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The red blood cell (RBC) storage lesion reflects cumulative damage to stored erythrocytes. Randomized clinical trials have yet to identify clinical consequences associated with prolonged RBC storage, however the majority of these trials have not incorporated dose-response analyses. In one of the subgroup analyses undertaken in the ABLE trial, a potential volume-dependent effect associated with storage was identified1. In this secondary analysis of the ABLE study, we conducted detailed analyses aiming to better characterize whether the number of RBC units administered to patients receiving either fresh or standard-issue blood is associated with mortality in critically-ill adults. We undertook a secondary evaluation of the 2510 patients enrolled in the ABLE trial. This randomized, controlled, clinical trial compared mortality rates and several secondary outcomes in mechanically-ventilated adults, who received either "fresh" RBC units (stored for ≤7 days) or "standard-issue" RBC units (first-in, first-out). Our secondary analysis consisted of comparing short- and long-term hazards of death between fresh and standard arms within pre-specified subgroups of patients that received ≤3 RBC units and those that received >3 units. Additional analyses using subgroups defined by 2-unit, and 1-unit increments were performed. Cox proportional hazards regression was used to model the hazard of death at the specified endpoints, adjusting for possible confounders. We examined interactions between randomization to fresh RBCs and number of RBC units transfused, as a means of establishing a dose-dependent relationship. We also undertook adjusted and unadjusted survival analyses between treatment arms within subgroups. In the subgroup that received ≤3 RBCs, there were 754 patients in the fresh arm and 789 in the standard arm; among patients transfused >3 RBCs, there were 457 in the fresh arm and 430 in the standard arm. When stratified by 2 unit increments, in the fresh and standard arms, respectively, there were 601 and 632 patients given ≤2 units, 279 and 272 given 3-4 units, 108 and 107 given 5-6 units, and 223 and 208 given ≥7 units. Baseline characteristics were comparable between treatment arms within major subgroups, aside from a slightly higher proportion of fresh RBC patients admitted due to trauma in the most transfused subgroups (>3 units: 11.4% of standard, 16.4% of fresh; ≥7 units: 11.5% of standard, 19.3% of fresh) and fewer patients admitted with medical causes in the same subgroups (>3 units: 77.7% of standard, 69.6% of fresh; ≥7 units: 77.9% of standard, 67.7% of fresh). There was significant interaction between fresh RBC unit transfusion and the volume of transfused RBC units on long-term (90 and 180 days) but not short-term (28-day, in-ICU, in-hospital) hazards of death for all subgroup analyses. This observation suggests that the effect of RBC storage differs with different transfusion volumes. In subgroups of ≤3 and >3 units, a trend was observed of increased hazard of death with fresh RBCs in the less-transfused subgroup, and decreased hazard of death with fresh RBCs in the more-transfused subgroup at all endpoints (Figure 1). Similar trends were observed with smaller RBC unit increments. At all endpoints, the hazard of death was higher with fresh RBCs in patients given 3-4 units and, after a threshold of 5 units, the trend reversed: patients given ≥7 fresh units had a lower hazard (Figure 2). Overall survival was not significantly different between treatment arms in any of the subgroups. This secondary analysis suggests a volume-dependent, threshold effect of prolonged red cell storage. Fresh RBCs were associated with a trend of decreased hazard of mortality when more than 5 units were transfused. The findings support current transfusion practice for patients requiring transfusion of The ABLE trial was funded by the Canadian Institutes of Health (grant #177453) and the Établissement français du sang. Dr. Mack is supported by a Fonds de recherche du Québec - Santé 'Resident Physician Health Research Career Training Program' award. 1. Lacroix J, Hébert PC, Fergusson DA, Tinmouth A, Cook DJ, Marshall JC, Clayton L, McIntyre L, Callum J, Turgeon AF, et al. Age of Transfused Blood in Critically Ill Adults. New England Journal of Medicine. 2015;372(15):1410-1418. Disclosures No relevant conflicts of interest to declare.

