Parenteral iron therapy and phosphorus homeostasis: A review.

Phosphorus has an essential role in cellular and extracellular metabolism; maintenance of normal phosphorus homeostasis is critical. Phosphorus homeostasis can be affected by diet and certain medications; some intravenous iron formulations can induce renal phosphate excretion and hypophosphatemia, likely through increasing serum concentrations of intact fibroblast growth factor 23. Case studies provide insights into two types of hypophosphatemia: acute symptomatic and chronic hypophosphatemia, while considering the role of pre-existing conditions and comorbidities, medications, and intravenous iron. This review examines phosphorus homeostasis and hypophosphatemia, with emphasis on effects of iron deficiency and iron replacement using intravenous iron formulations.

Frequency and Associated Costs of Anaphylaxis- and Hypersensitivity-Related Adverse Events for Intravenous Iron Products in the USA: An Analysis Using the US Food and Drug Administration Adverse Event Reporting System.

INTRODUCTION AND OBJECTIVE: Intravenous iron preparations rapidly correct iron deficiency anemia, with the notable drug class effect of rare, yet potentially life-threatening, administration-related hypersensitivity or anaphylactic reactions. The objective of this comparative study was to assess adverse events associated with four intravenous iron preparations and estimated medical costs, in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: Cases of hypersensitivity reactions and anaphylaxis/anaphylactic shock associated with iron dextran, iron sucrose, ferumoxytol, and ferric carboxymaltose, spontaneously reported to FAERS (1 January, 2014 to 31 December, 2019), were extracted. The reporting odds ratio lower bound 90% confidence interval (ROR05) > 1 and cases ≥ 5 defined a likely signal for a drug-adverse event association. Adverse event-associated medical costs were estimated using Agency for Healthcare Research and Quality/Healthcare Cost and Utilization Project 2016 data. RESULTS: For hypersensitivity reactions, ferumoxytol and iron dextran had the highest ROR05 values (5.00 and 4.35, respectively) and greatest proportions of associated deaths (7.1% and 5.3%), followed by iron sucrose (ROR05 3.94, deaths 2.4%), and ferric carboxymaltose (ROR05 3.03, deaths 0.2%). For anaphylaxis/anaphylactic shock, ROR05 for cases/deaths were: 39.32/13.4%, ferumoxytol; 37.80/4.5%, iron dextran; 17.60/4.7%, iron sucrose; and 8.77/no deaths, ferric carboxymaltose. Downstream medical costs per adverse event were highest with iron dextran (US$8615) and ferumoxytol (US$8164), followed by iron sucrose (US$4212), and ferric carboxymaltose (US$1832). CONCLUSIONS: Reporting rates of hypersensitivity and anaphylaxis with intravenous iron preparations were highest with ferumoxytol and lowest with ferric carboxymaltose in the US FAERS database. Adverse event-related medical costs were highest for iron dextran and ferumoxytol, and lowest for ferric carboxymaltose.

Iron Administration, Infection, and Anemia Management in CKD: Untangling the Effects of Intravenous Iron Therapy on Immunity and Infection Risk.

Patients with chronic kidney disease (CKD) are at increased risk for infection, attributable to immune dysfunction, increased exposure to infectious agents, loss of cutaneous barriers, comorbid conditions, and treatment-related factors (eg, hemodialysis and immunosuppressant therapy). Because iron plays a vital role in pathogen reproduction and host immunity, it is biologically plausible that intravenous iron therapy and/or iron deficiency influence infection risk in CKD. Available data from preclinical experiments, observational studies, and randomized controlled trials are summarized to explore the interplay between intravenous iron and infection risk among patients with CKD, particularly those receiving maintenance hemodialysis. The current evidence base, including data from a recent randomized controlled trial, suggests that proactive judicious use of intravenous iron (in a manner that minimizes the accumulation of non-transferrin-bound iron) beneficially replaces iron stores while avoiding a clinically relevant effect on infection risk. In the absence of an urgent clinical need, intravenous iron therapy should be avoided in patients with active infection. Although serum ferritin concentration and transferrin saturation can help guide clinical decision making about intravenous iron therapy, definition of an optimal iron status and its precise determination in individual patients remain clinically challenging in CKD and warrant additional study.

How I treat anemia in the perisurgical setting.

