Issues for Blood Management in Hematology/Oncology

Hematology/Oncology patients comprise a unique subpopulation for whom transfusion therapy is often necessary in both the acute care setting as well as for long-term support. Red blood cells (RBCs) and platelets are the most common components transfused particularly in patients undergoing high-dose chemotherapy, intensive radiation therapy and human hematopoietic stem cell transplantation (HSCT).

Restrictive transfusion practice has become the “new world order” particularly for general medical and surgical patients. Those with hematologic malignancies or solid tumors have not frequently been a large part of many of the randomized controlled trials that speak to this approach.  Literature is available, however, that provides evidence that judicious use of blood components via restrictive transfusion and single unit transfusions for inpatients and outpatients can be clinically effective, safe, and will decrease the potential for transfusion-associated adverse events.

Feasibility studies of restrictive RBC transfusion in the Hematology/Oncology population have been reported. These studies provide compelling evidence that lower transfusion triggers, targets and single unit use are not associated with increased bleeding episodes and will reduce overall transfusion exposure.¹ ² ³  The American Society of Hematology (ASH), as part of their Choosing Wisely Campaign, advises against liberal transfusion of RBCs with hemoglobin (Hgb)  targets of 7- 8 g/dL, along with implementation of single-unit transfusions when possible.

Recent RCTs and consensus from the AABB point to similar restrictive practice for platelet transfusion with a trigger of 10,000/µL for prophylactic transfusion in most patients.⁵ Subgroups of patients, such as those with autologous HSCTs, may not require prophylactic transfusion at this level, but can be effectively transfused using a therapeutic-only strategy.⁶  The use of lower doses of platelets has been shown to be safe and effective.⁷ Similar strategies may also be applicable for outpatients.⁸

Pursuant to those patients receiving radiation therapy, historically, there have been reports in the literature that found loco-regional control to be improved in patients whose Hgb is maintained at a higher level, typically > 10 g/dL.  Many, if not most of these studies had significant confounding and have not adjusted for comorbidities.  A publication in 2012, however, concluded “…that hypoxia is a well-established cause of radio-resistance, but modification of this cannot be achieved by correcting low Hgb levels by…transfusion and/or [ESAs[.”⁹  Similarly, a recent study covering over 30 years of experience with cervical cancer patients undergoing radiation therapy (the original target population from a historical perspective) adjusted for confounders and found no evidence that anemia represented an independent predictor of outcomes associated with diagnosis or treatment. ¹°  Transfusion, in and of itself,  has significant negative immunomodulatory effects via cell-to-cell interactions and cytokines.   Thus, maintenance of Hgb levels for these patients should not be considered an absolute necessity.

Other interventions may prove successful for Hematology/Oncology patients as part of a Blood Management Program.  Identification and treatment of concomitant iron deficiency anemia or other nutritional deficiencies can potentially decrease or eliminate the need for transfusion.  Drugs that might increase the risk for bleeding or hemolysis should be eliminated if possible as these cause or potentiate anemia.  Use of new targeted drugs such as lenalidomide in patients with 5q deletion-associated MDS may prevent the need for long-term transfusion dependence. The use of antifibrinolytics in patients who have become refractory to platelet transfusions can enable platelet function even at low levels and prevent the unnecessary use of limited platelet resources.

Outpatient transfusion in the Hematology/Oncology arena comes with some unique circumstances.  Many outpatients remain stable and will be capable of lower transfusion thresholds and longer intervals for both RBCs and platelets.  Evidence-based restrictive transfusion can and should be a part of outpatient treatment strategy, just as with inpatients if the accessibility to post-transfusion care is adequate. No national guidelines are available for outpatient transfusion and each patient scenario must be considered on an individual basis, but certainly the absolute need for “standing” transfusions and obligatory 2-unit transfusions should be discouraged.  Consider, as well, that patients often have their own view of the “need” for transfusion when symptoms and signs do not necessarily make it requisite.  Discussion with our patients is essential to allow them to understand transfusion decisions.

