Invasive and Noninvasive Strategies for Management of Suspected Ventilator-Associated Pneumonia

The diagnosis and treatment of ventilator-associated pneumonia, a nosocomial infection that develops in mechanically ventilated patients and causes considerable morbidity and mortality, remain a challenge (1-3). A presumptive clinical diagnosis of pneumonia is often made when a patient develops a new radiographic infiltrate associated with fever, leukocytosis, and purulent tracheal secretions and when microorganisms are isolated by nonquantitative analysis of endotracheal aspirates (4). This clinical approach leads to overestimation of the incidence of ventilator-associated pneumonia because cases of tracheobronchial colonization and noninfectious processes mimicking it are included (5-7). The nonspecificity of a strategy based on clinical evaluation has potentially deleterious consequences: Many patients may receive unneeded antibiotics; this exposes them to unnecessary toxicity, increases hospital costs, and favors the emergence of resistant microorganisms. In addition, antibiotic overuse in such patients delays diagnosis of the true cause of fever and pulmonary infiltrate. Concern about the inaccuracy of clinical approaches to diagnosis of ventilator-associated pneumonia led numerous investigators to postulate that invasive diagnostic methods, including quantitative cultures of specimens obtained by using bronchoscopic bronchoalveolar lavage or protected specimen brush, could improve identification of patients with true ventilator-associated pneumonia and selection of appropriate antibiotics (8-10). However, these procedures require rigorous adherence to bronchoscopic and microbiological techniques and are not universally available; moreover, in the absence of a definite gold standard for the diagnosis of ventilator-associated pneumonia, the value of such tests is uncertain, and their use in everyday practice remains controversial (4, 11, 12). To test the hypothesis that an invasive management strategy is superior to a clinical, noninvasive one in terms of improving clinical outcomes and minimizing antibiotic use, we initiated a multicenter, randomized, uncontrolled trial to compare these strategies in patients suspected of having ventilator-associated pneumonia. The primary end points were death from any cause, antibiotic use for any reason, and quantification of organ failure during the first 14 days of follow-up. Methods Patient Selection and Study Design After obtaining approval of the institutional review boards at each participating institution and informed consent from patients or their proxies, we enrolled patients at 31 intensive care units. Inclusion criteria were age older than 18 years; at least 48 hours of mechanical ventilation; and clinical suspicion of ventilator-associated pneumonia, defined by new and persistent infiltrate on chest radiography associated with at least one of the following: purulent tracheal secretions, body temperature of at least 38.3 C, and leukocytosis. Exclusion criteria were pregnancy; enrollment in another interventional study; little chance of survival, defined by a Simplified Acute Physiologic Score II (SAPS II) of more than 65 points (corresponding to a probability of death exceeding 77%) (13); and introduction or modification of antibiotic therapy, instigated by new clinical symptoms, during the 3 days before collection of respiratory samples. For patients in the clinical management group, the decision on whether to treat was based on clinical evaluation and results of immediate microscopic examination of Gram-stained endotracheal aspirates. The results of the Gram stain and recommendations of the American Thoracic Society on hospital-acquired pneumonia were used to guide the initial choice of antibiotics (3). Results of qualitative aspirate cultures were used to adjust the initial antibiotic regimen; when cultures were negative, no treatment was given (Figure 1 A). Figure 1. Diagnostic and therapeutic strategy applied to patients managed with the clinical strategy (A) or invasive strategy (B). The invasive strategy used fiberoptic bronchoscopy to obtain protected specimen brush samples or bronchoalveolar lavage samples for direct microscopic examination. Results of these examinations were used to diagnose ventilator-associated pneumonia, to decide to treat, and to guide the initial choice of antibiotics when specimens were positive. Results of quantitative cultures were used to adjust therapy; treatment was discontinued when results were negative, and use of antibiotics with narrower spectra of activity was based on identification of and susceptibility-test results for pathogens cultured at significant concentrations (protected specimen brush sample that yielded 103 colony-forming units [CFU]/mL or bronchoalveolar lavage fluid sample that yielded 104 CFU/mL [4, 8-10]) (Figure 1 B). For both groups, the recommended duration of therapy for ventilator-associated pneumonia was 14 