Patient blood management: Myths and facts about red blood cell transfusions.

Transfusion medicine resembles all of medicine in that expert opinion predominates because hard data on clinical outcomes from randomized controlled trials and high quality observational data are simply unavailable. Indeed, some of the first trials evaluating important outcomes are barely two decades old. Patient blood management (PBM) depends on high quality data for assisting clinicians in making clinical decisions. In this review, we focus on several red blood cell (RBC) transfusion practices that new data suggest need reconsideration. The practices that may need revision include transfusion for iron deficiency anaemia, except in life threatening situations, toleration of anaemia as a largely benign condition and use of haemoglobin/haematocrit as primary indications for RBC transfusion, as opposed to adjuncts to clinical judgement. In addition, the long-standing notion that the minimum transfusion should be two units needs to be abandoned due to the danger to patients and a lack of clinical evidence of benefit. Finally, the difference in indications for leucoreduction versus irradiation needs to be understood by all practitioners. PBM is one of the strategies for managing anaemia and bleeding that holds great promise for patients, and transfusion is only one facet of the bundle of practices.

Reduction of anti-A and anti-B isoagglutinin titers of group O whole blood units employing an ABO antibody immune adsorption column.

BACKGROUND: Massive hemorrhage is a leading cause of death from trauma. There is growing interest in group O whole blood transfusions to mitigate coagulopathy and hemorrhagic shock. Insufficient availability of low-titer group O whole blood is a barrier to routine use. We tested the efficacy of the Glycosorb® ABO immunoadsorption column to reduce anti-A/B titers in group O whole blood. METHODS: Six group O whole blood units were collected from healthy volunteers, and centrifuged to separate platelet poor plasma. Platelet-poor plasma was filtered through a Glycosorb® ABO antibody immunoabsorption column, then reconstituted to prepare post-filtration whole blood. Anti-A/B titers, CBC, free hemoglobin, and thromboelastography (TEG) assays were performed on pre-and post-filtration whole blood. RESULTS: Mean( ± SEM) anti-A (224 ± 65 pre vs 13 ± 4 post) and anti-B (138 ± 38 pre vs 11 ± 4 post) titers were significantly reduced (p = 0.004) in post-filtration whole blood. No significant changes were detected in CBC, free hemoglobin, and TEG parameters on day 0. Free hemoglobin increased throughout storage (48 mg/dl ± 24 Day 0 vs 73 ± 35 Day 7 vs 96 ± 44 Day 14; p = 0.14). CONCLUSIONS: The Glycosorb® ABO column can significantly reduce anti-A/B isoagglutinin titers of group O whole blood units. Glycosorb® ABO could be employed to provide whole blood with lower risk of hemolysis and other consequences of infusing ABO incompatible plasma. Preparation of group O whole blood with substantially reduced anti-A/B would also increase the supply of low-titer group O whole blood for transfusion.

Association of crystalloid fluid infusion with intravascular hemolysis and organ dysfunction in hematopoietic stem cell transplant patients.

Endothelial cell activation and injury is common after hematopoietic stem cell transplant (HSCT) and is associated with many post-transplant complications. An underexplored mechanism of endothelial cell damage in this population is the infusion of normal saline (NS, 0.9 % sodium chloride) and other crystalloids, as NS use is associated with adverse outcomes in other patient populations. We hypothesized that the infusion of unbalanced crystalloids during HSCT may lead to changes in biomarkers commonly associated with red blood cell (RBC) hemolysis in patients before and after infusion, and that markers of endothelial and end-organ damage during admission may be associated with markers of hemolysis and total crystalloid use. Samples were collected from 97 patients. From pre-fluid infusion to post-fluid infusion, mean haptoglobin decreased (11.7 ug/ml vs 8.4 ug/ml; p < 0.0001), hemopexin decreased (549 vs 512 µg/ml; p = 0.005), and red cell distribution width (RDW) decreased (15.7 vs 15.6; p = 0.0009). During admission (mean 19.4 days, SD 9.9), all markers of tissue and organ damage, including mean creatinine, lactate dehydrogenase (LDH), blood urea nitrogen (BUN), total bilirubin, AST, and ALT, increased from admission to peak levels (p < 0.0001). On linear regression, fluid volume (ml/kg) of crystalloid infusion positively predicted post-fluid infusion cell-free hemoglobin (r(96) = 0.34, p < 0.0001), free heme (r(96) = 0.36, p < 0.0001), and peak LDH during admission (r(75) = 0.23, p = 0.041), and negatively predicted post-fluid infusion hemopexin (r(96) = - 0.34, p < 0.0001). Unbalanced crystalloids may contribute to hemolysis and endothelial damage in HSCT patients. Alternatives such as buffered crystalloid solutions (PlasmaLyte, Lactated Ringer's) may be worth investigating in this population.

