[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
[Show abstract][Hide abstract] ABSTRACT: To determine if using freshest available rather than standard-issue red blood cells (RBCs) can reduce mortality in critically ill intensive care unit patients. Our study is the largest ongoing randomised controlled trial (RCT) of RBC age in critically ill patients and will help determine if the use of the freshest available RBCs should become standard policy for the critically ill.
A double-blind, multicentre, Phase III RCT of 5000 adult ICU patients in Australia, New Zealand, Europe and the Middle East.
Transfusion of the freshest available RBCs in place of standard-care RBCs until hospital discharge.
The primary outcome measure is 90-day all-cause mortality. Secondary outcome measures are time to death, 28-day and 180-day mortality, persistent organ dysfunction combined with death, days alive and free of mechanical ventilation and renal replacement therapy, bloodstream infection in the ICU, length of stay in the ICU and in hospital, proportion of patients with febrile non-haemolytic transfusion reactions, and quality of life at Day 180.
A detailed statistical analysis plan with predefined subgroups and secondary analyses has been finalised before results being available, to ensure an unbiased final analysis.
The pragmatic protocol design has been chosen to facilitate translation of the trial results into practice. The TRANSFUSE trial will have important clinical and policy implications, regardless of the outcome.
Critical care and resuscitation: journal of the Australasian Academy of Critical Care Medicine 12/2014; 16(4):255-61. · 2.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: RATIONALE: Observational studies link statin therapy with improved outcomes in patients with severe sepsis. OBJECTIVES: To test whether atorvastatin therapy affects biological and clinical outcomes in critically ill patients with severe sepsis. METHODS: Phase II, multicenter, prospective, randomized, double-blind, placebo controlled trial stratified by site and prior statin use. A cohort of 250 critically ill patients (123 statins, 127 placebo) with severe sepsis were administrated either atorvastatin (20 mg daily) or matched placebo. MEASUREMENTS AND MAIN RESULTS: There was no difference in IL-6 concentrations (primary end point) between the atorvastatin and placebo groups (p=0.76) and no interaction between treatment group and time to suggest that the groups behaved differently over time (p= 0.26). Baseline plasma IL-6, was lower among previous statin users [129(87-191) vs. 244 (187-317) pg/ml, p=0.01]. There was no difference in length of stay, change in SOFA scores or mortality at ICU discharge, hospital discharge, 28 days or 90 days (15 vs. 19%) or adverse effects between the two groups. Cholesterol was lower in atorvastatin treated patients [2.4(0.07) vs. 2.6(0.06) mmol/L, p=0.006]. In the pre -defined group of 77 prior statin users, those randomised to placebo had a greater 28 day mortality (28% vs.5%, P=0.01) compared to those who received atorvastatin. The difference was not statistically significant at 90 days (28 vs. 11%, p=0.06) CONCLUSIONS: Atorvastatin therapy in severe sepsis did not affect IL-6 levels. Prior statin use was associated with a lower baseline IL-6 concentration and continuation of atorvastatin in this cohort was associated with improved survival. Clinical trial registration information available at http://www.anzctr.org.au, i.d. = ACTRN12607000028404.
American Journal of Respiratory and Critical Care Medicine 01/2013; · 11.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Red blood cells (RBC) storage facilitates the supply of RBC to meet the clinical demand for transfusion and to avoid wastage. However, RBC storage is associated with adverse changes in erythrocytes and their preservation medium. These changes are responsible for functional alterations and for the accumulation of potentially injurious bioreactive substances. They also may have clinically harmful effects especially in critically ill patients. The clinical consequences of storage lesions, however, remain a matter of persistent controversy. Multiple retrospective, observational, and single-center studies have reported heterogeneous and conflicting findings about the effect of blood storage duration on morbidity and/or mortality in trauma, cardiac surgery, and intensive care unit patients. Describing the details of this controversy, this review not only summarizes the current literature but also highlights the equipoise that currently exists with regard to the use of short versus current standard (extended) storage duration red cells in critically ill patients and supports the need for large, randomized, controlled trials evaluating the clinical impact of transfusing fresh (short duration of storage) versus older (extended duration of storage) red cells in critically ill patients.
