Daily versus every other day oral iron supplementation in patients with iron deficiency anemia (DEODO): study protocol for a phase 3 multicentered, pragmatic, open-label, pilot randomized controlled trial.

BACKGROUND: Iron deficiency anemia (IDA) accounts for the majority of anemia cases across the globe and can lead to impairments in both physical and cognitive functioning. Oral iron supplementation is the first line of treatment to improve the hemoglobin level for IDA patients. However, gaps still exist in understanding the appropriate dosing regimen of oral iron. The current trial proposes to evaluate the feasibility of performing this study to examine the effectiveness and side-effect profile of oral iron once daily versus every other day. METHODS: In this open-label, pilot, feasibility, randomized controlled trial, 52 outpatients over 16 years of age with IDA (defined as hemoglobin < 12.0 g/dL in females and < 13.0 g/dL in males and ferritin < 30 mcg/L) will be enrolled across two large academic hospitals. Participants are randomized in a 1:1 ratio to receive 300 mg oral ferrous sulfate (60 mg of elemental iron) either every day or every other day for 12 weeks. Participants are excluded if they are as follows: (1) pregnant and/or currently breastfeeding, (2) have a disease history that would impair response to oral iron (e.g., thalassemia, celiac disease), (3) intolerant and/or have an allergy to oral iron or vitamin C, (4) on new anticoagulants in the past 6 months, (5) received IV iron therapy in the past 12 weeks, (6) have surgery, chemotherapy, or blood donation planned in upcoming 12 weeks, (7) a creatinine clearance < 30 mL/min, or (8) hemoglobin less than 8.0 g/dL with active bleeding. The primary outcome is feasibility to enroll 52 participants in this trial over a 2-year period to determine the effectiveness of daily versus every other day oral iron supplementation on hemoglobin at 12 weeks post-initiation and side-effect profile. DISCUSSION: The results of this trial will provide additional evidence for an appropriate dosing schedule for treating patients with IDA with oral iron supplementation. Additional knowledge will be gained on how the dosing regimen of oral iron impacts quality of life and hemoglobin repletion in IDA patients. If this trial is deemed feasible, it will inform the development and implementation of a larger multicenter definitive trial. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03725384 . Registered 31 October 2018.

Convalescent plasma for adults with acute COVID-19 respiratory illness (CONCOR-1): study protocol for an international, multicentre, randomized, open-label trial.

BACKGROUND: Convalescent plasma has been used for numerous viral diseases including influenza, severe acute respiratory syndrome, Middle East respiratory syndrome and Ebola virus; however, evidence to support its use is weak. SARS-CoV-2 is a novel coronavirus responsible for the 2019 global pandemic of COVID-19 community acquired pneumonia. We have undertaken a randomized controlled trial to assess the efficacy and safety of COVID-19 convalescent plasma (CCP) in patients with SARS-CoV-2 infection. METHODS: CONCOR-1 is an open-label, multicentre, randomized trial. Inclusion criteria include the following: patients > 16 years, admitted to hospital with COVID-19 infection, receiving supplemental oxygen for respiratory complications of COVID-19, and availability of blood group compatible CCP. Exclusion criteria are : onset of respiratory symptoms more than 12 days prior to randomization, intubated or imminent plan for intubation, and previous severe reactions to plasma. Consenting patients are randomized 2:1 to receive either approximately 500 mL of CCP or standard of care. CCP is collected from donors who have recovered from COVID-19 and who have detectable anti-SARS-CoV-2 antibodies quantified serologically. The primary outcome is intubation or death at day 30. Secondary outcomes include ventilator-free days, length of stay in intensive care or hospital, transfusion reactions, serious adverse events, and reduction in SARS-CoV-2 viral load. Exploratory analyses include patients who received CCP containing high titre antibodies. A sample size of 1200 patients gives 80% power to detect a 25% relative risk reduction assuming a 30% baseline risk of intubation or death at 30 days (two-sided test; α = 0.05). An interim analysis and sample size re-estimation will be done by an unblinded independent biostatistician after primary outcome data are available for 50% of the target recruitment (n = 600). DISCUSSION: This trial will determine whether CCP will reduce intubation or death non-intubated adults with COVID-19. The trial will also provide information on the role of and thresholds for SARS-CoV-2 antibody titres and neutralization assays for donor qualification. TRIAL REGISTRATION: Clinicaltrials.gov NCT04348656 . Registered on 16 April 2020.

