[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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).
[Show abstract][Hide abstract] ABSTRACT: Summary
Background Erythropoietin might have neurocytoprotective eff ects. In this trial, we studied its eff ect 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-affi liated 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
(0·9% sodium chloride subcutaneously) once per week for a maximum of three doses. Randomisation was stratifi ed
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 modifi ed 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] 0·99 [95% CI 0·83–1·18], p=0·90). In terms of safety,
erythropoietin did not signifi cantly aff ect 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 0·68 [95% CI 0·44–1·03],
p=0·07) or increase the occurrence of deep venous thrombosis of the lower limbs (48 [16%] of 305 vs 54 [18%] of 298;
RR 0·87 [95% CI 0·61–1·24], p=0·44).
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 eff ect of erythropoietin on mortality remains uncertain.
The Lancet 10/2015; DOI:10.1016/S0140-6736(15)00386-4 · 45.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Prophylactic hypothermia is effective in laboratory models, but clinical studies to date have been inconclusive, partly because of methodological limitations. Our Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury (POLAR) randomised controlled trial is currently underway comparing early, sustained hypothermia versus standard care in patients with severe TBI. We describe our study protocol and the challenges in conducting prophylactic hypothermia research in TBI.
We aim to randomise 500 patients to either prophylactic 33°C hypothermia initiated within 3 hours of injury and continued for at least 72 hours, or standard normothermic management. Patients will be enrolled by paramedic services in the prehospital setting, or by emergency department staff at participating sites in Australia, New Zealand and Europe. The primary outcome will be the eight-level extended Glasgow outcome scale (GOSE), dichotomised to favourable and unfavourable outcomes at 6 months after injury. Secondary outcomes will include mortality at hospital discharge and at 6 months, ordinal analyses of 6-month GOSE outcomes, quality of life with health economic evaluations and the differential proportion of adverse events. We will predefine subgroup and interaction analyses.
After a run-in phase, recruitment for our main study began in December 2010. When the study is completed, we aim to provide evidence on the efficacy of prophylactic hypothermia in TBI to guide clinicians in their management of this devastating condition.
Critical care and resuscitation: journal of the Australasian Academy of Critical Care Medicine 06/2015; 17(2):92-100. · 2.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute renal failure (ARF) is commonly encountered in the intensive care unit. It is associated with considerable morbidity and mortality. There are many possible aetiologies in the critically ill, including nephrotoxic agents, hypovolaemia and sepsis. Whilst many classification systems for ARF exist, the RIFLE (Risk, Injury, Failure, Loss, End-stage) criteria and the Acute Kidney Injury Network (AKIN) criteria are the most commonly utilized. Many supportive therapies are employed to minimize the degree of renal injury once recognized, such as fluid resuscitation and maintenance of an adequate mean arterial pressure (with the use of inotropes if persistent hypotension despite fluid and treatment of the underlying aetiology); however, if renal failure becomes established, then renal replacement therapy (RRT) may be needed to maintain homeostasis. A number of specific renal-protective agents have been studied (i.e. dopamine), however, to date none have demonstrated a clear benefit. While there are no clear guidelines with respect to the ideal mode or intensity of RRT we will discuss pros and cons of the various bedside options.
Anaesthesia & intensive care medicine 03/2015; 16(4). DOI:10.1016/j.mpaic.2015.01.016
[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. · 2.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Shock may result from a number of distinct disease processes and it is commonly associated with trauma, infection and cardiovascular dysfunction. Shock results in significant morbidity and mortality and is a leading causes of death in hospital patients. In order to improve patient outcomes it is important to recognize shock early, then assess and treat the shocked patient in a systematic way.
The clinical classification of shock into cardiogenic, obstructive, hypovolaemic or distributive shock can help the clinician to understand the underlying cause of the shock. However, it is important to note that considerable overlap between these different types of shock can exist in practice.
