Patient Blood Management Review 2015: New Knowledge, New Trials, New Possibilities
The tradition of highlighting the “Year in Review” of scientific literature supporting blood management originated with Strategic Healthcare Group and continues now with Mediware Consulting & Analytics. In both the December 2015 Live Learning Webinar and this blog, I plan to highlight a broad range of this year’s important literature that continues to catapult Patient Blood Management (PBM) into national and international venues. This cannot be all inclusive as SO much is available. Just pick up any subspecialty journal and you will likely find something specific to blood management! PBM has become the standard of care and the evidence for its implementation as a way to bring quality and safety to our patients has sewn deep roots. As the above quotation states, PBM is THE manner by which we “…prevent transfusion from becoming a thoughtless habit…”
2015 saw new standards and clinical guidance that build on the current five guidelines and nine RCTs that support restrictive transfusion practice. First quarter 2015, the Society for the Advancement of Blood Management published the 3rd edition of PBM program standards and the American Society of Anesthesiologists put out an excellent, comprehensive practice guideline. This included a supplement that reviews a broad range of PBM topics. These are both “must-haves”. ¹ ²
Holst et al. provided a robust meta-analysis of restrictive vs. liberal RBC transfusions across both adult and pediatric populations and found, among 31 trials, that liberal transfusion strategies confer no benefit to patients.³
The literature, as we know, has lagged behind pertaining to plasma and platelet transfusion, but 2015 brought some new important information re: the “yellow stuff”. An RCT to study prophylactic plasma transfusion was performed and reported by Muller et al.4 This multicenter trial focused on non-bleeding patients with INRs between 1.5-3.0, randomized to receive prophylactic plasma vs. no plasma prior to common minimally invasive procedures performed in critical care units. No differences in bleeding complications were observed regardless of whether or not plasma was utilized. This was a small study, but speaks to what we have seen in prior retrospective and observational studies i.e. the lack of effect that plasma has in these clinical situations.
The updated clinical practice guideline provided by Kumar and colleagues highlights the newest evidence for platelet transfusions.⁵ Although the recommendation for prophylactic platelets in patients with platelet counts <10K and hypoproliferative marrow has not changed, low-dose and single-unit transfusions are the new additions to the guidelines. Platelet transfusions for central venous catheter placement is now recommended at counts of <20K and those for LP of <50K. All three of these recommendations, based on GRADE evidence, limit transfusions, thus reducing transfusion exposure while at the same time, helping to maintain adequate platelet inventory for those patients who truly need them. Once again, a wonderful example of stewardship.
Previously, 2012 and 2014 brought two RCTs to evaluate fresh vs. older RBCs and clinical outcomes. Neither of these, the ARIPI or the RECESS trials, in premature infants and CVS patients respectively, showed adverse outcomes associated with the use of “older” red cell transfusions.⁶ ⁷ 2015 was the completion of the ABLE trial.⁸ This study similarly showed no differences in outcomes in critically ill patients, both medical and surgical, regardless of the storage duration of the RBCs used. Of course, these trials are all somewhat different in their definitions of “old” blood; they do not typically include units >35 days old and certainly have some subtle confounders. Thus, the age-of-blood debate persists. Studies such as the Red Cell Storage & Outcomes, INFORM, and TRANSFUSE will hopefully add to our body of knowledge. Perhaps the “storage lesion” (which we know exists from a laboratory perspective) needs to be viewed from a metabolomic and/or proteomic perspective.⁹ ¹° Expanding the role of recipient characteristics and not just those of the donor “bag” might bring us new insight. Teasing through these issues is important as we try to better utilize our components and more closely and personally match donors to recipients.
PBM focuses heavily, as it should, on avoidance of transfusion and providing alternatives to transfusion. But what about the hemorrhaging patient? We all recognize that blood can be absolutely life-saving in the exsanguinating patient. So how is this best done?
There has been an evolution of protocol-based and fixed-ratio massive hemorrhage practices over the years, its roots in combat and subsequent extension to civilian trauma. Solidification of these concepts came in 2015. On the heels of the prior PROMMTT study, where 1:1:1 and 1:1:2 platelet/plasma/RBC ratios improved outcomes, the most recent 2015 PROPPR study pushed the 1:1:1 agenda.¹¹ ¹² PROPPR randomized trauma patients to compare these two ratios and hemostasis within the first 3 hours was more rapidly and significantly achieved in the 1:1:1 group. There were no differences in 24-hour or long term mortality, but certainly this adds to the ever-growing clinical evidence that early use of plasma and platelets makes a difference. Ongoing basic science research also shows this effect. Additional useful recommendations and tools from the American College of Surgeons Trauma Quality Improvement Program (TQIP) can benefit our trauma centers and patients.¹³
As for adjuncts and alternatives to transfusion, 2015 pushed pharmaceuticals even further to the forefront. Extending the use of TXA in obstetric hemorrhage is a current hot topic and recent studies have shown decreases in blood loss and transfusion needs. 14 15 These studies have been well received but we also await the results of the largest RCT, the much-heralded WOMAN trial.¹⁶ Stay tuned!