Comparison of 4-Factor Prothrombin Complex Concentrate With Frozen Plasma for Management of Hemorrhage During and After Cardiac Surgery: A Randomized Pilot Trial.

Importance: Approximately 15% of patients undergoing cardiac surgery receive frozen plasma (FP) for bleeding. Four-factor prothrombin complex concentrates (PCCs) have logistical and safety advantages over FP and may be a suitable alternative. Objectives: To determine the proportion of patients who received PCC and then required FP, explore hemostatic effects and safety, and assess the feasibility of study procedures. Design, Setting, and Participants: Parallel-group randomized pilot study conducted at 2 Canadian hospitals. Adult patients requiring coagulation factor replacement for bleeding during cardiac surgery (from September 23, 2019, to June 19, 2020; final 28-day follow-up visit, July 17, 2020). Data analysis was initiated on September 15, 2020. Interventions: Prothrombin complex concentrate (1500 IU for patients weighing ≤60 kg and 2000 IU for patients weighing >60 kg) or FP (3 U for patients weighing ≤60 kg and 4 U for patients weighing >60 kg), repeated once as needed within 24 hours (FP used for any subsequent doses in both groups). Patients and outcome assessors were blinded to treatment allocation. Main Outcomes and Measures: Hemostatic effectiveness (whether patients received any hemostatic therapies from 60 minutes to 4 and 24 hours after initiation of the intervention, amount of allogeneic blood components administered within 24 hours after start of surgery, and avoidance of red cell transfusions within 24 hours after start of surgery), protocol adherence, and adverse events. The analysis set comprised all randomized patients who had undergone cardiac surgery, received at least 1 dose of either treatment, and provided informed consent after surgery. Results: Of 169 screened patients, 131 were randomized, and 101 were treated (54 with PCC and 47 with FP), provided consent, and were included in the analysis (median age, 64 years; interquartile range [IQR], 54-73 years; 28 [28%] were female; 82 [81%] underwent complex operations). The PCC group received a median 24.9 IU/kg (IQR, 21.8-27.0 IU/kg) of PCC (2 patients [3.7%; 95% CI, 0.4%-12.7%] required FP). The FP group received a median 12.5 mL/kg (IQR, 10.0-15.0 mL/kg) of FP (4 patients [8.5%; 95% CI, 2.4%-20.4%] required >2 doses of FP). Hemostatic therapy was not required at the 4-hour time point for 43 patients (80%) in the PCC group and for 32 patients (68%) in the FP group (P = .25) nor at the 24-hour time point for 41 patients (76%) in the PCC group and for 31 patients (66%) patients in the FP group (P = .28). The median numbers of units for 24-hour cumulative allogeneic transfusions (red blood cells, platelets, and FP) were 6.0 U (IQR, 4.0-11.0 U) in the PCC group and 14.0 U (IQR, 8.0-20.0 U) in the FP group (ratio, 0.58; 95% CI, 0.45-0.77; P < .001). After exclusion of FP administered as part of the investigational medicinal product, the median numbers of units were 6.0 U (IQR, 4.0-11.0 U) in the PCC group and 10.0 U (IQR, 6.0-16.0 U) in the FP group (ratio, 0.80; 95% CI, 0.59-1.08; P = .15). For red blood cells alone, the median numbers were 1.5 U (IQR, 0.0-4.0 U) in the PCC group and 3.0 U (IQR, 1.0-5.0 U) in the FP group (ratio, 0.69; 95% CI, 0.47-0.99; P = .05). During the first 24 hours after start of surgery, 15 patients in the PCC group (28%) and 8 patients in the FP group (17%) received no red blood cells (P = .24). Adverse event profiles were similar. Conclusions and Relevance: This randomized clinical trial found that the study protocols were feasible. Adequately powered randomized clinical trials are warranted to determine whether PCC is a suitable substitute for FP for mitigation of bleeding in cardiac surgery. Trial Registration: ClinicalTrials.gov Identifier: NCT04114643.

Multicenter observational study evaluating the impact of platelet transport bags on product wastage.

