Oct 102014
 

Blood transfusions have been a central component of protocols for care of severe sepsis and septic shock, ever since the single-center 2001 Rivers trial included them in its interventions. Any benefit (or harm) caused by red cell transfusion independently was unknowable, and so the therapy became standard care as part of the so-called sepsis bundle. The Surviving Sepsis guidelines have generally advised transfusion to a hematocrit of 30% or hemoglobin of 10 g/dL during the first 6 hours of septic shock if hypoperfusion (low central venous oxygenation) is present despite fluids and vasopressors.

However, the inclusion of red cell transfusion in sepsis bundles has been frequently challenged, based on the weak observational evidence for its benefit, compared to robust evidence from randomized trials showing transfusion above a hemoglobin of 7 g/dL is unhelpful generally. This finding has been shown in the critically ill (the TRICC trial), after hip surgery (FOCUS trial) and in non-critically ill patients.

With the publication of the TRISS trial in the New England Journal of Medicine, there may be little remaining justification for continuing existing transfusion practices in sepsis.

Authors enrolled 1,000 patients with septic shock in 32 ICUs in Denmark and Scandinavia who had hemoglobin >9 g/dL. Patients were randomized to be transfused throughout their ICU stay to maintain a hemoglobin of 7 g/dL, or 9 g/dL, one unit of leukoreduced red cells at a time.

Those with myocardia ischemia were excluded; new bleeding was transfused according to the attending's discretion.

Virtually all (99%) of the patients in the 9 g/dL threshold group were transfused (a median of 4 units RBC); almost two-thirds in the 7 g/dL group were transfused, but only a median of one unit.

At 90 days, mortality was statistically equal in both groups: 43% in the group transfused to 7 g/dL, and 45% in those transfused to 9 g/dL. Adverse events and need for life support (mechanical ventilation, vasopressors, renal replacement therapy, etc.) were also equivalent in both groups.

About half as much blood was transfused into the lower-threshold patients as into the higher-threshold patients. How much less? About 1,500 fewer units (~3,000 vs. ~1,500), or 463 liters, or 122 gallons of blood. That's enough to fill two 55 gallon barrels, and still have enough left over to fill a ten-gallon hat.

By the way, each of those barrels o' blood cost about $150,000 at a market price of ~$200 per unit of red cells. And this was just one trial, albeit at many ICUs.

Add to this finding the ProCESS and ARISE trials, which did not include transfusion to guideline-compliant hematocrit levels for patients in septic shock (in the usual care arms), and showed no harm from the practice, with about 50% fewer patients transfused compared to standard care.

Yet the Surviving Sepsis guidelines effectively encouraged early transfusion by implying that a low-threshold transfusion strategy is inadvisable in many critically ill patients: “Once hypoperfusion has resolved [emphasis added] and in the absence of ... myocardial ischemia, severe hypoxemia [ditto], acute hemorrhage, or ischemic coronary artery disease, we recommend [transfusing to a low threshold of 7 g/dL] ." Paul Hebert, lead author of TRICC, argues in an editorial that given the preponderance of the evidence, it's time for this portion of the guidelines to be re-written.

Nowhere in the article nor in the supplementary appendix did I see the timing of transfusion described. Also, they did not restrict transfusion to those with low central venous oxygen saturation. So, true believers can argue that TRISS doesn't definitively rule out any benefit of red cell transfusion in the first 6 hours of treatment for severe sepsis. Another point worth noting was the different mortality in ProCESS and ARISE (18-19%) vs. TRISS (44%). TRISS patients were sicker at enrollment, already in the ICU (not the ED), with 70% mechanically ventilated and very high SOFA organ failure score of ~10 (vs. 10% vented at enrollment in ProCESS, with not-bad APACHE II's of ~15).

takeawayClinical Takeaway: There is no apparent benefit from transfusing to hemoglobin > 7 g/dL in patients with septic shock without bleeding or myocardial ischemia. Some experts may conclude that the TRISS, ProCESS and ARISE trials together invalidate red cell transfusion past 7 g/dL as part of standard protocols for severe sepsis and septic shock. Anemia is an expected result of critical illness.

Source:  Holst LB et al for the Scandinavian Critical Care Trials Group. Lower versus higher hemoglobin threshold for transfusion in septic shock. (TRISS Trial). N Engl J Med. 2014 Oct 9;371(15):1381-91.

ProCESS Trial 

ARISE Trial

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Transfusion for hemoglobin above 7 g/dL: no benefit in septic shock (TRISS Trial)