Anemia is a common finding in the perioperative setting with significant untoward consequences including worsening of outcomes and diminished quality of life as well as increased risk of allogeneic blood transfusions. Here, we present 3 cases that illustrate how anemia can be perioperatively managed in patients undergoing cardiac, orthopedic, and oncology surgeries. Timely detection of anemia prior to high-blood loss surgeries can allow clinicians to manage it and optimize hemoglobin level, making patients better prepared for the surgery. Treatment of anemia should be guided by the etiology and may include erythropoietic agents, folic acid, B12, and iron preparations. Other blood management strategies geared toward reducing surgical blood loss such as autologous transfusion techniques and agents to optimize hemostasis are used during surgery and in the immediate postoperative period. Patients should be closely monitored following surgery for signs of ongoing bleeding in need of control. Finally, screening for and management of anemia should continue in the postoperative and postdischarge period, as persistence and recurrence of anemia can further undermine patient's outcomes.

Establishing a Satellite Transfusion Service Within an Academic Medical Center.

OBJECTIVES: Increasingly complex medical care requires specialized transfusion support close at hand. Hospital growth can necessitate expansion of blood bank services to new locations to ensure rapid delivery of blood products. We describe the opening of a new satellite transfusion service designed to serve the needs of a pediatric hospital. METHODS: Institutional transition teams and stakeholders collaborated to discuss options for providing blood at a new pediatric hospital. A staffed satellite transfusion service met the diverse needs of multiple services and was considered a compromise between a full new transfusion service and automated solutions. RESULTS: Initial challenges in establishing the laboratory included regulatory uncertainty and interactions between two hospitals' information technology services. Laboratory scientist staffing and actual use required adapting the satellite service to an emergency release-only model. CONCLUSIONS: A flexibly staffed satellite transfusion service met the most urgent needs of a pediatric hospital expansion. Review of implementation revealed potential process improvements for future expansions, including comprehensive routine and massive transfusion simulations. The challenges experienced in supplying staff and specialized blood products track with national trends. Other institutions may consider establishing a satellite transfusion service in the context of both increasingly sophisticated automated solutions and complex blood needs.

Anemia of inflammation.

Anemia of inflammation (AI), also known as anemia of chronic disease (ACD), is regarded as the most frequent anemia in hospitalized and chronically ill patients. It is prevalent in patients with diseases that cause prolonged immune activation, including infection, autoimmune diseases, and cancer. More recently, the list has grown to include chronic kidney disease, congestive heart failure, chronic pulmonary diseases, and obesity. Inflammation-inducible cytokines and the master regulator of iron homeostasis, hepcidin, block intestinal iron absorption and cause iron retention in reticuloendothelial cells, resulting in iron-restricted erythropoiesis. In addition, shortened erythrocyte half-life, suppressed erythropoietin response to anemia, and inhibition of erythroid cell differentiation by inflammatory mediators further contribute to AI in a disease-specific pattern. Although the diagnosis of AI is a diagnosis of exclusion and is supported by characteristic alterations in iron homeostasis, hypoferremia, and hyperferritinemia, the diagnosis of AI patients with coexisting iron deficiency is more difficult. In addition to treatment of the disease underlying AI, the combination of iron therapy and erythropoiesis-stimulating agents can improve anemia in many patients. In the future, emerging therapeutics that antagonize hepcidin function and redistribute endogenous iron for erythropoiesis may offer additional options. However, based on experience with anemia treatment in chronic kidney disease, critical illness, and cancer, finding the appropriate indications for the specific treatment of AI will require improved understanding and a balanced consideration of the contribution of anemia to each patient's morbidity and the impact of anemia treatment on the patient's prognosis in a variety of disease settings.

Real-Time Clinical Decision Support Decreases Inappropriate Plasma Transfusion.