After identification of patients in shock, immediate resuscitation with goal-directed therapy to prevent further deterioration and improve outcome is vital. ABCDE approach can be useful systematic way for initial assessment and resuscitation. Basic monitoring should be instituted as soon as possible and in severe or unresponsive shock this should be escalated to invasive monitoring. Immediate generic laboratory, microbiological and radiological tests should be carried out as soon as possible and should include a blood lactate level. Further targeted tests should then be tailored to the history and clinical findings. These targeted investigations should help to pin point the specific cause of the shock and drive definitive management.
Anaesthesia & intensive care medicine 02/2014; 15(2):64–67. DOI:10.1016/j.mpaic.2013.12.008
[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; 187(7). DOI:10.1164/rccm.201209-1718OC · 13.00 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.
Annals of Intensive Care 01/2013; 3(1):2. DOI:10.1186/2110-5820-3-2 · 3.31 Impact Factor
[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.
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.
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.
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.
[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. DOI:10.1016/j.mpaic.2012.02.005
[Show abstract][Hide abstract] ABSTRACT: Acute pancreatitis, a disease caused by inflammation of the pancreas often involving local tissues and systemic organs, is a serious condition that frequently requires intensive care management. The diagnosis of acute pancreatitis is based upon a combination of clinical symptoms, elevations in pancreatic enzymes and/or characteristic computed tomographic findings. The key to instigating appropriate intensive care management is the early identification of those patients with severe acute pancreatitis. Scoring systems such as the Acute Physiology and Chronic Health Evaluation II score and the newer Bedside Index of Severity in Acute Pancreatitis have been utilized to determine severity, however do not take into account the effect of early treatment on the parameters assessed. The focus for management in acute pancreatitis is physiological support with fluid resuscitation and support of vital organs. The use of antibiotic prophylaxis cannot be currently supported, however early nutrition is beneficial in reducing infectious complications. Only infected collections should be drained. This review article highlights recent and upcoming studies that explore the controversies of severity of illness assessment and management principles in an intensive care setting.
Anaesthesia & intensive care medicine 04/2012; 13(4):171–175. DOI:10.1016/j.mpaic.2012.01.011
[Show abstract][Hide abstract] ABSTRACT: Acute renal failure (ARF) is commonly encountered in the intensive care unit. It is associated with considerable morbidity and mortality. There are many possible aetiologies in the critically ill, including nephrotoxic agents, hypovolaemia, and sepsis. Whilst many classification systems for ARF exist, the RIFLE (Risk, Injury, Failure, Loss, End-stage) criteria and the Acute Kidney Injury Network (AKIN) criteria are the most commonly utilized. Many supportive therapies are employed to minimize the degree of renal injury once recognized, such as fluid resuscitation, maintenance of an adequate mean arterial pressure (with the use of inotropes if persistent hypotension despite fluid and treatment of the underlying aetiology); however, if renal failure becomes established, then renal replacement therapy (RRT) may be needed to maintain homeostasis. A number of specific renal-protective agents have been studied (i.e. dopamine); however, to date none have demonstrated a clear benefit. While there are no clear guidelines with respect to the ideal mode or intensity of RRT we will discuss pros and cons of the various bedside options.
Anaesthesia & intensive care medicine 04/2012; 13(4):166–170. DOI:10.1016/j.mpaic.2012.01.009
[Show abstract][Hide abstract] ABSTRACT: Status epilepticus (SE) is a major neurological emergency associated with significant morbidity and mortality. Whilst there are many definitions of SE, the operational definition as a seizure lasting greater than 5 minutes is widely implemented to ensure there is no delay in emergency treatment. After initial resuscitative assessment and first-line treatment these patients frequently require admission to the intensive care unit for both continuing physiological support and specific second- and third-line therapies of the SE if still unresolved. It is vital that the critical care clinician understands the potential aetiology, pathophysiology, appropriate investigations and the pharmacological management of patients with SE.
Anaesthesia & intensive care medicine 04/2012; 13(4):148–151. DOI:10.1016/j.mpaic.2012.01.010
[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. · 2.01 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. · 2.01 Impact Factor