ORCID Profile
0000-0002-4689-1238
Current Organisations
HRB Irish Critical Care-Clinical Trials Network
,
College of Intensive Care Medicine of Australia and New Zealand
,
Irish Critical Care-Clinical Trials Group (ICC-CTG)
,
The Alfred Hospital
,
University of Oxford
,
Monash University
,
Saint Vincent's University Hospital
,
University College Dublin
,
ANZIC-RC
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Publications
Trial Forge Guidance 3: randomised trials and how to recruit and retain individuals from ethnic minority groups-practical guidance to support better practice
Publisher: Springer Science and Business Media LLC
Date: 17-08-2022
DOI: 10.1186/S13063-022-06553-W
Abstract: Randomised trials, especially those intended to directly inform clinical practice and policy, should be designed to reflect all those who could benefit from the intervention under test should it prove effective. This does not always happen. The UK National Institute for Health and Care Research (NIHR) INCLUDE project identified many groups in the UK that are under-served by trials, including ethnic minorities. This guidance document presents four key recommendations for designing and running trials that include the ethnic groups needed by the trial. These are (1) ensure eligibility criteria and recruitment pathway do not limit participation in ways you do not intend, (2) ensure your trial materials are developed with inclusion in mind, (3) ensure staff are culturally competent and (4) build trusting partnerships with community organisations that work with ethnic minority groups. Each recommendation comes with best practice advice, public contributor testimonials, ex les of the inclusion problem tackled by the recommendation, or strategies to mitigate the problem, as well as a collection of resources to support implementation of the recommendations. We encourage trial teams to follow the recommendations and, where possible, evaluate the strategies they use to implement them. Finally, while our primary audience is those designing, running and reporting trials, we hope funders, grant reviewers and approvals agencies may also find our guidance useful.
Respiratory support in patients with severe COVID-19 in the International Severe Acute Respiratory and Emerging Infection (ISARIC) COVID-19 study: a prospective, multinational, observational study
Publisher: Springer Science and Business Media LLC
Date: 13-09-2022
DOI: 10.1186/S13054-022-04155-1
Abstract: Up to 30% of hospitalised patients with COVID-19 require advanced respiratory support, including high-flow nasal cannulas (HFNC), non-invasive mechanical ventilation (NIV), or invasive mechanical ventilation (IMV). We aimed to describe the clinical characteristics, outcomes and risk factors for failing non-invasive respiratory support in patients treated with severe COVID-19 during the first two years of the pandemic in high-income countries (HICs) and low middle-income countries (LMICs). This is a multinational, multicentre, prospective cohort study embedded in the ISARIC-WHO COVID-19 Clinical Characterisation Protocol. Patients with laboratory-confirmed SARS-CoV-2 infection who required hospital admission were recruited prospectively. Patients treated with HFNC, NIV, or IMV within the first 24 h of hospital admission were included in this study. Descriptive statistics, random forest, and logistic regression analyses were used to describe clinical characteristics and compare clinical outcomes among patients treated with the different types of advanced respiratory support. A total of 66,565 patients were included in this study. Overall, 82.6% of patients were treated in HIC, and 40.6% were admitted to the hospital during the first pandemic wave. During the first 24 h after hospital admission, patients in HICs were more frequently treated with HFNC (48.0%), followed by NIV (38.6%) and IMV (13.4%). In contrast, patients admitted in lower- and middle-income countries (LMICs) were less frequently treated with HFNC (16.1%) and the majority received IMV (59.1%). The failure rate of non-invasive respiratory support (i.e. HFNC or NIV) was 15.5%, of which 71.2% were from HIC and 28.8% from LMIC. The variables most strongly associated with non-invasive ventilation failure, defined as progression to IMV, were high leukocyte counts at hospital admission (OR [95%CI] 5.86 [4.83–7.10]), treatment in an LMIC (OR [95%CI] 2.04 [1.97–2.11]), and tachypnoea at hospital admission (OR [95%CI] 1.16 [1.14–1.18]). Patients who failed HFNC/NIV had a higher 28-day fatality ratio (OR [95%CI] 1.27 [1.25–1.30]). In the present international cohort, the most frequently used advanced respiratory support was the HFNC. However, IMV was used more often in LMIC. Higher leucocyte count, tachypnoea, and treatment in LMIC were risk factors for HFNC/NIV failure. HFNC/NIV failure was related to worse clinical outcomes, such as 28-day mortality. Trial registration This is a prospective observational study therefore, no health care interventions were applied to participants, and trial registration is not applicable.
Critical care services and the H1N1 (2009) influenza epidemic in Australia and New Zealand in 2010: the impact of the second winter epidemic
Publisher: Springer Science and Business Media LLC
Date: 2011
DOI: 10.1186/CC10266
Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19
Publisher: American Medical Association (AMA)
Date: 06-10-2020
Infection-induced lung injury is worsened after renal buffering of hypercapnic acidosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2009
Sodium Bicarbonate for Metabolic Acidosis in the ICU: Results of a Pilot Randomized Double-Blind Clinical Trial.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-06-2023
Clinical characteristics, risk factors and outcomes in patients with severe COVID-19 registered in the International Severe Acute Respiratory and Emerging Infection Consortium WHO clinical characteris
Publisher: European Respiratory Society (ERS)
Date: 10-12-2021
DOI: 10.1183/23120541.00552-2021
Abstract: Due to the large number of patients with severe coronavirus disease 2019 (COVID-19), many were treated outside the traditional walls of the intensive care unit (ICU), and in many cases, by personnel who were not trained in critical care. The clinical characteristics and the relative impact of caring for severe COVID-19 patients outside the ICU is unknown. This was a multinational, multicentre, prospective cohort study embedded in the International Severe Acute Respiratory and Emerging Infection Consortium World Health Organization COVID-19 platform. Severe COVID-19 patients were identified as those admitted to an ICU and/or those treated with one of the following treatments: invasive or noninvasive mechanical ventilation, high-flow nasal cannula, inotropes or vasopressors. A logistic generalised additive model was used to compare clinical outcomes among patients admitted or not to the ICU. A total of 40 440 patients from 43 countries and six continents were included in this analysis. Severe COVID-19 patients were frequently male (62.9%), older adults (median (interquartile range (IQR), 67 (55–78) years), and with at least one comorbidity (63.2%). The overall median (IQR) length of hospital stay was 10 (5–19) days and was longer in patients admitted to an ICU than in those who were cared for outside the ICU (12 (6–23) days versus 8 (4–15) days, p .0001). The 28-day fatality ratio was lower in ICU-admitted patients (30.7% (5797 out of 18 831) versus 39.0% (7532 out of 19 295), p .0001). Patients admitted to an ICU had a significantly lower probability of death than those who were not (adjusted OR 0.70, 95% CI 0.65–0.75 p .0001). Patients with severe COVID-19 admitted to an ICU had significantly lower 28-day fatality ratio than those cared for outside an ICU.
Age of red blood cells and mortality in the critically ill
Publisher: Springer Science and Business Media LLC
Date: 2011
DOI: 10.1186/CC10142
The effect of a low-dose naloxone infusion on the incidence of respiratory depression after intrathecal morphine administration for major open hepatobiliary surgery: a randomised controlled trial.
Publisher: Wiley
Date: 02-12-2019
DOI: 10.1111/ANAE.14931
Abstract: Intrathecal morphine is an analgesic option for major hepatopancreaticobiliary procedures but is associated with a risk of respiratory depression. We hypothesised that a postoperative low-dose naloxone infusion would reduce the incidence of respiratory depression without an increase in pain scores. Patients scheduled for major open hepatopancreaticobiliary surgery and who were receiving 10 μg.kg
Status epilepticus: an intensive care medicine problem
Publisher: Elsevier BV
Date: 2016
The effect of recombinant erythropoietin on long-term outcome after moderate-to-severe traumatic brain injury
Publisher: Springer Science and Business Media LLC
Date: 07-2023
Ventilation management and outcomes in out-of-hospital cardiac arrest: a protocol for a preplanned secondary analysis of the TTM2 trial
Publisher: BMJ
Date: 03-2022
DOI: 10.1136/BMJOPEN-2021-058001
Abstract: Mechanical ventilation is a fundamental component in the management of patients post cardiac arrest. However, the ventilator settings and the gas-exchange targets used after cardiac arrest may not be optimal to minimise post-anoxic secondary brain injury. Therefore, questions remain regarding the best ventilator management in such patients. This is a preplanned analysis of the international randomised controlled trial, targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (OHCA)–target temperature management 2 (TTM2). The primary objective is to describe ventilatory settings and gas exchange in patients who required invasive mechanical ventilation and included in the TTM2 trial. Secondary objectives include evaluating the association of ventilator settings and gas-exchange values with 6 months mortality and neurological outcome. Adult patients after an OHCA who were included in the TTM2 trial and who received invasive mechanical ventilation will be eligible for this analysis. Data collected in the TTM2 trial that will be analysed include patients’ prehospital characteristics, clinical examination, ventilator settings and arterial blood gases recorded at hospital and intensive care unit (ICU) admission and daily during ICU stay. The TTM2 study has been approved by the regional ethics committee at Lund University and by all relevant ethics boards in participating countries. No further ethical committee approval is required for this secondary analysis. Data will be disseminated to the scientific community by abstracts and by original articles submitted to peer-reviewed journals. NCT02908308 .
Australia: Political development and data for 2017
Publisher: Wiley
Date: 30-08-2018
Corrigendum to Effect of age of red cells for transfusion on patient outcomes: a systematic review and meta-analysis [Transfus Med Rev 32/2 (2018) 77-88].
Publisher: Elsevier BV
Date: 04-2020
Ionized calcium concentration and outcome in critical illness
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2011
Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest: a statistical analysis plan
Publisher: Springer Science and Business Media LLC
Date: 07-10-2020
DOI: 10.1186/S13063-020-04654-Y
Abstract: To date, targeted temperature management (TTM) is the only neuroprotective intervention after resuscitation from cardiac arrest that is recommended by guidelines. The evidence on the effects of TTM is unclear. The Targeted Hypothermia Versus Targeted Normothermia After Out-of-hospital Cardiac Arrest (TTM2) trial is an international, multicentre, parallel group, investigator-initiated, randomised, superiority trial in which TTM with a target temperature of 33 °C after cardiac arrest will be compared with a strategy to maintain normothermia and active treatment of fever (≥ 37.8 °C). Prognosticators, outcome assessors, the steering group, the trial coordinating team, and trial statisticians will be blinded to treatment allocation. The primary outcome will be all-cause mortality at 180 days after randomisation. We estimate a 55% mortality in the targeted normothermia group. To detect an absolute risk reduction of 7.5% with an alpha of 0.05 and 90% power, 1900 participants will be enrolled. The secondary neurological outcome will be poor functional outcome (modified Rankin scale 4–6) at 180 days after cardiac arrest. In this paper, a detailed statistical analysis plan is presented, including a comprehensive description of the statistical analyses, handling of missing data, and assessments of underlying statistical assumptions. Final analyses will be conducted independently by two qualified statisticians following the present plan. This SAP, which was prepared before completion of enrolment, should increase the validity of the TTM trial by mitigation of analysis-bias.
Genetic mechanisms of critical illness in COVID-19.
Publisher: Springer Science and Business Media LLC
Date: 11-12-2021
DOI: 10.1038/S41586-020-03065-Y
Abstract: Host-mediated lung inflammation is present
Biomarker Predictors of Adverse Acute Kidney Injury Outcomes in Critically Ill Patients: The Dublin Acute Biomarker Group Evaluation Study
Publisher: S. Karger AG
Date: 2019
DOI: 10.1159/000500231
Abstract: b i Background: /i /b The Dublin Acute Biomarker Group Evaluation (DAMAGE) Study is a prospective 2-center observational study investigating the utility of urinary biomarker combinations for the diagnostic and prognostic assessment of acute kidney injury (AKI) in a heterogeneous adult intensive care unit (ICU) population. The objective of this study is to evaluate whether serial urinary biomarker measurements, in combination with a simple clinical model, could improve biomarker performance in the diagnostic prediction of severe AKI and clinical outcomes such as death and need for renal replacement therapy (RRT). b i Methods: /i /b Urine was collected daily from patients admitted to the ICU, for a total of 7 post-admission days. Urine biomarker concentrations (neutrophil gelatinase-associated lipocalin [NGAL], α-glutathione S-transferase [GST], π-GST, kidney injury molecule-1 [KIM-1], liver-type fatty acid-binding protein [L-FABP], Cystatin C, creatinine, and albumin) were measured. Urine biomarkers were combined with a clinical prediction of AKI model, to determine ability to predict AKI (any stage, within 2 days or 7 days of ICU admission), or a 30-day composite clinical outcome (RRT – or death). b i Results: /i /b A total of 257 (38%) patients developed AKI within 7 days of ICU admission. Of those who developed AKI, 106 (41%) patients met stage 3 AKI within 7 days of ICU admission and 208 patients of the entire study cohort (31%) met the composite clinical endpoint of in-hospital mortality or RRT within 30 days of ICU admission. The addition of urinary NGAL/albumin to the clinical model modestly improved the prediction of AKI, in particular severe stage 3 AKI (area under the curve [AUC] of 0.9 from 0.87, i /i = 0.369) and the prediction of 30-day RRT or death (AUC 0.83 from 0.79, i /i = 0.139). b i Conclusion: /i /b A clinical model incorporating severity of illness, patient demographics, and chronic illness with currently available clinical biomarkers of renal function was strongly predictive of development of AKI and associated clinical outcomes in a heterogeneous adult ICU population. The addition of urinary NGAL/albumin to this simple clinical model improved the prediction of severe AKI, need for RRT and death, but not at a statistically or clinically significant level, when compared to the clinical model alone.
Craniectomy for traumatic intracranial hypertension
Publisher: Massachusetts Medical Society
Date: 15-12-2016
DOI: 10.1056/NEJMC1613479
Talking to the people that really matter about their participation in pandemic clinical research: A qualitative study in four European countries
Publisher: Wiley
Date: 27-09-2017
DOI: 10.1111/HEX.12634
Facing the Ethical Challenges: Consumer Involvement in COVID-19 Pandemic Research
Publisher: Springer Science and Business Media LLC
Date: 09-11-2020
Whole genome sequencing identifies multiple loci for critical illness caused by COVID-19
Publisher: Cold Spring Harbor Laboratory
Date: 02-09-2021
DOI: 10.1101/2021.09.02.21262965
Abstract: Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care 1 or hospitalisation 2 4 following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study recruits critically-ill cases and compares their genomes with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identify 15 new independent associations with critical COVID-19, including variants within genes involved in interferon signalling ( IL10RB, PLSCR1 ), leucocyte differentiation ( BCL11A ), and blood type antigen secretor status ( FUT2 ). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase ( ATP11A ), and increased mucin expression ( MUC1 ), in critical disease. We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.
Could treatment with immunomodulatory agents targeting IL-1, IL-6, or JAK signalling improve outcomes in patients with severe influenza pneumonia? A systematic and narrative review
Publisher: F1000 Research Ltd
Date: 28-11-2022
DOI: 10.12688/HRBOPENRES.13613.1
Abstract: Background: Influenza is a global cause of morbidity and mortality and a significant risk for a future pandemic infection. Host hyperinflammation, similar to that seen in COVID-19, may occur in response to influenza virus pneumonia, with Janus kinase (JAK) signalling and proinflammatory cytokines Interleukin (IL)-1 and IL-6 involved. Immune modulation treatment of hospitalised and critically ill COVID-19 patients, including with IL-6 and JAK inhibitors, has been found to be beneficial. Significant interest exists in the use of immunomodulatory agents targeting these pathways in the treatment of severe influenza pneumonia . Methods: We conducted a review with both systematic and narrative methods to assess whether, in patients with severe influenza pneumonia, treatment with immunomodulatory agents targeting IL-1, IL-6 or JAK signalling, in comparison to no immune modulation, is beneficial and improves clinical outcomes. Results: Our systematic search screened 5409 records and found no randomised controlled trials of IL-1, IL-6 or JAK immunomodulatory agents in patients with severe influenza pneumonia. To support this systematic search, we provide a narrative review of the biological rationale, previous use of these agents, including in hospitalised patients with COVID-19, and an overview of their safety profiles. Conclusions: Although immune modulation has proven successful in treating hospitalised and critically ill patients with COVID-19 and a biological rationale exists for testing these agents in influenza, no agents targeting IL-1, IL-6 or JAK signalling have been assessed in randomised controlled trials of patients with severe influenza pneumonia. This highlights a significant evidence gap.
Quality of Life and 1-Year Survival in Patients With Early Septic Shock: Long-Term Follow-Up of the Australasian Resuscitation in Sepsis Evaluation Trial
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2019
DOI: 10.1097/CCM.0000000000003762
Abstract: To examine long-term survival and quality of life of patients with early septic shock. Prospective, randomized, parallel-group trial. Fifty-one hospitals in Australia, New Zealand, Finland, Hong Kong, and the Republic of Ireland. One-thousand five-hundred ninety-one patients who presented to the emergency department with early septic shock between October 2008 and April 2014, and were enrolled in the Australasian Resuscitation in Sepsis Evaluation trial. Early goal-directed therapy versus usual care. Long-term survival was measured up to 12 months postrandomization. Health-related quality of life was measured using the EuroQoL-5D-3L, Short Form 36 and Assessment of Quality of Life 4D at baseline, and at 6 and 12 months following randomization. Mortality data were available for 1,548 patients (97.3%) and 1,515 patients (95.2%) at 6 and 12 months, respectively. Health-related quality of life data were available for 85.1% of survivors at 12 months. There were no significant differences in mortality between groups at either 6 months (early goal-directed therapy 21.8% vs usual care 22.6% p = 0.70) or 12 months (early goal-directed therapy 26.4% vs usual care 27.9% p = 0.50). There were no group differences in health-related quality of life at either 6 or 12 months (EuroQoL-5D-3L utility scores at 12 mo early goal-directed therapy 0.65 ± 0.33 vs usual care 0.64 ± 0.34 p = 0.50), with the health-related quality of life of both groups being significantly lower than population norms. In patients presenting to the emergency department with early septic shock, early goal-directed therapy compared with usual care did not reduce mortality nor improve health-related quality of life at either 6 or 12 months.
