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Search Results: 1 - 10 of 112565 matches for " Maureen O Meade "
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Pro/con clinical debate: It is acceptable to stop large multicentre randomized controlled trials at interim analysis for futility
David A Schoenfeld, Maureen O Meade
Critical Care , 2004, DOI: 10.1186/cc3013
Abstract: You are a clinician in an intensive care unit and you have recently heard that some very large trials have been stopped at interim analysis for futility. Although you have not yet seen the results, this cessation concerns you because you were anxiously awaiting the results of these trials since you felt they were very relevant clinical questions that would impact on your treatment decisions. Your concern is based on the fact that you are uncertain whether clinical trials should ever be stopped for futility.David A SchoenfeldA futility-stopping rule for a clinical trial is a plan in which the results of a clinical trial are periodically reviewed and the clinical trial is stopped if the treatment difference is smaller than some predetermined value. The idea is to stop trials that would not have shown statistical significance had they gone on to completion. A futility-stopping rule can drastically reduce the time and money spent on clinical trials, and can more rapidly find effective treatments. In the present paper I describe the available methods used for futility stopping. I then quantify the advantages of futility stopping in a drug development programme. Finally, I will discuss some of the problems of futility stopping and how clinicians should interpret trials that stop early for futility.There are two methods of futility stopping. The method that was used in early trials was based on the principal of stochastic curtailment [1]. A review committee would analyse the results of a trial and calculate the probability that the trial will give a significant result if it is completed. If this probability was small, say less than 25%, then the trial would be stopped. This probability calculation depends on an assumption about the actual success rates of the treatments. The safest assumption is to use the original difference that was used to calculate the sample size.The second method is to use asymmetric stopping boundaries [2,3]. The futility boundary can be based on ho
Drotrecogin alfa (activated) in patients with severe sepsis and a high risk of death
Jan O Friedrich, Neill KJ Adhikari, Maureen O Meade
Critical Care , 2006, DOI: 10.1186/cc5117
Abstract: We also support the pooling of individual patient data from these trials to generate hypotheses regarding appropriate patient selection for drotrecogin alfa (activated) that could be tested in subsequent trials [5]. Furthermore, we encourage public release of these data for the purposes of a meta-analysis of individual patient data to be undertaken by an independent group, using appropriate statistical methods that incorporate random effects, and that is subject to peer review.The authors declare that they have no competing interests.
Drotrecogin alfa (activated): down and not out, but not really in either
Jan O Friedrich, Neill KJ Adhikari, Maureen O Meade
Critical Care , 2006, DOI: 10.1186/cc5022
Abstract: Agarwal and Nath's letter highlights the surprising degree of statistical heterogeneity that remains between the Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) trial [3] and the Recombinant Human Activated Protein C Worldwide Evaluation of Severe Sepsis (PROWESS) trial [4] results despite minimal methodologic differences between these trials and further minimization of clinical heterogeneity by selecting a more uniform subgroup of patients with severe sepsis and a high risk of death. In particular, for the subgroup with an APACHE II score of 25 or more, I2 (the percentage of total variation in results across studies that is due to heterogeneity rather than chance [5]) is very high (84%). Given this degree of heterogeneity, we feel that one should account for, rather than ignore, its effects when pooling results.The APACHE II subgroup effect in PROWESS was one of about 80 prospectively defined subgroup comparisons [6].Using other definitions of high risk, the difference in treatment effect between high-risk and low-risk subgroups in PROWESS was not statistically significant (for example, patients with multiple organ failure) and in some cases not even directionally consistent (for example, patients requiring mechanical ventilation or vasopressor support) [7]. If the APACHE II high-risk and low-risk subgroup effect in PROWESS is due to chance, then the best estimate of the effect of DrotAA for any patient is the overall pooled result incorporating all patients. Interestingly, although the degree of between-study heterogeneity is significant when the overall data from all four trials presented in Figure 1 [2] are pooled (I2 = 59%), it disappears if PROWESS is excluded (I2 = 0%).Is there a role for DrotAA in severe sepsis? The inconsistent trial results and increased risk of serious bleeding highlight the importance of identifying patients for whom the benefits of DrotAA outweigh the risks. The high variability and very low proport
Drotrecogin alfa (activated): does current evidence support treatment for any patients with severe sepsis?