OBJECTIVES: To curtail inappropriate plasma transfusions, we instituted clinical decision support as an alert upon order entry if the patient's recent international normalized ratio (INR) was 1.7 or less. METHODS: The alert was suppressed for massive transfusion and within operative or apheresis settings. The plasma order was automatically removed upon alert acceptance while clinical exception reasons allowed for continued transfusion. Alert impact was studied comparing a 7-month control period with a 4-month intervention period. RESULTS: Monthly plasma utilization decreased 17.4%, from a mean ± SD of 3.40 ± 0.48 to 2.82 ± 0.6 plasma units per hundred patient days (95% confidence interval [CI] of difference, -0.1 to 1.3). Plasma transfused below an INR of 1.7 or less decreased from 47.6% to 41.6% (P = .0002; odds ratio, 0.78; 95% CI, 0.69-0.89). The alert recommendation was accepted 33% of the time while clinical exceptions were chosen in the remaining cases (active bleeding, 31%; other clinical indication, 33%; and apheresis, 2%). Alert acceptance rate varied significantly among different provider specialties. CONCLUSIONS: Clinical decision support can help curtail inappropriate plasma use but needs to be part of a comprehensive strategy including audit and feedback for comprehensive, long-term changes.

"Simplified International Recommendations for the Implementation of Patient Blood Management" (SIR4PBM).

BACKGROUND: More than 30% of the world's population are anemic with serious medical and economic consequences. Red blood cell transfusion is the mainstay to correct anemia, but it is also one of the top five overused procedures and carries its own risk and cost burden. Patient blood management (PBM) is a patient-centered and multidisciplinary approach to manage anemia, minimize iatrogenic blood loss, and harness tolerance to anemia in an effort to improve patient outcome. Despite resolution 63.12 of the World Health Organization in 2010 endorsing PBM and current guidelines which include evidence-based recommendations on the use of diagnostic/therapeutic resources to provide better health care, many hospitals have yet to implement PBM in routine clinical practice. METHOD AND RESULTS: A number of experienced clinicians developed the following "Simplified International Recommendations for Patient Blood Management." We propose a series of simple, cost-effective, best-practice, feasible, and evidence-based measures that will enable any hospital to reduce both anemia prevalence on the day of intervention/surgery and anemia-related unnecessary transfusion in surgical and medical patients, including obstetrics and gynecology.

Zika Virus and Patient Blood Management.

Sporadic Zika virus infections had only occurred in Africa and Asia until an outbreak in Micronesia (Oceania) in 2007. In 2013 to 2014, several outer Pacific Islands reported local outbreaks. Soon thereafter, the virus was likely introduced in Brazil from competing athletes from French Polynesia and other countries that participated in a competition there. Transmission is thought to have occurred through mosquito bites and spread to the immunologically naive population. Being also a flavivirus, the Zika virus is transmitted by the Aedes mosquito that is endemic in South and Central America that is also the vector of West Nile virus, dengue, and chikungunya. In less than a year, physicians in Brazil reported a many-fold increase in the number of babies born with microcephaly. Despite initial skepticism regarding the causal association of the Zika virus epidemic and birth defects, extensive basic and clinical research evidence has now confirmed this relationship. In the United States, more than 4000 travel-associated infections have been reported by the middle of 2016 to the Centers for Disease Control and Prevention. Furthermore, many local mosquito-borne infections have occurred in Puerto Rico and Florida. Considering that the virus causes a viremia in which 80% of infected individuals have no symptoms, the potential for transfusion transmission from an asymptomatic blood donor is high if utilizing donor screening alone without testing. Platelet units have been shown to infect 2 patients via transfusion in Brazil. Although there was an investigational nucleic acid test available for testing donors, not all blood centers were initially required to participate. Subsequently, the US Food and Drug Administration issued a guidance in August 2016 that recommended universal nucleic acid testing for the Zika virus on blood donors.In this report, we review the potentially devastating effects of Zika virus infection during pregnancy and its implication in cases of Guillain-Barre syndrome in adults. Furthermore, we urge hospital-based clinicians and transfusion medicine specialists to implement perisurgical patient blood management strategies to avoid blood component transfusions with their potential risks of emerging pathogens, illustrated here by the Zika virus. Ultimately, this current global threat, as described by the World Health Organization, will inevitably be followed by future outbreaks of other bloodborne pathogens; the principles and practices of perioperative patient blood management will reduce the risks from not only known, but also unknown risks of blood transfusion for our patients.

National and International Guidelines for Patient Blood Management in Obstetrics: A Qualitative Review.