Patient Blood Management: Improving Outcomes for Millions While Saving Billions. What Is Holding It Up?

Patient blood management (PBM) offers significantly improved outcomes for almost all medical and surgical patient populations, pregnant women, and individuals with micronutrient deficiencies, anemia, or bleeding. It holds enormous financial benefits for hospitals and payers, improves performance of health care providers, and supports public authorities to improve population health. Despite this extraordinary combination of benefits, PBM has hardly been noticed in the world of health care. In response, the World Health Organization (WHO) called for its 194 member states, in its recent Policy Brief, to act quickly and decidedly to adopt national PBM policies. To further support the WHO's call to action, this article addresses 3 aspects in more detail. The first is the urgency from a health economic perspective. For many years, growth in health care spending has outpaced overall economic growth, particularly in aging societies. Due to competing economic needs, the continuation of disproportionate growth in health care spending is unsustainable. Therefore, the imperative for health care leaders and policy makers is not only to curb the current spending rate relative to the gross domestic product (GDP) but also to simultaneously improve productivity, quality, safety of patient care, and the health status of populations. Second, while PBM meets these requirements on an exceptional scale, uptake remains slow. Thus, it is vital to identify and understand the impediments to broad implementation. This includes systemic challenges such as the so-called "waste domains" of failure of care delivery caused by malfunctions of health care systems, failure of care coordination, overtreatment, and low-value care. Other impediments more specific to PBM are the misperception of PBM and deeply rooted cultural patterns. Third, understanding how the 3Es-evidence, economics, and ethics-can effectively be used to motivate relevant stakeholders to take on their respective roles and responsibilities and follow the urgent call to implement PBM as a standard of care.

Preoperative anemia management program reduces blood transfusion in elective cardiac surgical patients, improving outcomes and decreasing hospital length of stay.

BACKGROUND: Anemia is an independent risk factor for hospitalization, readmission, prolonged length of stay (LOS), diminished quality of life, and mortality. A multidisciplinary program was implemented to manage anemia preoperatively as a patient blood management (PBM) initiative. METHODS AND MATERIALS: From March 2016 to August 2018, 240 patients were screened for anemia during their preoperative cardiovascular visit. About 52/240 (22%) were found to be anemic and met out inclusion criteria. Also, 45/52 (87%) had iron deficiency anemia and 7 (13%) had anemia without iron deficiency. A similar historical cohort of patients undergoing elective cardiovascular surgery with hemoglobin (Hb) < 12 g/dl from September 2014 to February /2016 (n = 52) served as control group. The primary outcome was perioperative red blood cell (RBC) transfusion. Secondary outcomes were date-of-surgery Hb, intensive care unit (ICU) and hospital LOS, complication rates, and transfusion cost. RESULTS: The two most common treatments were IV iron ± folate (n = 36/45; 80%) and oral iron (n = 9/45; 20%). As compared to historical patients, study patients had significantly higher day-of-surgery Hb (10.6 ± 1.4 vs. 9.8 ± 1.3 g/dl, p < .001), lower utilization of RBC transfusion (0.86 ± 1.4 vs. 2.78 ± 2.4, p < .001), fewer days in the ICU (2.1 ± 2.0 vs. 4.0 ± 3.5, p = .002), and shorter total LOS (6.9 ± 4.8 vs. 12.9 ± 6.8, p < .0001). Study patients also showed lower overall complication rates (p < .0001). Analysis of RBC acquisition cost and transfusion cost also showed significant saving of 69% ($293 vs. $945 and $656 vs. $2116, respectively). CONCLUSION: When corrected for type of procedures and surgeon, our pilot anemia program in elective cardiovascular surgeries showed higher day-of-surgery Hb and significant reduction in RBC transfusion rates, ICU and hospital LOS, and overall complication rates.

