Critical Care - Research Publications

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    Cost-Effectiveness of Erythropoietin in Traumatic Brain Injury: A Multinational Trial-Based Economic Analysis
    Knott, RJ ; Harris, A ; Higgins, A ; Nichol, A ; French, C ; Little, L ; Haddad, S ; Presneill, J ; Arabi, Y ; Bailey, M ; Cooper, DJ ; Duranteau, J ; Huet, O ; Mak, A ; McArthur, C ; Pettila, V ; Skrifvars, MB ; Vallance, S ; Varma, D ; Wills, J ; Bellomo, R (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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    Venous thromboembolic events in critically ill traumatic brain injury patients
    Skrifvars, MB ; Bailey, M ; Presneill, J ; French, C ; Nichol, A ; Little, L ; Duranteau, J ; Huet, O ; Haddad, S ; Arabi, Y ; McArthur, C ; Cooper, DJ ; Bellomo, R (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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    Erythropoietin in traumatic brain injury associated acute kidney injury: A randomized controlled trial
    Skrifvars, MB ; Moore, E ; Martensson, J ; Bailey, M ; French, C ; Presneill, J ; Nichol, A ; Little, L ; Duranteau, J ; Huet, O ; Haddad, S ; Arabi, Y ; McArthur, C ; Cooper, DJ ; Bellomo, R (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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    A Post Hoc Analysis of Osmotherapy Use in the Erythropoietin in Traumatic Brain Injury Study-Associations With Acute Kidney Injury and Mortality
    Skrifvars, MB ; Bailey, M ; Moore, E ; Martensson, J ; French, C ; Presneill, J ; Nichol, A ; Little, L ; Duranteau, J ; Huet, O ; Haddad, S ; Arabi, YM ; McArthur, C ; Cooper, DJ ; Bendel, S ; Bellomo, R (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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    Dynamic lactate indices as predictors of outcome in critically ill patients
    Nichol, A ; Bailey, M ; Egi, M ; Pettila, V ; French, C ; Stachowski, E ; Reade, MC ; Cooper, DJ ; Bellomo, R (BMC, 2011)
    INTRODUCTION: Dynamic changes in lactate concentrations in the critically ill may predict patient outcome more accurately than static indices. We aimed to compare the predictive value of dynamic indices of lactatemia in the first 24 hours of intensive care unit (ICU) admission with the value of more commonly used static indices. METHODS: This was a retrospective observational study of a prospectively obtained intensive care database of 5,041 consecutive critically ill patients from four Australian university hospitals. We assessed the relationship between dynamic lactate values collected in the first 24 hours of ICU admission and both ICU and hospital mortality. RESULTS: We obtained 36,673 lactate measurements in 5,041 patients in the first 24 hours of ICU admission. Both the time weighted average lactate (LACTW₂₄) and the change in lactate (LACΔ₂₄) over the first 24 hours were independently predictive of hospital mortality with both relationships appearing to be linear in nature. For every one unit increase in LACTW₂₄ and LACΔ₂₄ the risk of hospital death increased by 37% (OR 1.37, 1.29 to 1.45; P < 0.0001) and by 15% (OR 1.15, 1.10 to 1.20; P < 0.0001) respectively. Such dynamic indices, when combined with Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, improved overall outcome prediction (P < 0.0001) achieving almost 90% accuracy. When all lactate measures in the first 24 hours were considered, the combination of LACTW₂₄ and LACΔ₂₄ significantly outperformed (P < 0.0001) static indices of lactate concentration, such as admission lactate, maximum lactate and minimum lactate. CONCLUSIONS: In the first 24 hours following ICU admission, dynamic indices of hyperlactatemia have significant independent predictive value, improve the performance of illness severity score-based outcome predictions and are superior to simple static indices of lactate concentration.
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    Age of red blood cells and mortality in the critically ill
    Pettilae, V ; Westbrook, AJ ; Nichol, AD ; Bailey, MJ ; Wood, EM ; Syres, G ; Phillips, LE ; Street, A ; French, C ; Murray, L ; Orford, N ; Santamaria, JD ; Bellomo, R ; Cooper, DJ (BMC, 2011)
    INTRODUCTION: In critically ill patients, it is uncertain whether exposure to older red blood cells (RBCs) may contribute to mortality. We therefore aimed to evaluate the association between the age of RBCs and outcome in a large unselected cohort of critically ill patients in Australia and New Zealand. We hypothesized that exposure to even a single unit of older RBCs may be associated with an increased risk of death. METHODS: We conducted a prospective, multicenter observational study in 47 ICUs during a 5-week period between August 2008 and September 2008. We included 757 critically ill adult patients receiving at least one unit of RBCs. To test our hypothesis we compared hospital mortality according to quartiles of exposure to maximum age of RBCs without and with adjustment for possible confounding factors. RESULTS: Compared with other quartiles (mean maximum red cell age 22.7 days; mortality 121/568 (21.3%)), patients treated with exposure to the lowest quartile of oldest RBCs (mean maximum red cell age 7.7 days; hospital mortality 25/189 (13.2%)) had an unadjusted absolute risk reduction in hospital mortality of 8.1% (95% confidence interval = 2.2 to 14.0%). After adjustment for Acute Physiology and Chronic Health Evaluation III score, other blood component transfusions, number of RBC transfusions, pretransfusion hemoglobin concentration, and cardiac surgery, the odds ratio for hospital mortality for patients exposed to the older three quartiles compared with the lowest quartile was 2.01 (95% confidence interval = 1.07 to 3.77). CONCLUSIONS: In critically ill patients, in Australia and New Zealand, exposure to older RBCs is independently associated with an increased risk of death.