The risks of transfusion are both immediate and delayed, particularly for those with chronic transfusion needs. Febrile non-hemolytic, allergic, hemolytic reactions, TRALI and TACO may occur as in other patient populations and should be recognized and treated as appropriate. Alloimmunization and transfusion-related iron overload are more common in the Hem/Onc arena given the potential for increased component exposure during the acute care setting and the high percentage of those that necessitate chronic transfusion support. The potential for transfusion-associated graft vs. host disease is also more worrisome given the degree of immunosuppression in these patients. Specialized products are often necessary including leukoreduced, antigen negative, irradiated or HLA-matched components.  These specialized products may not be available on a STAT basis and add significantly to the overall transfusion cost. Careful consideration is warranted and inclusion of the Transfusion Service is key.

In the end, transfusion practice for Hematology/Oncology patients should include restrictive transfusion practices with assessment of the risks and benefits at the time of each potential transfusion episode. Each patient, whether inpatient or outpatient, should be evaluated based on their current state of stability, clinical course and availability and access to care. Nutritional assessments and subsequent interventions along with pharmaceutical agents may provide additional ways by which transfusion exposure can be decreased. Special products are often necessary and needs should be discussed with the Transfusion Service. Limiting transfusion ultimately avoids unpleasant, potentially severe acute and delayed adverse events as well as preserving resources within our communities.

References:

  1. Jansen et al.  Transfus Med 2004; 14: 33
  2. Berger et al.  Haematologica 2012; 97: 116
  3. Webert et al.  Transfus 2008; 48: 81
  4. www.choosingwisely.com
  5. Kaufman et al. Ann Intern Med 2014; doi: 10.7326/M14-1589
  6. Stanworth et al. Transfus 2014; 54: 2385
  7. Slichter et al. N Engl J Med 2010; 362: 600
  8. Sagmeister et al.  Blood 1999; 93: 3124
  9. Hoff  Acta Oncologica 2012; doi: 10.3109/0284186X.2011.653438
  10. Bishop et al. Int J Radiat Oncol Biol Phys 2014; doi: 10.1016/j.ijrobp.2014.09.023

Nursing roles in blood management

Improving patient safety should always be the top priority in patient care. When we expose patients to blood transfusion we expose them to the risk of harm. Nurses can improve the safety of transfused patients by utilizing best practices at the bed side. For example, start the transfusion slowly for RBC, platelet and plasma transfusions and conduct frequent patient assessments during and after transfusion with an emphasis on the three symptoms of transfusion reaction: fever, rash and dyspnea. Keep in mind the following points when transfusing a non-hemorrhaging patient: a blood transfusion is a human tissue transplant, anemia tolerance is based on the patient’s clinical signs and symptoms, all blood products must be verified at the patient’s bedside following facility policy, only one unit of RBC’s should be transfused at a time with patient reassessment after each transfusion, monitor the patient for six hours after transfusion for signs and symptoms of an adverse reaction.

  • Thinking critically and accurately communicating symptoms of anemia, if any, with lab values can be a simplistic pivotal avenue to appropriate treatment and restrictive transfusion practice.
  • In attempts to provide the best of care and do no harm, nurses along with physicians need to understand the current evidence regarding the risks versus benefits of transfusion therapy.
  • Every nurse can support transfusion safety by implementing current blood management strategies into nursing practice.

Infuse Platelets as Slowly as Medically Necessary

Bacterial contamination of platelet products is a serious risk of transfusion. As many as 1 in every 1000 units may be contaminated from the introduction of low concentrations of skin bacteria at the time of donation, less commonly from asymptomatic underlying infection at time of donation or rarely during processing.1 In the United States, transfusion-associated sepsis has been recognized and culture-confirmed in at least 1 of 100,000 recipients, and has led to immediate fatal outcome in 1 in 500,000 recipients.2 The actual risk of transfusion-associated sepsis is likely higher, as infections due to contaminated blood products are under-reported.2