[Show abstract][Hide abstract] ABSTRACT: Acute respiratory distress syndrome (ARDS) is an inflammatory condition of the lungs which can result in refractory and life-threatening hypoxaemic respiratory failure. The risk factors for the development of ARDS are many but include trauma, multiple blood transfusions, burns and major surgery, therefore this condition is not uncommon in the severely injured patient. When ARDS is severe, high-inspired oxygen concentrations are frequently required to minimise hypoxaemia. In these situations clinicians commonly utilise interventions termed 'hypoxaemic rescue therapies' in an attempt to improve oxygenation, as without these, conventional mechanical ventilation can be associated with high mortality. However, their lack of efficacy on mortality when used prophylactically in generalised ARDS cohorts has resulted in their use being confined to clinical trials and the subset of ARDS patients with refractory hypoxaemia. First line hypoxaemic rescue therapies include inhaled nitric oxide, prone positioning, alveolar recruitment manoeuvres and high frequency oscillatory ventilation, which have all been shown to be effective in improving oxygenation. In situations where these first line rescue therapies are inadequate extra-corporeal membrane oxygenation has emerged as a lifesaving second line rescue therapy. Rescue therapies in critically ill patients with traumatic injuries presents specific challenges and requires careful assessment of both the short and longer term benefits, therapeutic limitations, and specific adverse effects before their use.
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: The purpose of the study was to assess the long term outcome and quality of life of patients with acute respiratory distress syndrome (ARDS) receiving extracorporeal membrane oxygenation (ECMO) for refractory hypoxemia. METHODS: A retrospective observational study with prospective health related quality of life (HRQoL) assessment was conducted in ARDS patients who had ECMO as a rescue therapy for reversible refractory hypoxemia from January 2009 until April 2011 in a tertiary Australian centre. Survival and long-term quality of life assessment, using the Short-Form 36 (SF-36) and the EuroQol health related quality of life questionnaire (EQ5D) were assessed and compared to international data from other research groups. RESULTS: Twenty-one patients (mean age 36.3 years) with ARDS receiving ECMO for refractory hypoxemia were studied. Eighteen (86%) patients were retrieved from external intensive care units (ICUs) by a dedicated ECMO retrieval team. Eleven (55%) had H1N1 influenza A-associated pneumonitis. Eighteen (86%) patients survived to hospital discharge. Of the 18 survivors, ten (56%) were discharged to other hospitals and 8 (44%) were discharged directly home. Sequelae and health related quality of life were evaluated for 15 of the 18 (71%) long-term survivors (assessment at median 8 months). Mean SF-36 scores were significantly lower across all domains compared to age and sex matched Australian norms. Mean SF-36 scores were lower (minimum important difference at least 5 points) than previously described ARDS survivors in the domains of general health, mental health, vitality and social function. One patient had long-term disability as a result of ICU acquired weakness. Only 26% of survivors had returned to previous work levels at the time of follow-up. CONCLUSIONS: This ARDS cohort had a high survival rate (86%) after use of ECMO support for reversible refractory hypoxemia. Long term survivors had similar physical health but decreased mental health, general health, vitality and social function compared to other ARDS survivors and an unexpectedly poor return to work.
Critical care (London, England) 10/2012; 16(5):R202. · 5.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Severe sepsis is a heterogeneous condition affecting multiple organ systems, and is commonly encountered in the hospital setting due to both community and nosocomial infections. The incidence of severe sepsis has increased over the past decades, and mortality remains alarmingly high. Management of the septic patient involves rapid evaluation and prompt initiation of both supportive and specific therapies. Such patients commonly require admission to the intensive care unit (ICU) for invasive monitoring and haemodynamic support. Resuscitation, early initiation of broad-spectrum antimicrobial therapy and source control remain the cornerstones of therapy. Controversy persists about the roles and benefits of early goal-directed therapy (EGDT), corticosteroids and the advantage of albumin over saline as resuscitation fluid. This review summarizes the contemporary evidence regarding diagnostic and treatment strategies of severe sepsis, with emphasis on patients in critical care settings.
