Critical Care - Research Publications
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ItemStudy protocol for TARGET protein: The effect of augmented administration of enteral protein to critically ill adults on clinical outcomes: A cluster randomised, cross-sectional, double cross-over, clinical trial(ELSEVIER, 2023-09)BACKGROUND: It is unknown whether increasing dietary protein to 1.2-2.0 g/kg/day as recommended in international guidelines compared to current practice improves outcomes in intensive care unit (ICU) patients. The TARGET Protein trial will evaluate this. OBJECTIVE: To describe the study protocol for the TARGET Protein trial. DESIGN SETTING AND PARTICIPANTS: TARGET Protein is a cluster randomised, cross-sectional, double cross-over, pragmatic clinical trial undertaken in eight ICUs in Australia and New Zealand. Each ICU will be randomised to use one of two trial enteral formulae for three months before crossing over to the other formula, which is then repeated, with enrolment continuing at each ICU for 12 months. All patients aged ≥16 years in their index ICU admission commencing enteral nutrition will be eligible for inclusion. Eligible patients will receive the trial enteral formula to which their ICU is allocated. The two trial enteral formulae are isocaloric with a difference in protein dose: intervention 100g/1000 ml and comparator 63g/1000 ml. Staggered recruitment commenced in May 2022. MAIN OUTCOMES MEASURES: The primary outcome is days free of the index hospital and alive at day 90. Secondary outcomes include days free of the index hospital at day 90 in survivors, alive at day 90, duration of invasive ventilation, ICU and hospital length of stay, incidence of tracheostomy insertion, renal replacement therapy, and discharge destination. CONCLUSION: TARGET Protein aims to determine whether augmented enteral protein delivery reduces days free of the index hospital and alive at day 90. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12621001484831).
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ItemNo Preview AvailableCost-Effectiveness of Erythropoietin in Traumatic Brain Injury: A Multinational Trial-Based Economic Analysis(MARY ANN LIEBERT, INC, 2019-09-01)The EPO-TBI multi-national randomized controlled trial found that erythropoietin (EPO), when compared to placebo, did not affect 6-month neurological outcome, but reduced illness severity-adjusted mortality in patients with traumatic brain injury (TBI), making the cost-effectiveness of EPO in TBI uncertain. The current study uses patient-level data from the EPO-TBI trial to evaluate the cost-effectiveness of EPO in patients with moderate or severe TBI from the healthcare payers' perspective. We addressed the issue of transferability in multi-national trials by estimating costs and effects for specific geographical regions of the study (Australia/New Zealand, Europe, and Saudi Arabia). Unadjusted mean quality-adjusted life-years (QALYs; 95% confidence interval [CI]) at 6 months were 0.027 (0.020-0.034; p < 0.001) higher in the EPO group, with an adjusted QALY increment of 0.014 (0.000-0.028; p = 0.04). Mean unadjusted costs (95% CI) were $US5668 (-9191 to -2144; p = 0.002) lower in the treatment group; controlling for baseline IMPACT-TBI score and regional heterogeneity reduced this difference to $2377 (-12,446 to 7693; p = 0.64). For a willingness-to-pay threshold of $US50,000 per QALY, 71.8% of replications were considered cost-effective. Therefore, we did not find evidence that EPO was significantly cost-effective in the treatment of moderate or severe TBI at 6-month follow-up.
