title: Nebulization of Antiinfective Agents in Invasively Mechanically Ventilated Adults: A Systematic Review and Meta-analysis.
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; I = 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; I = 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; I = 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.
authors.affiliation: 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).
authors.forename: Candela
authors.initials: C
authors.lastname: Solé-Lleonart
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Rouby
authors.forename: Stijn
authors.initials: S
authors.lastname: Blot
authors.forename: Garyfallia
authors.initials: G
authors.lastname: Poulakou
authors.forename: Jean
authors.initials: J
authors.lastname: Chastre
authors.forename: Lucy B
authors.initials: LB
authors.lastname: Palmer
authors.forename: Matteo
authors.initials: M
authors.lastname: Bassetti
authors.forename: Charles-Edouard
authors.initials: CE
authors.lastname: Luyt
authors.forename: Jose M
authors.initials: JM
authors.lastname: Pereira
authors.forename: Jordi
authors.initials: J
authors.lastname: Riera
authors.forename: Tim
authors.initials: T
authors.lastname: Felton
authors.forename: Jayesh
authors.initials: J
authors.lastname: Dhanani
authors.forename: Tobias
authors.initials: T
authors.lastname: Welte
authors.forename: Jose M
authors.initials: JM
authors.lastname: Garcia-Alamino
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
authors.forename: Jordi
authors.initials: J
authors.lastname: Rello
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D016638:Critical Illness; D006801:Humans; D007362:Intensive Care Units; D009330:Nebulizers and Vaporizers; D053717:Pneumonia, Ventilator-Associated / Q000188:drug therapy*; D012121:Respiration, Artificial / Q000009:adverse effects*
chemical_list: D000900:Anti-Bacterial Agents