Platelets are the most common source of transfusion-associated sepsis because platelets must be stored at room temperature which allows bacterial proliferation and, platelets are often given to neutropenic patients with impaired immune system function.1

Common nursing transfusion practice today is to infuse platelet products within an hour from start time. There is no scientific evidence supporting this practice. Nurses have long been advised by Laboratorians and blood bankers to transfuse platelets “as rapidly as tolerated” by the patient. Busy nurses have interpreted this instruction to mean that the product should be infused rapidly for the benefit of the patient when in reality the laboratory professionals are advising nurses to use their critical thinking skills to determine a safe, patient specific infusion rate when the physician has not ordered an infusion rate.

By simply slowing down the infusion rate during the first 15 minutes of platelet transfusion for non-hemorrhaging patients, nurses can improve patient safety and reduce the incidence and severity of transfusion-associated sepsis. The same nursing intervention that allows nurses to immediately recognize a severe allergic or hemolytic transfusion reaction during the first 15 minutes of a pRBC transfusion should be employed with platelet transfusions. This slow rate of infusion will expose the patient to the least amount possible of a potentially contaminated product and continuous nursing assessment during the first 15 minutes allows the nurse to immediately stop the transfusion at the first sign of an adverse response to the product.

Appropriate critical nursing analysis of platelet transfusion would have the nurse recognize the risk of transfusion-associated sepsis and start platelet transfusions at a rate of 60 – 100 mL/hour for the first 15 minutes.3 After confirming that there has been no change in the patient’s clinical status by repeating the nursing assessment, the transfusion rate may be increased up to 300 mL/hour depending upon the patient’s ability to tolerate the volume.

The risk of transfusion-associated sepsis supports a cautious and deliberate approach to platelet transfusion. Nurses can reduce the risk of life threatening sepsis by slowly infusing platelets during the first 15 minutes and immediately stopping the infusion at the first sign of clinical comprise thus reducing the amount of potentially contaminated product exposure. Rather than infusing platelets as rapidly as the patient tolerates, transfuse all blood products as slowly as medically necessary.

References:

  1. Vamvakas EC. Blood still kills. Trans Med Rev 2010;24(2):77-124.
  2. http://www.CDC.gov/bloodsafety/bbp/bacterial-contamination-of-platelets.html
  3. AABB Technical Manual, 17th edition, Roback, J. et al: Bethesda, MD. 2011

Packed Red Blood Cell Transfusions and Health Care Associated Infections

Rohde J et al.  Health care-associated infection after red blood cell transfusion: A systematic review and meta-analysis. JAMA 2014; 311: 1317-1326

Transfusion of blood products is the most common procedure performed in U.S. hospitals with approximately 14 million units of blood products transfused in 2011.¹ Blood products today undergo rigorous testing to prevent disease transmission and the United States’ blood supply is safer than ever before. However, the testing of our blood supply does not prevent transfusion related immunomodulation (TRIM). TRIM represents an immune system suppression which may affect infection risk, although the pathophysiology has not been fully elucidated.

The recent meta-analysis by Rohde et al, JAMA, 2014, reviewed the link of health-care-associated infection (HCAI) and the relationship to restrictive vs. liberal transfusion practice. The researchers included 18 trials with 7593 patients. Trials were conducted in facilities in multiple countries. The meta-analysis included the well-known Transfusion Requirements in Critical Care (TRICC) trial, ³ the trial of symptomatic coronary artery disease by Carson et al.⁴ and the de Gast-Bakker and coauthors trial in pediatric cardiac patients.⁵ The study revealed an adult hemoglobin range of 6.4 g/dl to 9.7 g/dl in the restrictive groups and 9.0 g/dl to 11.3 g/dl in the liberal groups.