Jan O Friedrich, Neill KJ Adhikari, Maureen O Meade
Critical Care , 2006, DOI: 10.1186/cc4947
Abstract: Severe sepsis is a condition with important public health ramifications because it is common and has a high case-fatality rate [1]. Drotrecogin alfa (activated) (DrotAA), more commonly known as recombinant human activated protein C, is the first specific therapy for sepsis to show an important survival benefit. On the basis of the favourable results of the Recombinant Human Activated Protein C Worldwide Evaluation of Severe Sepsis (PROWESS) trial [2], DrotAA was approved for patients with severe sepsis and at high risk of death. However, regulatory approval for DrotAA was controversial [3,4], and the recently published Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) trial [5] has heightened this controversy. The results of this study demonstrated no evidence of benefit for DrotAA in patients with severe sepsis and at low risk of death, and unexpectedly raised concerns regarding its efficacy among patients at high risk of death [6]. In this commentary we argue that the cumulative evidence for a survival benefit in DrotAA-treated patients with severe sepsis and at high risk of death is weaker than originally believed. We also suggest methodological explanations for discrepant results of these two rigorous multicentre trials. These findings have important implications not only for clinicians treating patients with severe sepsis but also for the interpretation of other single, seemingly pivotal, randomised controlled trials.Figure 1 shows the effect of DrotAA therapy on 28-day survival, as observed in all three published trials (a phase II trial [7], PROWESS [2], and ADDRESS [5]) and in an additional unpublished trial in children with severe sepsis [8]. (A recent systematic review and health technology assessment of DrotAA [9] found no additional trials.) PROWESS suggested a survival benefit for all severely septic patients who received DrotAA. This survival benefit seemed to be concentrated in patients at high risk of death, define
Wean Earlier and Automatically with New technology (the WEAN study): a protocol of a multicentre, pilot randomized controlled trial
Karen EA Burns, Maureen O Meade, Martin R Lessard, Sean P Keenan, Francois Lellouche
Trials , 2009, DOI: 10.1186/1745-6215-10-81
Abstract: A pilot weaning randomized controlled trial (RCT) is underway in the ICUs of 8 Canadian hospitals. We will randomize 90 critically ill adults requiring invasive ventilation for at least 24 hours and identified at an early stage of the weaning process to either Automated Weaning (SmartCare?) or Protocolized Weaning. The results of a National Weaning Survey informed the design of the Protocolized Weaning arm. Both weaning protocols are operationalized in Pressure Support mode, include opportunities for Spontaneous Breathing Trials, and share a common sedation protocol, oxygen titration parameters, and extubation and reintubation criteria. The primary outcome of the WEAN study is to evaluate compliance with the proposed weaning and sedation protocols. A key secondary outcome of the pilot RCT is to evaluate clinician acceptance of the weaning and sedation protocols. Prior to initiating the WEAN Study, we conducted a run-in phase, involving two patients per centre (randomizing the first participant to either weaning strategy and assigning the second patient to the alternate strategy) to ensure that participating centres could implement the weaning and sedation protocols and complete the detailed case report forms.Mechanical ventilation studies are difficult to implement; requiring protocols to be operationalized continuously and entailing detailed daily data collection. As the first multicentre weaning RCT in Canada, the WEAN Study seeks to determine the feasibility of conducting a large scale future weaning trial and to establish a collaborative network of ICU clinicians dedicated to advancing the science of weaning.ISRCTN43760151Weaning is the process during which mechanical ventilation is gradually or abruptly withdrawn. In addition, it is the time during which work of breathing is transferred from the ventilator back to the patient until fully autonomous breathing is resumed. Weaning accounts for approximately 40% of the total time spent on mechanical ventilation [1,
Clinical review: Intra-abdominal hypertension: does it influence the physiology of prone ventilation?
