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1.
Hyperoncotic Albumin Solution in Continuous Renal Replacement Therapy Patients
O'Brien Z, Finnis M, Gallagher M, Bellomo R
Blood purification. 2021;:1-10
Abstract
AIM: The aim of this study was to investigate the association of hyperoncotic (20%) human albumin solution (HAS) with outcomes among critically ill patients receiving continuous renal replacement therapy (RRT). METHODS Analysis of the Randomized Evaluation of Normal versus Augmented Level (RENAL) RRT trial data. RESULTS Of 1,508 patients, 771 (51%) received albumin. Of these, 345 (45%) received 4% HAS only, 155 (20%) received 20% HAS only, and 271 (35%) received both. Patients who received combined 4% and 20% HAS were more severely ill, received more days of RENAL trial therapy and required mechanical ventilation for longer. Mean daily fluid balance was -288 mL (-904 to 261) with 20% HAS only versus 245 mL (-248 to 1,050) with 4% HAS only (p < 0.001). On Cox proportional hazards regression, 20% HAS exposure was not associated with greater 90-day mortality (odds ratio 1.12, 95% confidence interval [CI]: 0.77-1.62; p = 0.55) or longer recovery to RRT independence (sub-hazard ratio 1.04, 95% CI: 0.84-1.30; p = 0.70) compared to those who received 4% HAS only. CONCLUSIONS RENAL trial patients commonly received albumin in varying concentrations. The administration of 20% HAS was associated with a more negative fluid balance but was not independently associated with increased mortality or RRT dependence when compared to 4% HAS only.
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2.
Early Treatment with Human Albumin Solution in Continuous Renal Replacement Patients
O'Brien Z, Finnis M, Gallagher M, Bellomo R
Blood purification. 2020;:1-9
Abstract
AIMS: To study the impact of early human albumin solution (HAS) in continuous renal replacement therapy (RRT) patients. METHODS Analysis of Randomized Evaluation of Normal versus Augmented Level (RENAL) RRT trial data. RESULTS Of 1,464 patients, 500 (34%) received early albumin. These patients had higher illness severity scores, greater use of mechanical ventilation, and 90-day mortality (51 vs. 41%; p < 0.001). However, early albumin carried similar RRT dependence risk among survivors at day 90 (4.9 vs. 5.8%; p = 0.62). On Cox proportional hazards regression, with standardized inverse probability of treatment weighting, early albumin was not associated with increased mortality (hazard ratio [HR]: 1.23, 95% CI: 0.97-1.55; p = 0.09) or recovery to RRT independence (HR: 0.92, 95% CI: 0.78-1.10; p = 0.38). CONCLUSIONS Early albumin was administered to one-third of RENAL trial patients and in those with greater illness severity. Early albumin was not independently associated with mortality risk or rate of recovery to RRT independence.
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3.
Fresh Red Cells for Transfusion in Critically Ill Adults: An Economic Evaluation of the Standard Issue Transfusion versus Fresher Red-Cell Use in Intensive Care (TRANSFUSE) Clinical Trial
Irving A, Higgins A, Ady B, Bellomo R, Cooper DJ, French C, Gantner D, Harris A, Irving DO, Murray L, et al
Critical care medicine. 2019
Abstract
OBJECTIVES Trials comparing the effects of transfusing RBC units of different storage durations have considered mortality or morbidity as outcomes. We perform the first economic evaluation alongside a full age of blood clinical trial with a large population assessing the impact of RBC storage duration on quality-of-life and costs in critically ill adults. DESIGN Quality-of-life was measured at 6 months post randomization using the EuroQol 5-dimension 3-level instrument. The economic evaluation considers quality-adjusted life year and cost implications from randomization to 6 months. A generalized linear model was used to estimate incremental costs (2016 U.S. dollars) and quality-adjusted life years, respectively while adjusting for baseline characteristics. SETTING Fifty-nine ICUs in five countries. PATIENTS Adults with an anticipated ICU stay of at least 24 hours when the decision had been made to transfuse at least one RBC unit. INTERVENTIONS Patients were randomized to receive either the freshest or oldest available compatible RBC units (standard practice) in the hospital transfusion service. MEASUREMENTS AND MAIN RESULTS EuroQol 5-dimension 3-level utility scores were similar at 6 months-0.65 in the short-term and 0.63 in the long-term storage group (difference, 0.02; 95% CI, -0.00 to 0.04; p = 0.10). There were no significant differences in resource use between the two groups apart from 3.0 fewer hospital readmission days (95% CI, -5.3 to -0.8; p = 0.01) during follow-up in the short-term storage group. There were no significant differences in adjusted total costs or quality-adjusted life years between the short- and long-term storage groups (incremental costs, -$2,358; 95% CI, -$5,586 to $711) and incremental quality-adjusted life years: 0.003 quality-adjusted life years (95% CI, -0.003 to 0.008). CONCLUSIONS Without considering the additional supply cost of implementing a freshest available RBC strategy for critical care patients, there is no evidence to suggest that the policy improves quality-of-life or reduces other costs compared with standard transfusion practice.
