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The Fragility and Reliability of Conclusions of Anesthesia and Critical Care Randomized Trials With Statistically Significant Findings

A Systematic Review*

Grolleau, François, MD, MPH1,2; Collins, Gary S., PhD3; Smarandache, Andrei, BA, BSc4; Pirracchio, Romain, MD, PhD5–7; Gakuba, Clément, MD, PhD1,8; Boutron, Isabelle, MD, PhD9–12; Busse, Jason W., DC, PhD13; Devereaux, P. J., MD, PhD14; Le Manach, Yannick, MD, PhD2

doi: 10.1097/CCM.0000000000003527
Review Article

Objectives: The Fragility Index, which represents the number of patients responsible for a statistically significant finding, has been suggested as an aid for interpreting the robustness of results from clinical trials. A small Fragility Index indicates that the statistical significance of a trial depends on only a few events. Our objectives were to calculate the Fragility Index of statistically significant results from randomized controlled trials of anesthesia and critical care interventions and to determine the frequency of distorted presentation of results or “spin”.

Data Sources: We systematically searched MEDLINE from January 01, 2007, to February 22, 2017, to identify randomized controlled trials exploring the effect of critical care medicine or anesthesia interventions.

Study Selection: Studies were included if they randomized patients 1:1 into two parallel arms and reported at least one statistically significant (p < 0.05) binary outcome (primary or secondary).

Data Extraction: Two reviewers independently assessed eligibility and extracted data. The Fragility Index was determined for the chosen outcome. We assessed the level of spin in negative trials and the presence of recommendations for clinical practice in positive trials.

Data Synthesis: We identified 166 eligible randomized controlled trials with a median sample size of 207 patients (interquartile range, 109–497). The median Fragility Index was 3 (interquartile range, 1–7), which means that adding three events to one of the trials treatment arms eliminated its statistical significance. High spin was identified in 42% (n = 30) of negative randomized controlled trials, whereas 21% (n = 20) of positive randomized controlled trials provided recommendations. Lower levels of spin and recommendations were associated with publication in journals with high impact factors (p < 0.001 for both).

Conclusions: Statistically significant results in anesthesia and critical care randomized controlled trials are often fragile, and study conclusions are frequently affected by spin. Routine calculation of the Fragility Index in medical literature may allow for better understanding of trials and therefore enhance the quality of reporting.

1Department of Anesthesiology and Critical Care Medicine, CHU Caen Côte de Nacre, Caen, France.

2Departments of Anesthesia & Clinical Epidemiology and Biostatistics, Michael DeGroote School of Medicine, Faculty of Health Sciences, McMaster University and the Perioperative Research Group, Population Health Research Institute, Hamilton, ON, Canada.

3Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, United Kingdom.

4Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.

5Department of Anesthesiology and Critical Care Medicine, Hôpital Européen Georges Pompidou, APHP, Université Paris Descartes, Sorbonne Paris Cite, Paris, France.

6Department of Anesthesiology and Perioperative Care, University of California San Francisco, San Francisco General Hospital and Trauma Center, San Francisco, CA.

7Department of Biostatistics and Medical Informatics, INSERM U-1153, team ECSTRA, Université Paris Diderot, Sorbonne Paris Cite, Paris, France.

8Normandie Univ, UNICAEN, INSERM, INSERM UMR-S U1237, ‘Physiopathology and Imaging of Neurological Disorders’ PhIND, Caen, France.

9Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

10Centre de Recherche Epidémiologie et Statistique, INSERM U1153, Paris, France.

11Cochrane France, Paris, France.

12Centre d’Épidémiologie Clinique, Hôpital Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France.

13Departments of Anesthesia and Health Research Methods, Evidence & Impact, and the Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, ON, Canada.

14Departments of Medicine & Health Evidence and Impact, Michael DeGroote School of Medicine, Faculty of Health Sciences, McMaster University and the Perioperative Research Group, Population Health Research Institute, Hamilton, ON, Canada.

*See also p. 486.

Drs. Grolleau and Le Manach had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis and contributed to study concept and design and analysis and interpretation of data. Drs. Grolleau and Smarandache contributed to acquisition of data. Dr. Grolleau contributed in drafting of the article. Drs. Grolleau, Collins, Pirracchio, Gakuba, Boutron, Busse, Devereaux, and Le Manach contributed in critical revision of the article for important intellectual content.

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Dr. Collins was supported by the National Institute for Health Research Biomedical Research Centre, Oxford, United Kingdom. Dr. Devereaux’s institution received funding from Abbott Diagnostics, Boehringer-Ingelheim, Covidien, Octopharma, Philips Healthcare, Roche Diagnostics, and Stryker. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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