Andrew W Kirkpatrick, Paolo Pelosi, Jan J De Waele, Manu LNG Malbrain, Chad G Ball, Maureen O Meade, Henry T Stelfox, Kevin B Laupland
Critical Care , 2010, DOI: 10.1186/cc9099
Abstract: Patients with acute respiratory failure frequently require mechanical ventilation (MV). Unfortunately MV can further damage the lungs and worsen respiratory failure through a variety of mechanisms [1,2]. Prone ventilation (PV) by means of prone positioning (PP) has been proposed as a strategy that may rescue the sickest patient from refractory hypoxemia [1,3-6], although identifying a survival benefit has proven difficult [4,7-12]. PV may also ameliorate the underlying physical strain and generation of inflammatory mediators that compound ventilator-induced lung injury [13-16]. Further, as a technologically simple intervention, PV could conceivably benefit patients in countries where more expensive respiratory technologies are unavailable. There is therefore reason to further explore specific mechanisms and patient groups who might benefit [5,7,17-19].One of the most frequent causes of acute respiratory failure requiring MV is acute respiratory distress syndrome (ARDS), reflecting the more severe spectrum of acute lung injury (ALI) [20,21]. The initial consensus definitions recognized two inciting pathways for ALI/ARDS: pulmonary and extrapulmonary - reflecting either direct lung injury or indirect injuries to the pulmonary endothelium as mediated by the systemic inflammatory response [20,21]. In particular, the influence of the abdomen appears to differ between pulmonary and extrapulmonary causes, differently affecting chest wall mechanics [21-28] - with higher intra-abdominal pressure (IAP) in extrapulmonary ALI/ARDS often related to greater and more recruitable lung collapse [24,26].The World Society of the Abdominal Compartment Syndrome defines intra-abdominal hypertension (IAH) as sustained IAP ≥12 mmHg, and defines the abdominal compartment syndrome (ACS) as IAP >20 mmHg with new organ failure [29]. IAH is a condition that can complicate virtually any critical condition, greatly influences the respiratory system and associates with adverse clinical outcomes [3
The attributable mortality and length of intensive care unit stay of clinically important gastrointestinal bleeding in critically ill patients
Deborah J Cook, Lauren E Griffith, Stephen D Walter, Gordon H Guyatt, Maureen O Meade, Daren K Heyland, Ann Kirby, Michael Tryba, for the Canadian Critical Care Trials Group
Critical Care , 2001, DOI: 10.1186/cc1071
Abstract: Three strategies were used to estimate the mortality attributable to bleeding in two multicentre databases. The first method matched patients who bled with those who did not (matched cohort), using duration of ICU stay prior to the bleed, each of six domains of the Multiple Organ Dysfunction Score (MODS) measured 3 days prior to the bleed, APACHE II score, age, admitting diagnosis, and duration of mechanical ventilation. The second approach employed Cox proportional hazards regression to match bleeding and non-bleeding patients (model-based matched cohort). The third method, instead of matching, derived estimates based on regression modelling using the entire population (regression method). Three parallel analyses were conducted for the length of ICU stay attributable to clinically important bleeding.Sixteen Canadian university-affiliated ICUs.A total of 1666 critically ill patients receiving mechanical ventilation for at least 48 hours.We prospectively collected data on patient demographics, APACHE II score, admitting diagnosis, daily MODS, clinically important bleeding, length of ICU stay, and mortality. Independent adjudicators determined the occurrence of clinically important gastrointestinal bleeding, defined as overt bleeding in association with haemodynamic compromise or blood transfusion.Of 1666 patients, 59 developed clinically important gastrointestinal bleeding. The mean APACHE II score was 22.9 ± 8.6 among bleeding patients and 23.3 ± 7.7 among non-bleeding patients. The risk of death was increased in patients with bleeding using all three analytic approaches (matched cohort method: relative risk [RR]= 2.9, 95% confidence interval (CI)= 1.6–5.5; model-based matched cohort method: RR = 1.8, 95% CI = 1.1–2.9; and the regression method: RR = 4.1, 95% CI = 2.6–6.5). However, this was not significant for the adjusted regression method (RR = 1.0, 95% CI = 0.6–1.7). The median length of ICU stay attributable to clinically important bleeding for these three meth
Pressure and Volume Limited Ventilation for the Ventilatory Management of Patients with Acute Lung Injury: A Systematic Review and Meta-Analysis
Karen E. A. Burns,Neill K. J. Adhikari,Arthur S. Slutsky,Gordon H. Guyatt,Jesus Villar,Haibo Zhang,Qi Zhou,Deborah J. Cook,Thomas E. Stewart,Maureen O. Meade
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0014623
Abstract: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life threatening clinical conditions seen in critically ill patients with diverse underlying illnesses. Lung injury may be perpetuated by ventilation strategies that do not limit lung volumes and airway pressures. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing pressure and volume-limited (PVL) ventilation strategies with more traditional mechanical ventilation in adults with ALI and ARDS.
Auto-Retratos da Classe Média: Hierarquias de "Cultura" e Consumo em S?o Paulo
O?Dougherty, Maureen;
Dados , 1998, DOI: 10.1590/S0011-52581998000200005
Abstract: based on 17 months of field research in s?o paulo (1993-94), this paper examines how middle-class adults in 42 surveyed households verbalized their class identity during the inflation crisis. it concludes that consumption (goods and practices) are foundational to their class definitions, both in relation to other major classes and to other middle-class sectors.
Auto-Retratos da Classe Média: Hierarquias de "Cultura" e Consumo em S o Paulo
O?Dougherty Maureen
Dados , 1998,
Abstract: Based on 17 months of field research in S o Paulo (1993-94), this paper examines how middle-class adults in 42 surveyed households verbalized their class identity during the inflation crisis. It concludes that consumption (goods and practices) are foundational to their class definitions, both in relation to other major classes and to other middle-class sectors.
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