion injury andheart block—all of which impair cardiovascular physi-ologic responses to anemia.3,5 By their nature, these ele-ments also complicate feedback, which might signal stressor the need for transfusion.

Tissue hypoxia related to varying levels of anemiamay be manifest by biomarker stress signaling. It has beensuggested that biomarkers of tissue hypoxia, signalingsubsequent changes in hypoxic cellular response relatedto anemia, may be specific and dynamic enough to even-tually provide optimal patient-specific feedback indicat-ing that the lower Hb threshold has been reached and aRBC transfusion may be indicated.5,7-10 There is additionalevidence suggesting that the magnitude of Hb reductionassociated with acute anemia may have organ-specificeffects; that is, sensitivity to the negative effects of anemiamay vary by Hb threshold for different organs.6,8 Hence,tolerance of anemia may be relative to reduction in apatient-specific baseline, relative to the ability of thepatient to adaptively respond.3

CONSIDERING A NEW DYNAMIC

ExtrapolationCardiac surgery is a unique setting considering significantpatient comorbidity, extent of surgical incisions, degree of

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blood loss and arrest of the heart. Is there evidence tosuggest the authors’ study findings could be extrapolatedto less complicated operative or even nonoperative set-tings or is there a unique interaction between this particu-lar surgical milieu and exposure to acute anemia?

Data suggest that development of acute anemiaduring the course of hospitalization for both medical andsurgical patients places a patient at a heightened risk forbad outcomes. In a recent investigation of more than180,000 mixed medical and surgical hospitalizations,patients who were admitted with normal Hb values andwho developed acute anemia during the course of hospi-talization had higher risk-adjusted in-hospital mortalityand greater resource utilization. This relationship wasdose dependent with greater degrees of anemia associatedwith higher risk. Although relative Hb reduction was not ameasured variable, if one calculated relative reductionsfrom set normal Hb values, the overall relative reductionin Hb in the range of 25% was associated with increasedrisk, less than the more than 50% cutoff in this study.11

Continuity versus discontinuity: dichotomizingcontinuous dataRecognizing that the relative reduction of Hb by morethan 50% is a more dynamic indicator than an absolutethreshold, it is nonetheless dichotomous in nature. If thestudy by Hogervorst and colleagues treated data on a con-tinuum, would we find a more graded response to acuterelative reduction in Hb and poor outcomes? Althoughclinicians tend to dichotomize variables for decisionmaking, statistical methodologic literature discouragessuch practice, except for rare circumstances.12-15 Embrac-ing data measured on a continuum rather than categoriz-ing such data is recommended to avoid loss ofinformation and power.12-16 Examining a continuous spec-trum of anemia exposure and a patient’s ability toadaptively respond may get us closer to making betterpatient-specific decisions to address declining Hb values.

Use of a composite outcomeUse of a composite outcome does not allow insight intoorgan-specific sensitivity to reduction in Hb values orperhaps the benefit of more timely intervention. A smallerpercent reduction in Hb from baseline may be more det-rimental to renal function than other organ function, orthe ability of the kidney to adapt may depend on baselinerenal function in a specific relationship to the magnitudeof reduction. Findings in laboratory5,6,8 and clinicalstudies17 suggest that specific organs have varying sensi-tivity to varying levels of anemia. The strength of thecurrent study’s composite endpoint lies partly in itsstraightforward relationship to increasing risk withdecreasing levels of Hb and partially to the fact that all

components of the studies’ composite outcome behavedsimilarly in relationship of anemia.18-20 Still, it suggeststhat there is an abundance of understanding to be gainedby evaluating more organ-specific or patient-specificoutcomes.

CLINICAL IMPLICATIONS:OPERATIONALIZING THE STUDY FINDINGS

How can we integrate the study findings into patient care?This investigation excluded patients with preoperativeanemia; hence development of anemia was an acute eventoccurring as a result of either blood loss or hemodilution.Blood loss can be due to events such as surgical misad-venture or coagulopathy with microvascular bleeding. Thecontribution of the hemodilutional effects of intravenousfluids, cardiopulmonary bypass prime, and cardioplegiacan be substantial and is potentially modifiable. UsingKirklin’s algorithm21 for calculating patient-machinehematocrit (Hct) modified for pre–cardiopulmonary crys-talloid volume, estimates for cardiopulmonary bypassprime and cardioplegia volume could be simulated pre-operatively for an average cardiac surgical patient. Kirklinsuggested using this algorithm of calculating patient-machine Hct in an automated manner preoperatively. Issuch a formula useful for predicting what relative reduc-tions in Hb might be reached or specifically when relativereductions of more than 50% in baseline Hb would occur?Estimates of contributions to relative reductions in Hbmight change processes of care to reduce the role ofhemodilution in development of acute anemia.

The current study by Hogervorst and colleaguescomplements findings from other investigations that maysuggest that current guideline recommendations for Hbtriggers may be set too low.5,9,10 Relative reductions in Hbmight provide additional perspective from a clinical view-point. Certainly these observations at least represent a callto better understand the role of biomarkers of anemicstress in the clinical assessment of inadequate tissueoxygen delivery.5

CONCLUSION

The study by Hogervorst and colleagues provides animmediately useful, practical tool for evaluating anemiain the operative setting. Beyond this contribution, itechoes the call to develop a better understanding, moreadvanced technology, and practical applicability in thecomplex process of blood management in cardiac surgery.From the data, we can only comment on associationrather than causation. In this type of study design there isa likelihood of unmeasured confounding giving rise tounanswered questions, but also sowing the seeds of newdirections in research and treatment. However, across dis-ciplines, and in different settings, anemia appears to place

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patients at risk, as does the treatment to a point. Thisdilemma magnifies the mission to make research patientcentric with aggressive application of advances in tech-nology versus any practice that seems to be “one size fitsall.” The elegance of this study is not only the manage-ment tool it provides, but the question it raises about thecomplexity of adaptation to anemia.