Abstract 1114 Background: Determination of the optimal hemoglobin concentration (Hb) for red cell (RBCs) transfusion is essential for patients undergoing cardiac surgery as mortality may be dependent on the severity of anemia and administration of RBCs. As there is considerable variability in transfusion practices, a pilot feasibility study is required to ensure that adherence to proposed strategies can be achieved before conducting a definitive study requiring thousands of patients. The primary objective of this study was to assess overall adherence to two transfusion strategies. Methods: We conducted a single centre parallel randomized controlled pilot trial to assess adherence to two transfusion strategies. The randomization sequence was created using block randomization by age and Cardiac Anesthesia Risk Score in groups of 4. High risk patients were allocated to a “restrictive” transfusion strategy (RBCs if their Hb was 70 g/L or less intraoperatively during cardiopulmonary bypass (CPB) and 75 g/L or less postoperatively following CPB); or a “liberal” transfusion strategy (RBCs if their Hb was 95 g/L or less during CPB and less than 100 g/L postoperatively). We defined adherence as adherence to the transfusion strategies for each patient for more than 90% of their days in hospital. We also assessed reasons for non-adherence and clinical outcomes. A total sample size of 50 patients was estimated to produce a 97% confidence interval equal to the sample adherence prevalence plus or minus 8% when the true prevalence of adherence was hypothesized to be 90%. We estimated our sample size using PASS 2002 software. The significance level was set at p Results: Fifty patients were randomized, 25 in the liberal group and 25 in the restrictive group. Overall, 99 units of RBCs were transfused in the liberal group compared 50 units in the restrictive group (p Conclusions: This is the first randomized controlled trial that has assessed adherence rates to transfusion strategies in high-risk patients undergoing cardiac surgery. Determination of adherence rates to transfusion strategies is essential as adherence rates can impact outcomes if a considerable proportion of enrolled patients do not receive a transfusion according to their transfusion strategy. Poor adherence may impact outcomes despite the subsequent use of intention to treat analysis. Restrictive strategies can reduce transfusion, but further studies will be required to determine whether restrictive transfusions confer risk. Disclosures: Shehata: Canadian Blood Services: Employment, Research Funding.

Abstract 3143 Poster Board III-80 Background During storage, red blood cells (RBCs) undergo well-described biochemical and biomechanical changes, termed the red cell storage lesion. These changes may affect the ability of stored RBCs to deliver oxygen or have other adverse consequences. The transfusion of older RBCs has been associated with increased morbidity/mortality, and planned or on-going randomized controlled trials are exploring a possible causal relationship between the age of RBCs and mortality/morbidity. However, the age-related characteristics of the RBCs units in hospital inventories and of the RBCs units transfused are largely unknown. Method A descriptive observational study from 9 centres from 5 Canadian provinces was conducted. Using a randomly generated schedule, data was collected on one weekday for 30 consecutive weeks. Reports of the RBCs inventories and the transfused RBCs units for all ABO and Rh blood groups were collected and analyzed. Results Academic centers contributed more than half of the collected data, both for inventory and for transfused units. Overall, the median age of RBCs units in inventory was 14 days (IQR=10-20) and their median age upon transfusion was 16 days (IQR=12-22). The cumulative proportion of younger blood (less than 8 days) in inventory was 9% (range for individual centres: 5 to 20%) for units in inventory and 5% (range for individual centres: 1 to 17%) for transfused units. The cumulative proportion of older blood (more than 28 days) was 8% (range for individual centres: 6 to 14%) for units in inventory, and 13% (range for individual centres: 9 to 23%) for transfused units. Community centres tended to have the largest proportion of younger units transfused (12%) as well as in inventory (14%). Conclusion This study provides important data that may contribute to decision-making regarding blood bank inventory management and age-based transfusion practices. If the results of ongoing studies demonstrate an adverse effect from transfusing older RBCs, then significant changes to the inventory management may be required. In Canada, shortening the shelf-life for storage of RBC units to 28 days may be less problematic, but restricting the age of RBCs transfused to less than 8 days for all RBC units may pose significant challenges. Disclosures Tinmouth: Canadian Blood Services: Consultancy; Novartis: Research Funding; CSL: Research Funding; Bayer: Research Funding; Wyeth: Research Funding.

