Newly Published
Critical Care Medicine  |   March 2017
Nebulization of Antiinfective Agents in Invasively Mechanically Ventilated Adults: A Systematic Review and Meta-analysis
Author Notes
  • From the University Health Network and Mount Sinai Hospitals, Critical Care Department, University of Toronto, Toronto, Ontario, Canada (C.S.-L.); Soins Intensifs, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland (C.S.-L.); Universitat Autonòma de Barcelona, Medicine Department, Barcelona, Spain (C.S.-L.); Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, University Pierre et Marie Curie (UPMC) of Paris 6, Paris, France (J.-J.R.); Department of Internal Medicine, Faculty of Medicine and Health Science, Ghent University, Ghent, Belgium (S.B.); Fourth Department of Internal Medicine, Athens University School of Medicine, Attikon University General Hospital, Athens, Greece (G.P.); Service de Réanimation Médicale, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie of Paris, Paris, France (J.C., C.-E.L.); Pulmonary, Critical Care and Sleep Division, Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York (L.B.P.); Infectious Diseases Division, Santa Maria Misericordia University Hospital, Udine, Italy (M.B.); Emergency and Intensive Care Department, Centro Hospitalar io S. João EPE, Porto, Portugal (J.M.P.); Department of Medicine, Faculty of Medicine, University of Porto, Porto, Portugal (J.M.P.); Critical Care Department, Vall d’Hebrón University Hospital, Vall d’Hebrón Research Institute, CIBERES, Barcelona, Spain (J. Riera); Acute Intensive Care Unit, University Hospital of South Manchester, Manchester, United Kingdom (T.F.); Burns Trauma and Critical Care Research Centre, Pharmacy Department, The University of Queensland, Herston, Brisbane, Australia (J.D., J.A.R.); Department of Respiratory Medicine, German Center for Lung Research (DZL), Medizinische Hochschule, Hannover, Germany (T.W.); Nuffield Department of Primary Care Health Sciences, Oxford University, United Kingdom (J.M.G.-A.); and ESGCIP, CIBERES, Clinical Research and Epidemiology in Pneumonia and Sepsis (CRIPS), Vall d’Hebrón Institut of Research, Barcelona, Spain (J. Rello).
  • Presented in part in the Critical Care Canada Forum 2015, Toronto, Ontario, Canada, October 31, 2015. This research was carried out as a part of a Ph.D. program in Health Science at the Universitat Autònoma de Barcelona, Barcelona, Spain.
    Presented in part in the Critical Care Canada Forum 2015, Toronto, Ontario, Canada, October 31, 2015. This research was carried out as a part of a Ph.D. program in Health Science at the Universitat Autònoma de Barcelona, Barcelona, Spain.×
  • Submitted for publication April 25, 2016. Accepted for publication January 11, 2017.
    Submitted for publication April 25, 2016. Accepted for publication January 11, 2017.×
  • Acknowledgments: The results of the systematic review and meta-analysis will be translated into recommendations following the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system as part of an Institutional Position Paper convened by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID, Basel, Switzerland) Study Group for Infections in Critically Ill Patients (Basel, Switzerland) under the support of the ESCMID and in collaboration with the Iberoamerican Cochrane Center in Barcelona, Spain. The authors acknowledge Pablo Alonso, M.D., Ph.D., Ivan Solà, M.D., and Sandra Pequeño, M.D., of the Iberoamerican Cochrane Center, for their assessment on methodology. Ivan Solà, M.D., also acted as an independent reviewer for the inclusion of studies, and Sandra Pequeño, M.D., acted as an independent reviewer for the bias risk assessment.
    Acknowledgments: The results of the systematic review and meta-analysis will be translated into recommendations following the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system as part of an Institutional Position Paper convened by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID, Basel, Switzerland) Study Group for Infections in Critically Ill Patients (Basel, Switzerland) under the support of the ESCMID and in collaboration with the Iberoamerican Cochrane Center in Barcelona, Spain. The authors acknowledge Pablo Alonso, M.D., Ph.D., Ivan Solà, M.D., and Sandra Pequeño, M.D., of the Iberoamerican Cochrane Center, for their assessment on methodology. Ivan Solà, M.D., also acted as an independent reviewer for the inclusion of studies, and Sandra Pequeño, M.D., acted as an independent reviewer for the bias risk assessment.×
  • Research Support: This project has received funding from the European Society of Clinical Microbiology and Infectious Diseases (ESGCIP and EPASG, Basel, Switzerland), Fundació Catalana de Pneumologia (FUCAP; Barcelona, Spain), Centro de Investigación (CIBERES; Madrid, Spain), and European Regional Development Fund (FEDER; European Commission, Brussels, Belgium).
    Research Support: This project has received funding from the European Society of Clinical Microbiology and Infectious Diseases (ESGCIP and EPASG, Basel, Switzerland), Fundació Catalana de Pneumologia (FUCAP; Barcelona, Spain), Centro de Investigación (CIBERES; Madrid, Spain), and European Regional Development Fund (FEDER; European Commission, Brussels, Belgium).×
  • Competing Interests: Dr. Rouby received research grants and consulting fees from Bayer (Leverkusen, Germany) and Genentech (San Francisco, California). Dr. Roberts received consulting fees from Infectopharm (Heppenheim, Germany). Dr. Chastre received honoraria for lecture or advisory board from Bayer, Pfizer (New York, New York), Basilea (Basel, Switzerland), Astra-Zeneca (London, United Kingdom), Cubist-MSD (Lexington, Massachusetts), MSD (Kenilworth, New Jersey), Kenta-Aridis (San Jose, California), and Medimmune (Gaithersburg, Maryland). Dr. Palmer received research grants from Nektar Therapeutics (San Francisco, California) and consulting fees from Bayer and holds patents for the endobronchial delivery of antibiotics in ventilated patients through the Research Foundation of Stony Brook (Stony Brook, New York) and participated in the 2016 Infectious Diseases Society of America/American Thoracic Society Guidelines Committee for ventilator-associated pneumonia/hospital-acquired pneumonia. Dr. Luyt received honoraria for lecture or advisory board from Bayer, MSD (Kenilworth, New Jersey), ThermoFisher Brahms (Waltham, Massachusetts), and Astellas (Tokyo, Japan). The other authors declare no competing interests.
    Competing Interests: Dr. Rouby received research grants and consulting fees from Bayer (Leverkusen, Germany) and Genentech (San Francisco, California). Dr. Roberts received consulting fees from Infectopharm (Heppenheim, Germany). Dr. Chastre received honoraria for lecture or advisory board from Bayer, Pfizer (New York, New York), Basilea (Basel, Switzerland), Astra-Zeneca (London, United Kingdom), Cubist-MSD (Lexington, Massachusetts), MSD (Kenilworth, New Jersey), Kenta-Aridis (San Jose, California), and Medimmune (Gaithersburg, Maryland). Dr. Palmer received research grants from Nektar Therapeutics (San Francisco, California) and consulting fees from Bayer and holds patents for the endobronchial delivery of antibiotics in ventilated patients through the Research Foundation of Stony Brook (Stony Brook, New York) and participated in the 2016 Infectious Diseases Society of America/American Thoracic Society Guidelines Committee for ventilator-associated pneumonia/hospital-acquired pneumonia. Dr. Luyt received honoraria for lecture or advisory board from Bayer, MSD (Kenilworth, New Jersey), ThermoFisher Brahms (Waltham, Massachusetts), and Astellas (Tokyo, Japan). The other authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. Rello: Pg Vall d’Hebron, 129–AMI 14. E08035 Barcelona, Spain. jrello@crips.es. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Critical Care / Infectious Disease / Respiratory System
Critical Care Medicine   |   March 2017
Nebulization of Antiinfective Agents in Invasively Mechanically Ventilated Adults: A Systematic Review and Meta-analysis
Anesthesiology Newly Published on March 2, 2017. doi:10.1097/ALN.0000000000001570
Anesthesiology Newly Published on March 2, 2017. doi:10.1097/ALN.0000000000001570
Abstract