BACKGROUND: Platelets are the most commonly discarded blood product in Canada, with the most common cause of in-date product loss being improper storage. Transport containers to maintain temperature and extend acceptable return time may represent a method to reduce wastage. The objective of this study was to evaluate the impact of a validated Platelet Transport Bag (PTB) on platelet wastage. STUDY DESIGN AND METHODS: Thirty-six hospitals with the highest platelet discards were invited to participate in a before-after observational study. Hospitals were instructed to utilize a validated 4-h PTB for clinical situations where immediate transfusion was not planned. Five hospitals audited in-date platelet discards from July 2018 to November 2019 to characterize wastage causes. In-date platelet discard data 12 months before and after the start date for each site were analyzed to determine changes in wastage. RESULTS: Of 36 hospital sites, 16 agreed to participate. Pre- and postdiscards were 277 and 301, respectively, for all sites combined. There were no significant before-after change in wastage rate (+0.05%, p = .51). Fifty discards were included in the detailed audit; the most common reasons were return to the blood bank after more than 60 min outside a PTB (n = 17, 34%) and return in a red cell cooler (n = 10, 20%). CONCLUSION: Implementation of PTB did not improve wastage. Common causes of in-date discards were return after 1 h outside of a PTB and placement in a red cell cooler in error. Further research is required to investigate potential strategies to mitigate in-date platelet wastage.

A prospective multi-faceted interventional study of blood bank technologist screening of red blood cell transfusion orders: The START study.

BACKGROUND: Transfusion of red blood cells (RBC) is a common procedure, which when prescribed inappropriately can result in adverse patient outcomes. This study sought to determine the impact of a multi-faceted intervention on unnecessary RBC transfusions at hospitals with a baseline appropriateness below 90%. STUDY DESIGN AND METHODS: A prospective medical chart audit of RBC transfusions was conducted across 15 hospitals. For each site, 10 RBCs per month transfused to inpatients were audited for a 5-month pre- and 10-month post-intervention period, with each transfusion adjudicated for appropriateness based on pre-set criteria. Hospitals with appropriateness rates below 90% underwent a 3-month intervention which included: adoption of standardized RBC guidelines, staff education, and prospective transfusion order screening by blood bank technologists. Proportions of RBC transfusions adjudicated as appropriate and the total number of RBC units transfused per month in the pre- and post-intervention period were examined. RESULTS: Over the 15-month audit period, at the 13 hospital sites with a baseline appropriateness below 90%, 1950 patients were audited of which 81.2% were adjudicated as appropriate. Proportions of appropriateness and single-unit orders increased from 73.5% to 85% and 46.2% to 68.2%, respectively from pre- to post-intervention (P < .0001). Pre- and post-transfusion hemoglobin levels and the total number of RBCs transfused decreased from baseline (P < .05). The median pre-transfusion hemoglobin decreased from a baseline of 72.0 g/L to 69.0 g/L in the post-intervention period (P < .0001). RBC transfusions per acute inpatient days decreased significantly in intervention hospitals, but not in control hospitals (P < .001). The intervention had no impact on patient length of stay, need for intensive care support, or in-hospital mortality. CONCLUSION: This multifaceted intervention demonstrated a marked improvement in RBC transfusion appropriateness and reduced overall RBC utilization without impacts on patient safety.

A prospective observational study of the incidence, natural history, and risk factors for intravenous immunoglobulin-mediated hemolysis.

BACKGROUND: Intravenous Immune Globulin (IVIG) is used to treat numerous immune-mediated and inflammatory conditions. There is growing awareness of hemolysis, occasionally severe, as a side-effect of this therapy. While most cases are associated with anti-A and/or anti-B isoagglutinins, the frequency and mechanism of hemolysis remain poorly characterized. STUDY DESIGN AND METHODS: A prospective observational study was conducted to determine incidence, natural history and risk factors for IVIG-mediated hemolysis. A total of 99 infusions of high-dose IVIG (2 g/kg or higher) administered to 78 non-group O patients were monitored and graded according to Canadian IVIG Hemolysis Pharmacovigilance Group. Serum ferritin and C3/C4 levels were monitored as indicators of macrophage activation and complement consumption, respectively. Supplementary investigations included assessment for ABO zygosity, Secretor status, FcR polymorphisms, eluate IgG subclass, monocyte monolayer assay, and a panel of cytokines. RESULTS: Hemolysis was observed in 32 of 99 (32%) of infusions, with 19 of 99 (19%) grade 2 or higher. Hemolysis was only apparent 5-10 days after a completed IVIG infusion in 84% of cases and was associated with increases in serum ferritin without complement-consumption. In univariate analysis, increased risk was observed in group AB patients, first-time IVIG recipients, those not taking immuosuppressive medications, or patients treated with a specific IVIG brand; however, in multivariate analysis, product association was no longer observed. No other patient- or practice-related risk factors were identified. CONCLUSION: IVIG-mediated hemolysis is common and frequently severe. Monitoring for 5-10 days following an infusion should be considered in non-O patients receiving high-dose IVIG with known risk factors.