Background: Intravenous immunoglobulin (IVIG) is a scarce resource derived from pooled plasma of whole blood through industrial fractionation. IVIG for the prevention of infections and Graft versus host disease (GVHD) after Hematopoietic Stem cell transplantation (HSCT) is one of only 5 licensed indications; however, its use in HSCT is contentious with multiple conflicting reports. Given this uncertainty, we sought to summarize and quantify the clinical effects of prophylactic IVIG in the context of HSCT. Methods: We conducted a systematic review to summarize evidence from prospective randomized controlled trials (RCTs) addressing prophylactic IVIG use in patients undergoing HSCT. In particular, we included studies which addressed clinical outcomes and excluded studies that addressed only biochemical surrogates. The search strategy included MEDLINE (1966 to 4th week of July 2006), EMBASE (1980 to 4th week of July 2006) and all EBM Reviews (2ndquarter of 2006). A random effects model was used to summarize the outcome data. Results: Twenty two RCTs representing 3346 patients were included in the review; 16 RCTs addressing patients undergoing allogeneic HSCT, 4 RCTs addressing patients undergoing either allogeneic or autologous HSCT and 1 trial in patients undergoing autologous HSCT. Nine RCTs (n=1462) compared conventional IVIG to no treatment, 8 RCTs (n=538) compared CMV specific IVIG to no treatment, 2 RCTs (n=950) compared 2 different doses of conventional IVIG while 3 RCTs (n=212) compared conventional IVIG to CMV specific IVIG/plasma. Eleven RCTs comparing IVIG to no treatment did not demonstrate an overall survival advantage (RR 1.01; 95% 0.92–1.12). IVIG did not attenuate transplant related mortality (RR 1.24; 95% 0.83–1.85), acute GVHD (RR 0.95; 95% 0.80–1.14), chronic GVHD (RR 1.19; 95% 0.85–1.67), interstitial fibrosis (RR 1.00; 95% 0.50–2.00) or relapse (RR 0.76; 95% 0.38–1.52). Although CMV infections were reduced (RR 0.80; 95% 0.66–0.96), this did not result in a reduction in CMV disease (RR 0.90; 95% 0.52–1.56). Of concern, the risk of hepatic sinusoidal obstruction syndrome (HSOS) was increased (RR 3.09; 95% 1.11–8.58). Several a priori defined sensitivity analyses were performed including comparisons of the type of IVIG, dose of IVIG, type of HSCT and the quality of studies. Conclusions: There is no evidence to support the routine use of prophylactic IVIG in improving clinical outcomes in patients undergoing HSCT. Furthermore, no subgroups appear to benefit from IVIG use. The increased risk of HSOS merits further study. Given the lack of benefit of IVIG in patients undergoing HSCT, the labeled indications for IVIG should be reassessed.

Purpose: Given the increasing use of intravenous immunoglobulin for various neurological conditions, its significant cost and the uncertainty pertaining to its benefits and harms, we conducted a systematic review of randomized controlled trials that compared intravenous immunoglobulin to other current therapies. Methods: A systematic search strategy of Medline (1966-June 2003) and the Cochrane Registry of Controlled Trials (June 2003 edition) was developed to identify randomised controlled trials. Two authors (BH, DF) independently reviewed all citations retrieved from the electronic search to identify all potentially relevant trials for this review. In cases where a unanimous decision could not be reached, a third party was consulted. To be eligible, studies had to be randomised controlled trials comparing intravenous immunoglobulin to either placebo or an active control and evaluating clinical outcomes. Measures of effect were calculated for each trial independently, and studies were pooled based on clinical and methodologic judgment as to its appropriateness. Fixed effects and random effects models were selected for each meta-analysis based on appraisal of the clinical homogeneity of patients across studies, as well as from testing for heterogeneity between studies. In circumstances where pooling of trials was inappropriate or not feasible, a qualitative discussion of the findings was developed. Results: Thirty-seven trials representing 14 conditions were identified. Results from meta-analysis suggest that intravenous immunoglobulin therapy is effective for the treatment of multiple sclerosis (pooled 1-year EDSS change −0.46, 95% CI [−0.92,0.01] in favor of IVIG; pooled change in annual exacerbation rate −0.82, 95% CI [−1.54, −0.11] in favor of IVIG; pooled odds of remaining exacerbation free 0.24, 95% CI [0.12, 0.50] in favor of IVIG ) and idiopathic chronic inflammatory demyelinating polyneuropathy (pooled change in disability score −0.67, 95% CI [−1.04, −0.30] in favor of IVIG; pooled odds of achieving treatment response 4.43, 95% CI [2.20, 8.91] in favor of IVIG). There was insufficient evidence to determine whether this therapy was more effective for Guillain-Barré Syndrome than plasma exchange (pooled change in disability score −0.11, 95% CI [−0.37,0.14]; pooled odds of improving by 1 or more grades on the Hughes disability scale 1.91, 95% CI [1.11, 3.28] in favor of IVIG; pooled odds of mortality 0.84, 95% CI [0.31, 2.29]). There was also insufficient evidence regarding paraprotein-associated chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy. No evidence of benefit was observed for inclusion body myositis and myasthenia gravis. Based on evidence from lone randomised trials, there also exists evidence indicating that IVIG may be useful for treatment of dermatomyositis, stiff person syndrome and Lambert-Eaton Syndrome.