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ItemNo Preview AvailableVenous thromboembolic events in critically ill traumatic brain injury patients(SPRINGER, 2017-03)PURPOSE: To estimate the prevalence, risk factors, prophylactic treatment and impact on mortality for venous thromboembolism (VTE) in patients with moderate to severe traumatic brain injury (TBI) treated in the intensive care unit. METHODS: A post hoc analysis of the erythropoietin in traumatic brain injury (EPO-TBI) trial that included twice-weekly lower limb ultrasound screening. Venous thrombotic events were defined as ultrasound-proven proximal deep venous thrombosis (DVT) or clinically detected pulmonary embolism (PE). Results are reported as events, percentages or medians and interquartile range (IQR). Cox regression analysis was used to calculate adjusted hazard ratios (HR) with 95% confidence intervals (CI) for time to VTE and death. RESULTS: Of 603 patients, 119 (19.7%) developed VTE, mostly comprising DVT (102 patients, 16.9%) with a smaller number of PE events (24 patients, 4.0%). Median time to DVT diagnosis was 6 days (IQR 2-11) and to PE diagnosis 6.5 days (IQR 2-16.5). Mechanical prophylaxis (MP) was used in 91% of patients on day 1, 97% of patients on day 3 and 98% of patients on day 7. Pharmacological prophylaxis was given in 5% of patients on day 1, 30% of patients on day 3 and 57% of patients on day 7. Factors associated with time to VTE were age (HR per year 1.02, 95% CI 1.01-1.03), patient weight (HR per kg 1.01, 95% CI 1-1.02) and TBI severity according to the International Mission for Prognosis and Analysis of Clinical Trials risk of poor outcome (HR per 10% increase 1.12, 95% CI 1.01-1.25). The development of VTE was not associated with mortality (HR 0.92, 95% CI 0.51-1.65). CONCLUSIONS: Despite mechanical and pharmacological prophylaxis, VTE occurs in one out of every five patients with TBI treated in the ICU. Higher age, greater weight and greater severity of TBI increase the risk. The development of VTE was not associated with excess mortality.
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ItemErythropoietin in traumatic brain injury associated acute kidney injury: A randomized controlled trial(WILEY, 2019-02)BACKGROUND: Acute kidney injury (AKI) in traumatic brain injury (TBI) is poorly understood and it is unknown if it can be attenuated using erythropoietin (EPO). METHODS: Pre-planned analysis of patients included in the EPO-TBI (ClinicalTrials.gov NCT00987454) trial who were randomized to weekly EPO (40 000 units) or placebo (0.9% sodium chloride) subcutaneously up to three doses or until intensive care unit (ICU) discharge. Creatinine levels and urinary output (up to 7 days) were categorized according to the Kidney Disease Improving Global Outcome (KDIGO) classification. Severity of TBI was categorized with the International Mission for Prognosis and Analysis of Clinical Trials in TBI. RESULTS: Of 3348 screened patients, 606 were randomized and 603 were analyzed. Of these, 82 (14%) patients developed AKI according to KDIGO (60 [10%] with KDIGO 1, 11 [2%] patients with KDIGO 2, and 11 [2%] patients with KDIGO 3). Male gender (hazard ratio [HR] 4.0 95% confidence interval [CI] 1.4-11.2, P = 0.008) and severity of TBI (HR 1.3 95% CI 1.1-1.4, P < 0.001 for each 10% increase in risk of poor 6 month outcome) predicted time to AKI. KDIGO stage 1 (HR 8.8 95% CI 4.5-17, P < 0.001), KDIGO stage 2 (HR 13.2 95% CI 3.9-45.2, P < 0.001) and KDIGO stage 3 (HR 11.7 95% CI 3.5-39.7, P < 0.005) predicted time to mortality. EPO did not influence time to AKI (HR 1.08 95% CI 0.7-1.67, P = 0.73) or creatinine levels during ICU stay (P = 0.09). CONCLUSIONS: Acute kidney injury is more common in male patients and those with severe compared to moderate TBI and appears associated with worse outcome. EPO does not prevent AKI after TBI.