Integration of Equipoise into Eligibility Criteria in the STARRT-AKI Trial
Publisher: American Thoracic Society
Date: 15-07-2021
Diabetes and Overweight/Obesity Are Independent, Nonadditive Risk Factors for In-Hospital Severity of COVID-19: An International, Multicenter Retrospective Meta-analysis.
Publisher: American Diabetes Association
Date: 15-04-2021
DOI: 10.2337/DC20-2676
Abstract: Obesity is an established risk factor for severe coronavirus disease 2019 (COVID-19), but the contribution of overweight and/or diabetes remains unclear. In a multicenter, international study, we investigated if overweight, obesity, and diabetes were independently associated with COVID-19 severity and whether the BMI-associated risk was increased among those with diabetes. We retrospectively extracted data from health care records and regional databases of hospitalized adult patients with COVID-19 from 18 sites in 11 countries. We used standardized definitions and analyses to generate site-specific estimates, modeling the odds of each outcome (supplemental oxygen/noninvasive ventilatory support, invasive mechanical ventilatory support, and in-hospital mortality) by BMI category (reference, overweight, obese), adjusting for age, sex, and prespecified comorbidities. Subgroup analysis was performed on patients with preexisting diabetes. Site-specific estimates were combined in a meta-analysis. Among 7,244 patients (65.6% overweight/obese), those with overweight were more likely to require oxygen/noninvasive ventilatory support (random effects adjusted odds ratio [aOR], 1.44 95% CI 1.15–1.80) and invasive mechanical ventilatory support (aOR, 1.22 95% CI 1.03–1.46). There was no association between overweight and in-hospital mortality (aOR, 0.88 95% CI 0.74–1.04). Similar effects were observed in patients with obesity or diabetes. In the subgroup analysis, the aOR for any outcome was not additionally increased in those with diabetes and overweight or obesity. In adults hospitalized with COVID-19, overweight, obesity, and diabetes were associated with increased odds of requiring respiratory support but were not associated with death. In patients with diabetes, the odds of severe COVID-19 were not increased above the BMI-associated risk.
Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19
Publisher: Massachusetts Medical Society
Date: 26-08-2021
Optimal ventilator settings after return of spontaneous circulation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2020
A Post Hoc Analysis of Osmotherapy Use in the Erythropoietin in Traumatic Brain Injury Study—Associations With Acute Kidney Injury and Mortality
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-01-2021
DOI: 10.1097/CCM.0000000000004853
Abstract: 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. A post hoc analysis of the erythropoietin trial in traumatic brain injury (ClinicalTrials.gov NCT00987454) including daily data on mannitol and hypertonic saline use. Twenty-nine university-affiliated teaching hospitals in seven countries. 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. None. 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. 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.
Global outbreak research: harmony not hegemony
Publisher: Elsevier BV
Date: 07-2020
A Bayesian reanalysis of the Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial
Publisher: Springer Science and Business Media LLC
Date: 25-08-2022
DOI: 10.1186/S13054-022-04120-Y
Abstract: Timing of initiation of kidney-replacement therapy (KRT) in critically ill patients remains controversial. The Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial compared two strategies of KRT initiation (accelerated versus standard) in critically ill patients with acute kidney injury and found neutral results for 90-day all-cause mortality. Probabilistic exploration of the trial endpoints may enable greater understanding of the trial findings. We aimed to perform a reanalysis using a Bayesian framework. We performed a secondary analysis of all 2927 patients randomized in multi-national STARRT-AKI trial, performed at 168 centers in 15 countries. The primary endpoint, 90-day all-cause mortality, was evaluated using hierarchical Bayesian logistic regression. A spectrum of priors includes optimistic, neutral, and pessimistic priors, along with priors informed from earlier clinical trials. Secondary endpoints (KRT-free days and hospital-free days) were assessed using zero–one inflated beta regression. The posterior probability of benefit comparing an accelerated versus a standard KRT initiation strategy for the primary endpoint suggested no important difference, regardless of the prior used (absolute difference of 0.13% [95% credible interval [CrI] − 3.30% 3.40%], − 0.39% [95% CrI − 3.46% 3.00%], and 0.64% [95% CrI − 2.53% 3.88%] for neutral, optimistic, and pessimistic priors, respectively). There was a very low probability that the effect size was equal or larger than a consensus-defined minimal clinically important difference. Patients allocated to the accelerated strategy had a lower number of KRT-free days (median absolute difference of − 3.55 days [95% CrI − 6.38 − 0.48]), with a probability that the accelerated strategy was associated with more KRT-free days of 0.008. Hospital-free days were similar between strategies, with the accelerated strategy having a median absolute difference of 0.48 more hospital-free days (95% CrI − 1.87 2.72) compared with the standard strategy and the probability that the accelerated strategy had more hospital-free days was 0.66. In a Bayesian reanalysis of the STARRT-AKI trial, we found very low probability that an accelerated strategy has clinically important benefits compared with the standard strategy. Patients receiving the accelerated strategy probably have fewer days alive and KRT-free. These findings do not support the adoption of an accelerated strategy of KRT initiation.
Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19
Publisher: American Medical Association (AMA)
Date: 05-04-2022
The incidence of acute kidney injury in patients with traumatic brain injury
Publisher: Informa UK Limited
Date: 23-09-2010
Acute pancreatitis: an intensive care perspective
Publisher: Elsevier BV
Date: 04-2012
Heterogeneous Treatment Effects of Therapeutic-Dose Heparin in Patients Hospitalized for COVID-19
Publisher: American Medical Association (AMA)
Date: 04-04-2023
Abstract: Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across in iduals. Better understanding of HTE could facilitate in idualized clinical decision-making. To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. Organ support–free days, assigning a value of −1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge and hospital survival. Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years 38% female 32% known non-White race 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support–free days (median value for the posterior distribution of the OR, 1.05 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support–free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30 posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16 posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI & ) vs higher BMI groups (BMI ≥30 posterior probability of difference in ORs & % for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR & , 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR & , 87%). In effect-based analysis, a subset of patients identified at high risk of harm ( P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. ClinicalTrials.gov Identifiers: NCT02735707 , NCT04505774 , NCT04359277 , NCT04372589
Status epilepticus: an intensive care medicine problem
Publisher: Elsevier BV
Date: 04-2012
Early sedation with dexmedetomidine in ventilated critically ill patients and heterogeneity of treatment effect in the SPICE III randomised controlled trial
Publisher: Springer Science and Business Media LLC
Date: 08-03-2021
Long-term quality of life in patients with acute respiratory distress syndrome requiring extracorporeal membrane oxygenation for refractory hypoxaemia
Publisher: Springer Science and Business Media LLC
Date: 2012
DOI: 10.1186/CC11811
Therapeutic hypothermia: benefits, mechanisms and potential clinical applications in neurological, cardiac and kidney injury
Publisher: Elsevier BV
Date: 09-2011
DOI: 10.1016/J.INJURY.2011.03.027
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.
Whole-genome sequencing reveals host factors underlying critical COVID-19
Publisher: Springer Science and Business Media LLC
Date: 07-03-2022
DOI: 10.1038/S41586-022-04576-6
Abstract: Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care 1 or hospitalization 2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from in iduals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill in iduals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling ( IL10RB and PLSCR1 ), leucocyte differentiation ( BCL11A ) and blood-type antigen secretor status ( FUT2 ). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase ( ATP11A ), and increased expression of a mucin ( MUC1 )—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules ( SELE , ICAM5 and CD209 ) and the coagulation factor F8 , all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.
Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest
Publisher: Massachusetts Medical Society
Date: 17-06-2021
The Intensive Care Global Study on Severe Acute Respiratory Infection (IC-GLOSSARI): a multicenter, multinational, 14-day inception cohort study
Publisher: Springer Science and Business Media LLC
Date: 15-02-2016
Acute renal failure and the critically ill
Publisher: Elsevier BV
Date: 04-2012
A multicenter randomized clinical trial of pharmacological vitamin B1 administration to critically ill patients who develop hypophosphatemia during enteral nutrition (The THIAMINE 4 HYPOPHOSPHATEMIA t
Publisher: Elsevier BV
Date: 08-2021
DOI: 10.1016/J.CLNU.2021.07.024
Abstract: Hypophosphatemia may be a useful biomarker to identify thiamine deficiency in critically ill enterally-fed patients. The objective was to determine whether intravenous thiamine affects blood lactate, biochemical and clinical outcomes in this group. This randomized clinical trial was conducted across 5 Intensive Care Units. Ninety critically ill adult patients with a serum phosphate ≤0.65 mmol/L within 72 h of commencing enteral nutrition were randomized to intravenous thiamine (200 mg every 12 h for up to 14 doses) or usual care (control). The primary outcome was blood lactate over time and data are median [IQR] unless specified. Baseline variables were well balanced (thiamine: lactate 1.2 [1.0, 1.6] mmol/L, phosphate 0.56 [0.44, 0.64] mmol/L vs. control: lactate 1.0 [0.8, 1.3], phosphate 0.54 [0.44, 0.61]). Patients randomized to the intervention received a median of 11 [7.5, 13.5] doses for a total of 2200 [1500, 2700] mg of thiamine. Blood lactate over the entire 7 days of treatment was similar between groups (mean difference = -0.1 (95 % CI -0.2 to 0.1) mmol/L P = 0.55). The percentage change from lactate pre-randomization to T = 24 h was not statistically different (thiamine: -32 (-39, -26) vs. control: -24 (-31, -16) percent, P = 0.09). Clinical outcomes were not statistically different (days of vasopressor administration: thiamine 2 [1, 4] vs. control 2 [0, 5.5] days P = 0.37, and deaths 9 (21 %) vs. 5 (11 %) P = 0.25). In critically ill enterally-fed patients who developed hypophosphatemia, intravenous thiamine did not cause measurable differences in blood lactate or clinical outcomes. Australian and New Zealand Clinical Trials Registry (ACTRN12619000121167).
Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of fou
Publisher: Elsevier BV
Date: 02-2022
Characteristics and Outcomes of Critically Ill Trauma Patients in Australia and New Zealand (2005-2017).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2020
What the public think about participation in medical research during an influenza pandemic: an international cross-sectional survey
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.PUHE.2019.07.005
Abstract: The public and patients are primary contributors and beneficiaries of pandemic-relevant clinical research. However, their views on research participation during a pandemic have not been systematically studied. We aimed to understand public views regarding participation in clinical research during a hypothetical influenza pandemic. This is an international cross-sectional survey. We surveyed the views of nationally representative s les of people in Belgium, Poland, Spain, Ireland, the United Kingdom, Canada, Australia and New Zealand, using a scenario-based instrument during the 2017 regional influenza season. Descriptive and regression analyses were conducted. Of the 6804 respondents, 5572 (81.8%) thought pandemic-relevant research was important, and 5089 (74.8%) thought 'special rules' should be applied to make this research feasible. The respondents indicated willingness to take part in lower risk (4715, 69.3%) and higher risk (3585, 52.7%) primary care and lower risk (4780, 70.3%) and higher risk (4113, 60.4%) intensive care unit (ICU) study scenarios. For primary care studies, most (3972, 58.4%) participants preferred standard enrolment procedures such as prospective written informed consent, but 2327 (34.2%) thought simplified procedures would be acceptable. For ICU studies, 2800 (41.2%) preferred deferred consent, and 2623 (38.6%) preferred prospective third-party consent. Greater knowledge about pandemics, trust in a health professional, trust in the government, therapeutic misconception and having had ICU experience as a patient or carer predicted increased willingness to participate in pandemic-relevant research. Our study indicates current public support for pandemic-relevant clinical research. Tailored information and initiatives to advance research literacy and maintain trust are required to support pandemic-relevant research participation and engagement.
GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19
Publisher: Springer Science and Business Media LLC
Date: 17-05-2023
DOI: 10.1038/S41586-023-06034-3
Abstract: Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling ( JAK1 ), monocyte–macrophage activation and endothelial permeability ( PDE4A ), immunometabolism ( SLC2A5 and AK5 ), and host factors required for viral entry and replication ( TMPRSS2 and RAB2A ).
The implications of the PEPTIC trial for clinical practice
Publisher: Elsevier BV
Date: 02-03-2020
DOI: 10.51893/2020.1.ED1
Abstract: Proton pump inhibitors (PPIs) are among the most widely prescribed drugs in the intensive care unit (ICU). Many, if not most, prescriptions of PPIs in the ICU are for stress ulcer prophylaxis. Although PPIs are used most widely for this indication, histamine-2 receptor blockers (H2RBs) are used in preference to PPIs in some ICUs. This practice variation, which appears to be largely dependent on clinician preference rather than based on patient-specific factors, has continued for decades.
Economic evaluations for intensive care unit randomised clinical trials in Australia and New Zealand: Practical recommendations for researchers
Publisher: Elsevier BV
Date: 05-2023
DOI: 10.1016/J.AUCC.2022.02.002
Abstract: Economic evaluations of intensive care unit (ICU) interventions have specific considerations, including how to cost ICU stays and accurately measure quality of life in survivors. The aim of this article was to develop best practice recommendations for economic evaluations alongside future ICU randomised controlled trials (RCTs). We collated our experience based on expert consensus across several recent economic evaluations to provide best-practice, practical recommendations for researchers conducting economic evaluations alongside RCTs in the ICU. Recommendations were structured according to the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Consolidated Health Economic Evaluation Reporting Standards (CHEERS) Task Force Report. We discuss recommendations across the components of economic evaluations, including: types of economic evaluation, the population and s le size, study perspective, comparators, time horizon, choice of health outcomes, measurement of effectiveness, measurement and valuation of quality of life, estimating resources and costs, analytical methods, and the increment cost-effectiveness ratio. We also provide future directions for research with regard to developing more robust economic evaluations for the ICU. Economic evaluations should be built alongside ICU RCTs and should be designed a priori using appropriate follow-up and data collection to capture patient-relevant outcomes. Further work is needed to improve the quality of data available for linkage in Australia as well as developing costing methods for the ICU and appropriate quality of life measurements.
COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study
Publisher: Springer Science and Business Media LLC
Date: 25-06-2021
DOI: 10.1007/S15010-021-01599-5
Abstract: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69% at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23 85%), older adults (≥ 70 years: 61, 62, 65 90%), and women (66, 66, 64 90% vs. men 71, 70, 67 93%, each P 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men.
Continuation of therapeutic dose heparin for critically ill patients with COVID-19
Publisher: Springer Science and Business Media LLC
Date: 31-05-2023
An appraisal of respiratory system compliance in mechanically ventilated covid-19 patients
Publisher: Springer Science and Business Media LLC
Date: 09-06-2021
DOI: 10.1186/S13054-021-03518-4
Abstract: Heterogeneous respiratory system static compliance ( C RS ) values and levels of hypoxemia in patients with novel coronavirus disease (COVID-19) requiring mechanical ventilation have been reported in previous small-case series or studies conducted at a national level. We designed a retrospective observational cohort study with rapid data gathering from the international COVID-19 Critical Care Consortium study to comprehensively describe C RS —calculated as: tidal volume/[airway plateau pressure-positive end-expiratory pressure (PEEP)]—and its association with ventilatory management and outcomes of COVID-19 patients on mechanical ventilation (MV), admitted to intensive care units (ICU) worldwide. We studied 745 patients from 22 countries, who required admission to the ICU and MV from January 14 to December 31, 2020, and presented at least one value of C RS within the first seven days of MV. Median (IQR) age was 62 (52–71), patients were predominantly males (68%) and from Europe/North and South America (88%). C RS , within 48 h from endotracheal intubation, was available in 649 patients and was neither associated with the duration from onset of symptoms to commencement of MV ( p = 0.417) nor with PaO 2 /FiO 2 ( p = 0.100). Females presented lower C RS than males (95% CI of C RS difference between females-males: − 11.8 to − 7.4 mL/cmH 2 O p 0.001), and although females presented higher body mass index (BMI), association of BMI with C RS was marginal ( p = 0.139). Ventilatory management varied across C RS range, resulting in a significant association between C RS and driving pressure (estimated decrease − 0.31 cmH 2 O/L per mL/cmH 2 0 of C RS , 95% CI − 0.48 to − 0.14, p 0.001). Overall, 28-day ICU mortality, accounting for the competing risk of being discharged within the period, was 35.6% (SE 1.7). Cox proportional hazard analysis demonstrated that C RS (+ 10 mL/cm H 2 O) was only associated with being discharge from the ICU within 28 days (HR 1.14, 95% CI 1.02–1.28, p = 0.018). This multicentre report provides a comprehensive account of C RS in COVID-19 patients on MV. C RS measured within 48 h from commencement of MV has marginal predictive value for 28-day mortality, but was associated with being discharged from ICU within the same period. Trial documentation: Available at tudy . Trial registration : ACTRN12620000421932.