Anaesthesia & intensive care medicine 05/2012; 13(5):199–203.
[Show abstract][Hide abstract] ABSTRACT: Intensive care patients with traumatic brain injury (TBI) are at high risk of developing deep vein thrombosis (DVT). A high rate of DVT was reported before routine thromboprophylaxis, but the current DVT rate in TBI patients receiving best-practice mechanical and pharmacological prophylaxis is unknown.
To determine the prevalence of DVT among TBI patients.
A prospective observational pilot study of adult patients admitted to the intensive care unit of a level 1 trauma centre within 72 hours of sustaining a TBI (Glasgow Coma Scale score _14).
Rate of DVT determined using twice-weekly compression ultrasound; rate of pulmonary embolism (PE) and length of stay.
36 patients (28 men; mean age, 40.3 years) were included. Six had moderate and 21 had severe TBI. Two patients (6%) developed a DVT and two patients (6%) developed a PE. The proximal leg DVT rate was 3%, but the overall venous thromboembolism rate was 11% (4 patients).
Mechanical and pharmacological prophylaxis appeared to be effective. The incidence of clinically identified PE is of concern and suggests that thromboembolic sources other than large leg veins may not be being adequately controlled by modern thromboprophylaxis regimens.
Critical care and resuscitation: journal of the Australasian Academy of Critical Care Medicine 03/2012; 14(1):10-3. · 2.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There are conflicting data that suggest that hyperoxia may be associated with either worse or better outcomes in patients suffering a stroke.
To investigate the association between PaO(2) in the first 24 hours in the intensive care unit and mortality among ventilated patients with acute ischaemic stroke.
Retrospective cohort study.
Data were extracted from the Australian and New Zealand Intensive Care Society Adult Patient Database.
Adults ventilated for ischaemic stroke in 129 ICUs in Australia and New Zealand, 2000-2009.
The primary outcome was the odds ratio for in hospital mortality associated with "worst" PaO(2) considered as a categorical variable, with data divided into deciles and compared with the mortality of the 10th decile. For patients on an FiO(2) of _50% at any time in the first 24 hours, "worst" PaO(2) was defined as the PaO(2) associated with the highest alveolar-arterial (A-a) gradient. For patients on an FiO(2) of <50%, it was defined as the lowest PaO(2). Secondary outcomes were ICU and hospital length of stay and the proportion of patients in each decile discharged home.
Of the 2643 patients eligible for study inclusion, 1507 (57%) died in hospital. The median "worst" PaO(2) was 117mmHg (interquartile range, 87-196mmHg). There was no association between worst PaO(2) and mortality, length of stay or likelihood of discharge home.
We found no association between worst arterial oxygen tension in the first 24 hours in ICU and outcome in ventilated patients with ischaemic stroke.
Critical care and resuscitation: journal of the Australasian Academy of Critical Care Medicine 03/2012; 14(1):14-9. · 2.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prolonged storage of red blood cells (RBCs) may increase posttransfusion adverse events in critically ill patients. We aimed to evaluate in intensive care unit (ICU) patients 1) the feasibility of allocating freshest available compatible RBCs versus standard care and 2) the suitability of this approach in the design of a large randomized controlled trial (RCT).
Eligible patients from two adult ICUs were randomly assigned to receive either the freshest available compatible RBCs or the standard care (the oldest compatible available RBCs) for all transfusions during their ICU stay. Study group allocation was concealed from patients and bedside clinicians, but the transfusion service was unblinded. The study endpoints were the feasibility of the study procedures, including success of the ICU Web randomization, the ICU staff blinding, and the correct delivery of the RBC units by the transfusion service in accordance with the allocated study group. In addition, we measured the difference in age of RBC units between the two groups.