Whole blood haemostatic function throughout a 28-day cold storage period: an in vitro study.

BACKGROUND: In recent years, there has been renewed interest in whole blood (WB) transfusion, particularly in damage control resuscitation, in part due to the ability to provide the adequate ratio of blood components in a single transfusion. However, there is insufficient evidence to suggest that WB units maintain their haemostatic function during storage, which could compromise their quality and efficacy if transfused. Here, we evaluate the in vitro haemostatic function of stored WB units over a 28-day refrigeration period. METHODS: Standard WB units were collected from healthy volunteers and stored at 4°C for 28 days. Samples were collected from each unit on several days throughout the storage period and tested for complete blood count (CBC), WB aggregation, clot kinetics as measured by thromboelastography (TEG), closure time and plasma-free haemoglobin. RESULTS: Throughout the storage period, there were gradual, significant decreases in platelet count and function, including WB aggregation in response to collagen (P < 0·05) and closure time with epinephrine (P < 0·0005). Plasma-free haemoglobin increased substantially (by 163%) throughout the storage period. However, TEG results remained relatively stable for 3 weeks, indicating possible preservation of haemostatic function during that time. CONCLUSION: This study shows that clot kinetics (as measured by TEG) in WB units stored at 4°C are preserved for up to 21 days. However, high levels of free haemoglobin raise concern for the potential risks of transfusing stored WB. Clinical studies are required to evaluate optimal storage times and outcomes of patients resuscitated with WB as compared to blood components.

Evaluation of the procoagulant properties of a newly developed platelet modified lysate product.

BACKGROUND: Platelet transfusion is associated with logistical problems with the national storage guidelines of platelets. This results in decreased function in vivo as a result of the platelet storage lesion, and complications such as allergic or hemolytic reactions and thrombosis. We evaluated a new, freshly prepared platelet modified lysate (PML) product designed to be more procoagulant than fresh and stored platelets. METHODS: Fresh platelets were concentrated, sonicated, and centrifuged to produce PML. Samples of both washed and unwashed PML were evaluated for particle size, concentration, and activity, and then tested for clot kinetics and thrombin generation. PML samples were also stored at various temperatures for durations up to 6 months and evaluated for clot kinetics and thrombin generation throughout. RESULTS: PML showed significantly higher concentration of platelet microparticles, increased procoagulant properties, and increased thrombin generation as compared to fresh and stored platelets. In addition, PML maintained its clot kinetics over a 6-month storage period with variable storage conditions. CONCLUSIONS: The newly proposed PML product is more procoagulant, stable, and has additional potential applications than currently available platelet products. Further studies will be performed to assess its functions in vivo and to assess thrombotic potential.

Allogeneic Leukocyte-Reduced Red Blood Cell Transfusion Is Associated with Postoperative Infectious Complications and Cancer Recurrence after Colon Cancer Resection.

BACKGROUND/AIMS: Transfusion rates in colon cancer surgery are traditionally very high. Allogeneic red blood cell (RBC) transfusions are reported to induce immunomodulation that contributes to infectious morbidity and adverse oncologic outcomes. In an effort to attenuate these effects, the study institution implemented a universal leukocyte reduction protocol. The purpose of this study was to examine the impact of leukocyte-reduced (LR) transfusions on postoperative infectious complications, recurrence-free survival, and overall survival (OS). METHODS: In a retrospective study, patients with stage I-III adenocarcinoma of the colon from 2003 to 2010 who underwent elective resection were studied. The primary outcome measures were postoperative infectious complications and recurrence-free and OS in patients that received a transfusion. Bivariate and multivariable regression analyses were performed for each endpoint. RESULTS: Of 294 patients, 66 (22%) received a LR RBC transfusion. After adjustment, transfusion of LR RBCs was found to be independently associated with increased infectious complications (OR 3.10, 95% CI 1.24-7.73), increased odds of cancer recurrence (hazard ratio [HR] 3.74, 95% CI 1.94-7.21), and reduced OS when ≥3 units were administered (HR 2.24, 95% CI 1.12-4.48). CONCLUSION: Transfusion of LR RBCs is associated with an increased risk of infectious complications and worsened survival after elective surgery for colon cancer, irrespective of leukocyte reduction.

Total plasma heme concentration increases after red blood cell transfusion and predicts mortality in critically ill medical patients.