Background: Nebulization of antiinfective agents is a common but unstandardized practice in critically ill patients.

Methods: A systematic review of 1,435 studies was performed in adults receiving invasive mechanical ventilation. Two different administration strategies (adjunctive and substitute) were considered clinically relevant. Inclusion was restricted to studies using jet, ultrasonic, and vibrating-mesh nebulizers. Studies involving children, colonized-but-not-infected adults, and cystic fibrosis patients were excluded.

Results: Five of the 11 studies included had a small sample size (fewer than 50 patients), and only 6 were randomized. Diversity of case-mix, dosage, and devices are sources of bias. Only a few patients had severe hypoxemia. Aminoglycosides and colistin were the most common antibiotics, being safe regarding nephrotoxicity and neurotoxicity, but increased respiratory complications in 9% (95% CI, 0.01 to 0.18; I2 = 52%), particularly when administered to hypoxemic patients. For tracheobronchitis, a significant decrease in emergence of resistance was evidenced (risk ratio, 0.18; 95% CI, 0.05 to 0.64; I2 = 0%). Similar findings were observed in pneumonia by susceptible pathogens, without improvement in mortality or ventilation duration. In pneumonia caused by resistant pathogens, higher clinical resolution (odds ratio, 1.96; 95% CI, 1.30 to 2.96; I2 = 0%) was evidenced. These findings were not consistently evidenced in the assessment of efficacy against pneumonia caused by susceptible pathogens.

Conclusions: Performance of randomized trials evaluating the impact of nebulized antibiotics with more homogeneous populations, standardized drug delivery, predetermined clinical efficacy, and safety outcomes is urgently required. Infections by resistant pathogens might potentially have higher benefit from nebulized antiinfective agents. Nebulization, without concomitant systemic administration of the drug, may reduce nephrotoxicity but may also be associated with higher risk of respiratory complications.