Monday, January 14, 2013

Hemoglobin In Limbo: How Low Can [should] It Go?

In this post about transfusion thresholds in elderly patients undergoing surgery for hip fracture, I indulged in a rant about the irresistible but dodgy lure of transfusing hospitalized patients with anemia (which I attributed to the normalization heuristic) and the wastefullness and potential harms it entails.  But I also hedged my bets, stating that I could get by with transfusing only one unit of blood a month in non-acutely bleeding patients, while noting in a comment that a Cochrane review of this population was equivocal and the authors suggested an RCT of transfusion in acute upper gastrointestinal hemorrhage.  Little did I know at the time that just such a trial was nearing completion, and that 12 units of PRBCs could probably get me by for a year in just about all the patients I see.

In this article by Villanueva in the January 3, 2013 issue of the NEJM, Spanish investigators report the results of a trial of transfusion thresholds in patients with acute upper gastrointestinal hemorrhage.  After receiving one unit of PRBCs for initial stabalization, such patients were randomized to receive transfusions at a hemoglobin threshold of 7 versus 9 mg/dL.  And lo! - the probability of transfusion was reduced 35%, survival increased by 4%, rebleeding decreased by 4%, and adverse events decreased by 8% in the lower threshold group - all significant!  So it is becoming increasingly clear that the data belie the sophomoric logic of transfusion.

And this sophomoric logic betrays an arrogance which has infiltrated medicine in the last several generations and which often leads it astray.  As physicians and scientists have successfully penetrated the mysteries of biochemistry and the secrets of physiology in the laboratory, they have become emboldened about the transfer and application of their ex-vivo results and surrogate endpoints to intact human patients who are more concerned with clinical outcomes.  No sooner do we develop the ability to measure some physiological or biochemical parameter (how many are there?) than we naively begin to manipulate it in the hopes achieving a desirable outcome.  But a leap of faith is required, and this leap is more easily undertaken when propelled by arrogance.  That we understand the transport of oxygen in the intact organism; the structure of hemoglobin; the oxy-hemoglobin dissociation curve; blood typing; component separation and storage; testing for diseases; the ability of transfusion to raise hemoglobin; the decrement in oxygen carrying capacity with PRBC age - does not mean that we understand whether or not transfusion improves clinical outcomes.  Max Perutz, winner of the 1962 Nobel Prize in Chemistry for elucidating the molecular structure of hemoglobin once said "Evolution is a brilliant chemist."  I would point out that it is far easier to figure out how something works than it is to improve upon it.

Physicians and scientists may be excused for their enthusiasm and for overestimating the applicability of their discoveries to the treatment of patients with associated diseases.  Indeed, the evidence based medicine movement was borne of recognition that surrogate endpoints are sometimes misleading and often unreliable.  But the ease and confidence with which we proffer physiological explanations for observed phenomena such as hypoxemia and the like reveals an underlying attitude - an arrogance about our understanding of how things work and how accurately we can anticipate the results of interventions based on what we know or think we know about associated physiological processes in the absence of data from clinical trials specifically testing our naive assumptions.

As regards transfusion, it appears that all we understood about the biochemistry of hemoglobin and the physiology of oxygen transport was not enough to allow us to predict the effects of transfusion on clinical outcomes.  As a broad theme, we now have compelling evidence that transfusions outside of extreme reductions in hemoglobin concentrations are not of benefit to patients, as well as reaffirmation of the need for clinical trials to test our well-intentioned hypotheses and the interventions that stem from them.  The sobering reality is that we generally know much less than we think we know.  And the answer to the question "how low can it [safely] go" is "I don't know."

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