Erythropoietin in traumatic brain injury associated acute kidney injury: A randomized controlled trial
Publisher: Wiley
Date: 21-08-2019
DOI: 10.1111/AAS.13244
Abstract: Acute kidney injury (AKI) in traumatic brain injury (TBI) is poorly understood and it is unknown if it can be attenuated using erythropoietin (EPO). 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. 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). 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.
Shock: causes, initial assessment and investigations
Publisher: Elsevier BV
Date: 03-2017
Validation of extracorporeal membrane oxygenation mortality prediction and severity of illness scores in an international COVID ‐19 cohort
Publisher: Wiley
Date: 04-05-2023
DOI: 10.1111/AOR.14542
Abstract: Veno‐venous extracorporeal membrane oxygenation (V‐V ECMO) is a lifesaving support modality for severe respiratory failure, but its resource‐intensive nature led to significant controversy surrounding its use during the COVID‐19 pandemic. We report the performance of several ECMO mortality prediction and severity of illness scores at discriminating survival in a large COVID‐19 V‐V ECMO cohort. We validated ECMOnet, PRESET (PREdiction of Survival on ECMO Therapy‐Score), Roch, SOFA (Sequential Organ Failure Assessment), APACHE II (acute physiology and chronic health evaluation), 4C (Coronavirus Clinical Characterisation Consortium), and CURB‐65 (Confusion, Urea nitrogen, Respiratory Rate, Blood Pressure, age years) scores on the ISARIC (International Severe Acute Respiratory and emerging Infection Consortium) database. We report discrimination via Area Under the Receiver Operative Curve (AUROC) and Area under the Precision Recall Curve (AURPC) and calibration via Brier score. We included 1147 patients and scores were calculated on patients with sufficient variables. ECMO mortality scores had AUROC (0.58–0.62), AUPRC (0.62–0.74), and Brier score (0.286–0.303). Roch score had the highest accuracy (AUROC 0.62), precision (AUPRC 0.74) yet worst calibration (Brier score of 0.3) despite being calculated on the fewest patients (144). Severity of illness scores had AUROC (0.52–0.57), AURPC (0.59–0.64), and Brier Score (0.265–0.471). APACHE II had the highest accuracy (AUROC 0.58), precision (AUPRC 0.64), and best calibration (Brier score 0.26). Within a large international multicenter COVID‐19 cohort, the evaluated ECMO mortality prediction and severity of illness scores demonstrated inconsistent discrimination and calibration highlighting the need for better clinically applicable decision support tools.
Age of red blood cells and transfusion in critically ill patients
Publisher: Springer Science and Business Media LLC
Date: 2013
Association of Positive End-Expiratory Pressure and Lung Recruitment Selection Strategies with Mortality in Acute Respiratory Distress Syndrome: A Systematic Review and Network Meta-analysis
Publisher: American Thoracic Society
Date: 06-2022
Advancing preparedness for clinical research during infectious disease epidemics
Publisher: European Respiratory Society (ERS)
Date: 04-2019
A Multicenter Randomized Trial of Atorvastatin Therapy in Intensive Care Patients with Severe Sepsis
Publisher: American Thoracic Society
Date: 04-2013
Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials
Publisher: Springer Science and Business Media LLC
Date: 20-11-2021
DOI: 10.1186/S12879-021-06829-7
Abstract: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, 0.17605/OSF.IO/GEHFX ). In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung–Knapp–Sidik–Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92 1.02) with between-study heterogeneity not beyond chance (I 2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.
Effects of brain tissue oxygen (PbtO2) guided management on patient outcomes following severe traumatic brain injury: A systematic review and meta-analysis.
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.JOCN.2022.03.017
Abstract: Monitoring and optimisation of brain tissue oxygen tension (PbtO
Statistical analysis plan for the POLAR-RCT: The Prophylactic hypOthermia trial to Lessen trAumatic bRain injury-Randomised Controlled Trial
Publisher: Springer Science and Business Media LLC
Date: 27-04-2018
Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support–Free Days in Patients Hospitalized With COVID-19
Publisher: American Medical Association (AMA)
Date: 11-04-2023
Abstract: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor n = 10), or no RAS inhibitor (control n = 264) for up to 10 days. The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. ClinicalTrials.gov Identifier: NCT02735707
Changes in Temperature Management of Cardiac Arrest Patients Following Publication of the Target Temperature Management Trial.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2018
DOI: 10.1097/CCM.0000000000003339
Abstract: To evaluate knowledge translation after publication of the target temperature management 33°C versus 36°C after out-of-hospital cardiac arrest trial and associated patient outcomes. Our primary hypothesis was that target temperature management at 36°C was rapidly adopted in Australian and New Zealand ICUs. Secondary hypotheses were that temporal reductions in mortality would be seen and would have accelerated after publication of the target temperature management trial. Retrospective cohort study (January 2005 to December 2016). The Australian and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation adult patient database containing greater than 2 million admission episodes from 186 Australian and New Zealand ICUs. Sixteen-thousand two-hundred fifty-two adults from 140 hospitals admitted to ICU after out-of-hospital cardiac arrest. The primary exposure of interest was admission before versus after publication of the target temperature management trial. The primary outcome variable to evaluate changes in temperature management was lowest temperature in the first 24 hours in ICU. The primary clinical outcome variable of interest was inhospital mortality. Secondary outcomes included proportion of patients with fever in the first 24 hours in ICU. Mean ± sd lowest temperature in the first 24 hours in ICU in pre- and posttarget temperature management trial patients was 33.80 ± 1.71°C and 34.70 ± 1.39°C, respectively (absolute difference, 0.98°C [99% CI, 0.89–1.06°C]). Inhospital mortality rate decreased by 1.3 (99% CI, –1.8 to –0.9) percentage points per year from January 2005 until December 2013 and increased by 0.6 (99% CI, –1.4 to 2.6) percentage points per year from January 2014 until December 2016 (change in slope 1.9 percentage points per year [99% CI, –0.6 to 4.4]). Fever occurred in 568 (12.8%) of 4,450 pretarget temperature management trial patients and 853 (16.5%) of 5,184 posttarget temperature management trial patients (odds ratio, 1.35 [99% CI, 1.16–1.57]). The average lowest temperature of postcardiac arrest patients in the first 24 hours in ICU rose after publication of the target temperature management trial. This change was associated with an increased frequency of fever not seen in the target temperature management trial.
Inhibition of Rho-Kinase Attenuates Hypoxia-Induced Angiogenesis in the Pulmonary Circulation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-07-2005
DOI: 10.1161/01.RES.0000174287.17953.83
Abstract: Pulmonary hypertension (PH) is a common complication of chronic hypoxic lung diseases, which increase morbidity and mortality. Hypoxic PH has previously been attributed to structural changes in the pulmonary vasculature including narrowing of the vascular lumen and loss of vessels, which produce a fixed increase in resistance. Using quantitative stereology, we now show that chronic hypoxia caused PH and remodeling of the blood vessel walls in rats but that this remodeling did not lead to structural narrowing of the vascular lumen. Sustained inhibition of the RhoA/Rho-kinase pathway throughout the period of hypoxic exposure attenuated PH and prevented remodeling in intra-acinar vessels without enlarging the structurally determined lumen diameter. In chronically hypoxic lungs, acute Rho kinase inhibition markedly decreased PVR but did not alter the alveolar to arterial oxygen gap. In addition to increased vascular resistance, chronic hypoxia induced Rho kinase–dependent capillary angiogenesis. Thus, hypoxic PH was not caused by fixed structural changes in the vasculature but by sustained vasoconstriction, which was largely Rho kinase dependent. Importantly, this vasoconstriction had no role in ventilation-perfusion matching and optimization of gas exchange. Rho kinase also mediated hypoxia-induced capillary angiogenesis, a previously unrecognized but potentially important adaptive response.
Effect of age of red cells for transfusion on patient outcomes: a systematic review and meta-analysis.
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.TMRV.2018.02.002
Abstract: Longer storage duration of red blood cell (RBC) units prior to transfusion has been associated with worse outcomes in observational studies. We performed a systematic review, including recently published randomized trials, to determine if storage age of RBCs is associated with mortality, morbidity or adverse events in patients. Searches were performed up to 21
Mapping the human genetic architecture of COVID-19
Publisher: Springer Science and Business Media LLC
Date: 08-07-2021
DOI: 10.1038/S41586-021-03767-X
Abstract: The genetic make-up of an in idual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
Sustained hypercapnic acidosis during pulmonary infection increases bacterial load and worsens lung injury*
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2008
Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity
Publisher: Springer Science and Business Media LLC
Date: 10-12-2021
DOI: 10.1007/S00439-021-02397-7
Abstract: The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive in iduals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management.
An international observational study to assess the impact of the Omicron variant emergence on the clinical epidemiology of COVID-19 in hospitalised patients
Publisher: eLife Sciences Publications, Ltd
Date: 05-10-2022
DOI: 10.7554/ELIFE.80556
Abstract: Whilst timely clinical characterisation of infections caused by novel SARS-CoV-2 variants is necessary for evidence-based policy response, in idual-level data on infecting variants are typically only available for a minority of patients and settings. Here, we propose an innovative approach to study changes in COVID-19 hospital presentation and outcomes after the Omicron variant emergence using publicly available population-level data on variant relative frequency to infer SARS-CoV-2 variants likely responsible for clinical cases. We apply this method to data collected by a large international clinical consortium before and after the emergence of the Omicron variant in different countries. Our analysis, that includes more than 100,000 patients from 28 countries, suggests that in many settings patients hospitalised with Omicron variant infection less often presented with commonly reported symptoms compared to patients infected with pre-Omicron variants. Patients with COVID-19 admitted to hospital after Omicron variant emergence had lower mortality compared to patients admitted during the period when Omicron variant was responsible for only a minority of infections (odds ratio in a mixed-effects logistic regression adjusted for likely confounders, 0.67 [95% confidence interval 0.61–0.75]). Qualitatively similar findings were observed in sensitivity analyses with different assumptions on population-level Omicron variant relative frequencies, and in analyses using available in idual-level data on infecting variant for a subset of the study population. Although clinical studies with matching viral genomic information should remain a priority, our approach combining publicly available data on variant frequency and a multi-country clinical characterisation dataset with more than 100,000 records allowed analysis of data from a wide range of settings and novel insights on real-world heterogeneity of COVID-19 presentation and clinical outcome. Bronner P. Gonçalves, Peter Horby, Gail Carson, Piero L. Olliaro, Valeria Balan, Barbara Wanjiru Citarella, and research costs were supported by the UK Foreign, Commonwealth and Development Office (FCDO) and Wellcome [215091/Z/18/Z, 222410/Z/21/Z, 225288/Z/22/Z] and Janice Caoili and Madiha Hashmi were supported by the UK FCDO and Wellcome [222048/Z/20/Z]. Peter Horby, Gail Carson, Piero L. Olliaro, Kalynn Kennon and Joaquin Baruch were supported by the Bill & Melinda Gates Foundation [OPP1209135] Laura Merson was supported by University of Oxford’s COVID-19 Research Response Fund - with thanks to its donors for their philanthropic support. Matthew Hall was supported by a Li Ka Shing Foundation award to Christophe Fraser. Moritz U.G. Kraemer was supported by the Branco Weiss Fellowship, Google.org, the Oxford Martin School, the Rockefeller Foundation, and the European Union Horizon 2020 project MOOD (#874850). The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views of the European Commission. Contributions from Srinivas Murthy, Asgar Rishu, Rob Fowler, James Joshua Douglas, François Martin Carrier were supported by CIHR Coronavirus Rapid Research Funding Opportunity OV2170359 and coordinated out of Sunnybrook Research Institute. Contributions from Evert-Jan Wils and David S.Y. Ong were supported by a grant from foundation Bevordering Onderzoek Franciscus and Andrea Angheben by the Italian Ministry of Health “Fondi Ricerca corrente–L1P6” to IRCCS Ospedale Sacro Cuore–Don Calabria. The data contributions of J.Kenneth Baillie, Malcolm G. Semple, and Ewen M. Harrison were supported by grants from the National Institute for Health Research (NIHR award CO-CIN-01), the Medical Research Council (MRC grant MC_PC_19059), and by the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE) (award 200907), NIHR HPRU in Respiratory Infections at Imperial College London with PHE (award 200927), Liverpool Experimental Cancer Medicine Centre (grant C18616/A25153), NIHR Biomedical Research Centre at Imperial College London (award IS-BRC-1215-20013), and NIHR Clinical Research Network providing infrastructure support. All funders of the ISARIC Clinical Characterisation Group are listed in the appendix.
Neurological manifestations of COVID-19 in adults and children
Publisher: Oxford University Press (OUP)
Date: 10-09-2022
Abstract: Different neurological manifestations of coronavirus disease 2019 (COVID-19) in adults and children and their impact have not been well characterized. We aimed to determine the prevalence of neurological manifestations and in-hospital complications among hospitalized COVID-19 patients and ascertain differences between adults and children. We conducted a prospective multicentre observational study using the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) cohort across 1507 sites worldwide from 30 January 2020 to 25 May 2021. Analyses of neurological manifestations and neurological complications considered unadjusted prevalence estimates for predefined patient subgroups, and adjusted estimates as a function of patient age and time of hospitalization using generalized linear models. Overall, 161 239 patients (158 267 adults 2972 children) hospitalized with COVID-19 and assessed for neurological manifestations and complications were included. In adults and children, the most frequent neurological manifestations at admission were fatigue (adults: 37.4% children: 20.4%), altered consciousness (20.9% 6.8%), myalgia (16.9% 7.6%), dysgeusia (7.4% 1.9%), anosmia (6.0% 2.2%) and seizure (1.1% 5.2%). In adults, the most frequent in-hospital neurological complications were stroke (1.5%), seizure (1%) and CNS infection (0.2%). Each occurred more frequently in intensive care unit (ICU) than in non-ICU patients. In children, seizure was the only neurological complication to occur more frequently in ICU versus non-ICU (7.1% versus 2.3%, P & 0.001). Stroke prevalence increased with increasing age, while CNS infection and seizure steadily decreased with age. There was a dramatic decrease in stroke over time during the pandemic. Hypertension, chronic neurological disease and the use of extracorporeal membrane oxygenation were associated with increased risk of stroke. Altered consciousness was associated with CNS infection, seizure and stroke. All in-hospital neurological complications were associated with increased odds of death. The likelihood of death rose with increasing age, especially after 25 years of age. In conclusion, adults and children have different neurological manifestations and in-hospital complications associated with COVID-19. Stroke risk increased with increasing age, while CNS infection and seizure risk decreased with age.
Hypothermia for Intracranial Hypertension after Traumatic Brain Injury
Publisher: Massachusetts Medical Society
Date: 07-04-2016
DOI: 10.1056/NEJMC1600339
Bending the Pandemic Curve: Improving Decision-Making With Clinical Research
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2018
Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19
Publisher: Massachusetts Medical Society
Date: 26-08-2021
Cerebrovascular Complications of COVID-19 on Venovenous Extracorporeal Membrane Oxygenation*
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-04-2023
DOI: 10.1097/CCM.0000000000005861
Abstract: Evidence of cerebrovascular complications in COVID-19 requiring venovenous extracorporeal membrane oxygenation (ECMO) is limited. Our study aims to characterize the prevalence and risk factors of stroke secondary to COVID-19 in patients on venovenous ECMO. We analyzed prospectively collected observational data, using univariable and multivariable survival modeling to identify risk factors for stroke. Cox proportional hazards and Fine-Gray models were used, with death and discharge treated as competing risks. Three hundred eighty institutions in 53 countries in the COVID-19 Critical Care Consortium (COVID Critical) registry. Adult COVID-19 patients who were supported by venovenous ECMO. None. Five hundred ninety-five patients (median age [interquartile range], 51 yr [42–59 yr] male: 70.8%) had venovenous ECMO support. Forty-three patients (7.2%) suffered strokes, 83.7% of which were hemorrhagic. In multivariable survival analysis, obesity (adjusted hazard ratio [aHR], 2.19 95% CI, 1.05–4.59) and use of vasopressors before ECMO (aHR, 2.37 95% CI, 1.08–5.22) were associated with an increased risk of stroke. Forty-eight-hour post-ECMO Pa co 2 –pre-ECMO Pa co 2 re-ECMO Pa co 2 (relative ΔPa co 2 ) of negative 26% and 48-hour post-ECMO Pa o 2 –pre-ECMO Pa o 2 re-ECMO Pa o 2 (relative ΔPa o 2 ) of positive 24% at 48 hours of ECMO initiation were observed in stroke patients in comparison to relative ΔPa co 2 of negative 17% and relative ΔPa o 2 of positive 7% in the nonstroke group. Patients with acute stroke had a 79% in-hospital mortality compared with 45% mortality for stroke-free patients. Our study highlights the association of obesity and pre-ECMO vasopressor use with the development of stroke in COVID-19 patients on venovenous ECMO. Also, the importance of relative decrease in Pa co 2 and moderate hyperoxia within 48 hours after ECMO initiation were additional risk factors.