The meta-analysis showed an association with lower risk of serious infection in the restrictive groups even when leukoreduction was considered. The authors concluded that one patient could potentially avoid a HCAI for every 20 patients who were treated if using the restrictive strategy (target Hgb <7.0 g/dl). The authors also state that this review further supports the clinical practice guidelines set up by the AABB on restrictive use of blood and blood products.⁶

So what does this mean for those of us performing transfusion at the bedside, in our operating suites, and other clinical areas? What can we do to help prevent HCA transfusion infections in our patients?

We must remember that blood management is an evidence-based, multidisciplinary approach that includes transfusion safety. The first step in a patient-centered blood management program is to determine if the transfusion is medically necessary. Nurses and mid-level providers can have great influence, helping to reduce the number of transfusions and the total number of products transfused. The medical decision to transfuse should be considered by all members of the clinical team. The decision to transfuse a patient must include a clinical picture of the patient and is not made solely on the hemoglobin level.

The number of units of PRBCs transfused has an effect on increased patient morbidity and mortality.⁷ When transfusion is clearly indicated to improve the patient’s condition, it might not be necessary to transfuse multiple units. Single unit transfusion with reassessment of the clinical condition should be considered outside of the context of massive hemorrhage.

In conclusion, this recent review and meta-analysis by Rohde and colleagues once again highlights TRIM and the association of transfusion with HCAI. This amplifies the need for adherence to a restrictive transfusion practice for the majority of hospitalized patients.

It is vital that the health care professionals ordering or performing transfusions stay up–to-date with the latest evidence, become pro-active in preventing adverse reactions, and remain vigilant in recognizing and responding to possible transfusion-associate adverse events, including HCAIs. 

  1. Whitaker B and Hinkins S. The 2011 national blood collection and utilization survey. http://www.bloodsurvey.org.
  2. Hebert P et al. N Engl J Med. 1999; 340: 409-417
  3. Carson J et al. Am Heart J.  2013; 165: 964-971
  4. deGast-Bakker D et al. Intensive Care Med. 2013; 39: 2011-2019
  5. Carson J et al Ann Intern Med. 2012; 157: 49-58
  6. Bernard A et al.  J Am Coll Surg. 2009; 208: 931-939

The Rise of “Designer” Blood Products: 4 Factor PCCs

Blood factor concentrates are not new, but most U.S. physicians are only vaguely familiar with them.  Single or multiple blood factor concentrates were originally developed to treat patients with congenital clotting deficiencies, such as hemophilia A or B.  Although some of these clotting factors are made with recombinant technologies (such as recombinant factor VIIa), most are derived by extracting and purifying clotting factors from pooled plasma.  The post-HIV concern with this approach was that these clotting factor extracts come from pooled plasma from hundreds or thousands of donors, but the EU and now the FDA feel that pooled blood products are “safe” using mini-pool testing techniques to screen for transmissible diseases along with pathogen inactivation methods such as solvent- detergent technology.  The latest iteration of these concentrated blood factors include a combination of clotting factors designed to treat acquired clotting deficiencies from vitamin K antagonist drugs (warfarin/ Coumadin®).  These so-called four factor prothrombin complex concentrates (4F-PCCs) contain therapeutic doses of clotting factors II, VII, IX and X.  Previously available in Europe, the FDA has now approved a 4F-PCC (KCentra®) with the specific indication for the urgent reversal of vitamin K antagonist (VKA) drugs in adults with acute major bleeding.  Most recently,  Kcentra® was also approved for the urgent reversal of VKA drugs in adults needing urgent surgery or an invasive procedure. There is also active investigation on the use of 4F-PCCs as part of a management strategy for patients with bleeding on novel oral anticoagulant drugs (NOACs) such as rivaroxaban, apixaban and dabigatran1.

Sarode published a head to head study comparing safety and efficacy of a 4F-PCC (Beriplex®) to plasma (the standard of care) in patients on VKAs with an acute major bleed2.  This RCT looked at hemostatic efficacy at 24 hours (rated as excellent/good/none), time to INR correction, plasma levels of clotting factors, and adverse effects.  Overall, the 4F-PCC patients did as well or better than the plasma patients:

  • 4F-PCC was non-inferior to plasma for hemostatic efficacy at 24 hours (71% vs. 68%);
  • 4F-PCC was superior to plasma in INR reversal at 30 min post-treatment (62% vs. 10%);
  • 4F-PCC had a faster increment of FII, VII, IX, X and proteins C and S than plasma;
  • 4F- PCC had a much lower volume delivered (100 vs. 820 mL).