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4.
A randomized, controlled pilot clinical trial of cryopreserved platelets for perioperative surgical bleeding: the CLIP-I trial
Reade MC, Marks DC, Bellomo R, Deans R, Faulke DJ, Fraser JF, Gattas DJ, Holley AD, Irving DO, Johnson L, et al
Transfusion. 2019
Abstract
BACKGROUND Cryopreservation extends platelet (PLT) shelf life from 5 to 7 days to 2 to 4 years. However, only 73 patients have been transfused cryopreserved PLTs in published randomized controlled trials (RCTs), making safety data insufficient for regulatory approval. STUDY DESIGN AND METHODS The Cryopreserved vs. Liquid Platelet (CLIP) study was a double-blind, pilot, multicenter RCT involving high-risk cardiothoracic surgical patients in four Australian hospitals. The objective was to test, as the primary outcome, the feasibility and safety of the protocol. Patients were allocated to study group by permuted block randomization, with patients and clinicians blinded by use of an opaque shroud placed over each study PLT unit. Up to 3 units of cryopreserved or liquid-stored PLTs were administered per patient. No other aspect of patient care was affected. Adverse events were actively sought. RESULTS A total of 121 patients were randomized, of whom 23 received cryopreserved PLTs and 18 received liquid-stored PLTs. There were no differences in blood loss (median, 715 mL vs. 805 mL at 24 hr; difference between groups 90 mL [95% CI, -343.8 to 163.8 mL], p = 0.41), but the Bleeding Academic Research Consortium criterion for significant postoperative hemorrhage in cardiac surgery composite bleeding endpoint occurred in nearly twice as many patients in the liquid-stored group (55.6% vs. 30.4%, p = 0.10). Red blood cell transfusion requirements were a median of 3 units in the cryopreserved group versus 4 units with liquid-stored PLTs (difference between groups, 1 unit [95% CI, -3.1 to 1.1 units]; p = 0.23). Patients in the cryopreserved group were more likely to be transfused fresh-frozen plasma (78.3% vs. 27.8%, p = 0.002) and received more study PLT units (median, 2 units vs. 1 unit; difference between groups, 1 unit [95% CI, -0.03 to 2.0 units]; p = 0.012). There were no between-group differences in potential harms including deep venous thrombosis, myocardial infarction, respiratory function, infection, and renal function. No patient had died at 28 days, and postoperative length of stay was similar in each group. CONCLUSION In this pilot RCT, compared to liquid-stored PLTs, cryopreserved PLTs were associated with no evidence of harm. A definitive study testing safety and hemostatic effectiveness is warranted.
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5.
Restricted fluid resuscitation in suspected sepsis associated hypotension (REFRESH): a pilot randomised controlled trial
Macdonald SPJ, Keijzers G, Taylor DM, Kinnear F, Arendts G, Fatovich DM, Bellomo R, McCutcheon D, Fraser JF, Ascencio-Lane JC, et al
Intensive Care Medicine. 2018;44((12):):2070-2078.