BACKGROUND: Relationships between red blood cell (RBC) transfusion, circulating cell-free heme, and clinical outcomes in critically ill transfusion recipients are incompletely understood. The goal of this study was to determine whether total plasma heme increases after RBC transfusion and predicts mortality in critically ill patients. STUDY DESIGN AND METHODS: This was a prospective cohort study of 111 consecutive medical intensive care patients requiring RBC transfusion. Cell-free heme was measured in RBC units before transfusion and in the patients' plasma before and after transfusion. RESULTS: Total plasma heme levels increased in response to transfusion, from a median (interquartile range [IQR]) of 35 (26-76) µmol/L to 47 (35-73) µmol/L (p < 0.001). Posttransfusion total plasma heme was higher in nonsurvivors (54 [35-136] µmol/L) versus survivors (44 [31-65] µmol/L, p = 0.03). Posttransfusion total plasma heme predicted hospital mortality (odds ratio [95% confidence interval] per quartile increase in posttransfusion plasma heme, 1.76 [1.17-2.66]; p = 0.007). Posttransfusion total plasma heme was not correlated with RBC unit storage duration and weakly correlated with RBC unit cell-free heme concentration. CONCLUSIONS: Total plasma heme concentration increases in critically ill patients after RBC transfusion and is independently associated with mortality. This transfusion-associated increase in total plasma heme is not fully explained by RBC unit storage age or cell-free heme content. Additional studies are warranted to define mechanisms of transfusion-related plasma heme accumulation and test prevention strategies.

The effect of red blood cell transfusion on iron metabolism in critically ill patients.

BACKGROUND: Anemia of inflammation (AI) has a high prevalence in critically ill patients. In AI, iron metabolism is altered, as high levels of inflammation-induced hepcidin reduce the amount of iron available for erythropoiesis. AI is treated with red blood cell (RBC) transfusions. The effect of RBC transfusion on iron metabolism during inflammatory processes in adults is unknown. We investigated the effect of RBC transfusion on iron metabolism in critically ill patients. METHODS: In a prospective cohort study in 61 critically ill patients who received 1 RBC unit, levels of iron variables were determined before, directly after, and 24 hours after transfusion in septic and nonseptic patients. RESULTS: Serum iron levels were low and increased after transfusion (p = 0.02). However, RBC transfusion had no effect on transferrin saturation (p = 0.14) and ferritin levels (p = 0.74). Hepcidin levels increased after RBC transfusion (p = 0.01), while interleukin-6 levels decreased (p = 0.03). In septic patients, RBC transfusion induced a decrease in haptoglobin levels compared to baseline, which did not occur in nonseptic patients (p = 0.01). The effect of RBC transfusion on other iron variables did not differ between septic and nonseptic patients. CONCLUSION: Transfusion of a RBC unit transiently increases serum iron levels in intensive care unit patients. The increase in hepcidin levels after transfusion can further decrease iron release from intracellular storage making it available for erythropoiesis. RBC transfusion is associated with a decrease in haptoglobin levels in septic compared to nonseptic patients, but did not affect other markers of hemolysis.

Sickle red blood cells are more susceptible to in vitro haemolysis when exposed to normal saline versus Plasma-Lyte A.

BACKGROUND: Normal saline has been the fluid of choice for resuscitation, rehydration and fluid replacement during plasma or red cell exchange/cytapheresis. There are increased concerns about its clinical effects and data showing it causes more haemolysis in vitro than buffered solutions such as Plasma-Lyte A. METHODS: We investigated whether normal saline or Plasma-Lyte A was associated with greater haemolysis during hours of in vitro incubation with both normal red cells and samples from patients with sickle cell anaemia. RESULTS: Sickle red cells haemolysed more than normal red cells did in both crystalloid solutions. The results of 24-hour exposure to saline were particularly striking (median of 163 mg/dl (IQ range 105-247) for sickle red cells vs. 53 (48-92) for normal red cells (P < 0·0001). In patient samples containing variable quantities of haemoglobin S red cells, increased haemoglobin S was associated with increased haemolysis. This effect was greater for normal saline than Plasma-Lyte A (P = 0·12). CONCLUSIONS: These in vitro models demonstrate that short-term ex vivo exposure of sickle red cells to normal saline leads to greater haemolysis than short-term exposure of normal red cells, and this effect is exacerbated by normal saline. Whether use of normal saline causes increased haemolysis in vivo is unknown. Given recent evidence that normal saline increases renal failure and mortality in critically ill patients, further studies are urgently needed.