Of equal importance, safety endpoints were generally similar between the 4F-PCC and plasma groups and consistent with patients experiencing acute major bleeding.  Significantly, fluid overload and pulmonary edema were the most frequent adverse events, and all fluid overload events possibly related to treatment occurred in the plasma group.  This is of particular importance since transfusion associated circulatory overload (TACO) is now the leading serious transfusion related adverse event, with an incidence of 5- 6% and a mortality rate of 1- 2%3.

Given the results of this study, it should be clear that 4F-PCC will become the treatment of choice in bleeding patients on VKAs who require a rapid, low volume reversal strategy, such as patients with intracranial bleeding.  Of note, plasma is no longer indicated for the reversal of VKAs in Europe given the widespread availability of 4F-PCCs along with safety concerns for plasma. The U.S. leads the world in a number of areas of medicine, but we continue to lag behind Europe and Canada in transfusion safety.  The arrival of 4F-PCCs gives us another tool to improve patient care in a select group of patients.

Selected References

1. Levy JH, Faraoni D, Spring JL, Douketis JD, Samama CM. Managing new oral anticoagulants in the perioperative and intensive care unit setting. Anesthesiology. 2013;118(6):1466–74. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23416382. Accessed November 14, 2013.

2. Sarode R, Milling TJ, Refaai M a, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013;128(11):1234–43. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23935011. Accessed November 12, 2013.

3. Alam A, Lin Y, Lima A, Hansen M, Callum JL. The prevention of transfusion-associated circulatory overload. Transfus. Med. Rev. 2013;27(2):105–12. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23465703. Accessed December 2, 2013.

Blood Management Year in Review: Part I

This is Part I of a blog based upon my Blood Management University® year-end webinar by the same title, where I tried to hit the high points of the transfusion medicine literature.  Having been involved in implementing and continuously improving blood management programs for the past 20 years, I find it both gratifying and challenging to try and sort out the most pertinent articles since there has been an explosion of publications in this area. Continue reading

Premedication for Prevention of Transfusion Reactions: A Practice Without Evidence

Premedication-TransfusionFebrile non-hemolytic (FNHTR) and allergic transfusion (ATR) reactions have historically been reported to occur in up to 30% of transfusions, however with the use of leukoreduction and single-donor apheresis platelet products these now occur in 2-3% of patients.1-2 This might be slightly higher in those patients that are transfusion dependent. Although these reactions, if indeed isolated, tend to be mild in their symptomatology, they may also be harbingers of more serious transfusion-associated adverse events. These reactions also cause concern for patients, most of whom have critical diseases necessitating concomitant complex therapies. Continue reading

Stewardship: Waste Not, Want Not

STEWARDSHIP-GRAHPIC-RED

A publication in the upcoming Transfusion journal reports on a successful and practical initiative to reduce blood component wastage via a targeted team approach surrounding blood transport and storage. 1

The national wastage rate for blood products within the United States may be as high as 6% with up to 70% of wastage occurring within our operating suites.2 Most of this is due to improper transport and storage. Continue reading

Transfusion in sepsis: the controversy continues

sepsis-bullseyeRed blood cell (RBC) transfusion in septic patients remains a controversial topic. The well-known and often quoted article by Rivers et al. in New England Journal of Medicine, 2001, was one of the first to attempt to define a protocol for transfusion along with primary use of fluid resuscitation, vasopressors and inotropic agents.¹ The assumption and hope of incorporating RBC transfusion into what was deemed “Early Goal-Directed Therapy” (EGDT) was that anemic septic patients would acquire an increased O₂ delivery during this critical timeframe. Continue reading