In developed countries, rates of postpartum hemorrhage (PPH) requiring transfusion have been increasing. As a result, anesthesiologists are being increasingly called upon to assist with the management of patients with severe PPH. First responders, including anesthesiologists, may adopt Patient Blood Management (PBM) recommendations of national societies or other agencies. However, it is unclear whether national and international obstetric societies' PPH guidelines account for contemporary PBM practices. We performed a qualitative review of PBM recommendations published by the following national obstetric societies and international groups: the American College of Obstetricians and Gynecologists; The Royal College of Obstetricians and Gynecologists, United Kingdom; The Royal Australian and New Zealand College of Obstetricians and Gynecologists; The Society of Obstetricians and Gynecologists of Canada; an interdisciplinary group of experts from Austria, Germany, and Switzerland, an international multidisciplinary consensus group, and the French College of Gynaecologists and Obstetricians. We also reviewed a PPH bundle, published by The National Partnership for Maternal Safety. On the basis of our review, we identified important differences in national and international societies' recommendations for transfusion and PBM. In the light of PBM advances in the nonobstetric setting, obstetric societies should determine the applicability of these recommendations in the obstetric setting. Partnerships among medical, obstetric, and anesthetic societies may also help standardize transfusion and PBM guidelines in obstetrics.

How do I implement an automated screen for high-titer ABO antibody as an inventory management tool for ABO plasma-incompatible platelets?

BACKGROUND: Plasma volume reduction (PVR) may reduce the risk of hemolysis associated with transfusion of plateletpheresis blood products (PLTs) containing ABO-incompatible plasma. But PVR may delay PLT issue. In collaboration with our blood donor center we evaluated an automated screen of PLT for high-titer ABO antibody and to apply PVR to high-titer PLTs. STUDY DESIGN AND METHODS: At the donor center, plasma from PLT donors was tested using an automated microplate system (PK7300, Beckman). PK settings were set for a detection cutoff equivalent to 1 in 256 using a manual tube method. The donors associated with high-titer PLTs were characterized by sex and age. In the transfusion service, the number of PVR procedures was evaluated before and after implementation of the high-titer screen. RESULTS: During validation, 157 of 1008 PLT units (15%) were positive by the automated method versus 121 (12%) by manual method. After implementation, 2112 of 15,240 PLT units were high-titer, with higher frequency in donations from females versus males (18% vs. 12%, p < 0.0001). The PLT PVR rate was reduced by 50%. CONCLUSION: Implementation of an automated method to screen PLTs for high-titer ABO antibody at the donor center improves the inventory management of PLTs containing ABO-incompatible plasma at the hospital transfusion service.

Transfusion and coagulation management in major obstetric hemorrhage.

PURPOSE OF REVIEW: Major obstetric hemorrhage is a leading cause of maternal morbidity and mortality. We will review transfusion strategies and the value of monitoring the maternal coagulation profile during severe obstetric hemorrhage. RECENT FINDINGS: Epidemiologic studies indicate that rates of severe postpartum hemorrhage (PPH) in well resourced countries are increasing. Despite these increases, rates of transfusion in obstetrics are low (0.9-2.3%), and investigators have questioned whether a predelivery 'type and screen' is cost-effective for all obstetric patients. Instead, blood ordering protocols specific to obstetric patients can reduce unnecessary antibody testing. When severe PPH occurs, a massive transfusion protocol has attracted interest as a key therapeutic resource by ensuring sustained availability of blood products to the labor and delivery unit. During early postpartum bleeding, recent studies have shown that hypofibrinogenemia is an important predictor for the later development of severe PPH. Point-of-care technologies, such as thromboelastography and rotational thromboelastometry, can identify decreased fibrin clot quality during PPH, which correlate with low fibrinogen levels. SUMMARY: A massive transfusion protocol provides a key resource in the management of severe PPH. However, future studies are needed to assess whether formula-driven vs. goal-directed transfusion therapy improves maternal outcomes in women with severe PPH.

How I use fibrinogen replacement therapy in acquired bleeding.