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    Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock The VITAMINS Randomized Clinical Trial
    Fujii, T ; Luethi, N ; Young, PJ ; Frei, DR ; Eastwood, GM ; French, CJ ; Deane, AM ; Shehabi, Y ; Hajjar, LA ; Oliveira, G ; Udy, AA ; Orford, N ; Edney, SJ ; Hunt, AL ; Judd, HL ; Bitker, L ; Cioccari, L ; Naorungroj, T ; Yanase, F ; Bates, S ; McGain, F ; Hudson, EP ; Al-Bassam, W ; Dwivedi, DB ; Peppin, C ; McCracken, P ; Orosz, J ; Bailey, M ; Bellomo, R ; French, CJ ; Deane, AM ; Hajjar, LA ; Oliveira, G ; Orford, N ; Shehabi, Y ; Udy, AA ; Young, PJ ; McCracken, P ; Board, J ; Martin, E ; Vallance, S ; Young, M ; Bellomo, R ; Eastwood, GM ; Cioccari, L ; Bitker, L ; Yanase, F ; Naorungroj, T ; Hessels, L ; Peck, L ; Young, H ; Percy, N ; Shepherd, K ; Peppin, C ; Dwivedi, DB ; Lukas, G ; Fazli, F ; Murfin, B ; Bates, S ; Morgan, R ; Marshall, F ; Tippett, A ; Towns, M ; Elderkin, T ; Bone, A ; Salerno, T ; Hudson, EP ; Barge, D ; Anstey, J ; Abdelhamid, YA ; Jelbart, B ; Byrne, K ; Tascone, B ; Doherty, S ; Beehre, N ; Hunt, A ; Judd, H ; Latimer-Bell, C ; Lawrence, C ; Robertson, Y ; Smellie, H ; Vucago, AM ; Bailey, M ; Fujii, T ; Howe, BD ; Luethi, N ; Murray, L ; Trapani, T (AMER MEDICAL ASSOC, 2020-02-04)
    IMPORTANCE: It is unclear whether vitamin C, hydrocortisone, and thiamine are more effective than hydrocortisone alone in expediting resolution of septic shock. OBJECTIVE: To determine whether the combination of vitamin C, hydrocortisone, and thiamine, compared with hydrocortisone alone, improves the duration of time alive and free of vasopressor administration in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, open-label, randomized clinical trial conducted in 10 intensive care units in Australia, New Zealand, and Brazil that recruited 216 patients fulfilling the Sepsis-3 definition of septic shock. The first patient was enrolled on May 8, 2018, and the last on July 9, 2019. The final date of follow-up was October 6, 2019. INTERVENTIONS: Patients were randomized to the intervention group (n = 109), consisting of intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours), or to the control group (n = 107), consisting of intravenous hydrocortisone (50 mg every 6 hours) alone until shock resolution or up to 10 days. MAIN OUTCOMES AND MEASURES: The primary trial outcome was duration of time alive and free of vasopressor administration up to day 7. Ten secondary outcomes were prespecified, including 90-day mortality. RESULTS: Among 216 patients who were randomized, 211 provided consent and completed the primary outcome measurement (mean age, 61.7 years [SD, 15.0]; 133 men [63%]). Time alive and vasopressor free up to day 7 was 122.1 hours (interquartile range [IQR], 76.3-145.4 hours) in the intervention group and 124.6 hours (IQR, 82.1-147.0 hours) in the control group; the median of all paired differences was -0.6 hours (95% CI, -8.3 to 7.2 hours; P = .83). Of 10 prespecified secondary outcomes, 9 showed no statistically significant difference. Ninety-day mortality was 30/105 (28.6%) in the intervention group and 25/102 (24.5%) in the control group (hazard ratio, 1.18; 95% CI, 0.69-2.00). No serious adverse events were reported. CONCLUSIONS AND RELEVANCE: In patients with septic shock, treatment with intravenous vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days. The finding suggests that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03333278.