Antidotes for anticoagulants, the old and the new, are fast becoming an integral part of the PBM armamentarium. Kcentra, FDA approved in late 2013, is a prothrombin complex concentrate and a mainstay, along with IV vitamin K, for emergent or urgent warfarin reversal in the bleeding patient. This was further cemented into practice by Goldstein et al. with their Phase 3b study publication.¹⁷ Fall 2015 saw FDA approval of idarucizimab (Praxbind®) for dabigatran reversal.¹⁸ This has been long awaited and much needed as no antidote for this direct thrombin inhibitor has been available. Conventional blood components are ineffective in this situation and would expose patients to unnecessary and useless transfusion.
Another issue that remains important for all of us on our PBM quest is the overarching safety of the blood supply. Transfusion-transmitted disease has always loomed large and continues to be of concern. The transfusion community and, in particular, our donor centers do an excellent job screening and testing donors that our risk of diseases such as HIV and HCV are exquisitely low. However, new and emerging pathogens, including viruses, bacteria and parasites still pose a threat. Pathogen inactivation has been on the horizon and utilized in the EU for several years. One methodology, Intercept®, has now, in 2015, received FDA approval for use with platelets in the U.S. Pathogen inactivation can potentially reduce transfusion-transmitted disease, allow for extended platelet storage and mitigate against transfusion-associated graft vs. host disease. Continued study, prior to implementation, will be forthcoming. Considerations include advantages, disadvantages, scope of effect on various pathogens, and cost for our donor centers and hospital transfusion services. A recent publication by McCullough and colleagues has shown the potential off-setting cost reductions with use of this technology.¹⁹
2015 has given us a host of new evidence and opportunities to push the agenda of PBM even further. New and ongoing trials include: Transfusion in Cardiovascular Surgery (TRICS-III), use of TXA in UGI hemorrhage (HALT-IT), TXA for traumatic brain injury (CRASH-3), fibrinogen concentrates in CVS and OB hemorrhage (REPLACE and OBS2), and the PREVENTT trial to study the use of IV iron for anemia management prior to major surgery. So keep your antennae up and your ear to the ground!
PBM remains THE multimodal, multidisciplinary, evidence-based practice that undoubtedly improves patient care and sustains a vital community resource. Through share experience and continued research, further advances of PBM principles will drive this ever forward. It takes all of us pushing this mission and vision for better, safer, more effective practice.
As always, Patient Blood Management: it’s not the “why”, it is clearly the “why not”!
1. SABM, 2015, www.sabm.org
2. ASA Task Force Anesthesiology 2 2015; V 122: 241. doi:10.1097/ALN.0000000000000463
3. Holst L et al. BMJ 2015; 350:h1354. doi: 10.1136/bmj.h1354
4. Műller M et al. 2015 Transfusion 55: 26-35 doi: 10.1111/trf.12750
5. Kumar A et al. 2015 Transfusion 55: 1116-1127 doi: 10.1111/trf.12943
6. Fergusson D et al. JAMA, 2012; 308(14):1443-1451. doi:10.1001/2012.jama.11953.
7. Steiner M et al. 2014 Transfusion 54 Supplement S2: 15A
8. Lacroix J et al. N Engl J Med. 2015; 372: 1410-1418. doi: 10.1056/NEJMoa1500704
9. D’Allessandro A et al. 2015 Transfusion, 55: 205–219. doi: 10.1111/trf.12804Zimring J et al. Blood 2015; 125: 2185
10. Ho A et al. Anesthesiology 32012, Vol. 116, 716-728 doi:10.1097/ALN.0b013e318245c47b
11. Holcomb J et al. JAMA 2015;313(5): 471-482 doi:10.1001/jama.2015.12
13. Wang HY et al. J Perinatol 2015 Oct;35(10):818-25. doi: 10.1038/jp.2015.93
14. Alam A et al. Transfus Med Rev. 2015 Oct;29(4):231-41. doi: 10.1016/j.tmrv.2015.07.002.
15. Shakur H. Trials. 2010 Apr 16; 11: 40. doi: 10.1186/1745-6215-11-40.
16. Goldstein J et al. Lancet 2015; 385: 2077-2087. doi: 10.1016/S0140-6736(14)61685-8
17. Pollack C et al. N Engl J Med. 2015 Aug 6;373(6):511-52. doi: 10.1056/NEJMoa1502000
18. McCullough J et al. 2015 Transfusion 55: 2312-2320. doi: 10.1111/trf.13149
Author: Carolyn Burns, MD