Registration errors among patients receiving blood transfusions: a national analysis from 2008 to 2017.

BACKGROUND AND OBJECTIVES: The key first step for a safe blood transfusion is patient registration for identification and linking to past medical and transfusion history. In Canada, any deviation from standard operating procedures in transfusion is an error voluntarily reportable to a national database (Transfusion Error Surveillance System [TESS]). We used this database to characterize the subset of registration-related errors impacting transfusion care, including where, when and why the errors occurred, and to identify frequent high-risk errors. MATERIALS AND METHODS: A retrospective analysis was conducted on transfusion errors reported to TESS by sentinel reporting sites relating to patient registration and patient armbands, between 2008 and 2017. Free-text comments describing the error were coded to further categorize into common error types. The number of specimens received in the transfusion laboratory was used as the denominator for rates to allow for comparison between hospital sites. RESULTS: Five hundred and fifty-four registration errors were reported from 10 hospitals, for a global error rate of 5·4/10 000 samples (median 5·0 [interquartile range 3·7-7·0]). The potential severity was high in 85·7% of errors (n = 475). The patient experienced a consequence in 10·8% of errors (n = 60), but none resulted in patient harm. Rates varied widely and differed by nature across sites. Errors most commonly occurred in outpatient clinics or procedure units (n = 160, 28·8%) and in emergency departments (n = 130, 23·5%). CONCLUSION: Registration errors affect transfusion at every step and location in the hospital and are commonly high risk. Further research into common root causes is warranted to identify preventative strategies.

TACO-BEL-3: a feasibility study and a retrospective audit of diuretics for patients receiving blood transfusion at ten hospitals.

BACKGROUND AND OBJECTIVES: Transfusion-associated circulatory overload (TACO) is the leading cause of transfusion-related morbidity and mortality. A recently completed pilot trial randomized patients to pre-transfusion furosemide versus placebo but had a slower than expected enrollment rate. We sought to determine whether the lack of recruitment was due to a paucity of eligible patients or excessively restrictive eligibility criteria. MATERIALS AND METHODS: At 10 sites, eligible patients were retrospectively identified by first screening blood bank databases over one month for all transfusion episodes meeting trial inclusion criteria, defined as non-surgical patients receiving single RBC unit transfusions. The age threshold was decreased from 65 to 50 years. The first 10 patients meeting inclusion criteria then underwent detailed chart review for the exclusion criteria. The incidence of TACO and furosemide use was also recorded. RESULTS: At the 10 sites, 11 969 red cell units were transfused over 1 month and 1356 met the inclusion criteria. Of the 100 charts reviewed, 60 (60%) had no exclusion criteria. Active bleeding was the most common reason for ineligibility. There were 813 eligible transfusion episodes. Of the eligible patients, 17 (28·3%) had evidence of congestive heart failure, and furosemide was prescribed in 24 (40%). Despite the use of a lower age threshold, three cases of TACO were detected with an incidence of 3%. CONCLUSION: A large number of transfusion episodes met eligibility criteria. With a 3% incidence of TACO, 50% decrease through the use pre-transfusion furosemide and a target consent rate of 30%, a definitive trial of approximately 3000 patients could be completed within 1 year.

Can furosemide prevent transfusion-associated circulatory overload? Results of a pilot, double-blind, randomized controlled trial.

BACKGROUND: Transfusion-associated circulatory overload (TACO) is a leading cause of transfusion-attributable morbidity. It is unclear whether diuretics are safe and effective in preventing this reaction. MATERIALS AND METHODS: In a pilot controlled feasibility trial, inpatients 65 years or older ordered a single unit of red blood cells were randomized to pre-transfusion furosemide 20 mg or placebo intravenously. Primary outcome was the ability to enroll 80 patients within a 2-month time period. Secondary feasibility outcomes included proportion of RBC transfusions meeting eligibility criteria, proportion of eligible patients enrolled, and compliance to study protocol. Clinical outcomes included the incidence of TACO and associated complications. RESULTS: Nine months of enrollment were required for 80 patients to complete the study, due primarily to fewer transfusions than expected meeting eligibility criteria and lower than anticipated consent rates. Protocol compliance was below target due to missing chart documentation of patient fluid balance, and transfusion infusion time. Blinding was maintained throughout the study and treatment arms were well-balanced. A single case of TACO occurred in each arm, for an overall incidence of 2.5%. No differences in peri-transfusion vital signs, B-natriuretic peptide, or signs of furosemide toxicity were observed. CONCLUSION: The study protocol was not feasible as designed, primarily due to challenges in patient enrollment. Modifications to trial design to improve feasibility in future studies have been identified.