Rationale: No published randomized trials have compared low molecular weight heparin (LMWH) to unfractionated heparin (UFH) for thromboprophylaxis in medical-surgical ICU patients. Objectives: A) Our Feasibility Objectives were to assess: 1) timely enrollment and complete, blinded study drug administration, 2) LMWH bioaccumulation in renal insufficiency, 3) twice weekly leg ultrasounds, and 4) recruitment rates for a future trial. B) Our Clinical Objectives were to assess 1) the effectiveness of LMWH vs UFH by estimating DVT, and pulmonary embolism (PE) rates, and 2) the safety of LMWH vs UFH regarding bleeding, thrombocytopenia and HIT. Methods: In this prospective randomized stratified concealed blinded multicenter trial, we included patients ≥18 with expected ICU stay ≥72h. We excluded trauma, orthopaedic, cardiac, or neurosurgery, severe hypertension, DVT, PE or hemorrhage within 3 mos, INR >2ULN, PTT >2ULN, platelets 2 doses of heparin, and palliative care patients. By centralized telephone randomization, we allocated patients to dalteparin 5,000 IU QD SC or UFH 5,000 IU BID SC. All clinicians caring for patients were blinded except the pharmacist. Bilateral leg compression ultrasounds were performed within 48h of ICU admission, twice weekly, on suspicion of DVT, and 7 days post ICU discharge. Results: A) Feasibility Objectives: 1) Timely, complete study drug administration occurred for >99% of scheduled doses; every dose was blinded. 2) No LWMH bioaccumulation was observed as measured by anti-Xa levels when creatinine clearance decreased to Conclusions: DVT rates remain high in medical-surgical ICU patients despite universal heparin thromboprophylaxis. This pilot study suggests that a randomized clinical trial comparing LMWH vs UFH feasible. An adequately powered trial is needed to achieve the clinical objectives.

Purpose: Few recent studies have examined approaches to transfusion practice in high-risk patients. We therefore documented practice variation following repair of hip fracture or cardiac surgery, as well as those requiring intensive care following a surgical intervention or multiple trauma. Methods: We documented rates of red cell transfusion in 41,568 patients admitted to 11 hospitals across Canada between August 1998 and August 2000 as part of a retrospective observational cohort study. Adjusted odds of transfusion, median number of transfusions per patient and median number of transfusions per patient day were compared across sites. We also compared mean nadir hemoglobin concentrations from center to center in the subgroup of 7,552 patients that received red cells. Results: The overall rate of red cell transfusion was 38.7 %, and ranged from 23.8% to 51.9% across centers among the 41,568 peri-operative and critically ill patients. Women were more likely to be transfused (43.7% versus 35.3%, p Conclusions: We noted significant differences in the rates of red cell transfusion and nadir hemoglobin concentrations in various surgical and critical care settings. Such variation provides the impetus for investigators to explore its potential causes, and furthermore to attempt to define optimal transfusion practice in a variety of clinical settings by conducting randomized controlled trials.

Decisions about when to transfuse patients having coronary artery disease may impact on patient morbidity and mortality. There is no published data about the factors that influence physicians’ decisions to transfuse red blood cells (RBCs) to patients having coronary artery bypass graft surgeries (CABGs). The objective of this study was to determine the hemoglobin transfusion thresholds and the factors that influence physicians’ decisions when transfusing CABG patients. Methods: This was a cross-sectional study using self-administered mailed questionnaires sent to all anesthesiologists and cardiovascular surgeons in Canada. The survey included a series of patient scenarios for which respondents were to indicate the Hb concentration below which they would transfuse the patient. Factors assessed in the survey included patient age, sex, cardiac index (CI), and myocardial ischemia (MI). Each factor was introduced consecutively in the case scenarios to allow for analysis of each factor separately and the interaction of factors. Data on physicians’ characteristics were also collected. Univariate analysis and mixed effects regression modelling were used to analyze the data. Results: The overall response rate was a 69.3%(n=339/489); 66.8% of all anesthesiologists and 75.7% of all cardiac surgeons responded. Responses were received from anesthesiologists in all 32 cardiac centres in Canada and from cardiac surgeons in 31/32 centres. The mean age of physicians was 46 years (standard deviation (sd)=8.6 years), years of practice was 14 years (sd=8.7 years), CABG cases/centre was 940 (sd=479) and CABG cases/individual was 121 (sd=77). The Hb transfusion thresholds for 6/24 case scenarios are illustrated in the Table. The Hb thresholds were similar for male patients. Univariate analysis revealed that for the base case scenario (i.e. 55 year old male/female), Hb thresholds did not differ significantly according to physician age, sex, years in practice, specialty, academic centre, the number of CABGs/centre/year, or patient sex but differed according to the number of CABGs/individual physician/year (p=0.009 for female case scenario and p=0.02 for the male case scenario), patient age (p Conclusion: Patient age, CI, MI and the number of CABGs/individual physician were found to influence physicians’ transfusion decisions. Future studies are required to elucidate whether transfusions based on these variables affect patient morbidity and mortality. Table: Mean Hemoglobin Transfusion Thresholds For 6 Case Scenarios Case Scenario Mean Hemoglobin (g/L) Standard Deviation (g/L) yo=year old, CI=cardiac index, MI=myocardial ischemia 55 yo female 70 8 55 yo female, CI