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  • Letter
  • Open Access

Importance of a registered and structured protocol when conducting systematic reviews: comments about nebulized antibiotics for ventilator-associated pneumonia

  • 1, 2, 3,
  • 1, 2, 4,
  • 1, 5,
  • 2, 6,
  • 7 and
  • 1, 7, 8, 9Email author
Critical Care201519:298

Published: 20 August 2015


  • Confidence Interval
  • Observational Study
  • Mechanical Ventilation
  • Control Design
  • Clinical Success

We appreciate Gu’s [1] interest in our study. We apologize and agree with his comment about attributing units to standardized mean difference (SMD). Nevertheless, similar to the SMD, results in mean difference (control – nebulized) were unaffected by nebulized antibiotics (2.67 days, 95 % confidence interval (CI) –2.89, 8.23 for ICU length of stay (LOS); and 0.70 days, 95 % CI −3.40, 4.80 for mechanical ventilation). However, we strongly disagree with other points raised by the letter.

First, the study protocol was defined a priori [2]. We disagree that combining observational studies with intervention studies is reserved only for safety evaluation. This topic has been discussed in the literature and combining both types of studies was adequate for our aim [3]. Furthermore, we presented the main results separating interventional studies from observational studies, thereby allowing the reader to interpret both analyses independently.

Second, both of the studies cited as “case–control studies” [1] received this denomination in their title and abstract. However, by reading their methods it becomes clear that they are actually matched cohort studies [4, 5]. Indeed, they matched exposed patients (“nebulized group”) to unexposed patients (“no-nebulized group”). A case–control design starts with the outcome (case = “clinical success”) and matches them with controls (“clinical failures”). Therefore, our measure of effect was correct [5]. For exploration, we report the analysis for clinical cure using the odds ratio (OR) (Fig. 1). The results are unchanged.
Figure 1
Fig. 1

Forest plot for clinical cure using odds ratios (OR). P for overall effect = 0.015. CI confidence interval

Third, Kalin’s study was included because it fulfilled our inclusion/exclusion criteria [2]. Gu’s suggestion to exclude this study based solely on its effects in heterogeneity could be considered selective reporting [1].

Our study provided data for further trials aiming to evaluate the effect of nebulized antibiotics in ventilator-associated pneumonia (VAP) [2].




Confidence interval


Length of stay


Odds ratio


Standardized mean difference


Ventilator-associated pneumonia


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Authors’ Affiliations

Cooperative Network for Research—AMIB-Net, Associação de Medicina Intensiva Brasileira, São Paulo, Brazil
Emergency Medicine Discipline, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
Intensive Care Unit, Hospital Alemão Oswaldo Cruz, São Paulo, Brazil
Adult Intensive Care Unit, A.C. Camargo Cancer Center, São Paulo, Brazil
Intensive Care Unit, University Hospital Prof. Edgar Santos, Universidade Federal da Bahia, Rua Augusto Viana, Salvador, Brazil
Research and Education Institute (IEP), Hospital Sirio-Libanes, São Paulo, Brazil
Department of Pulmonology, Hospital Clinic of Barcelona, Institut D’investigacions August Pi I Sunyer (IDIBAPS), University of Barcelona, Ciber de Enfermedades Respiratorias (CIBERES), Barcelona, Spain
Amil Critical Care Group, Hospital Paulistano, São Paulo, Brazil
Respiratory Intensive Care Unit, Pulmonary Division, Heart Institute, Hospital das Clínicas, University of São Paulo, Sao Paulo, Brazil


  1. Gu WJ. Nebulized antibiotics for ventilator-associated pneumonia: misleading analysis and interpretation of the data. Crit Care. 2015;19:236.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Zampieri FG, Nassar AP, Gusmao-Flores D, Taniguchi LU, Torres A, Ranzani OT. Nebulized antibiotics for ventilator-associated pneumonia: a systematic review and meta-analysis. Crit Care. 2015;19:150.PubMed CentralView ArticlePubMedGoogle Scholar
  3. Shrier I, Boivin JF, Steele RJ, Platt RW, Furlan A, Kakuma R, et al. Should meta-analyses of interventions include observational studies in addition to randomized controlled trials? A critical examination of underlying principles. Am J Epidemiol. 2007;166:1203–9.View ArticlePubMedGoogle Scholar
  4. Cummings P, McKnight B, Greenland S. Matched cohort methods for injury research. Epidemiol Rev. 2003;25:43–50.View ArticlePubMedGoogle Scholar
  5. Rothman KJ, Greenland S, Lash TL. Modern epidemiology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.Google Scholar


© Zampieri et al. 2015