Abstract
PURPOSE To determine if a regimen of restricted fluids and early vasopressor compared to usual care is feasible for initial resuscitation of hypotension due to suspected sepsis. METHODS A prospective, randomised, open-label, clinical trial of a restricted fluid resuscitation regimen in the first 6 h among patients in the emergency department (ED) with suspected sepsis and a systolic blood pressure under 100 mmHg, after minimum 1000 ml of IV fluid. Primary outcome was total fluid administered within 6 h post randomisation. RESULTS There were 99 participants (50 restricted volume and 49 usual care) in the intention-to-treat analysis. Median volume from presentation to 6 h in the restricted volume group was 2387 ml [first to third quartile (Q1-Q3) 1750-2750 ml]; 30 ml/kg (Q1-Q3 32-39 ml/kg) vs. 3000 ml (Q1-Q3 2250-3900 ml); 43 ml/kg (Q1-Q3 35-50 ml/kg) in the usual care group (p < 0.001). Median duration of vasopressor support was 21 h (Q1-Q3 9-42 h) vs. 33 h (Q1-Q3 15-50 h), (p = 0.13) in the restricted volume and usual care groups, respectively. At 90-days, 4 of 48 (8%) in the restricted volume group and 3 of 47 (6%) in the usual care group had died. Protocol deviations occurred in 6/50 (12%) in restricted group and 11/49 (22%) in the usual care group, and serious adverse events in four cases (8%) in each group. CONCLUSIONS A regimen of restricted fluids and early vasopressor in ED patients with suspected sepsis and hypotension appears feasible. Illness severity was moderate and mortality rates low. A future trial is necessary with recruitment of high-risk patients to determine effects on clinical outcomes in this setting.
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6.
Small volume resuscitation with 20% albumin in intensive care: physiological effects : The SWIPE randomised clinical trial
Martensson J, Bihari S, Bannard-Smith J, Glassford NJ, Lloyd-Donald P, Cioccari L, Luethi N, Tanaka A, Crisman M, Rey de Castro N, et al
Intensive Care Medicine. 2018;44((11):):1797-1806.
Abstract
PURPOSE We set out to assess the resuscitation fluid requirements and physiological and clinical responses of intensive care unit (ICU) patients resuscitated with 20% albumin versus 4-5% albumin. METHODS We performed a randomised controlled trial in 321 adult patients requiring fluid resuscitation within 48 h of admission to three ICUs in Australia and the UK. RESULTS The cumulative volume of resuscitation fluid at 48 h (primary outcome) was lower in the 20% albumin group than in the 4-5% albumin group [median difference - 600 ml, 95% confidence interval (CI) - 800 to - 400; P < 0.001]. The 20% albumin group had lower cumulative fluid balance at 48 h (mean difference - 576 ml, 95% CI - 1033 to - 119; P = 0.01). Peak albumin levels were higher but sodium and chloride levels lower in the 20% albumin group. Median (interquartile range) duration of mechanical ventilation was 12.0 h (7.6, 33.1) in the 20% albumin group and 15.3 h (7.7, 58.1) in the 4-5% albumin group (P = 0.13); the proportion of patients commenced on renal replacement therapy after randomization was 3.3% and 4.2% (P = 0.67), respectively, and the proportion discharged alive from ICU was 97.4% and 91.1% (P = 0.02). CONCLUSIONS Resuscitation with 20% albumin decreased resuscitation fluid requirements, minimized positive early fluid balance and was not associated with any evidence of harm compared with 4-5% albumin. These findings support the safety of further exploration of resuscitation with 20% albumin in larger randomised trials. TRIAL REGISTRATION http://www.anzctr.org.au . Identifier ACTRN12615000349549.
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7.
Age of red cells for transfusion and outcomes in critically ill adults
Cooper DJ, McQuilten ZK, Nichol A, Ady B, Aubron C, Bailey M, Bellomo R, Gantner D, Irving DO, Kaukonen KM, et al
The New England Journal of Medicine. 2017;377((19):):1858-1867
Abstract
Background It is uncertain whether the duration of red-cell storage affects mortality after transfusion among critically ill adults. Methods In an international, multicenter, randomized, double-blind trial, we assigned critically ill adults to receive either the freshest available, compatible, allogeneic red cells (short-term storage group) or standard-issue (oldest available), compatible, allogeneic red cells (long-term storage group). The primary outcome was 90-day mortality. Results From November 2012 through December 2016, at 59 centers in five countries, 4994 patients underwent randomization and 4919 (98.5%) were included in the primary analysis. Among the 2457 patients in the short-term storage group, the mean storage duration was 11.8 days. Among the 2462 patients in the long-term storage group, the mean storage duration was 22.4 days. At 90 days, there were 610 deaths (24.8%) in the short-term storage group and 594 (24.1%) in the long-term storage group (absolute risk difference, 0.7 percentage points; 95% confidence interval [CI], -1.7 to 3.1; P=0.57). At 180 days, the absolute risk difference was 0.4 percentage points (95% CI, -2.1 to 3.0; P=0.75). Most of the prespecified secondary measures showed no significant between-group differences in outcome. Conclusions The age of transfused red cells did not affect 90-day mortality among critically ill adults. (Funded by the Australian National Health and Medical Research Council and others; TRANSFUSE Australian and New Zealand Clinical Trials Registry number, ACTRN12612000453886 ; ClinicalTrials.gov number, NCT01638416 .).