The effect of blood pressure on mortality following out-of-hospital cardiac arrest: a retrospective cohort study of the United Kingdom Intensive Care National Audit and Research Centre database
Publisher: Springer Science and Business Media LLC
Date: 05-01-2023
DOI: 10.1186/S13054-022-04289-2
Abstract: Hypotension following out-of-hospital cardiac arrest (OHCA) may cause secondary brain injury and increase mortality rates. Current guidelines recommend avoiding hypotension. However, the optimal blood pressure following OHCA is unknown. We hypothesised that exposure to hypotension and hypertension in the first 24 h in ICU would be associated with mortality following OHCA. We conducted a retrospective analysis of OHCA patients included in the Intensive Care National Audit and Research Centre Case Mix Programme from 1 January 2010 to 31 December 2019. Restricted cubic splines were created following adjustment for important prognostic variables. We report the adjusted odds ratio for associations between lowest and highest mean arterial pressure (MAP) and systolic blood pressure (SBP) in the first 24 h of ICU care and hospital mortality. A total of 32,349 patients were included in the analysis. Hospital mortality was 56.2%. The median lowest and highest MAP and SBP were similar in survivors and non-survivors. Both hypotension and hypertension were associated with increased mortality. Patients who had a lowest recorded MAP in the range 60–63 mmHg had the lowest associated mortality. Patients who had a highest recorded MAP in the range 95–104 mmHg had the lowest associated mortality. The association between SBP and mortality followed a similar pattern to MAP. We found an association between hypotension and hypertension in the first 24 h in ICU and mortality following OHCA. The inability to distinguish between the median blood pressure of survivors and non-survivors indicates the need for research into in idualised blood pressure targets for survivors following OHCA.
Critical Care Services and 2009 H1N1 Influenza in Australia and New Zealand
Publisher: Massachusetts Medical Society
Date: 12-11-2009
Key stakeholder perceptions about consent to participate in acute illness research: a rapid, systematic review to inform epi/pandemic research preparedness
Publisher: Springer Science and Business Media LLC
Date: 12-2015
Protocol and statistical analysis plan for the phase 3 randomised controlled Treatment of Invasively Ventilated Adults with Early Activity and Mobilisation (TEAM III) trial
Publisher: Elsevier BV
Date: 06-09-2021
DOI: 10.51893/2021.3.OA3
Abstract: OBJECTIVE: To describe the protocol and statistical analysis plan for the Treatment of Invasively Ventilated Adults with Early Activity and Mobilisation (TEAM III) trial. DESIGN: An international, multicentre, parallel-group, randomised controlled phase 3 trial. SETTING: Intensive care units (ICUs) in Australia, New Zealand, Germany, Ireland, the United Kingdom and Brazil. PATIENTS: 750 adult patients expected to receive mechanical ventilation for more than 48 hours. INTERVENTIONS: Early activity and mobilisation delivered to critically ill patients in an ICU for up to 28 days compared with standard care. MAIN OUTCOME MEASURES: The primary outcome is the number of days alive and out of hospital at 180 days after randomisation. Secondary outcomes include ICU-free days, ventilator-free days, delirium-free days, all-cause mortality at 28 and 180 days after randomisation, and functional outcome at 180 days after randomisation. RESULTS: Recruitment at 46 research sites passed 576 patients in March 2021. Final collection of all 180-day outcome data for the target of 750 patients is anticipated by May 2022. CONCLUSIONS: Consistent with international guidelines, a detailed protocol and prospective analysis plan has been developed for the TEAM III trial. This plan specifies the statistical models for evaluating primary and secondary outcomes, defines covariates for adjusted analyses, and defines methods for exploratory analyses. Application of this protocol and statistical analysis plan to the forthcoming TEAM III trial will facilitate unbiased analyses of the clinical data collected. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03133377.
Can we improve neurological outcomes in severe traumatic brain injury? Something old (early prophylactic hypothermia) and something new (erythropoietin).
Publisher: Elsevier BV
Date: 05-2009
DOI: 10.1016/J.INJURY.2009.01.002
Abstract: Traumatic brain injury is a leading cause of mortality and long-term morbidity, particularly affecting young people. With our best therapies, one half of the patients with severe traumatic brain injury are never capable of living independently. Two interventions, which have real potential to improve neurological outcomes in patients with traumatic brain injury, are (i) very early induction of prophylactic hypothermia and (ii) exogenous erythropoietin therapy. There is substantial experimental evidence, a plausible biological rationale, and supportive clinical evidence from clinical trials to suggest a possible beneficial effect of prophylactic hypothermia and also for exogenous erythropoietin therapy in severe traumatic brain injury. Despite the recent guidelines and publications recommending these interventions, critical care clinicians should be conservative towards implementing these therapies outside clinical trials due to substantial efficacy and safety concerns. Nevertheless the high morbidity and mortality associated with severe traumatic brain injury (TBI) demands that we investigate the safety and efficacy of these promising potential therapies as a matter of urgency.
Awake prone positioning for COVID-19 acute hypoxaemic respiratory failure: a randomised, controlled, multinational, open-label meta-trial
Publisher: Elsevier BV
Date: 12-2021
Early short course of neuromuscular blocking agents in patients with COVID-19 ARDS: a propensity score analysis
Publisher: Springer Science and Business Media LLC
Date: 17-05-2022
DOI: 10.1186/S13054-022-03983-5
Abstract: The role of neuromuscular blocking agents (NMBAs) in coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS) is not fully elucidated. Therefore, we aimed to investigate in COVID-19 patients with moderate-to-severe ARDS the impact of early use of NMBAs on 90-day mortality, through propensity score (PS) matching analysis. We analyzed a convenience s le of patients with COVID-19 and moderate-to-severe ARDS, admitted to 244 intensive care units within the COVID-19 Critical Care Consortium, from February 1, 2020, through October 31, 2021. Patients undergoing at least 2 days and up to 3 consecutive days of NMBAs (NMBA treatment), within 48 h from commencement of IMV were compared with subjects who did not receive NMBAs or only upon commencement of IMV (control). The primary objective in the PS-matched cohort was comparison between groups in 90-day in-hospital mortality, assessed through Cox proportional hazard modeling. Secondary objectives were comparisons in the numbers of ventilator-free days (VFD) between day 1 and day 28 and between day 1 and 90 through competing risk regression. Data from 1953 patients were included. After propensity score matching, 210 cases from each group were well matched. In the PS-matched cohort, mean (± SD) age was 60.3 ± 13.2 years and 296 (70.5%) were male and the most common comorbidities were hypertension (56.9%), obesity (41.1%), and diabetes (30.0%). The unadjusted hazard ratio (HR) for death at 90 days in the NMBA treatment vs control group was 1.12 (95% CI 0.79, 1.59, p = 0.534). After adjustment for smoking habit and critical therapeutic covariates, the HR was 1.07 (95% CI 0.72, 1.61, p = 0.729). At 28 days, VFD were 16 (IQR 0–25) and 25 (IQR 7–26) in the NMBA treatment and control groups, respectively (sub-hazard ratio 0.82, 95% CI 0.67, 1.00, p = 0.055). At 90 days, VFD were 77 (IQR 0–87) and 87 (IQR 0–88) (sub-hazard ratio 0.86 (95% CI 0.69, 1.07 p = 0.177). In patients with COVID-19 and moderate-to-severe ARDS, short course of NMBA treatment, applied early, did not significantly improve 90-day mortality and VFD. In the absence of definitive data from clinical trials, NMBAs should be indicated cautiously in this setting.
ISARIC-COVID-19 dataset: A Prospective, Standardized, Global Dataset of Patients Hospitalized with COVID-19
Publisher: Springer Science and Business Media LLC
Date: 30-07-2022
DOI: 10.1038/S41597-022-01534-9
Abstract: The International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) COVID-19 dataset is one of the largest international databases of prospectively collected clinical data on people hospitalized with COVID-19. This dataset was compiled during the COVID-19 pandemic by a network of hospitals that collect data using the ISARIC-World Health Organization Clinical Characterization Protocol and data tools. The database includes data from more than 705,000 patients, collected in more than 60 countries and 1,500 centres worldwide. Patient data are available from acute hospital admissions with COVID-19 and outpatient follow-ups. The data include signs and symptoms, pre-existing comorbidities, vital signs, chronic and acute treatments, complications, dates of hospitalization and discharge, mortality, viral strains, vaccination status, and other data. Here, we present the dataset characteristics, explain its architecture and how to gain access, and provide tools to facilitate its use.
Incidence and management of metabolic acidosis with sodium bicarbonate in the ICU: An international observational study
Publisher: Springer Science and Business Media LLC
Date: 02-02-2021
DOI: 10.1186/S13054-020-03431-2
Abstract: Metabolic acidosis is a major complication of critical illness. However, its current epidemiology and its treatment with sodium bicarbonate given to correct metabolic acidosis in the ICU are poorly understood. This was an international retrospective observational study in 18 ICUs in Australia, Japan, and Taiwan. Adult patients were consecutively screened, and those with early metabolic acidosis (pH 7.3 and a Base Excess –4 mEq/L, within 24-h of ICU admission) were included. Screening continued until 10 patients who received and 10 patients who did not receive sodium bicarbonate in the first 24 h (early bicarbonate therapy) were included at each site. The primary outcome was ICU mortality, and the association between sodium bicarbonate and the clinical outcomes were assessed using regression analysis with generalized linear mixed model. We screened 9437 patients. Of these, 1292 had early metabolic acidosis (14.0%). Early sodium bicarbonate was given to 18.0% (233/1292) of these patients. Dosing, physiological, and clinical outcome data were assessed in 360 patients. The median dose of sodium bicarbonate in the first 24 h was 110 mmol, which was not correlated with bodyweight or the severity of metabolic acidosis. Patients who received early sodium bicarbonate had higher APACHE III scores, lower pH, lower base excess, lower PaCO 2 , and a higher lactate and received higher doses of vasopressors. After adjusting for confounders, the early administration of sodium bicarbonate was associated with an adjusted odds ratio (aOR) of 0.85 (95% CI, 0.44 to 1.62) for ICU mortality. In patients with vasopressor dependency, early sodium bicarbonate was associated with higher mean arterial pressure at 6 h and an aOR of 0.52 (95% CI, 0.22 to 1.19) for ICU mortality. Early metabolic acidosis is common in critically ill patients. Early sodium bicarbonate is administered by clinicians to more severely ill patients but without correction for weight or acidosis severity. Bicarbonate therapy in acidotic vasopressor-dependent patients may be beneficial and warrants further investigation.
Inflammation, immunity and allergy
Publisher: Elsevier BV
Date: 10-2018
Challenging issues in randomised controlled trials.
Publisher: Elsevier BV
Date: 07-2010
DOI: 10.1016/J.INJURY.2010.03.033
Abstract: WHAT THIS TOPIC IS ABOUT: Randomised controlled trials (RCTs) are the most rigorous way of determining whether a cause-effect relation exists between treatment and outcome and are an integral component in the hierarchy of evidence which guide current clinical practice. Whether ensuring the success of a RCT or interpreting the medical literature, it is important to understand the key components of RCT design to assess their quality and therefore the weight which should be attributed to its findings. This article will highlight some of these key components by using a number of ongoing trauma studies being co-ordinated by the Australian and New Zealand Intensive Care Research Centre, Monash University. COMMON PROBLEMS AND CHALLENGES: The quality of many RCTs could be improved by avoiding some common pitfalls, such as (i) unclear hypotheses and multiple objectives, (ii) poor selection of endpoints, (iii) inappropriate subject selection criteria, (iv) non-clinically relevant or feasible treatment/intervention regimens, (v) inadequate randomisation, stratification, blinding, (vi) lack of stratification in small RCTs (vii) inadequate blinding of trials, (viii) insufficient s le size ower, (ix) failure to use intention to treat analysis and (x) failure to anticipate common practical problems encountered during the conduct of a RCT. TIPS FOR RESEARCHERS: The RCTs most likely to be funded and/or be of high quality always address these issues.
Hypercapnia and Acidosis in Sepsis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2010
DOI: 10.1097/ALN.0B013E3181CA361F
Abstract: Acute respiratory distress syndrome is a devastating disease that causes substantial morbidity and mortality. Mechanical ventilation can worsen lung injury, whereas ventilatory strategies that reduce lung stretch, resulting in a "permissive" hypercapnic acidosis (HCA), improve outcome. HCA directly reduces nonsepsis-induced lung injury in preclinical models and, therefore, has therapeutic potential in these patients. These beneficial effects are mediated via inhibition of the host immune response, particularly cytokine signaling, phagocyte function, and the adaptive immune response. Of concern, these immunosuppressive effects of HCA may hinder the host response to microbial infection. Recent studies suggest that HCA is protective in the earlier phases of bacterial pneumonia-induced sepsis but may worsen injury in the setting of prolonged lung sepsis. In contrast, HCA is protective in preclinical models of early and prolonged systemic sepsis. Buffering of the HCA is not beneficial and may worsen pneumonia-induced injury.
Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19
Publisher: Massachusetts Medical Society
Date: 22-04-2021
Open source clinical science for emerging infections
Publisher: Elsevier BV
Date: 2014
Ambient pressure CO2 hydrogenation over a cobalt/manganese-oxide nanostructured interface: A combined in situ and ex situ study
Publisher: Elsevier BV
Date: 06-2020
Comment on Rishu et al. Time required to initiate outbreak and pandemic observational research
Publisher: Elsevier BV
Date: 08-2017
Hypercapnic Acidosis Reduces Oxidative Reactions in Endotoxin-induced Lung Injury
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2010
DOI: 10.1097/ALN.0B013E3181DFD2FE
Abstract: Hypercapnic acidosis frequently occurs when patients with acute lung injury are initially ventilated with low tidal volume "protective" strategies. Hypercapnic acidosis per se, in the absence of any change in tidal volume or airway pressure, is protective when instituted before the onset of injury. However, the mechanisms by which hypercapnic acidosis confers this protection are incompletely understood, in particular, the effects on pulmonary oxidative reactions, which are potent mediators of tissue damage, have not been previously examined in vivo. After anesthesia, tracheostomy, and the intratracheal instillation of endotoxin to establish lung injury, rats were mechanically ventilated for 6 h in normocapnia (21% O2, 0% CO2). Rats were then randomized to either normocapnic (21% O2, 0% CO2) or hypercapnic (21% O2, 5% CO2) ventilation and a nonspecific nitric oxide synthase inhibitor (N-monomethyl-L-arginine) or vehicle. Dihydrorhodamine was administered intravenously, and the lungs were removed for determination of the oxidative formation of rhodamine by spectrofluorimetry after 20 min. Thus, rats were randomly assigned to either: normocapnia-endotoxin (n = 12), normocapnia-endotoxin-N-monomethyl-L-arginine (n = 9), hypercapnia-endotoxin (n = 11), or hypercapnia-endotoxin-N-monomethyl-L-arginine (n = 10). Hypercapnic acidosis significantly reduced the pulmonary oxidative reactions in the inflamed lung compared with normocapnia. Nitric oxide synthase blockade did not alter endotoxin-induced oxidative reactions. Hypercapnic acidosis reduced oxidative reactions in the acutely injured lung in vivo, within minutes of onset and was not reliant on nitric oxide-dependent peroxynitrite production. This rapid onset antioxidant action is a previously undescribed mechanism by which hypercapnic acidosis could act, even when acute lung injury is well established.
Galectin-3 Inhibition in COVID-19
Publisher: American Thoracic Society
Date: 15-01-2023
Targeted hypothermia versus targeted Normothermia after out-of-hospital cardiac arrest (TTM2): A randomized clinical trial—Rationale and design
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.AHJ.2019.06.012
Abstract: Less than 500 participants have been included in randomized trials comparing hypothermia with regular care for out-of-hospital cardiac arrest patients, and many of these trials were small and at a high risk of bias. Consequently, the accrued data on this potentially beneficial intervention resembles that of a drug following small phase II trials. A large confirmatory trial is therefore warranted. The TTM2-trial is an international, multicenter, parallel group, investigator-initiated, randomized, superiority trial in which a target temperature of 33°C after cardiac arrest will be compared with a strategy to maintain normothermia and early treatment of fever (≥37.8°C). Participants will be randomized within 3 hours of return of spontaneous circulation with the intervention period lasting 40 hours in both groups. Sedation will be mandatory for all patients throughout the intervention period. The clinical team involved with direct patient care will not be blinded to allocation group due to the inherent difficulty in blinding the intervention. Prognosticators, outcome-assessors, the steering group, the trial coordinating team, and trial statistician will be blinded. The primary outcome will be all-cause mortality at 180 days after randomization. We estimate a 55% mortality in the control group. To detect an absolute risk reduction of 7.5% with an alpha of 0.05 and 90% power, 1900 participants will be enrolled. The main secondary neurological outcome will be poor functional outcome (modified Rankin Scale 4-6) at 180 days after arrest. The TTM2-trial will compare hypothermia to 33°C with normothermia and early treatment of fever (≥37.8°C) after out-of-hospital cardiac arrest.
Normalising comparative effectiveness trials as clinical practice
Publisher: Springer Science and Business Media LLC
Date: 15-09-2021
DOI: 10.1186/S13063-021-05566-1
Abstract: There is a lack of high-quality evidence underpinning many contemporary clinical practice guidelines embedded in the healthcare systems, leading to treatment uncertainty and practice variation in most medical disciplines. Comparative effectiveness trials (CETs) represent a erse range of research that focuses on optimising health outcomes by comparing currently approved interventions to generate high-quality evidence to inform decision makers. Yet, despite their ability to produce real-world evidence that addresses the key priorities of patients and health systems, many implementation challenges exist within the healthcare environment. This manuscript aims to highlight common barriers to conducting CETs and describes potential solutions to normalise their conduct as part of a learning healthcare system.
