Multicenter, randomized, controlled trials evaluating mortality in intensive care: Doomed to fail?

Ospina-Tascón, Gustavo Adolfo; Büchele, Gustavo Luiz; Vincent, Jean‐Louis

doi:10.1097/ccm.0b013e318168ea3e

Cited by 157 publications

(98 citation statements)

References 103 publications

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“…Briefly, a group of physicians, epidemiologists, and statisticians, guided by the 2007 CONSORT (20) (Consolidated Standards of Reporting Trials) statement, Jadad scale (21,22), and prior work and commentaries on the topic (2-5, 10, 14-18, 23), identified RCT elements to be abstracted. We began our search for published RCTs in 2007, as this approximated the end of prior review periods (2,3), and continued our search through May 2013. We examined only RCTs of diagnostic, therapeutic, or process and systems interventions among adult patients conducted in an ICU published in 16 prominent general or critical care journals (see Tables E1 and E2 in the online supplement).…”

Section: Methodsmentioning

confidence: 99%

“…Unfortunately, most published RCTs of critical care interventions that aim to reduce mortality have produced negative results (2)(3)(4)(5), and even these reports may be overly optimistic because negative trials are less likely to be published and identified. Although several RCTs have revolutionized critical care practice (6)(7)(8), the results of critical care trials on the whole have been so disappointing that some leaders in the field have suggested a renewed focus on nonexperimental study designs (9,10).…”

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confidence: 99%

“…Furthermore, there are many reasons that trials may not demonstrate a treatment effect, including ineffective interventions, difficulty recruiting adequate sample sizes, postrandomization patient attrition, heterogeneous patient populations or treatment-effect heterogeneity, use of inappropriate outcomes, unreasonable assumptions (e.g., predicted effect sizes) used in power calculations, and/or smaller than appreciated attributable morbidity and mortality fractions (2)(3)(4)(5)(14)(15)(16)(17)(18). Understanding an evidence base requires the ability to distinguish among these reasons so as to differentiate trials that are truly negative from those that may be falsely negative.…”

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confidence: 99%

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Outcomes and Statistical Power in Adult Critical Care Randomized Trials

Harhay

Wagner²,

Ratcliffe³

et al. 2014

Am J Respir Crit Care Med

149

136

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Rationale: Intensive care unit (ICU)-based randomized clinical trials (RCTs) among adult critically ill patients commonly fail to detect treatment benefits.Objectives: Appraise the rates of success, outcomes used, statistical power, and design characteristics of published trials.Methods: One hundred forty-six ICU-based RCTs of diagnostic, therapeutic, or process/systems interventions published from January 2007 to May 2013 in 16 high-impact general or critical care journals were studied.Measurement and Main Results: Of 146 RCTs, 54 (37%) were positive (i.e., the a priori hypothesis was found to be statistically significant). The most common primary outcomes were mortality (n = 40 trials), infection-related outcomes (n = 33), and ventilationrelated outcomes (n = 30), with positive results found in 10, 58, and 43%, respectively. Statistical power was discussed in 135 RCTs (92%); 92 cited a rationale for their power parameters. Twenty trials failed to achieve at least 95% of their reported target sample size, including 11 that were stopped early due to insufficient accrual/ logistical issues. Of 34 superiority RCTs comparing mortality between treatment arms, 13 (38%) accrued a sample size large enough to find an absolute mortality reduction of 10% or less. In 22 of these trials the observed control-arm mortality rate differed from the predicted rate by at least 7.5%.Conclusions: ICU-based RCTs are commonly negative and powered to identify what appear to be unrealistic treatment effects, particularly when using mortality as the primary outcome. Additional concerns include a lack of standardized methods for assessing common outcomes, unclear justifications for statistical power calculations, insufficient patient accrual, and incorrect predictions of baseline event rates.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Outcomes and Statistical Power in Adult Critical Care Randomized Trials

Harhay

Wagner²,

Ratcliffe³

et al. 2014

Am J Respir Crit Care Med

149

136

View full text Add to dashboard Cite

show abstract

“…34 The complexity of critical illness and ICU interventions renders them extremely difficult to study in a reasonably controlled fashion, and mechanistic interventions in these patients seem unlikely to produce a measurable impact. For ALI and other hospital-acquired conditions, enrollment of patients in clinical trials after the onset of organ failures and critical illness syndromes limits available interventions to state-of-the-art supportive care.…”

Section: Limitations Of Interventional Trials In Critical Carementioning

confidence: 99%

Acute Lung Injury: Prevention May Be the Best Medicine

et al. 2011

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Acute lung injury affects a subset of hospitalized patients but is not universal. This syndrome can substantially delay ventilator liberation, prolong intensive care unit (ICU) stay, and increase mortality. As with many critical illness syndromes, the available treatment options are limited in number and impact. Once a patient develops lung injury, the best known strategy is supportive care. Observational studies have identified potential risk factors and have suggested that the use and timing of certain critical care interventions may influence the likelihood of developing lung injury. These findings suggest that a well designed screening tool and the systematic application of best practices in critical care may limit the risk of lung injury. An effective prediction score may also facilitate enrollment in pharmacopreventive trials. Development of such tools is accelerated by multicenter collaboration.

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“…Unfortunately, more than 30 years of extensive clinical research resulted in mainly non-significant results. According to a recent review of 72 prospective randomised trials with mortality being the primary endpoint, 55 ended up with non-significant results, also including several studies on adjuvant therapies [4,5]. Promising positive results of single-centre studies were often contradicted later by large multicentre trials [5].…”

Section: Introductionmentioning

confidence: 99%

Can procalcitonin levels indicate the need for adjunctive therapies in sepsis?

Becze¹,

Molnár

Fazakas

2015

International Journal of Antimicrobial Agents

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a b s t r a c tAfter decades of extensive experimental and clinical research, septic shock and the related multiple organ dysfunction still remain the leading cause of mortality in intensive care units (ICUs) worldwide. Defining sepsis is a difficult task, but what is even more challenging is differentiating infection-induced from non-infection-induced systemic inflammatory response-related multiple organ dysfunction. As conventional signs of infection are often unreliable in intensive care, biomarkers are used, of which one of the most frequently investigated is procalcitonin. Early stabilisation of vital functions via adequate supportive therapy and antibiotic treatment has resulted in substantial improvements in outcome over the last decades. However, there are certain patients who may need extra help, hence modulation of the immune system and the host's response may also be an important therapeutic approach in these situations. Polyclonal intravenous immunoglobulins have been used in critical care for decades. A relatively new potential approach could be attenuation of the overwhelming cytokine storm by specific cytokine adsorbents. Both interventions have been applied in daily practice on a large scale, with firm pathophysiological rationale but weak evidence supported by clinical trials. The purpose of this review is to give an overview on the pathophysiology of sepsis as well as the role and interpretation of biomarkers and their potential use in assisting adjunctive therapies in sepsis in the future.

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Multicenter, randomized, controlled trials evaluating mortality in intensive care: Doomed to fail?

Cited by 157 publications

References 103 publications

Outcomes and Statistical Power in Adult Critical Care Randomized Trials

Outcomes and Statistical Power in Adult Critical Care Randomized Trials

Acute Lung Injury: Prevention May Be the Best Medicine

Can procalcitonin levels indicate the need for adjunctive therapies in sepsis?

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