days. Randomization and Data Collection Patients were randomly assigned to receive the clinical or the invasive management strategy. Computer-generated random-number tables were used to assign patients in blocks of 8, with stratification according to treatment center. At admission to the intensive care unit, we recorded each patient's age; sex; severity of underlying medical condition, stratified as rapidly fatal, ultimately fatal, or not fatal according to the criteria of McCabe and Jackson (14); SAPS II score (range, 0 to 174; higher scores indicate more severe illness) (13); Sepsis-related Organ Failure Assessment (SOFA) score (range, 0 to 24, with scores for each organ system [respiration, coagulation, liver, cardiovascular, central nervous system, and kidney] ranging from 0 [normal] to 4 [most abnormal]) (15); the Organ Dysfunction and Infection (ODIN) score (range, 0 to 7, according to the presence or absence of cardiovascular, respiratory, renal, hepatic, hematologic, and neurologic dysfunctions or infection) (16); classification as medical patient, surgical patient with trauma, or surgical patient without trauma according to the admitting diagnosis; and reason for initiating mechanical ventilation (17). The following baseline variables were recorded before randomization: SAPS II score; SOFA score; ODIN score; body temperature; leukocyte count; radiologic score (range, 0 to 12 according to the density of radiologic infiltration) (18); ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (Pao 2/Fio 2); presence of shock, defined as systolic arterial pressure less than 90 mm Hg with signs of peripheral hypoperfusion or need for continuous infusion of vasopressor or inotropic agents (19); and presence of the acute respiratory distress syndrome, defined as the presence of a generalized pulmonary infiltrate and a lung injury score more than 2.5 (20); duration of previous mechanical ventilation; and use or no use of antibiotics. These baseline variables (except SAPS II score) were measured again 3, 7, 14, 21, and 28 days after the day of inclusion. All infections requiring specific therapeutic measures during the first 3 days after inclusion were recorded. Antibiotic use was recorded daily until day 28. Specimen Collection and Microbiological Processing Patients who received invasive management underwent fiberoptic bronchoscopy according to each center's protocol. Premedication, use of a short-acting neuromuscular blocking agent, and adjustment of Fio 2 to 95% or more were recommended; protected specimen brush, bronchoalveolar lavage, or both were performed at the investigator's discretion. Processing of microbiological specimens has been described in detail elsewhere (10, 21). Briefly, recovered bronchoalveolar lavage fluid was divided into two samples: one for direct microscopic examination of cytocentrifuge preparations after Gram or modified Wright-Giemsa staining to determine the percentages of cells containing intracellular bacteria, and the other for quantitative cultures. The tip of the protected specimen brush was cut, dropped into 1 mL of sterile water, and vortexed for 1 minute; samples were examined directly and serially diluted for culture. The number of bacteria in the original specimens was estimated by colony counts and is expressed as CFU/mL. Patients in the invasive treatment group were considered to have ventilator-associated pneumonia if more than 5% of the cells in cytocentrifuge preparations of bronchoalveolar lavage fluid contained intracellular bacteria or at least one bacterial species grew at a significant concentration from the protected specimen brush sample ( 103 CFU/mL) or from bronchoalveolar lavage fluid ( 104 CFU/mL) (10, 22). In patients who received clinical treatment, endotracheal aspirates were collected sterilely by using a suction catheter in a mucus collector; secretions were aspirated without instilling saline. Aspirates were vortexed for 1 minute; Gram staining and qualitative aerobic cultures were performed for all patients. Definitions Inappropriate treatment, evaluated initially and at 3 days, was defined as the use of antibiotics to which at least one cultured isolate was resistant in vitro. For patients in the clinical management group, all pathogens grown in qualitative endotracheal aspirate cultures were considered for this analysis; for patients in the invasive management group, only pathogens cultured at significant concentrations were taken into account. Resistant bacteria were defined as ticarcillin-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia; extended-spectrum -lactamase-producing Enterobacteriaceae; and methicillin-resistant Staphylococcus aureus. We calculated the number of antibiotic-free days (days without antibiotic therapy) at 14 and 28 days after inclusion. For example, a patient who survived 28 days and received no antibiotics was assigned a value of 28. If antibiotics had been given for 10 days and the patient died on day 14, a value of 4 was assign