Ventilatory settings in the initial 72 h and their association with outcome in out-of-hospital cardiac arrest patients: a preplanned secondary analysis of the targeted hypothermia versus targeted norm
Publisher: Springer Science and Business Media LLC
Date: 02-07-2022
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
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2019
DOI: 10.1097/CCM.0000000000003781
Abstract: 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. 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. Fifty-nine ICUs in five countries. Adults with an anticipated ICU stay of at least 24 hours when the decision had been made to transfuse at least one RBC unit. Patients were randomized to receive either the freshest or oldest available compatible RBC units (standard practice) in the hospital transfusion service. 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). 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.
Arterial hyperoxia and in-hospital mortality after resuscitation from cardiac arrest
Publisher: Springer Science and Business Media LLC
Date: 2011
DOI: 10.1186/CC10090
Comparison of baseline characteristics, treatment and clinical outcomes of critically ill COVID-19 patients admitted in the first and second waves in Australia
Publisher: Elsevier BV
Date: 06-09-2021
DOI: 10.51893/2021.3.OA8
Abstract: OBJECTIVE: To report longitudinal differences in baseline characteristics, treatment, and outcomes in patients with coronavirus disease 2019 (COVID-19) admitted to intensive care units (ICUs) between the first and second waves of COVID-19 in Australia. DESIGN, SETTING AND PARTICIPANTS: SPRINT-SARI Australia is a multicentre, inception cohort study enrolling adult patients with COVID-19 admitted to participating ICUs. The first wave of COVID-19 was from 27 February to 30 June 2020, and the second wave was from 1 July to 22 October 2020. RESULTS: A total of 461 patients were recruited in 53 ICUs across Australia a higher number were admitted to the ICU during the second wave compared with the first: 255 (55.3%) versus 206 (44.7%). Patients admitted to the ICU in the second wave were younger (58.0 v 64.0 years P = 0.001) and less commonly male (68.9% v 60.0% P = 0.045), although Acute Physiology and Chronic Health Evaluation (APACHE) II scores were similar (14 v 14 P = 0.998). High flow oxygen use (75.2% v 43.4% P 0.001) and non-invasive ventilation (16.5% v 7.1% P = 0.002) were more common in the second wave, as was steroid use (95.0% v 30.3% P 0.001). ICU length of stay was shorter (6.0 v 8.4 days P = 0.003). In-hospital mortality was similar (12.2% v 14.6% P = 0.452), but observed mortality decreased over time and patients were more likely to be discharged alive earlier in their ICU admission (hazard ratio, 1.43 95% CI, 1.13–1.79 P = 0.002). CONCLUSION: During the second wave of COVID-19 in Australia, ICU length of stay and observed mortality decreased over time. Multiple factors were associated with this, including changes in clinical management, the adoption of new evidence-based treatments, and changes in patient demographic characteristics but not illness severity.
Statistical 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
Publisher: Springer Science and Business Media LLC
Date: 12-2014
Effect of Human Recombinant Alkaline Phosphatase on 7-Day Creatinine Clearance in Patients With Sepsis-Associated Acute Kidney Injury
Publisher: American Medical Association (AMA)
Date: 20-11-2018
Nutrition delivery across hospitalisation in critically ill patients with COVID-19: An observational study of the Australian experience
Publisher: Elsevier BV
Date: 05-2023
Shock: causes, initial assessment and investigations
Publisher: Elsevier BV
Date: 02-2014
The value of open-source clinical science in pandemic response: lessons from ISARIC
Publisher: Elsevier BV
Date: 12-2021
Clinician-researcher’s perspectives on clinical research during the COVID19 pandemic
Publisher: Public Library of Science (PLoS)
Date: 09-12-2020
DOI: 10.1371/JOURNAL.PONE.0243525
Abstract: The outcome of well-performed clinical research is essential for evidence-based patient management during pandemics. However, conducting clinical research amidst a pandemic requires researchers to balance clinical and research demands. We seek to understand the values, experiences, and beliefs of physicians working at the onset of the COVID-19 pandemic in order to inform clinical research planning. We aim to understand whether pandemic settings affect physician comfort with research practices, and how physician experiences shape their understanding of research in a pandemic setting. A survey tool was adapted to evaluate familiarity and comfort with research during a pandemic. A cross-sectional, online questionnaire was distributed across Canadian research networks early in the COVID-19 outbreak. The survey was administered between March 11 th and 17 th , 2020, during a time of local transmission but prior to the surge of cases. We aimed to recruit into the survey physicians in infectious disease and critical care research networks across Canada. Of the 133 physician respondents, 131 (98%) considered it important to conduct clinical research during the COVID-19 pandemic. Respondents were more accepting of adaptations to the research process in during a pandemic compared to in a non-pandemic setting, including conducting research with deferred consent (χ 2 = 8.941, 95% CI: -0.264, -0.085, p = 0.003), using non-identifiable observational data with a waiver of consent with a median score of 97 out of 100 (IQR: 79.25–100) vs median 87 out of 100 (IQR: 63–79) (95% CI: -12.43, 0.054, p = 0.052). The majority felt that research quality is not compromised during pandemics. Physicians consider it important to conduct research during a pandemic, highlighting the need to expedite research activities in pandemic settings. Respondents were more accepting of adaptations to the research process for research conducted during a pandemic, compared to that conducted in its absence of a pandemic.
High-frequency oscillation in acute respiratory distress syndrome: who rescues the rescuer?
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2007
Potential Impact of the 2016 Consensus Definitions of Sepsis and Septic Shock on Future Sepsis Research
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.ANNEMERGMED.2017.04.007
Abstract: The influence of the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) on the conduct of future sepsis research is unknown. We seek to examine the potential effect of the new definitions on the identification and outcomes of patients enrolled in a sepsis trial. This was a post hoc analysis of the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial of early goal-directed therapy that recruited 1,591 adult patients presenting to the emergency department (ED) with early septic shock diagnosed by greater than or equal to 2 systemic inflammatory response syndrome criteria and either refractory hypotension or hyperlactatemia. The proportion of participants who would have met the Sepsis-3 criteria for quick Sequential Organ Failure Assessment (qSOFA) score, sepsis (an increased Sequential Organ Failure Assessment score ≥2 because of infection) and septic shock before randomization, their baseline characteristics, interventions delivered, and mortality were determined. There were 1,139 participants who had a qSOFA score of greater than or equal to 2 at baseline (71.6% [95% confidence interval {CI} 69.4% to 73.8%]). In contrast, 1,347 participants (84.7% [95% CI 82.9% to 86.4%]) met the Sepsis-3 criteria for sepsis. Only 1,010 participants were both qSOFA positive and met the Sepsis-3 criteria for sepsis (63.5% [95% CI 61.1% to 65.8%]). The Sepsis-3 definition for septic shock was met at baseline by 203 participants (12.8% [95% CI 11.2% to 14.5%]), of whom 175 (86.2% [95% CI 81.5% to 91.0%]) were also qSOFA positive. Ninety-day mortality for participants fulfilling the Sepsis-3 criteria for sepsis and septic shock was 20.4% (95% CI 18.2% to 22.5%) (274/1,344) and 29.6% (95% CI 23.3% to 35.8% [60/203]) versus 9.4% (95% CI 5.8% to 13.1%) (23/244) and 17.1% (95% CI 15.1% to 19.1% [237/1,388]), respectively, for participants not meeting the criteria (risk differences 11.0% [95% CI 6.2% to 14.8%] and 12.5% [95% CI 6.3% to 19.4%], respectively). Most ARISE participants did not meet the Sepsis-3 definition for septic shock at baseline. However, the majority fulfilled the new sepsis definition and mortality was higher than for participants not fulfilling the criteria. A quarter of participants meeting the new sepsis definition did not fulfill the qSOFA screening criteria, potentially limiting its utility as a screening tool for sepsis trials with patients with suspected infection in the ED. The implications of the new definitions for patients not eligible for recruitment into the ARISE trial are unknown.
Red blood cell transfusion and mortality
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2009
Erythropoietin for traumatic brain injury.
Publisher: American Medical Association (AMA)
Date: 12-11-2014
Potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the LUNG SAFE study
Publisher: Springer Science and Business Media LLC
Date: 18-10-2016
DOI: 10.1007/S00134-016-4571-5
Abstract: To improve the outcome of the acute respiratory distress syndrome (ARDS), one needs to identify potentially modifiable factors associated with mortality. The large observational study to understand the global impact of severe acute respiratory failure (LUNG SAFE) was an international, multicenter, prospective cohort study of patients with severe respiratory failure, conducted in the winter of 2014 in a convenience s le of 459 ICUs from 50 countries across five continents. A pre-specified secondary aim was to examine the factors associated with outcome. Analyses were restricted to patients (93.1 %) fulfilling ARDS criteria on day 1-2 who received invasive mechanical ventilation. 2377 patients were included in the analysis. Potentially modifiable factors associated with increased hospital mortality in multivariable analyses include lower PEEP, higher peak inspiratory, plateau, and driving pressures, and increased respiratory rate. The impact of tidal volume on outcome was unclear. Having fewer ICU beds was also associated with higher hospital mortality. Non-modifiable factors associated with worsened outcome from ARDS included older age, active neoplasm, hematologic neoplasm, and chronic liver failure. Severity of illness indices including lower pH, lower PaO Higher PEEP, lower peak, plateau, and driving pressures, and lower respiratory rate are associated with improved survival from ARDS. ClinicalTrials.gov NCT02010073.
What Is the Optimal Approach to Weaning and Liberation from Mechanical Ventilation?
Publisher: Elsevier
Date: 2010
Prophylaxis in healthcare workers during a pandemic: a model for a multi-centre international randomised controlled trial using Bayesian analyses
Publisher: Springer Science and Business Media LLC
Date: 27-06-2022
DOI: 10.1186/S13063-022-06402-W
Abstract: Coronavirus disease 2019 (COVID-19) has exposed the disproportionate effects of pandemics on frontline workers and the ethical imperative to provide effective prophylaxis. We present a model for a pragmatic randomised controlled trial (RCT) that utilises Bayesian methods to rapidly determine the efficacy or futility of a prophylactic agent. We initially planned to undertake a multicentre, phase III, parallel-group, open-label RCT, to determine if hydroxychloroquine (HCQ) taken once a week was effective in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in healthcare workers (HCW) aged ≥ 18 years in New Zealand (NZ) and Ireland. Participants were to be randomised 2:1 to either HCQ (800 mg stat then 400 mg weekly) or no prophylaxis. The primary endpoint was time to Nucleic Acid Amplification Test-proven SARS-CoV-2 infection. Secondary outcome variables included mortality, hospitalisation, intensive care unit admissions and length of mechanical ventilation. The trial had no fixed s le size or duration of intervention. Bayesian adaptive analyses were planned to occur fortnightly, commencing with a weakly informative prior for the no prophylaxis group hazard rate and a moderately informative prior on the intervention log hazard ratio centred on ‘no effect’. Stopping for expected success would be executed if the intervention had a greater than 0.975 posterior probability of reducing the risk of SARS-CoV-2 infection by more than 10%. Final success would be declared if, after completion of 8 weeks of follow-up (reflecting the long half-life of HCQ), the prophylaxis had at least a 0.95 posterior probability of reducing the risk of SARS-CoV-2 infection by more than 10%. Futility would be declared if HCQ was shown to have less than a 0.10 posterior probability of reducing acquisition of SARS-CoV-2 infection by more than 20%. This study did not begin recruitment due to the marked reduction in COVID-19 cases in NZ and concerns regarding the efficacy and risks of HCQ treatment in COVID-19. Nonetheless, the model presented can be easily adapted for other potential prophylactic agents and pathogens, and pre-established collaborative models like this should be shared and incorporated into future pandemic preparedness planning. The decision not to proceed with the study was made before trial registration occurred.
Early Active Mobilization during Mechanical Ventilation in the ICU.
Publisher: Massachusetts Medical Society
Date: 10-11-2022
Is it too early to recommend a restrictive transfusion strategy in critically ill patients with ischemic heart disease?
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2008
Treatment of severe sepsis
Publisher: Elsevier BV
Date: 05-2012
Erythropoietin in patients with traumatic brain injury and extracranial injury-A post hoc analysis of the erythropoietin traumatic brain injury trial
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2017
Outcomes for patients with COVID-19 admitted to Australian intensive care units during the first four months of the pandemic
Publisher: AMPCo
Date: 15-12-2021
DOI: 10.5694/MJA2.50883
Letter by Bellomo et al regarding article, relationship between supranormal oxygen tension and outcome after resuscitation from cardiac arrest
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-01-2012
Acute kidney injury and the critically ill
Publisher: Elsevier BV
Date: 03-2018
Maximal Recruitment Open Lung Ventilation in Acute Respiratory Distress Syndrome (PHARLAP): A Phase II, Multicenter, Randomized, Controlled Trial
Publisher: American Thoracic Society
Date: 12-2019
Impact of renal-replacement therapy strategies on outcomes for patients with chronic kidney disease: a secondary analysis of the STARRT-AKI trial
Publisher: Springer Science and Business Media LLC
Date: 04-11-2022
DOI: 10.1007/S00134-022-06912-W
Abstract: To assess whether pre-existing chronic kidney disease (CKD) modified the relationship between the strategy for renal-replacement theraphy (RRT) initiation and clinical outcomes in the STARRT-AKI trial. This was a secondary analysis of a multi-national randomized trial. We included patients who had documented pre-existing estimated glomerular filtration rate (eGFR) data prior to hospitalization, and we defined CKD as an eGFR ≤ 59 mL/min/1.73 m We studied 1121 patients who had pre-hospital measures of kidney function. Of these, 432 patients (38.5%) had CKD. The median (IQR) baseline serum creatinine was 130 (114-160) and 76 (64-90) µmol/L for those with and without CKD, respectively. Patients with CKD were older and more likely to have cardiovascular comorbidities and diabetes mellitus. Patients with CKD had higher 90-day mortality (47% vs. 40%, p < 0.001) compared to those without CKD, though this was not significant after covariate adjustment (adjusted odds ratio [aOR], 1.05 95% CI, 0.79-1.41). Patients with CKD were more likely to remain RRT dependent at 90 days (14% vs. 8% aOR, 1.89 95% CI, 1.05-3.43). CKD status did not modify the effect of RRT initiation strategy on 90-day mortality. Among patients with CKD, allocation to the accelerated strategy conferred more than threefold greater odds of RRT dependence at 90 days (aOR 3.18 95% CI, 1.41-7.91) compared with the standard strategy, whereas RRT initiation strategy had no effect on this outcome among those without CKD (aOR 0.71 95% CI, 0.34-1.47, p value for interaction, 0.009). In this secondary analysis of the STARRT-AKI trial, an accelerated strategy of RRT initiation conferred a higher risk of 90-day RRT dependence among patients with pre-existing CKD however, no effect was observed in the absence of CKD.
Acute pancreatitis: an intensive care perspective
Publisher: Elsevier BV
Date: 03-2018
Mild Hypercapnia or Normocapnia after Out-of-Hospital Cardiac Arrest
Publisher: Massachusetts Medical Society
Date: 06-07-2023
Weaning from mechanical ventilation in intensive care units across 50 countries (WEAN SAFE): a multicentre, prospective, observational cohort study
Publisher: Elsevier BV
Date: 05-2023
Nutrition care processes across hospitalisation in critically ill patients with COVID-19 in Australia: A multicentre prospective observational study
Publisher: Elsevier BV
Date: 2023
Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries
Publisher: American Medical Association (AMA)
Date: 23-02-2016
Abstract: Limited information exists about the epidemiology, recognition, management, and outcomes of patients with the acute respiratory distress syndrome (ARDS). To evaluate intensive care unit (ICU) incidence and outcome of ARDS and to assess clinician recognition, ventilation management, and use of adjuncts-for ex le prone positioning-in routine clinical practice for patients fulfilling the ARDS Berlin Definition. The Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) was an international, multicenter, prospective cohort study of patients undergoing invasive or noninvasive ventilation, conducted during 4 consecutive weeks in the winter of 2014 in a convenience s le of 459 ICUs from 50 countries across 5 continents. Acute respiratory distress syndrome. The primary outcome was ICU incidence of ARDS. Secondary outcomes included assessment of clinician recognition of ARDS, the application of ventilatory management, the use of adjunctive interventions in routine clinical practice, and clinical outcomes from ARDS. Of 29,144 patients admitted to participating ICUs, 3022 (10.4%) fulfilled ARDS criteria. Of these, 2377 patients developed ARDS in the first 48 hours and whose respiratory failure was managed with invasive mechanical ventilation. The period prevalence of mild ARDS was 30.0% (95% CI, 28.2%-31.9%) of moderate ARDS, 46.6% (95% CI, 44.5%-48.6%) and of severe ARDS, 23.4% (95% CI, 21.7%-25.2%). ARDS represented 0.42 cases per ICU bed over 4 weeks and represented 10.4% (95% CI, 10.0%-10.7%) of ICU admissions and 23.4% of patients requiring mechanical ventilation. Clinical recognition of ARDS ranged from 51.3% (95% CI, 47.5%-55.0%) in mild to 78.5% (95% CI, 74.8%-81.8%) in severe ARDS. Less than two-thirds of patients with ARDS received a tidal volume 8 of mL/kg or less of predicted body weight. Plateau pressure was measured in 40.1% (95% CI, 38.2-42.1), whereas 82.6% (95% CI, 81.0%-84.1%) received a positive end-expository pressure (PEEP) of less than 12 cm H2O. Prone positioning was used in 16.3% (95% CI, 13.7%-19.2%) of patients with severe ARDS. Clinician recognition of ARDS was associated with higher PEEP, greater use of neuromuscular blockade, and prone positioning. Hospital mortality was 34.9% (95% CI, 31.4%-38.5%) for those with mild, 40.3% (95% CI, 37.4%-43.3%) for those with moderate, and 46.1% (95% CI, 41.9%-50.4%) for those with severe ARDS. Among ICUs in 50 countries, the period prevalence of ARDS was 10.4% of ICU admissions. This syndrome appeared to be underrecognized and undertreated and associated with a high mortality rate. These findings indicate the potential for improvement in the management of patients with ARDS. clinicaltrials.gov Identifier: NCT02010073.