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8.
Epidemiology of RBC transfusions in patients with severe acute kidney injury: analysis from the Randomized Evaluation of Normal Versus Augmented Level Study
Bellomo R, Martensson J, Kaukonen KM, Lo S, Gallagher M, Cass A, Myburgh J, Finfer S, Randomized Evaluation of Normal Versus Augmented Level of Replacement Therapy Study Investigators
Critical Care Medicine. 2016;44((5)):892-900.
Abstract
OBJECTIVE To assess the epidemiology and outcomes associated with RBC transfusion in patients with severe acute kidney injury requiring continuous renal replacement therapy. DESIGN Post hoc analysis of data from a multicenter, randomized, controlled trial. SETTING Thirty-five ICUs in Australia and New Zealand. PATIENTS Cohort of 1,465 patients enrolled in the Randomized Evaluation of Normal versus Augmented Level replacement therapy study. INTERVENTIONS Daily information on morning hemoglobin level and amount of RBC transfused were prospectively collected in the Randomized Evaluation of Normal versus Augmented Level study. We analyzed the epidemiology of such transfusions and their association with clinical outcomes. MEASUREMENTS AND MAIN RESULTS Overall, 977 patients(66.7%) received a total of 1,192 RBC units. By day 5, 785 of 977 transfused patients (80.4%) had received at least one RBC transfusion. Hemoglobin at randomization was lower in transfused than in nontransfused patients (94 vs 111g/L; p < 0.001). Mean daily hemoglobin was 88+/-7 and 99+/-12g/L in transfused and nontransfused patients. Among transfused patients, 228 (46.7%) had died by day 90 when compared with 426 (43.6%) of nontransfused patients (p = 0.27). Survivors received on average 316+/-261mL of RBC, whereas nonsurvivors received 302+/-362mL (p = 0.42). On multivariate Cox regression analysis, RBC transfusion was independently associated with lower 90-day mortality (hazard ratio, 0.55; 95% CI, 0.38-0.79). However, we found no independent association between RBC transfusions and mortality when the analyses were restricted to patients surviving at least 5 days (hazard ratio, 1.29; 95% CI, 0.90-1.85). We found no independent association between RBC transfusion and renal replacement therapy-free days, mechanical ventilator-free days, or length of stay in ICU or hospital. CONCLUSIONS In patients with severe acute kidney injury treated with continuous renal replacement therapy, we found no association of RBC transfusion with 90-day mortality or other patient-centered outcomes. The optimal hemoglobin threshold for RBC transfusion in such patients needs to be determined in future randomized controlled trials.
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9.
Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial
Nichol A, French C, Little L, Haddad S, Presneill J, Arabi Y, Bailey M, Cooper DJ, Duranteau J, Huet O, et al
Lancet. 2015;386((10012)):2499-506.