During a 3-month period, 177 RBC units were delivered to 51 patients. All study procedures, including randomization, blinding, and delivery of blood in accordance with the study group were successful. The mean (±SD) of the mean age of the RBC received by each patient was lower in the "fresher blood" group compared with the standard care group (12.1 [±3.8] days vs. 23 [±8.4] days; p<0.001).
Randomized delivery of the freshest available RBCs versus standard care to ICU patients who were prescribed transfusion for clinical reasons is feasible, with a clinically relevant degree of storage duration separation achievable between the two study groups. These findings support the feasibility of a future large pragmatic RCT.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
Critical care (London, England) 10/2011; 15(5):R242. · 5.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tidal volume and plateau pressure minimisation are the standard components of a protective lung ventilation strategy for patients with acute respiratory distress syndrome (ARDS). Open lung strategies, including higher positive end-expiratory pressure (PEEP) and recruitment manoeuvres to date have not proven efficacious. This study examines the effectiveness and safety of a novel open lung strategy, which includes permissive hypercapnia, staircase recruitment manoeuvres (SRM) and low airway pressure with PEEP titration.
Twenty ARDS patients were randomised to treatment or ARDSnet control ventilation strategies. The treatment group received SRM with decremental PEEP titration and targeted plateau pressure < 30 cm H2O. Gas exchange and lung compliance were measured daily for 7 days and plasma cytokines in the first 24 hours and on days 1, 3, 5 and 7 (mean ± SE). Duration of ventilation, ICU stay and hospital stay (median and interquartile range) and hospital survival were determined.
There were significant overall differences between groups when considering plasma IL-8 and TNF-α. For plasma IL-8, the control group was 41% higher than the treatment group over the seven-day period (ratio 1.41 (1.11 to 1.79), P = 0.01), while for TNF-α the control group was 20% higher over the seven-day period (ratio 1.20 (1.01 to 1.42) P = 0.05). PaO2/FIO2 (204 ± 9 versus 165 ± 9 mmHg, P = 0.005) and static lung compliance (49.1 ± 2.9 versus 33.7 ± 2.7 mls/cm H2O, P < 0.001) were higher in the treatment group than the control group over seven days. There was no difference in duration of ventilation (180 (87 to 298) versus 341 (131 to 351) hrs, P = 0.13), duration of ICU stay (9.9 (5.6 to 14.8) versus 16.0 (8.1 to 19.3) days, P = 0.19) and duration of hospital stay (17.9 (13.7 to 34.5) versus 24.7 (20.5 to 39.8) days, P = 0.16) between the treatment and control groups.
This open lung strategy was associated with greater amelioration in some systemic cytokines, improved oxygenation and lung compliance over seven days. A larger trial powered to examine clinically-meaningful outcomes is warranted.
Critical care (London, England) 06/2011; 15(3):R133. · 5.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Erythropoietin is a 30.4 kDa glycoprotein produced by the kidney, which is mostly known for its physiological function in regulating red blood cell production in the bone marrow Accumulating evidence, however suggests that erythropoietin has additional organ protective effects, which may specifically be useful in protecting the brain and kidneys from injury. Experimental evidence suggests that these protective mechanisms are multi-factorial in nature and may include inhibition of apoptotic cell death, stimulation of cellular regeneration, inhibition of deleterious pathways and promotion of recovery. In this article we review the physiology of erythropoietin, assess previous work that supports the role of erythropoietin as a general tissue protective agent and explain the mechanisms by which it may achieve this tissue protective effect. We then focus on specific laboratory and clinical data that suggest that erythropoietin has a strong brain protective and kidney protective effect. In addition, we comment on the implications of these studies for clinicians at the bedside and for researchers designing controlled trials to further elucidate the true clinical utility of erythropoietin as a neuroprotective and nephroprotective agent. Finally, we describe EPO-TBI, a double-blinded multi-centre randomised controlled trial involving the authors that is being conducted to investigate the organ protective effects of erythropoietin on the brain, and also assesses its effect on the kidneys.
