Authors’ response to commentaries on rosuvastatin for delirium and cognitive impairment in sepsis-associated acute respiratory distress syndrome
Correspondence

Authors’ response to commentaries on rosuvastatin for delirium and cognitive impairment in sepsis-associated acute respiratory distress syndrome

Victor D. Dinglas1,2, Elizabeth Colantuoni1,3, E. Wesley Ely4,5, Catherine L. Hough6, Peter E. Morris7, Pedro A. Mendez-Tellez1,8, Amy W. Wozniak1,3, Ramona O. Hopkins9,10, Dale M. Needham1,2,11

1Outcomes after Critical Illness and Surgery (OACIS) Group, Johns Hopkins University, Baltimore, Maryland, USA;2Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA;3Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA;4Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA;5Geriatric Research, Education and Clinical Center Service, Department of Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, TN, USA;6Division of Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, Seattle, WA, USA;7Division of Pulmonary, Critical Care & Sleep Medicine, University of Kentucky, Lexington, KY, USA;8Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA;9Division of Pulmonary and Critical Care, Department of Medicine, Intermountain Medical Center, Murray, Utah, USA;10Psychology Department and Neuroscience Center, Brigham Young University, Provo, Utah;11Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Correspondence to: Victor D. Dinglas, MPH. Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, 1830 E. Monument St, 5th Floor, Baltimore, MD 21287, USA. Email: victor.dinglas@jhmi.edu.

Submitted Sep 23, 2016. Accepted for publication Oct 12, 2016.

doi: 10.21037/jtd.2016.11.53

We are encouraged by the interest (1,2) in our publication that evaluated the effect of rosuvastatin vs. placebo on delirium in the intensive care unit (ICU) and subsequent cognitive impairment (3). We appreciate the critique of our publication by Pourafkari et al. (2). Pourafkari et al. commented about our study being underpowered for secondary analyses of cognitive impairment at 6- and 12-month follow-up. We reported a 2% absolute reduction in the proportion of patients with cognitive impairment for rosuvastatin vs. placebo at 6-month follow-up (36% vs. 38%). This 2% reduction was not statistically significant (treatment effect 0.93; 95% CI: 0.39–2.22; P=0.87), which may be due to the study being underpowered (i.e., too few patients to detect such a small effect). However, the subsequent comparison of cognitive impairment at 12-month (30% vs. 28% for rosuvastatin vs. placebo, respectively) and the vast majority of the individual standardized tests used to evaluate cognitive impairment favored placebo relative to rosuvastatin. Hence, to be convinced that the lack of statistical significance at 6 months was attributable to the trial’s sample size, we would have expected non-significant results consistently favoring rosuvastatin, which was not the case.

Another comment by Pourafkari et al focused on our study not adjusting for unmeasured confounders. We have less concern for unmeasured confounders affecting our analysis of delirium (the primary outcome) due to the randomized treatment assignment utilized in the trial. Additionally, descriptions of risk factors for delirium were similar between treatment groups (see the first appendix table of our original paper). Lastly, as part of our a priori analyses plan, we used multiple imputations for missing delirium data, and demonstrated consistent results with the primary analysis, suggesting less concern for any differential missingness of data between treatment groups after randomization.

Pourafkari et al. also indicated concern for elimination of “higher risk” patients in our cohort. Mechanically ventilated patients are at high risk for delirium (4), and indeed, a large proportion of patients (72%) in our cohort had delirium. Furthermore, as part of our post-hoc analyses (3), we adjusted for known baseline risk factors for delirium and there was no qualitative change in our results.

Finally, we want to clarify a comment made by Pourafkari et al. regarding exclusion of patients who are comatose (Richmond-Agitation Sedation Scores of –4 or –5). In our methods section, we report that the individual ICU days during which patients were comatose were excluded from analysis since delirium status cannot be evaluated when a patient is comatose (3). Only these specific ICU days, rather than all patients ever having coma, were excluded. We have further expanded on this issue in our recent commentary regarding use of joint modelling statistical methods for evaluating delirium in the ICU (5). Our recent commentary highlights that this statistical method has the advantage of only evaluating for delirium on days when patients are at risk for delirium (i.e., not on days with coma) (5).

