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Original Investigation
July 8, 2019

Effectiveness of a Bundled Intervention Including Adjunctive Corticosteroids on Outcomes of Hospitalized Patients With Community-Acquired Pneumonia: A Stepped-Wedge Randomized Clinical Trial

Author Affiliations
  • 1Department of Physiotherapy, Western Health, The University of Melbourne, Melbourne, Australia
  • 2Department of Medicine, Western Health, University of Melbourne, Melbourne, Australia
  • 3Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
  • 4General Internal Medicine Unit, Western Health, The University of Melbourne, Melbourne, Australia
  • 5School of Primary and Allied Health Care, Monash University, Melbourne, Australia
  • 6Division of Population Health and Immunity, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
JAMA Intern Med. 2019;179(8):1052-1060. doi:10.1001/jamainternmed.2019.1438
Key Points

Question  Does a bundle of evidence-supported treatments (including adjunctive corticosteroids) improve the outcomes of patients with community-acquired pneumonia under conditions of routine care?

Findings  In this stepped-wedge, cluster-randomized effectiveness trial of 816 patients hospitalized with community-acquired pneumonia, a bundled intervention aiming to optimize treatment with corticosteroids, early mobilization, early switch to oral antibiotics, and screening for malnutrition had no significant effect on length of hospital stay, readmissions, mortality, or other complications of community-acquired pneumonia and resulted in a higher incidence of gastrointestinal bleeding when compared with usual care.

Meaning  This process-of-care bundle failed to improve outcomes and may have increased risks of adverse events; it cannot be recommended for patients hospitalized with community-acquired pneumonia.

Abstract

Importance  Community-acquired pneumonia remains a leading cause of hospitalization, mortality, and health care costs worldwide. Randomized clinical trials support the use of adjunctive corticosteroids, early progressive mobilization, antibiotic switching rules, and dietary interventions in improving outcomes. However, it is uncertain whether implementing these interventions will translate into effectiveness under routine health care conditions.

Objective  To evaluate the effectiveness of a bundle of evidence-supported treatments under conditions of routine care in a representative population hospitalized for community-acquired pneumonia.

Design, Setting, and Participants  A double-blind, stepped-wedge, cluster-randomized clinical trial with 90-day follow-up was conducted between August 1, 2016, and October 29, 2017, in the general internal medicine service at 2 tertiary hospitals in Melbourne, Australia, among a consecutive sample of patients with community-acquired pneumonia. The primary analysis and preparation of results took place between May 14 and November 25, 2018.

Interventions  Treating clinical teams were advised to prescribe prednisolone acetate, 50 mg/d, for 7 days (in the absence of any contraindication) and de-escalate from parenteral to oral antibiotics according to standardized criteria. Algorithm-guided early mobilization and malnutrition screening and treatment were also implemented.

Main Outcomes and Measures  Hospital length of stay, mortality, readmission, and intervention-associated adverse events (eg, gastrointestinal bleeding and hyperglycemia).

Results  A total of 917 patients were screened, and 816 (351 women and 465 men; mean [SD] age, 76 [13] years) were included in the intention-to-treat analysis, with 401 patients receiving the intervention and 415 patients in the control group. An unadjusted geometric mean ratio of 0.95 (95% CI, 0.78-1.16) was observed for the difference in length of stay (days) between the intervention and control groups. Similarly, no significant differences were observed for the secondary outcomes of mortality and readmission, and the results remained unchanged after further adjustment for sex and age. The study reported higher proportions of gastrointestinal bleeding in the intervention group (9 [2.2%]) compared with the controls (3 [0.7%]), with an unadjusted estimated difference in mean proportions of 0.008 (95% CI, 0.005-0.010).

Conclusions and Relevance  This bundled intervention including adjunctive corticosteroids demonstrated no evidence of effectiveness and resulted in a higher incidence of gastrointestinal bleeding. Efficacy of individual interventions demonstrated in clinical trials may not necessarily translate into effectiveness when implemented in combination and may even result in net harm.

Trial Registration  ClinicalTrials.gov identifier: NCT02835040

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    1 Comment for this article
    EXPAND ALL
    Fragile Data Requires High Statistical Caution
    Thomas Heston, MD | Washington State University
    This article looking at the effect of a bundled intervention on hospitalized patients with community acquired pneumonia concludes that the bundled care resulted in increased gastrointestinal bleeding (GIB).(1) The authors state in their discussion that the increased bleeding almost certainly was due to the corticosteroid component of the bundled intervention. The data presented, however, are highly fragile making such a conclusion regarding corticosteroids tenuous at best.

    To support their conclusion of increased GIB in the intervention group, the authors calculated confidence intervals of the unadjusted difference between 2.2% (9 out of 401 intervention group patients) and 0.7% (3 out
    of 415 control group patients) showing a statistically significant result. However, this statistical analysis is highly fragile, having a fragility index of 0. This indicates a highly unstable result for which statistical inferences probably should not be made at all, but if done, should be viewed cautiously.(2)

    Perhaps most importantly, the use of corticosteroids wasn’t 100% in the intervention group. In the 9 intervention group patients with a GIB (supp table 8), only 7 of 9 received any corticosteroids at all. Therefore, out of all patients experiencing a GIB (total = 12), only 7 of these 12 received corticosteroids. This rate of 58% is not statistically different than a rate of 50% which would be expected if no association between corticosteroid administration and GIB existed.

    Finally, these results almost certainly would be affected by the type of prophylaxis given for deep venous thromboembolism and whether or not gastrointestinal protective agents were used. These variables did not appear to be accounted for in the authors’ analysis, increasing uncertainty over exactly what was responsible for the difference in GIB observed between the control and intervention groups.

    Bibliography
    1. Lloyd M, Karahalios A, Janus E, Skinner EH, Haines T, De Silva A, et al. Effectiveness of a Bundled Intervention Including Adjunctive Corticosteroids on Outcomes of Hospitalized Patients With Community-Acquired Pneumonia: A Stepped-Wedge Randomized Clinical Trial. JAMA Intern Med. 2019 Jul 8;
    2. Walsh M, Srinathan SK, McAuley DF, Mrkobrada M, Levine O, Ribic C, et al. The statistical significance of randomized controlled trial results is frequently fragile: a case for a Fragility Index. J Clin Epidemiol. 2014 Jun;67(6):622–8.
    CONFLICT OF INTEREST: None Reported
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