Transfusion practice and guidelines in Australian and New Zealand intensive care units.
Publisher: Springer Science and Business Media LLC
Date: 04-05-2010
Biomarkers of brain injury after cardiac arrest; a statistical analysis plan from the TTM2 trial biobank investigators
Publisher: Elsevier BV
Date: 06-2022
Gender differences in mortality and quality of life after septic shock: A post-hoc analysis of the ARISE study
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.JCRC.2019.11.002
Abstract: To assess the impact of gender and pre-menopausal state on short- and long-term outcomes in patients with septic shock. Cohort study of the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial, an international randomized controlled trial comparing early goal-directed therapy (EGDT) to usual care in patients with early septic shock, conducted between October 2008 and April 2014. The primary exposure in this analysis was legal gender and the secondary exposure was pre-menopausal state defined by chronological age (≤ 50 years). 641 (40.3%) of all 1591 ARISE trial participants in the intention-to-treat population were females and overall, 337 (21.2%) (146 females) patients were 50 years of age or younger. After risk-adjustment, we could not identify any survival benefit for female patients at day 90 in the younger (≤50 years) (adjusted Odds Ratio (aOR): 0.91 (0.46-1.89), p = .85) nor in the older (>50 years) age-group (aOR: 1.10 (0.81-1.49), p = .56). Similarly, there was no gender-difference in ICU, hospital, 1-year mortality nor quality of life measures. This post-hoc analysis of a large multi-center trial in early septic shock has shown no short- or long-term survival effect for women overall as well as in the pre-menopausal age-group.
A ustralasian R esuscitation I n S epsis E valuation trial statistical analysis plan
Publisher: Wiley
Date: 09-09-2013
Abstract: The Australasian Resuscitation In Sepsis Evaluation (ARISE) study is an international, multicentre, randomised, controlled trial designed to evaluate the effectiveness of early goal-directed therapy compared with standard care for patients presenting to the ED with severe sepsis. In keeping with current practice, and taking into considerations aspects of trial design and reporting specific to non-pharmacologic interventions, this document outlines the principles and methods for analysing and reporting the trial results. The document is prepared prior to completion of recruitment into the ARISE study, without knowledge of the results of the interim analysis conducted by the data safety and monitoring committee and prior to completion of the two related international studies. The statistical analysis plan was designed by the ARISE chief investigators, and reviewed and approved by the ARISE steering committee. The data collected by the research team as specified in the study protocol, and detailed in the study case report form were reviewed. Information related to baseline characteristics, characteristics of delivery of the trial interventions, details of resuscitation and other related therapies, and other relevant data are described with appropriate comparisons between groups. The primary, secondary and tertiary outcomes for the study are defined, with description of the planned statistical analyses. A statistical analysis plan was developed, along with a trial profile, mock-up tables and figures. A plan for presenting baseline characteristics, microbiological and antibiotic therapy, details of the interventions, processes of care and concomitant therapies, along with adverse events are described. The primary, secondary and tertiary outcomes are described along with identification of subgroups to be analysed. A statistical analysis plan for the ARISE study has been developed, and is available in the public domain, prior to the completion of recruitment into the study. This will minimise analytic bias and conforms to current best practice in conducting clinical trials.
Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial
Publisher: Elsevier BV
Date: 09-2018
Stability Conditions for Remote State Estimation of Multiple Systems Over Semi-Markov Fading Channels
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2022
Comparative effectiveness of neutralising monoclonal antibodies in high risk COVID-19 patients: a Bayesian network meta-analysis.
Publisher: Springer Science and Business Media LLC
Date: 20-10-2022
DOI: 10.1038/S41598-022-22431-6
Abstract: The purpose of this work was to review and synthesise the evidence on the comparative effectiveness of neutralising monoclonal antibody (nMAB) therapies in in iduals exposed to or infected with SARS-CoV-2 and at high risk of developing severe COVID-19. Outcomes of interest were mortality, healthcare utilisation, and safety. A rapid systematic review was undertaken to identify and synthesise relevant RCT evidence using a Bayesian Network Meta-Analysis. Relative treatment effects for in idual nMABs (compared with placebo and one another) were estimated. Pooled effects for the nMAB class compared with placebo were estimated. Relative effects were combined with baseline natural history models to predict the expected risk reductions per 1000 patients treated. Eight articles investigating four nMABs (bamlanivimab, bamlanivimab/etesevimab, casirivimab/imdevimab, sotrovimab) were identified. All four therapies were associated with a statistically significant reduction in hospitalisation (70–80% reduction in relative risk absolute reduction of 35–40 hospitalisations per 1000 patients). For mortality, ICU admission, and invasive ventilation, the risk was lower for all nMABs compared with placebo with moderate to high uncertainty due to small event numbers. Rates of serious AEs and infusion reactions were comparable between nMABs and placebo. Pairwise comparisons between nMABs were typically uncertain, with broadly comparable efficacy. In conclusion, nMABs are effective at reducing hospitalisation among infected in iduals at high-risk of severe COVID-19, and are likely to reduce mortality, ICU admission, and invasive ventilation rates the effect on these latter outcomes is more uncertain. Widespread vaccination and the emergence of nMAB-resistant variants make the generalisability of these results to current patient populations difficult.
Prophylactic Hypothermia for Severe Traumatic Brain Injury-Reply.
Publisher: American Medical Association (AMA)
Date: 07-05-2019
ISARIC COVID-19 Clinical Data Report issued: 27 March 2022
Publisher: Cold Spring Harbor Laboratory
Date: 25-07-2020
DOI: 10.1101/2020.07.17.20155218
Abstract: ISARIC (International Severe Acute Respiratory and emerging Infections Consortium) partnerships and outbreak preparedness initiatives enabled the rapid launch of standardised clinical data collection on COVID-19 in Jan 2020. Extensive global participation has resulted in a large, standardised collection of comprehensive clinical data from hundreds of sites across dozens of countries. Data are analysed regularly and reported publicly to inform patient care and public health response. This report, our 17th report, is a part of a series published over the past 2 years. Data have been entered for 800,459 in iduals from 1701 partner institutions and networks across 60 countries. The comprehensive analyses detailed in this report includes hospitalised in iduals of all ages for whom data collection occurred between 30 January 2020 and up to and including 5 January 2022, AND who have laboratory-confirmed SARS-COV-2 infection or clinically diagnosed COVID-19. For the 699,014 cases who meet eligibility criteria for this report, selected findings include: median age of 58 years, with an approximately equal (50/50) male:female sex distribution 29% of the cohort are at least 70 years of age, whereas 4% are 0-19 years of age the most common symptom combination in this hospitalised cohort is shortness of breath, cough, and history of fever, which has remained constant over time the five most common symptoms at admission were shortness of breath, cough, history of fever, fatigue/malaise, and altered consciousness/confusion, which is unchanged from the previous reports age-associated differences in symptoms are evident, including the frequency of altered consciousness increasing with age, and fever, respiratory and constitutional symptoms being present mostly in those 40 years and above 16% of patients with relevant data available were admitted at some point during their illness into an intensive care unit (ICU), which is slightly lower than previously reported (19%) antibiotic agents were used in 35% of patients for whom relevant data are available (669,630), a significant reduction from our previous reports (80%) which reflects a shifting proportion of data contributed by different institutions in ICU/HDU admitted patients with data available (50,560), 91% received antibiotics use of corticosteroids was reported in 24% of all patients for whom data were available (677,012) in ICU/HDU admitted patients with data available (50,646), 69% received corticosteroids outcomes are known for 632,518 patients and the overall estimated case fatality ratio (CFR) is 23.9% (95%CI 23.8-24.1), rising to 37.1% (95%CI 36.8-37.4) for patients who were admitted to ICU/HDU, demonstrating worse outcomes in those with the most severe disease To access previous versions of ISARIC COVID-19 Clinical Data Report please use the link below: esearch/covid-19-clinical-research-resources/evidence-reports/
Ten months of temporal variation in the clinical journey of hospitalised patients with COVID-19: An observational cohort
Publisher: eLife Sciences Publications, Ltd
Date: 23-11-2021
DOI: 10.7554/ELIFE.70970
Abstract: There is potentially considerable variation in the nature and duration of the care provided to hospitalised patients during an infectious disease epidemic or pandemic. Improvements in care and clinician confidence may shorten the time spent as an inpatient, or the need for admission to an intensive care unit (ICU) or high dependency unit (HDU). On the other hand, limited resources at times of high demand may lead to rationing. Nevertheless, these variables may be used as static proxies for disease severity, as outcome measures for trials, and to inform planning and logistics. We investigate these time trends in an extremely large international cohort of 142,540 patients hospitalised with COVID-19. Investigated are: time from symptom onset to hospital admission, probability of ICU/HDU admission, time from hospital admission to ICU/HDU admission, hospital case fatality ratio (hCFR) and total length of hospital stay. Time from onset to admission showed a rapid decline during the first months of the pandemic followed by peaks during August/September and December 2020. ICU/HDU admission was more frequent from June to August. The hCFR was lowest from June to August. Raw numbers for overall hospital stay showed little variation, but there is clear decline in time to discharge for ICU/HDU survivors. Our results establish that variables of these kinds have limitations when used as outcome measures in a rapidly evolving situation. This work was supported by the UK Foreign, Commonwealth and Development Office and Wellcome [215091/Z/18/Z] and the Bill & Melinda Gates Foundation [OPP1209135]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Clinical and organizational factors associated with mortality during the peak of first COVID-19 wave: the global UNITE-COVID study
Publisher: Springer Science and Business Media LLC
Date: 21-05-2022
Higher PEEP for acute respiratory distress syndrome: a Bayesian meta-analysis of randomised clinical trials
Publisher: Elsevier BV
Date: 07-06-2021
DOI: 10.51893/2021.2.OA4
Abstract: Objective: Benefit or harm of higher positive end expiratory pressure (PEEP) for acute respiratory distress syndrome (ARDS) is controversial. We aimed to assess the impact of higher levels of PEEP in patients with ARDS under a Bayesian framework. Design: Systematic review and Bayesian meta-analysis of randomised clinical trials comparing higher to lower PEEP in adult patients with ARDS. Data sources: MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials from 1996 to 1 March 2020. Review methods: We extracted data from high quality randomised clinical trials comparing higher to lower levels of PEEP in adult patients, using low tidal volume in both arms, and conducted a Bayesian meta-analysis using aggregate data from these studies. Results: Eight clinical trials including 3703 patients (n = 1833 for higher PEEP, n = 1870 for lower PEEP) were included. Under a minimally informative prior, the posterior probability of benefit with higher PEEP was 65% (relative risk, 0.97 [95% credible interval, 0.78–1.14]). In patients with moderate-to-severe ARDS, the posterior probability of benefit with higher PEEP was 77% (relative risk, 0.94 [95% credible interval, 0.77–1.13]). Down-weighting studies that employed a maximum recruitment strategy by 100% increased the posterior probability of benefit to 92% under a minimally informative prior. Conclusions: The probability of benefit or harm from routine use of higher PEEP for patients with ARDS ranges from 27% to 86%, and from 14% to 73% depending on one’s prior, suggesting continued uncertainty and equipoise regarding the benefit of PEEP. If data from trials using a maximum recruitment strategy is discounted to some extent because of uncertainty over the appropriateness of this approach, the available evidence suggests that higher PEEP could be beneficial for moderate-to-severe ARDS. However, well powered randomised clinical trials are needed to confirm these findings.
Author Correction: GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19
Publisher: Springer Science and Business Media LLC
Date: 11-07-2023
Hypothermia for Intracranial Hypertension after Traumatic Brain Injury.
Publisher: No publisher found
Date: 2016
Acute respiratory distress syndrome phenotypes with distinct clinical outcomes in PHARLAP trial cohort
Publisher: Elsevier BV
Date: 07-06-2021
DOI: 10.51893/2021.2.OA3
Abstract: Background: The Permissive Hypercapnia, Alveolar Recruitment and Low Airway Pressure (PHARLAP) randomised controlled trial compared an open lung ventilation strategy with control ventilation, and found that open lung ventilation did not reduce the number of ventilator-free days (VFDs) or mortality in patients with moderate-to-severe acute respiratory distress syndrome (ARDS). Parsimonious models can identify distinct phenotypes of ARDS (hypo-inflammatory and hyperinflammatory) which are associated with different outcomes and treatment responses. Objective: To test the hypothesis that a parsimonious model would identify patients with distinctly different clinical outcomes in the PHARLAP study. Design, setting and participants: Blood and lung lavage s les were collected in a subset of PHARLAP patients who were recruited in Australian and New Zealand centres. A previously validated parsimonious model (interleukin-8, soluble tumour necrosis factor receptor-1 and bicarbonate) was used to classify patients with blood s les into hypo-inflammatory and hyperinflammatory groups. Generalised linear modelling was used to examine the interaction between inflammatory phenotype and treatment group (intervention or control). Main outcome measure: The primary outcome was number of VFDs at Day 28. Results: Data for the parsimonious model were available for 56 of 115 patients (49%). Within this subset, 38 patients (68%) and 18 patients (32%) were classified as having hypo-inflammatory and hyperinflammatory phenotypes, respectively. Patients with the hypo-inflammatory phenotype had more VFDs at Day 28 when compared with those with the hyperinflammatory phenotype (median [IQR], 19.5 [11–24] versus 8 [0–21] P = 0.03). Patients with the hyperinflammatory phenotype had numerically fewer VFDs when managed with an open lung strategy than when managed with control “protective” ventilation (median [IQR], 0 [0–19] versus 16 [8–22]). Conclusion: In the PHARLAP trial, ARDS patients classified as having a hyperinflammatory phenotype, with a parsimonious three-variable model, had fewer VFDs at Day 28 compared with patients classified as having a hypo-inflammatory phenotype. Future clinical studies of ventilatory strategies should consider incorporating distinct ARDS phenotypes into their trial design.
Ventilator Weaning and Discontinuation Practices for Critically Ill Patients.
Publisher: American Medical Association (AMA)
Date: 23-03-2021
Impact of renin–angiotensin–aldosterone system inhibition on mortality in critically ill COVID-19 patients with pre-existing hypertension: a prospective cohort study
Publisher: Springer Science and Business Media LLC
Date: 23-03-2022
DOI: 10.1186/S12872-022-02565-1
Abstract: The influence of renin–angiotensin–aldosterone system (RAAS) inhibitors on the critically ill COVID-19 patients with pre-existing hypertension remains uncertain. This study examined the impact of previous use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) on the critically ill COVID-19 patients. Data from an international, prospective, observational cohort study involving 354 hospitals spanning 54 countries were included. A cohort of 737 COVID-19 patients with pre-existing hypertension admitted to intensive care units (ICUs) in 2020 were targeted. Multi-state survival analysis was performed to evaluate in-hospital mortality and hospital length of stay up to 90 days following ICU admission. A total of 737 patients were included—538 (73%) with pre-existing hypertension had received ACEi/ARBs before ICU admission, while 199 (27%) had not. Cox proportional hazards model showed that previous ACEi/ARB use was associated with a decreased hazard of in-hospital death (HR, 0.74, 95% CI 0.58–0.94). Sensitivity analysis adjusted for propensity scores showed similar results for hazards of death. The average length of hospital stay was longer in ACEi/ARB group with 21.2 days (95% CI 19.7–22.8 days) in ICU and 6.7 days (5.9–7.6 days) in general ward compared to non-ACEi/ARB group with 16.2 days (14.1–18.6 days) and 6.4 days (5.1–7.9 days), respectively. When analysed separately, results for ACEi or ARB patient groups were similar for both death and discharge. In critically ill COVID-19 patients with comorbid hypertension, use of ACEi/ARBs prior to ICU admission was associated with a reduced risk of in-hospital mortality following adjustment for baseline characteristics although patients with ACEi/ARB showed longer length of hospital stay. Clinical trial registration The registration number: ACTRN12620000421932 The date of registration: 30, March 2020 The URL of the registration: www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12620000421932 .
Extracorporeal membrane oxygenation and Extracorporeal Membrane Oxygenation Cardiopulmonary Resusciation (ECPR) research priorities in Australia: A clinician survey
Publisher: Elsevier BV
Date: 09-2023
Defining the characteristics and expectations of fluid bolus therapy: A worldwide perspective
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.JCRC.2016.05.017
Abstract: The purpose of the study is to understand what clinicians believe defines fluid bolus therapy (FBT) and the expected response to such intervention. We asked intensive care specialists in 30 countries to participate in an electronic questionnaire of their practice, definition, and expectations of FBT. We obtained 3138 responses. Despite much variation, more than 80% of respondents felt that more than 250 mL of either colloid or crystalloid fluid given over less than 30 minutes defined FBT, with crystalloids most acceptable. The most acceptable crystalloid and colloid for use as FBT were 0.9% saline and 4% albumin solution, respectively. Most respondents believed that one or more of the following physiological changes indicates a response to FBT: a mean arterial pressure increase greater than 10 mm Hg, a heart rate decrease greater than 10 beats per minute, an increase in urinary output by more than 10 mL/h, an increase in central venous oxygen saturation greater than 4%, or a lactate decrease greater than 1 mmol/L. Despite wide variability between in iduals and countries, clear majority views emerged to describe practice, define FBT, and identify a response to it. Further investigation is now required to describe actual FBT practice and to identify the magnitude and duration of the physiological response to FBT and its relationship to patient-centered outcomes.