Fibrinogen is a critical protein for hemostasis and clot formation. However, transfusion guidelines have variable recommendations for maintaining fibrinogen levels in bleeding patients. An increasing number of studies support the practice of fibrinogen replacement therapy for acquired coagulopathies, and additional studies are underway. Fibrinogen therapy can be administered with cryoprecipitate or fibrinogen concentrates, and clinical practice varies according to their availability and licensing status. Fibrinogen concentrate therapy has been studied in animal models and clinical trials and supports the critical role of fibrinogen repletion in bleeding patients. Point-of-care testing will have an important role in guiding fibrinogen replacement for hemostatic therapy in clinical settings such as cardiovascular surgery, postpartum hemorrhage, and trauma. Fibrinogen therapy is an important component of a multimodal strategy for the treatment of coagulopathic bleeding.

Blood utilization and hemoglobin levels in cancer patients after label and coverage changes for erythropoiesis-stimulating agents.

A comprehensive literature search was performed to examine the influence of changes in erythropoietin-stimulating agent (ESA) label and reimbursement policies on utilization of red blood cell transfusions and patient hemoglobin levels in US cancer patients receiving chemotherapy or anemia management. Studies conducted in ESA-treated patients showed an increase in transfusion rates when comparing the post-intervention period with pre-intervention period (range of relative change: 15-125%). Results from studies conducted in patients receiving chemotherapy irrespective of anemia treatment were variable; single-institution-based studies tended to show a decrease in transfusion rates (range of relative change: -3.2 to -24.1%), while multiple-institution-based studies suggested an increase in transfusion rates (range of relative change: 12-182%). Studies showed decreases in hemoglobin levels during chemotherapy or at ESA initiation, and decreased ESA utilization.

Restrictive blood transfusion practices are associated with improved patient outcomes.

BACKGROUND: Blood transfusion has been cited as one of the five most overutilized therapeutic procedures in the United States. We assessed the impact of clinical decision support at computerized physician order entry and education on red blood cell (RBC) transfusions and clinical patient outcomes at our institution. STUDY DESIGN AND METHODS: Clinical patient outcomes and RBC transfusions were assessed before and after implementation of a best practice alert triggered for transfusions when the hemoglobin level was higher than 7 g/dL for all inpatient discharges from January 2008 through December 2013. Retrospective clinical and laboratory data related to RBC transfusions were extracted: case-mix complexity, patient discharges and selected surgical volumes, and patient outcomes (mortality, 30-day readmissions, length of stay). RESULTS: There was a significant improvement in RBC utilization as assessed by RBC units transfused per 100 patient-days-at-risk. Concurrently, hospital-wide clinical patient outcomes showed improvement (mortality, p = 0.034; length of stay, p = 0.003) or remained stable (30-day readmission rates, p = 0.909). Outcome improvements were even more pronounced in patients who received blood transfusions, with decreased mortality rate (55.2 to 33.0, p < 0.001), length of stay (mean, 10.1 to 6.2 days, p < 0.001), and 30-day readmission rate (136.9 to 85.0, p < 0.001). The mean number of units transfused per patient also declined (3.6 to 2.7, p < 0.001). Acquisition costs of RBC units per 1000 patient discharges decreased from $283,130 in 2009 to $205,050 in 2013 with total estimated savings of $6.4 million and likely far greater impact on total transfusion-related costs. CONCLUSION: Improved blood utilization is associated with improved clinical patient outcomes.

Iron deficiency anemia--bridging the knowledge and practice gap.

Despite its high prevalence, anemia often does not receive proper clinical attention, and detection, evaluation, and management of iron deficiency anemia and iron-restricted erythropoiesis can possibly be an unmet medical need. A multidisciplinary panel of clinicians with expertise in anemia management convened and reviewed recent published data on prevalence, etiology, and health implications of anemia as well as current therapeutic options and available guidelines on management of anemia across various patient populations and made recommendations on the detection, diagnostic approach, and management of anemia. The available evidence confirms that the prevalence of anemia is high across all populations, especially in hospitalized patients. Anemia is associated with worse clinical outcomes including longer length of hospital stay, diminished quality of life, and increased risk of morbidity and mortality, and it is a modifiable risk factor of allogeneic blood transfusion with its own inherent risks. Iron deficiency is usually present in anemic patients. An algorithm for detection and management of anemia was discussed, which incorporated iron study (with primary emphasis on transferrin saturation), serum creatinine and glomerular filtration rate, and vitamin B12 and folic acid measurements. Management strategies included iron therapy (oral or intravenous), erythropoiesis-stimulating agents, and referral as needed.