Cardiac stress biomarkers after red blood cell transfusion in patients at risk for transfusion-associated circulatory overload: a prospective observational study.

BACKGROUND: Transfusion-associated circulatory overload (TACO) is a leading cause of serious reactions. In regard to TACO, little is known regarding biomarkers as a predictor, their most informative timing, or thresholds of significance or differentiation from other reactions. STUDY DESIGN AND METHODS: In this study of inpatients at risk for TACO (age ≥ 50 years) receiving 1 red blood cell unit, cardiac biomarkers, brain natriuretic peptide (BNP), N-terminal pro-BNP (NT-proBNP), and high-sensitivity troponin were measured at baseline, 6 to 12 hours (except troponin) posttransfusion, and 18 to 24 hours posttransfusion. Primary outcome was a critical increase in biomarkers (>1.5-fold increase and supranormal) at 18 to 24 hours. RESULTS: Fifty-one patients were analyzed; 29% had cardiovascular disease, 73% had one or more cardiac risk factors, and 50% took cardiac or antihypertensive therapies. Although eight (16%) developed an increase in systolic pressure of at least 30 mmHg and four (8%) reported dyspnea and/or cough, none had TACO. At baseline, BNP level was more than 100 ng/L in 59% and NT-proBNP was more than 300 pg/mL in 83%. A total of 25% had a BNP critical increase, 33% had a NT-proBNP critical increase, and 2% had a troponin critical increase at 18 to 24 hours. Overall, 38% had at least one biomarker critical increase and NT-proBNP/BNP concordance was 84%. An increase in the NT-proBNP (>1.5-fold increase and >300 pg/mL) at 18 to 24 hours was the commonest biomarker change. CONCLUSIONS: An increase of the NT-proBNP at 18 to 24 hours may be the preferred surrogate marker for identifying a patient experiencing physiologic difficulty in handling the volume challenge. Larger studies are needed to clarify the risk of TACO for a given pretransfusion biomarker profile and the correlation between TACO and increase in biomarkers after transfusion.

Evaluating appropriate red blood cell transfusions: a quality audit at 10 Ontario hospitals to determine the optimal measure for assessing appropriateness.

BACKGROUND: Evaluating the appropriateness of red blood cell (RBC) transfusion requires labor-intensive medical chart audits and expert adjudication. We sought to determine the appropriateness of RBC transfusions at 10 hospitals using retrospective chart review and to determine whether simple metrics (proportion of single-unit transfusions, RBCs/100 acute inpatient days, proportion of transfusions with pretransfusion hemoglobin <80 g/L or posttransfusion hemoglobin <90 g/L) could be used as surrogate markers of appropriateness by comparing their values with the results from the audit. STUDY DESIGN AND METHODS: An initial block of 30 RBC units was dually adjudicated for appropriateness followed by additional blocks of 10 units until the difference between the cumulative percentage of appropriate RBC units in the preceding block and final block was <3%. Pearson correlation tests were used to evaluate associations between the metrics and percentages of appropriate transfusions per hospital. Two-by-two tables were used to assess the utility of the metrics to classify transfusions for appropriateness. RESULTS: Of the 498 units audited, 78% were adjudicated as appropriate (κ = 0.9603), with significant variability between institutions (p < 0.0001). Fifty audits or less were required at nine of the institutions. The values of the metrics were not found to have significant correlations with appropriateness, and the metric that misclassified the smallest proportion of transfusions for appropriateness was pretransfusion hemoglobin <80 g/L, at 24%. CONCLUSIONS: Our findings suggest that a chart audit of 50 RBC transfusions with adjudication using robust criteria is the optimal means of evaluating RBC transfusion appropriateness at an institution for benchmarking and quality-improvement initiatives.