Assessment of 28-Day In-Hospital Mortality in Mechanically Ventilated Patients With Coronavirus Disease 2019: An International Cohort Study
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2021
Genetic mechanisms of critical illness in Covid-19
Publisher: Cold Spring Harbor Laboratory
Date: 25-09-2020
DOI: 10.1101/2020.09.24.20200048
Abstract: The subset of patients who develop critical illness in Covid-19 have extensive inflammation affecting the lungs 1 and are strikingly different from other patients: immunosuppressive therapy benefits critically-ill patients, but may harm some non-critical cases. 2 Since susceptibility to life-threatening infections and immune-mediated diseases are both strongly heritable traits, we reasoned that host genetic variation may identify mechanistic targets for therapeutic development in Covid-19. 3 GenOMICC (Genetics Of Mortality In Critical Care, genomicc.org ) is a global collaborative study to understand the genetic basis of critical illness. Here we report the results of a genome-wide association study (GWAS) in 2244 critically-ill Covid-19 patients from 208 UK intensive care units (ICUs), representing % of all ICU beds. Ancestry-matched controls were drawn from the UK Biobank population study and results were confirmed in GWAS comparisons with two other population control groups: the 100,000 genomes project and Generation Scotland. We identify and replicate three novel genome-wide significant associations, at chr19p13.3 (rs2109069, p = 3.98 × 10 −12 ), within the gene encoding dipeptidyl peptidase 9 ( DPP9 ), at chr12q24.13 (rs10735079, p =1.65 × 10 −8 ) in a gene cluster encoding antiviral restriction enzyme activators ( OAS1, OAS2, OAS3 ), and at chr21q22.1 (rs2236757, p = 4.99 × 10 −8 ) in the interferon receptor gene IFNAR2 . Consistent with our focus on extreme disease in younger patients with less comorbidity, we detect a stronger signal at the known 3p21.31 locus than previous studies (rs73064425, p = 4.77 × 10 −30 ). We identify potential targets for repurposing of licensed medications. Using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2 , and high expression of TYK2 , to life-threatening disease. Transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms, and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted treatment with existing drugs. Large-scale randomised clinical trials will be essential before any change to clinical practice.
Hypoxaemic rescue therapies in acute respiratory distress syndrome: Why, when, what and which one?
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.INJURY.2012.11.017
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.
Public attitudes towards research participation during an infectious disease pandemic: a qualitative study across four European countries
Publisher: Elsevier BV
Date: 11-2016
Hypothermia in patients with brain injury: the way forward?
Publisher: Elsevier BV
Date: 05-2011
Preparing accessible and understandable clinical research participant information leaflets and consent forms: a set of guidelines from an expert consensus conference
Publisher: Springer Science and Business Media LLC
Date: 18-05-2021
DOI: 10.1186/S40900-021-00265-2
Abstract: In line with Good Clinical Practice and the Declaration of Helsinki, it is the investigator’s responsibility to ensure that research participants are sufficiently informed, to enable the provision of informed consent. The Participant Information Leaflet/Informed Consent Form is key to facilitating this communication process. Although studies have indicated that clinical research Participant Information Leaflets/Informed Consent Forms are not optimal in terms of accessibility, there is little or no specific guidance available. The aim of this research was to propose and agree a set of guidelines for academic researchers and sponsors for preparing accessible and understandable Participant Information Leaflets/Informed Consent Forms. A literature review identified guidance for the preparation of patient-facing documents. Following critical appraisal, key recommendations were extracted and a set of recommendations which can be applied to clinical research Participant Information Leaflets/Informed Consent Forms were prepared. These recommendations were evaluated and amended by an Expert Consensus Conference consisting of a group of key stakeholders. The stakeholders included members of a Research Ethics Committee (both lay and expert), a patient advocate, experienced clinical researchers, a plain English editor and a Data Protection Officer. Consensus was reached regarding a final set of recommendations. 44 recommendations were agreed upon and grouped into five categories: Layout, Formatting, Content, Language and Confirming Readability. These recommendations aimed to maximize accessibility for lay participants, including readers with dyslexia, literacy or numeracy challenges, thereby improving the quality of the consent process. More empirical research is needed to further improve the informed consent process for research participants. However, these recommendations are informed by the current literature and have been ratified by expert stakeholders. It is hoped that these recommendations will help investigators and sponsors to consistently and efficiently produce more accessible clinical research Participant Information Leaflets/Informed Consent Forms.
Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial
Publisher: American Medical Association (AMA)
Date: 03-01-2023
Abstract: The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm) futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. Among 4869 randomized patients (mean age, 59.3 years 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR & .83) was high for therapeutic anticoagulation (99.9% HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2% HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6% HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9% HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8% HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.
Erythropoietin in traumatic brain injury: study protocol for a randomised controlled trial
Publisher: Springer Science and Business Media LLC
Date: 08-02-2015
Author Correction: Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials
Publisher: Springer Science and Business Media LLC
Date: 14-05-2021
Death in hospital following ICU discharge: insights from the LUNG SAFE study
Publisher: Springer Science and Business Media LLC
Date: 13-04-2021
DOI: 10.1186/S13054-021-03465-0
Abstract: To determine the frequency of, and factors associated with, death in hospital following ICU discharge to the ward. The Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE study was an international, multicenter, prospective cohort study of patients with severe respiratory failure, conducted across 459 ICUs from 50 countries globally. This study aimed to understand the frequency and factors associated with death in hospital in patients who survived their ICU stay. We examined outcomes in the subpopulation discharged with no limitations of life sustaining treatments (‘treatment limitations’), and the subpopulations with treatment limitations. 2186 (94%) patients with no treatment limitations discharged from ICU survived, while 142 (6%) died in hospital. 118 (61%) of patients with treatment limitations survived while 77 (39%) patients died in hospital. Patients without treatment limitations that died in hospital after ICU discharge were older, more likely to have COPD, immunocompromise or chronic renal failure, less likely to have trauma as a risk factor for ARDS. Patients that died post ICU discharge were less likely to receive neuromuscular blockade, or to receive any adjunctive measure, and had a higher pre- ICU discharge non-pulmonary SOFA score. A similar pattern was seen in patients with treatment limitations that died in hospital following ICU discharge. A significant proportion of patients die in hospital following discharge from ICU, with higher mortality in patients with limitations of life-sustaining treatments in place. Non-survivors had higher systemic illness severity scores at ICU discharge than survivors. Trial Registration : ClinicalTrials.gov NCT02010073 .
Co-infection and ICU-acquired infection in COVID-19 ICU patients: a secondary analysis of the UNITE-COVID data set
Publisher: Springer Science and Business Media LLC
Date: 03-08-2022
DOI: 10.1186/S13054-022-04108-8
Abstract: The COVID-19 pandemic presented major challenges for critical care facilities worldwide. Infections which develop alongside or subsequent to viral pneumonitis are a challenge under sporadic and pandemic conditions however, data have suggested that patterns of these differ between COVID-19 and other viral pneumonitides. This secondary analysis aimed to explore patterns of co-infection and intensive care unit-acquired infections (ICU-AI) and the relationship to use of corticosteroids in a large, international cohort of critically ill COVID-19 patients. This is a multicenter, international, observational study, including adult patients with PCR-confirmed COVID-19 diagnosis admitted to ICUs at the peak of wave one of COVID-19 (February 15th to May 15th, 2020). Data collected included investigator-assessed co-infection at ICU admission, infection acquired in ICU, infection with multi-drug resistant organisms (MDRO) and antibiotic use. Frequencies were compared by Pearson’s Chi-squared and continuous variables by Mann–Whitney U test. Propensity score matching for variables associated with ICU-acquired infection was undertaken using R library MatchIT using the “full” matching method. Data were available from 4994 patients. Bacterial co-infection at admission was detected in 716 patients (14%), whilst 85% of patients received antibiotics at that stage. ICU-AI developed in 2715 (54%). The most common ICU-AI was bacterial pneumonia (44% of infections), whilst 9% of patients developed fungal pneumonia 25% of infections involved MDRO. Patients developing infections in ICU had greater antimicrobial exposure than those without such infections. Incident density (ICU-AI per 1000 ICU days) was in considerable excess of reports from pre-pandemic surveillance. Corticosteroid use was heterogenous between ICUs. In univariate analysis, 58% of patients receiving corticosteroids and 43% of those not receiving steroids developed ICU-AI. Adjusting for potential confounders in the propensity-matched cohort, 71% of patients receiving corticosteroids developed ICU-AI vs 52% of those not receiving corticosteroids. Duration of corticosteroid therapy was also associated with development of ICU-AI and infection with an MDRO. In patients with severe COVID-19 in the first wave, co-infection at admission to ICU was relatively rare but antibiotic use was in substantial excess to that indication. ICU-AI were common and were significantly associated with use of corticosteroids. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021).
Age of Red Cells for Transfusion and Outcomes in Critically Ill Adults.
Publisher: Massachusetts Medical Society
Date: 09-11-2017
Relative hyperlactatemia and hospital mortality in critically ill patients: A retrospective multi-centre study
Publisher: Springer Science and Business Media LLC
Date: 2010
DOI: 10.1186/CC8888
Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury
Publisher: American Medical Association (AMA)
Date: 04-12-2018
Age of Red Cells for Transfusion and Outcomes in Critically Ill Adults.
Publisher: Massachusetts Medical Society
Date: 29-08-2019
DOI: 10.1056/NEJMX180024
Cause and Timing of Death and Subgroup Differential Effects of Erythropoietin in the EPO-TBI Study
Publisher: Mary Ann Liebert Inc
Date: 15-01-2018
Abstract: The EPO-TBI study randomized 606 patients with moderate or severe traumatic brain injury (TBI) to be treated with weekly epoetin alfa (EPO) or placebo. Six month mortality was lower in EPO treated patients in an analysis adjusting for TBI severity. Knowledge of possible differential effects by TBI injury subtype and acute neurosurgical treatment as well as timing and cause of death (COD) will facilitate the design of future interventional TBI trials. We defined COD as cerebral (brain death, cerebral death with withdrawal, or death during maximal care) and non-cerebral (death following withdrawal or during maximal care, which had a non-cerebral cause). The study included 305 patients treated with EPO and 297 treated with placebo, with COD recorded in 77 (99%) out of 78 non-survivors. Median time to death in patients dying of cerebral COD was 8 days (interquartile range [IQR] 5-16) compared with 29 days (IQR 7-56) (p = 0.01) for non-cerebral COD. When assessing subgroups by admission CT scan injury findings, we found no significant differential effects of EPO compared with placebo. However, EPO appeared more effective in patients with an injury type not requiring a neurosurgical operation prior to intensive care unit (ICU) admission (odds ratio [OR] 0.29, 95% confidence interval [CI] 0.14-0.61, p = 0.001, p for interaction = 0.003) and in this subgroup, fewer patients died of cerebral causes in the EPO than in the placebo group (5% compared with 14%, p = 0.03). In conclusion, most TBI deaths were from cerebral causes that occurred during the first 2 weeks, and were related to withdrawal of care. EPO appeared to specifically reduce cerebral deaths in the important subgroup of patients with a diffuse type of injury not requiring a neurosurgical intervention prior to randomization.
Respiratory Support in the Time of COVID-19.
Publisher: American Medical Association (AMA)
Date: 27-09-2022
Priority Needs for Conducting Pandemic-relevant Clinical Research With Children in Europe
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2019
Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis
Publisher: Massachusetts Medical Society
Date: 08-06-2017
A Randomised Controlled Trial Of Staircase Recruitment Manoeuvres, High PEEP And Low Airway Pressure (PHARLAP)
Publisher: American Thoracic Society
Date: 05-2010
DOI: 10.1164/AJRCCM-CONFERENCE.2010.181.1_MEETINGABSTRACTS.A1686
Paediatric COVID-19 mortality: a database analysis of the impact of health resource disparity
Publisher: BMJ
Date: 10-2022
DOI: 10.1136/BMJPO-2022-001657
Abstract: The impact of the COVID-19 pandemic on paediatric populations varied between high-income countries (HICs) versus low-income to middle-income countries (LMICs). We sought to investigate differences in paediatric clinical outcomes and identify factors contributing to disparity between countries. The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) COVID-19 database was queried to include children under 19 years of age admitted to hospital from January 2020 to April 2021 with suspected or confirmed COVID-19 diagnosis. Univariate and multivariable analysis of contributing factors for mortality were assessed by country group (HICs vs LMICs) as defined by the World Bank criteria. A total of 12 860 children (3819 from 21 HICs and 9041 from 15 LMICs) participated in this study. Of these, 8961 were laboratory-confirmed and 3899 suspected COVID-19 cases. About 52% of LMICs children were black, and more than 40% were infants and adolescent. Overall in-hospital mortality rate (95% CI) was 3.3% [=(3.0% to 3.6%), higher in LMICs than HICs (4.0% (3.6% to 4.4%) and 1.7% (1.3% to 2.1%), respectively). There were significant differences between country income groups in intervention profile, with higher use of antibiotics, antivirals, corticosteroids, prone positioning, high flow nasal cannula, non-invasive and invasive mechanical ventilation in HICs. Out of the 439 mechanically ventilated children, mortality occurred in 106 (24.1%) subjects, which was higher in LMICs than HICs (89 (43.6%) vs 17 (7.2%) respectively). Pre-existing infectious comorbidities (tuberculosis and HIV) and some complications (bacterial pneumonia, acute respiratory distress syndrome and myocarditis) were significantly higher in LMICs compared with HICs. On multivariable analysis, LMIC as country income group was associated with increased risk of mortality (adjusted HR 4.73 (3.16 to 7.10)). Mortality and morbidities were higher in LMICs than HICs, and it may be attributable to differences in patient demographics, complications and access to supportive and treatment modalities.
A pilot feasibility trial of allocation of freshest available red blood cells versus standard care in critically ill patients
Publisher: Wiley
Date: 14-11-2011
DOI: 10.1111/J.1537-2995.2011.03437.X
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.
Effect of Stress Ulcer Prophylaxis With Proton Pump Inhibitors vs Histamine-2 Receptor Blockers on In-Hospital Mortality Among ICU Patients Receiving Invasive Mechanical Ventilation
Publisher: American Medical Association (AMA)
Date: 18-02-2020
Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials
Publisher: Springer Science and Business Media LLC
Date: 15-04-2021
DOI: 10.1038/S41467-021-22446-Z
Abstract: Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications reprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications reprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total s le size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20 I² = 0% 26 trials 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0% 4 trials 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.
Care bundles for improving outcomes in patients with COVID-19 or related conditions in intensive care - a rapid scoping review.
Publisher: Wiley
Date: 21-12-2020
The association between time of in hospital cardiac arrest and mortality; a retrospective analysis of two UK databases
Publisher: Elsevier BV
Date: 05-2023
Decisive role of Cu/Co interfaces in copper cobaltite derivatives for high performance CO2 methanation catalyst
Publisher: Elsevier BV
Date: 09-2023
Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial
Publisher: Springer Science and Business Media LLC
Date: 12-07-2021
Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial
Publisher: Elsevier BV
Date: 12-2015
Early Sedation with Dexmedetomidine in Critically Ill Patients
Publisher: Massachusetts Medical Society
Date: 27-06-2019
Major adverse cardiovascular events (MACE) in patients with severe COVID-19 registered in the ISARIC WHO clinical characterization protocol: A prospective, multinational, observational study
Publisher: Elsevier BV
Date: 10-2023
Venous thromboembolic events in critically ill traumatic brain injury patients
Publisher: Springer Science and Business Media LLC
Date: 27-12-2017
DOI: 10.1007/S00134-016-4655-2
Abstract: 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. 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. 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). 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.
The cost-effectiveness of early goaldirected therapy: an economic evaluation alongside the ARISE trial
Publisher: Elsevier BV
Date: 06-09-2021
DOI: 10.51893/2021.3.OA10
Abstract: OBJECTIVE: To determine the cost-effectiveness of early goal-directed therapy (EGDT) for patients with early septic shock. DESIGN: Within-trial cost-effectiveness evaluation. SETTING: Nineteen hospitals in Australia and New Zealand. PARTICIPANTS AND INTERVENTIONS: Patients with early septic shock enrolled in the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial were randomly assigned to EGDT versus usual care. A subgroup of patients participated in a nested economic evaluation study in which detailed resource use data were collected until 12 months after randomisation. OUTCOME MEASURES: Clinical outcomes included lives saved, life-years gained and quality-adjusted life-years (QALYs), with mortality collected until 12 months and health-related quality of life assessed at baseline, 6 and 12 months using the 3-level EuroQol five dimensions questionnaire (EQ-5D-3L). Economic outcomes included health care resource use, costs and cost-effectiveness from the Australian health care payer perspective. RESULTS: A total of 205 patients (100 EGDT, 105 usual care) participated in the nested economic evaluation study, of which 203 had complete resource use data. Unadjusted mean health care costs to 12 months were $67 223 (standard deviation [SD], $72 397) in the EGDT group and $54 179 (SD, $61 980) in the usual care group, with a mean difference of $13 044 (95% CI, −$5791 to $31 878). There was no difference between groups with regards to lives saved (EGDT, 69.4% v usual care, 68.6% P = 1.0), life-years gained (mean EGDT, 0.746 [SD, 0.406] v usual care, 0.725 [SD, 0.417] P = 0.72) or QALYs (mean EGDT, 0.318 [SD, 0.291] v usual care, 0.367 [SD, 0.295] P = 0.24). EGDT was dominated (higher costs, lower effectiveness) by usual care in 80.4% of bootstrap replications. For a willingness-to-pay threshold of $50 000 per QALY, the probability of EGDT being cost-effective was only 6.4%. CONCLUSIONS: In patients presenting to the emergency department with early septic shock, EGDT compared with usual care was not cost-effective. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number NCT00975793.