Abstract
BACKGROUND Erythropoietin might have neurocytoprotective effects. In this trial, we studied its effect on neurological recovery, mortality, and venous thrombotic events in patients with traumatic brain injury. METHODS Erythropoietin in Traumatic Brain Injury (EPO-TBI) was a double-blind, placebo-controlled trial undertaken in 29 centres (all university-affiliated teaching hospitals) in seven countries (Australia, New Zealand, France, Germany, Finland, Ireland, and Saudi Arabia). Within 24 h of brain injury, 606 patients were randomly assigned by a concealed web-based computer-generated randomisation schedule to erythropoietin (40,000 units subcutaneously) or placebo (09% sodium chloride subcutaneously) once per week for a maximum of three doses. Randomisation was stratified by severity of traumatic brain injury (moderate vs severe) and participating site. With the exception of designated site pharmacists, the site dosing nurses at all sites, and the pharmacists at the central pharmacy in France, all study personnel, patients, and patients' relatives were masked to treatment assignment. The primary outcome, assessed at 6 months by modified intention-to-treat analysis, was improvement in the patients' neurological status, summarised as a reduction in the proportion of patients with an Extended Glasgow Outcome Scale (GOS-E) of 1-4 (death, vegetative state, and severe disability). Two equally spaced preplanned interim analyses were done (after 202 and 404 participants were enrolled). This study is registered with ClinicalTrials.gov, number NCT00987454. FINDINGS Between May 3, 2010, and Nov 1, 2014, 606 patients were enrolled and randomly assigned to erythropoietin (n=308) or placebo (n=298). Ten of these patients (six in the erythropoietin group and four in the placebo group) were lost to follow up at 6 months; therefore, data for the primary outcome analysis was available for 596 patients (302 in the erythropoietin group and 294 in the placebo group). Compared with placebo, erythropoietin did not reduce the proportion of patients with a GOS-E level of 1-4 (134 [44%] of 302 patients in the erythropoietin group vs 132 [45%] of 294 in the placebo group; relative risk [RR] 099 [95% CI 083-118], p=090). In terms of safety, erythropoietin did not significantly affect 6-month mortality versus placebo (32 [11%] of 305 patients had died at 6 months in the erythropoietin group vs 46 [16%] of 297 [16%] in the placebo group; RR 068 [95% CI 044-103], p=007) or increase the occurrence of deep venous thrombosis of the lower limbs (48 [16%] of 305 vs 54 [18%] of 298; RR 087 [95% CI 061-124], p=044). INTERPRETATION Following moderate or severe traumatic brain injury, erythropoietin did not reduce the number of patients with severe neurological dysfunction (GOS-E level 1-4) or increase the incidence of deep venous thrombosis of the lower limbs. The effect of erythropoietin on mortality remains uncertain. FUNDING The National Health and Medical Research Council and the Transport Accident Commission.Copyright © 2015 Elsevier Ltd. All rights reserved.
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10.
Erythropoietin in traumatic brain injury: study protocol for a randomised controlled trial
Nichol A, French C, Little L, Presneill J, Cooper DJ, HaddadS, Duranteau J, Huet O, Skrifvars M, Arabi Y, et al
Trials [Electronic Resource]. 2015;16((1):):528.
Abstract
BACKGROUND Traumatic brain injury is a leading cause of death and disability worldwide. Laboratory and clinical studies demonstrate a possible beneficial effect of erythropoietin in improving outcomes in the traumatic brain injury cohort. However, there are concerns regarding the association of erythropoietin and thrombosis in the critically ill. A large-scale, multi-centre, blinded, parallel-group, placebo-controlled, randomised trial is currently underway to address this hypothesis. METHODS/DESIGN The erythropoietin in traumatic brain injury trial is a stratified prospective, multi-centre, randomised, blinded, parallel-group, placebo-controlled phase III trial. It aims to determine whether the administration of erythropoietin compared to placebo improves neurological outcome in patients with moderate or severe traumatic brain injury at six months after injury. The trial is designed to recruit 606 patients between 15 and 65 years of age with severe (Glasgow Coma Score: 3 to 8) or moderate (Glasgow Coma Score: 9 to 12) traumatic brain injury in Australia, New Zealand, Kingdom of Saudi Arabia, France, Finland, Germany and Ireland. Trial patients will receive either subcutaneous erythropoietin or placebo within 24 hours of injury, and weekly thereafter for up to three doses during the intensive care unit admission. The primary outcome will be the combined proportion of unfavourable neurological outcomes at six months: severe disability or death. Secondary outcomes will include the rate of proximal deep venous thrombosis detected by compression Doppler ultrasound, six-month mortality, the proportion of patients with composite vascular events (deep venous thrombosis, pulmonary embolism, myocardial infarction, cardiac arrest and cerebrovascular events) at six months and quality of life with health economic evaluations. DISCUSSION When completed, the trial aims to provide evidence on the efficacy and safety of erythropoietin in traumatic brain injury patients, and to provide clear guidance for clinicians in their management of this devastating condition. TRIAL REGISTRATION Australian New Zealand Clinical Trials registry: ACTRN12609000827235 (registered on 22 September 2009). Clinicaltrials.gov: NCT00987454 (registered on 29 September 2009). European Drug Regulatory Authorities Clinical Trials: 2011-005235-22 (registered on 18 January 2012).