Anaesthesia and intensive care 05/2011; 39(3):356-72. · 1.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
In critically ill patients, in Australia and New Zealand, exposure to older RBCs is independently associated with an increased risk of death.
Critical care (London, England) 04/2011; 15(2):R116. · 5.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Therapeutic hypothermia involves the controlled reduction of core temperature to attenuate the secondary organ damage which occurs following a primary injury. Clinicians have been increasingly using therapeutic hypothermia to prevent or ameliorate various types of neurological injury and more recently for some forms of cardiac injury. In addition, some recent evidence suggests that therapeutic hypothermia may also provide benefit following acute kidney injury. In this review we will examine the potential mechanisms of action and current clinical evidence surrounding the use of therapeutic hypothermia. We will discuss the ideal methodological attributes of future studies using hypothermia to optimise outcomes following organ injury, in particular neurological injury. We will assess the importance of target hypothermic temperature, time to achieve target temperature, duration of cooling, and re-warming rate on outcomes following neurological injury to gain insights into important factors which may also influence the success of hypothermia in other organ injuries, such as the heart and the kidney. Finally, we will examine the potential of therapeutic hypothermia as a future kidney protective therapy.
[Show abstract][Hide abstract] ABSTRACT: Hyperoxia has recently been reported as an independent risk factor for mortality in patients resuscitated from cardiac arrest. We examined the independent relationship between hyperoxia and outcomes in such patients.
We divided patients resuscitated from nontraumatic cardiac arrest from 125 intensive care units (ICUs) into three groups according to worst PaO2 level or alveolar-arterial O2 gradient in the first 24 hours after admission. We defined 'hyperoxia' as PaO2 of 300 mmHg or greater, 'hypoxia/poor O2 transfer' as either PaO2 < 60 mmHg or ratio of PaO2 to fraction of inspired oxygen (FiO2 ) < 300, 'normoxia' as any value between hypoxia and hyperoxia and 'isolated hypoxemia' as PaO2 < 60 mmHg regardless of FiO2. Mortality at hospital discharge was the main outcome measure.
Of 12,108 total patients, 1,285 (10.6%) had hyperoxia, 8,904 (73.5%) had hypoxia/poor O2 transfer, 1,919 (15.9%) had normoxia and 1,168 (9.7%) had isolated hypoxemia (PaO2 < 60 mmHg). The hyperoxia group had higher mortality (754 (59%) of 1,285 patients; 95% confidence interval (95% CI), 56% to 61%) than the normoxia group (911 (47%) of 1,919 patients; 95% CI, 45% to 50%) with a proportional difference of 11% (95% CI, 8% to 15%), but not higher than the hypoxia group (5,303 (60%) of 8,904 patients; 95% CI, 59% to 61%). In a multivariable model controlling for some potential confounders, including illness severity, hyperoxia had an odds ratio for hospital death of 1.2 (95% CI, 1.1 to 1.6). However, once we applied Cox proportional hazards modelling of survival, sensitivity analyses using deciles of hypoxemia, time period matching and hyperoxia defined as PaO2 > 400 mmHg, hyperoxia had no independent association with mortality. Importantly, after adjustment for FiO2 and the relevant covariates, PaO2 was no longer predictive of hospital mortality (P = 0.21).
Among patients admitted to the ICU after cardiac arrest, hyperoxia did not have a robust or consistently reproducible association with mortality. We urge caution in implementing policies of deliberate decreases in FiO2 in these patients.
Critical care (London, England) 03/2011; 15(2):R90. · 5.04 Impact Factor