Measuring functional and quality of life outcomes following major head injury: Common scales and checklists
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.INJURY.2010.11.047
Abstract: Traumatic brain injury (TBI) is a major public health issue, which results in significant mortality and long term disability. The profound impact of TBI is not only felt by the in iduals who suffer the injury but also their care-givers and society as a whole. Clinicians and researchers require reliable and valid measures of long term outcome not only to truly quantify the burden of TBI and the scale of functional impairment in survivors, but also to allow early appropriate allocation of rehabilitation supports. In addition, clinical trials which aim to improve outcomes in this devastating condition require high quality measures to accurately assess the impact of the interventions being studied. In this article, we review the properties of an ideal measure of outcome in the TBI population. Then, we describe the key components and performance of the measurement tools most commonly used to quantify outcome in clinical studies in TBI. These measurement tools include: the Glasgow Outcome Scale (GOS) and extended Glasgow Outcome Scale (GOSe) Disability Rating Scale (DRS) Functional Independence Measure (FIM) Functional Assessment Measure (FAM) Functional Status Examination (FSE) and the TBI-specific and generic quality of life measures used in TBI patients (SF-36 and SF-12, WHOQOL-BREF, SIP, EQ-5D, EBIQ, and QOLIBRI).
Mechanical ventilation in patients with cardiogenic pulmonary edema: a sub-analysis of the LUNG SAFE study
Publisher: Springer Science and Business Media LLC
Date: 25-12-2022
DOI: 10.1186/S40560-022-00648-X
Abstract: Patients with acute respiratory failure caused by cardiogenic pulmonary edema (CPE) may require mechanical ventilation that can cause further lung damage. Our aim was to determine the impact of ventilatory settings on CPE mortality. Patients from the LUNG SAFE cohort, a multicenter prospective cohort study of patients undergoing mechanical ventilation, were studied. Relationships between ventilatory parameters and outcomes (ICU discharge/hospital mortality) were assessed using latent mixture analysis and a marginal structural model. From 4499 patients, 391 meeting CPE criteria (median age 70 [interquartile range 59–78], 40% female) were included. ICU and hospital mortality were 34% and 40%, respectively. ICU survivors were younger (67 [57–77] vs 74 [64–80] years, p 0.001) and had lower driving (12 [8–16] vs 15 [11–17] cmH 2 O, p 0.001), plateau (20 [15–23] vs 22 [19–26] cmH 2 O, p 0.001) and peak (21 [17–27] vs 26 [20–32] cmH 2 O, p 0.001) pressures. Latent mixture analysis of patients receiving invasive mechanical ventilation on ICU day 1 revealed a subgroup ventilated with high pressures with lower probability of being discharged alive from the ICU (hazard ratio [HR] 0.79 [95% confidence interval 0.60–1.05], p = 0.103) and increased hospital mortality (HR 1.65 [1.16–2.36], p = 0.005). In a marginal structural model, driving pressures in the first week (HR 1.12 [1.06–1.18], p 0.001) and tidal volume after day 7 (HR 0.69 [0.52–0.93], p = 0.015) were related to survival. Higher airway pressures in invasively ventilated patients with CPE are related to mortality. These patients may be exposed to an increased risk of ventilator-induced lung injury. Trial registration Clinicaltrials.gov NCT02010073
A randomised controlled trial of an open lung strategy with staircase recruitment, titrated PEEP and targeted low airway pressures in patients with acute respiratory distress syndrome
Publisher: Springer Science and Business Media LLC
Date: 2011
DOI: 10.1186/CC10249
Association of Country Income Level With the Characteristics and Outcomes of Critically Ill Patients Hospitalized With Acute Kidney Injury and COVID-19
Publisher: Elsevier BV
Date: 08-2023
Quality Of Survival In Patients With Acute Respiratory Distress Syndrome Requiring Extracorporeal Membrane Oxygenation For Refractory Hypoxaemia
Publisher: American Thoracic Society
Date: 05-2012
DOI: 10.1164/AJRCCM-CONFERENCE.2012.185.1_MEETINGABSTRACTS.A2287
The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) Study. Rationale and Design
Publisher: American Thoracic Society
Date: 07-2020
The NAPRESSIM trial: the use of low-dose, prophylactic naloxone infusion to prevent respiratory depression with intrathecally administered morphine in elective hepatobiliary surgery: a study protocol and statistical analysis plan for a randomised controlled trial.
Publisher: Springer Science and Business Media LLC
Date: 12-2017
Validation and utility of ARDS subphenotypes identified by machine-learning models using clinical data: an observational, multicohort, retrospective analysis
Publisher: Elsevier BV
Date: 04-2022
Timing of Initiation of Renal-Replacement Therapy in Acute Kidney Injury
Publisher: Massachusetts Medical Society
Date: 16-07-2020
Simvastatin in the Acute Respiratory Distress Syndrome
Publisher: Massachusetts Medical Society
Date: 30-10-2014
Erythropoietin to Reduce Mortality in Traumatic Brain Injury
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2018
Emerging pharmacological therapies for ARDS: COVID-19 and beyond
Publisher: Springer Science and Business Media LLC
Date: 11-07-2020
People in intensive care with COVID-19: demographic and clinical features during the first, second, and third pandemic waves in Australia
Publisher: Wiley
Date: 09-06-2022
DOI: 10.5694/MJA2.51590
Effect of Convalescent Plasma on Organ Support–Free Days in Critically Ill Patients With COVID-19
Publisher: American Medical Association (AMA)
Date: 02-11-2021
In‐Depth Extracorporeal Cardiopulmonary Resuscitation in Adult Out‐of‐Hospital Cardiac Arrest
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-05-2020
Abstract: The use of extracorporeal cardiopulmonary resuscitation (E‐ CPR ) for the treatment of patients with out‐of‐hospital cardiac arrest who do not respond to conventional cardiopulmonary resuscitation CPR) has increased significantly in the past 10 years, in response to case reports and observational studies reporting encouraging results. However, no randomized controlled trials comparing E‐ CPR with conventional CPR have been published to date. The evidence from systematic reviews of the available observational studies is conflicting. The inclusion criteria for published E‐ CPR studies are variable, but most commonly include witnessed arrest, immediate bystander CPR , an initial shockable rhythm, and an estimated time from CPR start to establishment of E‐ CPR (low‐flow time) of minutes. A shorter low‐flow time has been consistently associated with improved survival. In an effort to reduce low‐flow times, commencement of E‐ CPR in the prehospital setting has been reported and is currently under investigation. The provision of an E‐ CPR service, whether hospital based or prehospital, carries considerable cost and technical challenges. Despite increased adoption, many questions remain as to which patients will derive the most benefit from E‐ CPR , when and where to implement E‐ CPR , optimal post‐arrest E‐ CPR care, and whether this complex invasive intervention is cost‐effective. Results of ongoing trials are awaited to determine whether E‐ CPR improves survival when compared with conventional CPR .
Oxygen targets and 6-month outcome after out of hospital cardiac arrest: a pre-planned sub-analysis of the targeted hypothermia versus targeted normothermia after Out-of-Hospital Cardiac Arrest (TTM2)
Publisher: Springer Science and Business Media LLC
Date: 21-10-2022
DOI: 10.1186/S13054-022-04186-8
Abstract: Optimal oxygen targets in patients resuscitated after cardiac arrest are uncertain. The primary aim of this study was to describe the values of partial pressure of oxygen values (PaO 2 ) and the episodes of hypoxemia and hyperoxemia occurring within the first 72 h of mechanical ventilation in out of hospital cardiac arrest (OHCA) patients. The secondary aim was to evaluate the association of PaO 2 with patients’ outcome. Preplanned secondary analysis of the targeted hypothermia versus targeted normothermia after OHCA (TTM2) trial. Arterial blood gases values were collected from randomization every 4 h for the first 32 h, and then, every 8 h until day 3. Hypoxemia was defined as PaO 2 60 mmHg and severe hyperoxemia as PaO 2 300 mmHg. Mortality and poor neurological outcome (defined according to modified Rankin scale) were collected at 6 months. 1418 patients were included in the analysis. The mean age was 64 ± 14 years, and 292 patients (20.6%) were female. 24.9% of patients had at least one episode of hypoxemia, and 7.6% of patients had at least one episode of severe hyperoxemia. Both hypoxemia and hyperoxemia were independently associated with 6-month mortality, but not with poor neurological outcome. The best cutoff point associated with 6-month mortality for hypoxemia was 69 mmHg (Risk Ratio, RR = 1.009, 95% CI 0.93–1.09), and for hyperoxemia was 195 mmHg (RR = 1.006, 95% CI 0.95–1.06). The time exposure, i.e., the area under the curve (PaO 2 -AUC), for hyperoxemia was significantly associated with mortality ( p = 0.003). In OHCA patients, both hypoxemia and hyperoxemia are associated with 6-months mortality, with an effect mediated by the timing exposure to high values of oxygen. Precise titration of oxygen levels should be considered in this group of patients. Trial registration : clinicaltrials.gov NCT02908308 , Registered September 20, 2016.
Inflammation, immunity and allergy
Publisher: Elsevier BV
Date: 07-2015
Development of the Consumer Involvement & Engagement Toolkit: a digital resource to build capacity for undertaking patient-centred clinical trials in Australia.
Publisher: The Sax Institute
Date: 2022
Abstract: This manuscript describes the novel approach to developing a toolkit to support meaningful consumer involvement in clinical trials in Australia to help guide others in considering the development of similar resources.The toolkit aims to support greater consumer involvement in shaping how clinical research is prioritised, designed and conducted. Type of program or service: A working group of researchers, research organisations and consumers was established to co-develop the Consumer Involvement and Engagement Toolkit (the 'Toolkit'), a digital resource to guide researchers and organisations regarding consumer involvement in clinical trials. A literature review and international scan of best practice revealed numerous resources outlining best practice for consumer involvement in clinical research and clear evidence of its impact and value. Through a novel content-sharing process, we were able to utilise these resources to develop a comprehensive Toolkit for researchers and research organisations that provides world-class guidance. There is a growing movement to ensure consumer involvement in healthcare, including in clinical research. We discovered its proponents were willing to share their tools and resources to promote international consumer involvement. Although these international tools and resources needed adaptation to suit the Australian research environment, this was achievable with far less effort than developing them from scratch.
Targeted therapeutic mild hypercapnia after cardiac arrest.
Publisher: Springer Science and Business Media LLC
Date: 31-07-2017
Dynamic lactate indices as predictors of outcome in critically ill patients
Publisher: Springer Science and Business Media LLC
Date: 2011
DOI: 10.1186/CC10497
Inflammation, immunity and allergy
Publisher: Elsevier BV
Date: 08-2021
Nitrogen doped carbon aerogel composites with TiO2 and ZnO prepared by atomic layer deposition
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/C9TC05953A
Abstract: A nitrogen doped carbon aerogel was used as a substrate for the atomic layer deposition of TiO 2 and ZnO layers in various thicknesses.
Goal-Directed Resuscitation for Patients with Early Septic Shock
Publisher: Massachusetts Medical Society
Date: 16-10-2014
Future perspectives for the treatment of traumatic brain injury patients: decompressive craniectomy, hypothermia and erythropoietin
Publisher: Cambridge University Press
Date: 19-07-2012
Cost-Effectiveness of Erythropoietin in Traumatic Brain Injury: A Multinational Trial-Based Economic Analysis
Publisher: Mary Ann Liebert Inc
Date: 09-2019
Abstract: 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
Use of an extended KDIGO definition to diagnose acute kidney injury in patients with COVID-19: A multinational study using the ISARIC–WHO clinical characterisation protocol
Publisher: Public Library of Science (PLoS)
Date: 20-04-2022
DOI: 10.1371/JOURNAL.PMED.1003969
Abstract: Acute kidney injury (AKI) is one of the most common and significant problems in patients with Coronavirus Disease 2019 (COVID-19). However, little is known about the incidence and impact of AKI occurring in the community or early in the hospital admission. The traditional Kidney Disease Improving Global Outcomes (KDIGO) definition can fail to identify patients for whom hospitalisation coincides with recovery of AKI as manifested by a decrease in serum creatinine (sCr). We hypothesised that an extended KDIGO (eKDIGO) definition, adapted from the International Society of Nephrology (ISN) 0by25 studies, would identify more cases of AKI in patients with COVID-19 and that these may correspond to community-acquired AKI (CA-AKI) with similarly poor outcomes as previously reported in this population. All in iduals recruited using the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC)–World Health Organization (WHO) Clinical Characterisation Protocol (CCP) and admitted to 1,609 hospitals in 54 countries with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection from February 15, 2020 to February 1, 2021 were included in the study. Data were collected and analysed for the duration of a patient’s admission. Incidence, staging, and timing of AKI were evaluated using a traditional and eKDIGO definition, which incorporated a commensurate decrease in sCr. Patients within eKDIGO diagnosed with AKI by a decrease in sCr were labelled as deKDIGO. Clinical characteristics and outcomes—intensive care unit (ICU) admission, invasive mechanical ventilation, and in-hospital death—were compared for all 3 groups of patients. The relationship between eKDIGO AKI and in-hospital death was assessed using survival curves and logistic regression, adjusting for disease severity and AKI susceptibility. A total of 75,670 patients were included in the final analysis cohort. Median length of admission was 12 days (interquartile range [IQR] 7, 20). There were twice as many patients with AKI identified by eKDIGO than KDIGO (31.7% versus 16.8%). Those in the eKDIGO group had a greater proportion of stage 1 AKI (58% versus 36% in KDIGO patients). Peak AKI occurred early in the admission more frequently among eKDIGO than KDIGO patients. Compared to those without AKI, patients in the eKDIGO group had worse renal function on admission, more in-hospital complications, higher rates of ICU admission (54% versus 23%) invasive ventilation (45% versus 15%), and increased mortality (38% versus 19%). Patients in the eKDIGO group had a higher risk of in-hospital death than those without AKI (adjusted odds ratio: 1.78, 95% confidence interval: 1.71 to 1.80, p -value 0.001). Mortality and rate of ICU admission were lower among deKDIGO than KDIGO patients (25% versus 50% death and 35% versus 70% ICU admission) but significantly higher when compared to patients with no AKI (25% versus 19% death and 35% versus 23% ICU admission) (all p -values × 10 −5 ). Limitations include ad hoc sCr s ling, exclusion of patients with less than two sCr measurements, and limited availability of sCr measurements prior to initiation of acute dialysis. An extended KDIGO definition of AKI resulted in a significantly higher detection rate in this population. These additional cases of AKI occurred early in the hospital admission and were associated with worse outcomes compared to patients without AKI.
Acute pancreatitis: an intensive care perspective
Publisher: Elsevier BV
Date: 04-2015
Characteristics and outcomes of an international cohort of 600 000 hospitalized patients with COVID-19
Publisher: Oxford University Press (OUP)
Date: 28-02-2023
DOI: 10.1093/IJE/DYAD012
Abstract: We describe demographic features, treatments and clinical outcomes in the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) COVID-19 cohort, one of the world's largest international, standardized data sets concerning hospitalized patients. The data set analysed includes COVID-19 patients hospitalized between January 2020 and January 2022 in 52 countries. We investigated how symptoms on admission, co-morbidities, risk factors and treatments varied by age, sex and other characteristics. We used Cox regression models to investigate associations between demographics, symptoms, co-morbidities and other factors with risk of death, admission to an intensive care unit (ICU) and invasive mechanical ventilation (IMV). Data were available for 689 572 patients with laboratory-confirmed (91.1%) or clinically diagnosed (8.9%) SARS-CoV-2 infection from 52 countries. Age [adjusted hazard ratio per 10 years 1.49 (95% CI 1.48, 1.49)] and male sex [1.23 (1.21, 1.24)] were associated with a higher risk of death. Rates of admission to an ICU and use of IMV increased with age up to age 60 years then dropped. Symptoms, co-morbidities and treatments varied by age and had varied associations with clinical outcomes. The case-fatality ratio varied by country partly due to differences in the clinical characteristics of recruited patients and was on average 21.5%. Age was the strongest determinant of risk of death, with a ∼30-fold difference between the oldest and youngest groups each of the co-morbidities included was associated with up to an almost 2-fold increase in risk. Smoking and obesity were also associated with a higher risk of death. The size of our international database and the standardized data collection method make this study a comprehensive international description of COVID-19 clinical features. Our findings may inform strategies that involve prioritization of patients hospitalized with COVID-19 who have a higher risk of death.
Acute kidney injury and the critically ill
Publisher: Elsevier BV
Date: 04-2015
Related Organisations
College Of Intensive Care Medicine Of Australia And New Zealand
Location: Australia
Irish Critical Care-Clinical Trials Group (ICC-CTG)
Location: Ireland
University Of Oxford
Location: United Kingdom of Great Britain and Northern Ireland
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