In addition to delirium and cognitive outcomes, our study evaluated rosuvastatin’s effects on an extensive set of physical outcomes (including both patient-reported outcomes and performance-based measures) and mental health outcomes, finding no significant effect of rosuvastatin vs. placebo (6). Lange and Maier (1) commented that a strength of our study is the rigorous assessment of outcomes using standardized neuropsychological instruments, which have been validated in ICU populations. As new studies are designed to evaluate statins for delirium in the ICU, it is important to develop a core outcomes set (COS) to facilitate comparison of studies and synthesis of findings (7), as Lange and Maier highlighted in their commentary (1). A proposal for developing such a COS is currently registered with the Core Outcome Measures in Effectiveness Trials (COMET) website (8). Moreover, we have an ongoing National Heart, Lung, and Blood Institute-funded project (grant #R24HL111895, www.improveLTO.com) that includes one specific aim focused on creating a COS for post-discharge outcomes in studies of acute respiratory failure survivors (9,10). The methodology used in this project (as outlined in the appendix of our recent publication (11), as well as the resulting COS, may be helpful in considering recommendations for post-discharge outcomes measures in a delirium COS.

In addition to creating a delirium COS, we believe that use of appropriate statistical methods for evaluating delirium outcomes in studies of critically ill patients is another important methodological issue. For example, the use of joint modelling statistical methods allows for recurring events (e.g., daily delirium status) and accounts for terminating events that preclude further assessment of the events (e.g., death in the ICU) (5). A delirium COS and use of appropriate statistical methods are both important next steps in advancing methodology for clinical trials aimed at evaluating interventions to prevent and treat delirium in critically ill patients.

Acknowledgements

Funding: National Heart, Lung and Blood Institute funded this follow-up study (N01HR56170, R01HL091760 and 3R01HL091760-02S1), and the SAILS trial (contracts HHSN268200536165C to HHSN268200536176C and HHSN268200536179C), along with the Johns Hopkins Institute for Clinical and Translational Research (ICTR) (UL1 TR 000424-06).

Footnote

Provenance: This is an invited article commissioned by the Section Editor Zhongheng Zhang (Department of Emergency Medicine, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China).

Conflicts of Interest: The authors have no conflicts of interest to declare.

Response to: Lange PW, Maier AB. Statins for delirium in ICU patients: a negative trial but a positive step. J Thorac Dis 2016;8:E1063-E1066.
Pourafkari L, Nader ND, Porhomayon J. Association of rosuvastatin and delirium in severe sepsis with acute respiratory distress syndrome. J Thorac Dis 2016;8:E775-7.

References

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  2. Pourafkari L, Nader ND, Porhomayon J. Association of rosuvastatin and delirium in severe sepsis with acute respiratory distress syndrome. J Thorac Dis 2016;8:E775-7. [Crossref] [PubMed]
  3. Needham DM, Colantuoni E, Dinglas VD, et al. Rosuvastatin versus placebo for delirium in intensive care and subsequent cognitive impairment in patients with sepsis-associated acute respiratory distress syndrome: an ancillary study to a randomised controlled trial. Lancet Respir Med 2016;4:203-12. [Crossref] [PubMed]
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  5. Colantuoni E, Dinglas VD, Ely EW, et al. Statistical methods for evaluating delirium in the ICU. Lancet Respir Med 2016;4:534-6. [Crossref] [PubMed]
  6. Dinglas VD, Hopkins RO, Wozniak AW, et al. One-year outcomes of rosuvastatin versus placebo in sepsis-associated acute respiratory distress syndrome: prospective follow-up of SAILS randomised trial. Thorax 2016;71:401-10. [Crossref] [PubMed]
  7. Blackwood B, Marshall J, Rose L. Progress on core outcome sets for critical care research. Curr Opin Crit Care 2015;21:439-44. [Crossref] [PubMed]
  8. Developing a core outcome set for delirium prevention and/or treatment trials. Core Outcome Measures in Effectiveness Trials. Available online: http://www.comet-initiative.org/studies/details/796, accessed on 9-8-2016.
  9. Improving Long-Term Outcomes Research for Acute Respiratory Failure. Available online: www.improveLTO.com, accessed on 9-7-2016.
  10. Improving Long-Term Outcomes Research for Acute Respiratory Failure. Core Outcome Measures in Effectiveness Trials (COMET) Initiative. Available online: http://www.comet-initiative.org/studies/details/360, accessed on 8-29-2016.
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Cite this article as: Dinglas VD, Colantuoni E, Ely EW, Hough CL, Morris PE, Mendez-Tellez PA, Wozniak AW, Hopkins RO, Needham DM. Authors’ response to commentaries on rosuvastatin for delirium and cognitive impairment in sepsis-associated acute respiratory distress syndrome. J Thorac Dis 2016;8(11):E1534-E1536. doi: 10.21037/jtd.2016.11.53

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