Placental Chorionic Cyst Fluid Has Prothrombotic Properties and Differs From Amniotic Fluid.

INTRODUCTION: Chorionic cysts of the chorion laeve, fetal chorionic plate, septum, and free membranes have been associated with placental hypoxia, but they have no clear clinical significance. Although immunohistochemistry has identified fibronectin and collagen IV in cyst fluid, the contents have yet to be fully characterized. METHODS: Placental chorionic cysts (N = 10) were sampled by fluid extraction and hemotoxylin and eosin-stained sections. Amniotic fluid samples (N = 8) were obtained from pregnant women who had cytogenetic evaluation. The content of the cysts was tested for thrombogenicity using thromboelastography. The cyst content was tested by Luminex multiplex and ELISA assays and for known prothrombotic and proinflammatory factors. RESULTS: We identified cysts, especially those in the chorionic plate, adjacent to intervillous thrombi with apparent cyst rupture. Thromboelastography revealed a significantly shorter R time compared to whole blood control samples. Concentration of creatinine, α-fetoprotein, and surfactant D in the cyst fluid differed significantly from amniotic fluid. Cyst fluids had a significantly higher expression of all prothrombotic and some proinflammatory factors. DISCUSSION: Our data provide the first evidence that chorionic cyst fluid is prothrombotic and different from amniotic fluid. The association of ruptured cysts with adjacent thrombi and the prothrombotic properties of cyst fluid suggest a causal relationship; however, further studies are needed.

Transfusion medicine: A research agenda for the coming years.

The important scientific and clinical advances of the last century in transfusion medicine include methods for avoiding hemolytic transfusion reactions and preventing transmission of viral infectious diseases. The next great clinical advances will require improving the efficacy and safety of transfusions, as well as acknowledgement of the now proven serious complications of transfusion, including nosocomial infection, thrombosis, inflammation and multi-organ failure. Possible strategies include (1) universal leukoreduction to mitigate transfusion immunomodulation effects and improve storage conditions, (2) minimizing transfusion of ABO incompatible antibodies and cellular/soluble antigens, (3) substituting use of safer solutions for normal saline during apheresis, component infusion and washing (4) new techniques to improve the efficacy and safety of blood components, including improved storage solutions/conditions, supernatant removal by washing, and rejuvenation and (5) maximizing the risk to benefit ratio of transfusions by employing more restrictive and physiologic indications for transfusion (including patient blood management) and improving clinical decision making through novel laboratory and bedside tests such as thromboelastography.

Transfusion of fresher vs older red blood cells in hospitalized patients: a systematic review and meta-analysis.

The impact of transfusing fresher vs older red blood cells (RBCs) on patient-important outcomes remains controversial. Two recently published large trials have provided new evidence. We summarized results of randomized trials evaluating the impact of the age of transfused RBCs. We searched MEDLINE, EMBASE, CINAHL, the Cochrane Database for Systematic Reviews, and Cochrane CENTRAL for randomized controlled trials enrolling patients who were transfused fresher vs older RBCs and reported outcomes of death, adverse events, and infection. Independently and in duplicate, reviewers determined eligibility, risk of bias, and abstracted data. We conducted random effects meta-analyses and rated certainty (quality or confidence) of evidence using the GRADE approach. Of 12 trials that enrolled 5229 participants, 6 compared fresher RBCs with older RBCs and 6 compared fresher RBCs with current standard practice. There was little or no impact of fresher vs older RBCs on mortality (relative risk [RR], 1.04; 95% confidence interval [CI], 0.94-1.14; P = .45; I(2) = 0%, moderate certainty evidence) or on adverse events (RR, 1.02; 95% CI, 0.91-1.14; P = .74; I(2) = 0%, low certainty evidence). Fresher RBCs appeared to increase the risk of nosocomial infection (RR, 1.09; 95% CI, 1.00-1.18; P = .04; I(2) = 0%, risk difference 4.3%, low certainty evidence). Current evidence provides moderate certainty that use of fresher RBCs does not influence mortality, and low certainty that it does not influence adverse events but could possibly increase infection rates. The existing evidence provides no support for changing practices toward fresher RBC transfusion.