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ItemA Post Hoc Analysis of Osmotherapy Use in the Erythropoietin in Traumatic Brain Injury Study-Associations With Acute Kidney Injury and Mortality(LIPPINCOTT WILLIAMS & WILKINS, 2021-04)OBJECTIVES: Mannitol and hypertonic saline are used to treat raised intracerebral pressure in patients with traumatic brain injury, but their possible effects on kidney function and mortality are unknown. DESIGN: A post hoc analysis of the erythropoietin trial in traumatic brain injury (ClinicalTrials.gov NCT00987454) including daily data on mannitol and hypertonic saline use. SETTING: Twenty-nine university-affiliated teaching hospitals in seven countries. PATIENTS: A total of 568 patients treated in the ICU for 48 hours without acute kidney injury of whom 43 (7%) received mannitol and 170 (29%) hypertonic saline. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We categorized acute kidney injury stage according to the Kidney Disease Improving Global Outcome classification and defined acute kidney injury as any Kidney Disease Improving Global Outcome stage-based changes from the admission creatinine. We tested associations between early (first 2 d) mannitol and hypertonic saline and time to acute kidney injury up to ICU discharge and death up to 180 days with Cox regression analysis. Subsequently, acute kidney injury developed more often in patients receiving mannitol (35% vs 10%; p < 0.001) and hypertonic saline (23% vs 10%; p < 0.001). On competing risk analysis including factors associated with acute kidney injury, mannitol (hazard ratio, 2.3; 95% CI, 1.2-4.3; p = 0.01), but not hypertonic saline (hazard ratio, 1.6; 95% CI, 0.9-2.8; p = 0.08), was independently associated with time to acute kidney injury. In a Cox model for predicting time to death, both the use of mannitol (hazard ratio, 2.1; 95% CI, 1.1-4.1; p = 0.03) and hypertonic saline (hazard ratio, 1.8; 95% CI, 1.02-3.2; p = 0.04) were associated with time to death. CONCLUSIONS: In this post hoc analysis of a randomized controlled trial, the early use of mannitol, but not hypertonic saline, was independently associated with an increase in acute kidney injury. Our findings suggest the need to further evaluate the use and choice of osmotherapy in traumatic brain injury.
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ItemStatistical analysis plan for the Erythropoietin in Traumatic Brain Injury trial: a randomised controlled trial of erythropoietin versus placebo in moderate and severe traumatic brain injury.(Springer Science and Business Media LLC, 2014-12-20)BACKGROUND: The Erythropoietin in Traumatic Brain Injury (EPO-TBI) trial aims to determine whether the administration of erythropoietin to patients with moderate or severe traumatic brain injury improves patient-centred outcomes. METHODS: EPO-TBI is a multicentre, blinded, randomised, parallel groups, placebo-controlled, phase III superiority trial of erythropoietin in ICU patients with traumatic brain injury conducted in Australia and New Zealand, Saudi Arabia and Europe; 606 critically ill patients aged 15 to 65 years with moderate or severe acute traumatic brain injury will be enrolled. Trial patients will receive either 40,000 IU erythropoietin or placebo by subcutaneous injection administered weekly for up to three doses during their ICU admission. The primary outcome measure is the proportion of unfavourable neurological outcomes, comprising death or severe disability, observed at 6 months following randomisation utilizing the Extended Glasgow Outcome Scale. Secondary outcomes, also assessed at 6 months following randomisation, include the probability of an equal or greater Extended Glasgow Outcome Scale level, mortality, the proportions of patients with proximal deep venous thrombosis or with composite thrombotic vascular events, as well as assessment of quality of life and cost-effectiveness. The planned sample size will allow 90% power to detect a reduction from 50% to 36% in unfavourable neurological outcomes at a two-sided alpha of 0.05. DISCUSSION: A detailed analysis plan has been developed for EPO-TBI that is consistent with international guidelines. This plan specifies the statistical models for evaluation of primary and secondary outcomes, as well as defining covariates for adjusted analyses. Application of this statistical analysis plan to the forthcoming EPO-TBI trial will facilitate unbiased analyses of these important clinical data. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12609000827235 (22 September 2009). ClinicalTrials.gov: NCT00987454 (29 September 2009). European Drug Regulatory Authorities Clinical Trials: 2011-005235-22 (18 January 2012).