CONFLICT OF INTEREST

The author has disclosed no conflicts of interest.

Colleen G. Koch, MD, MS, MBAe-mail: ckoch11@jhmi.edu

Department of Cardiothoracic AnesthesiaCleveland Clinic

Cleveland, OH

REFERENCES

1. Ferraris VA, Ferraris SP, Saha SP, et al. Perioperative blood

transfusion and blood conservation in cardiac surgery: the

Society of Thoracic Surgeons and The Society of Cardiovas-

cular Anesthesiologists clinical practice guideline. Ann

Thorac Surg 2007;83(Suppl):S27-86.

2. Hogervorst E, Rosseel P, van der Bom J, et al. Tolerance of

intraoperative hemoglobin decrease during cardiac

surgery. Transfusion 2014;54:2696-704.

3. Hare GM. Tolerance of anemia: understanding the adap-

tive physiological mechanisms which promote survival.

Transfus Apher Sci 2014;50:10-2.

4. Hare GM, Tsui AK, McLaren AT, et al. Anemia and cerebral

outcomes: many questions, fewer answers. Anesth Analg

2008;107:1356-70.

5. Tsui AK, Dattani ND, Marsden PA, et al. Reassessing the

risk of hemodilutional anemia: some new pieces to an old

puzzle. Can J Anaesth 2010;57:779-91.

6. van Bommel J, Siegemund M, Henny CP, et al. Heart,

kidney, and intestine have different tolerances for anemia.

Transl Res 2008;151:110-7.

7. Hare GM, Tsui AK, Ozawa S, et al. Anaemia: can we define

haemoglobin thresholds for impaired oxygen homeostasis

and suggest new strategies for treatment? Best Pract Res

Clin Anaesthesiol 2013;27:85-98.

8. Tsui AK, Marsden PA, Mazer CD, et al. Priming of hypoxia-

inducible factor by neuronal nitric oxide synthase is

essential for adaptive responses to severe anemia. Proc

Natl Acad Sci U S A 2011;108:17544-9.

9. Hare GM, Tsui AK, Crawford JH, et al. Is methemoglobin an

inert bystander, biomarker or a mediator of oxidative

stress—the example of anemia? Redox Biol 2013;1:65-9.

10. Hare GM, Mu A, Romaschin A, et al. Plasma methemoglo-

bin as a potential biomarker of anemic stress in humans.

Can J Anaesth 2012;59:348-56.

11. Koch CG, Li L, Sun Z, et al. Hospital-acquired anemia:

prevalence, outcomes, and healthcare implications. J Hosp

Med 2013;8:506-12.

12. MacCallum RC, Zhang S, Preacher KJ, et al. On the practice

of dichotomization of quantitative variables. Psychol

Methods 2002;7:19-40.

13. Barratt-Boyes K. Chapter 6: Generating knowledge from

information, data and analyses. In: Kouchoukos N,

Blackstone E, Hanley F, et al., editors. Kirklan/Barratt-

Boyes cardiac surgery. 4th ed. Philadelphia: Elsevier; 2013.

p. 260-1.

14. Bochner S. Continuity and discontinuity in nature and

knowledge. In: Wiener PP, editor. Dictionary of the history

of ideas: studies of selected pivotal ideas, Vol. 1. New York:

Charles Scribner’s Sons; 1968. p. 492.

15. Dawson NV, Weiss R. Dichotomizing continuous variables

in statistical analysis: a practice to avoid. Med Decis

Making 2012;32:225-6.

16. Streiner DL. Breaking up is hard to do: the heartbreak of

dichotomizing continuous data. Can J Psychiatry 2002;47:

262-6.

17. Loor G, Li L, Sabik JF 3rd, et al. Nadir hematocrit during

cardiopulmonary bypass: end-organ dysfunction and mor-

tality. J Thorac Cardiovasc Surg 2012;144:654-662 e654.

18. Pocock SJ, Ariti CA, Collier TJ, et al. The win ratio: a new

approach to the analysis of composite endpoints in clinical

trials based on clinical priorities. Eur Heart J 2012;33:176-

82.

19. Tong BC, Huber JC, Ascheim DD, et al. Weighting compos-

ite endpoints in clinical trials: essential evidence for the

heart team. Ann Thorac Surg 2013;94:1908-13.

20. Dmitrienko A, Wiens BL, Tamhane AC, et al. Tree-

structured gatekeeping tests in clinical trials with hierar-

chically ordered multiple objectives. Stat Med 2007;26:

2465-78.

21. Barrett-Boyes K. Chapter 2: Hypothermia, circulatory

arrest, and cardiopulmonary bypass. In: Kouchoukos N,

Blackstone E, Hanley F, et al., editors. Kirklin/Barrett-

Boyes cardiac surgery. 4th ed. Philadelphia: Elsevier; 2013.

p. 85.

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