Mechanisms of red blood cell transfusion-related immunomodulation.

Red blood cell (RBC) transfusion is common in critically ill, postsurgical, and posttrauma patients in whom both systemic inflammation and immune suppression are associated with adverse outcomes. RBC products contain a multitude of immunomodulatory mediators that interact with and alter immune cell function. These interactions can lead to both proinflammatory and immunosuppressive effects. Defining clinical outcomes related to immunomodulatory effects of RBCs in transfused patients remains a challenge, likely due to complex interactions between individual blood product characteristics and patient-specific risk factors. Unpacking these complexities requires an in-depth understanding of the mechanisms of immunomodulatory effects of RBC products. In this review, we outline and classify potential mediators of RBC transfusion-related immunomodulation and provide suggestions for future research directions.

Elevated free hemoglobin and decreased haptoglobin levels are associated with adverse clinical outcomes, unfavorable physiologic measures, and altered inflammatory markers in pediatric cardiac surgery patients.

BACKGROUND: There are data suggesting that free hemoglobin (Hb), heme, and iron contribute to infection, thrombosis, multiorgan failure, and death in critically ill patients. These outcomes may be mitigated by haptoglobin. STUDY DESIGN AND METHODS: 164 consecutively treated children undergoing surgery for congenital heart disease were evaluated for associations between free Hb and haptoglobin and clinical outcomes, physiologic metrics, and biomarkers of inflammation RESULTS: Higher perioperative free Hb levels (and lower haptoglobin levels) were associated with mortality, nosocomial infection, thrombosis, hours of intubation and inotropes, increased interleukin-6, peak serum lactate levels, and lower nadir mean arterial pressures. The median free Hb in patients without infection (30 mg/dL; 29 interquartile range [IQR], 24-52 mg/dL) was lower than in those who became infected (39 mg/dL; IQR, 33-88 mg/ 31 dL; p = 0.0046). The median mechanical ventilation requirements were 19 (IQR, 7-72) hours in patients with higher levels of haptoglobin versus 48 (IQR, 18-144) hours in patients with lower levels (p = 0.0047). Transfusion dose, bypass duration, and complexity of surgery were all significantly correlated with Hb levels and haptoglobin levels. Multivariate analyses demonstrated that these variables were independently and significantly associated with outcomes. CONCLUSIONS: Elevated pre- and postoperative levels of free Hb and decreased levels of haptoglobin were associated with adverse clinical outcomes, inflammation, and unfavorable physiologic metrics. Transfusion, RACHS score, and duration of bypass were associated with increased free Hb and decreased haptoglobin. Further investigation of the role of hemolysis and haptoglobin as potential mediators or markers of outcomes is warranted.

Indications for red cell transfusions in pediatric patients.

Red cell transfusions are amongst the most common therapeutic procedures in seriously ill children, particularly in the inpatient setting. This is despite the fact that there is no evidence base for most clinical settings, with the exception of patients with hemoglobinopathies, particularly thalassemia and sickle cell anemia. Obviously exsanguinating hemorrhage and life threatening anemia are urgent indications for which no other therapeutic approach is currently available. Most transfusions are, however, given prophylactically to prevent the complications of hypoxia or hemodynamic stability, based upon expert opinion and a faith in the oxygen carrying capacity and beneficial hemodynamic properties of transfused red cells. The question confronting current day pediatric practice is to what extent transfused red cells prevent adverse events, other than in thalassemia and sickle cell anemia, as opposed to causing them. Do transfusions of red cells prevent organ failure, stroke, etc. or not? There is epidemiologic evidence in the adult randomized trial literature that liberal red cell transfusion likely causes more such adverse events than it prevents. The relevance of such studies to children, particularly neonates, is uncertain. Randomized trials in critically ill neonates have yielded little to no evidence that liberal red cell transfusion is beneficial, but the data are not definitive. In critically ill older children the data suggest there is no benefit to liberal red cell transfusion, but the indications for red cell transfusion are uncertain. Most practitioners would agree that combining laboratory data such hemoglobin/hematocrit with clinical indications for transfusions (evidence of end organ hypoxia such as tachycardia, shortness of breath, etc.) is the only viable strategy at present, until more definitive randomized trial data are available.