Incidence of and Risk Factors for Ventilator-Associated Pneumonia in Critically Ill Patients

A recent international prevalence study involving more than 1000 intensive care units indicated that pneumonia is responsible for almost half of the infections in critically ill patients in Europe [1]. Ventilator-associated pneumonia accounts for approximately 90% of infections in patients requiring assisted ventilation [2, 3]. An independent contribution to mortality conferred by ventilator-associated pneumonia was recently suggested [4, 5]. Although debate persists about the mortality attributable to ventilator-associated pneumonia among other causes of death in critically ill patients [1, 4-7], there is little doubt that ventilator-associated pneumonia causes substantial morbidity by increasing the duration of mechanical ventilation and intensive care unit stay [4, 5]. It is therefore important to understand the factors that are predictive of ventilator-associated pneumonia, to identify patients at highest risk, and to target these patients for the most effective preventive strategies as determined by randomized trials [8, 9]. Risk factors for nosocomial pneumonia have been evaluated in hospitalized elderly persons [10], heterogeneous groups of hospitalized patients breathing spontaneously or requiring assisted ventilation [11], and similar mixed populations admitted to the intensive care unit [2, 12-15]. Investigations in ventilated critically ill patients only are needed to identify independent predictors of ventilator-associated pneumonia. Most studies of risk factors for ventilator-associated pneumonia have been conducted at single institutions, and different predictors have been examined. In cohort studies using multivariable analyses [16-21], only reintubation [17, 19, 21] and antibiotic use [18, 20] were identified as risk factors in more than one report. However, a direct relation between antibiotics and pneumonia was found in one study [18], whereas an inverse relation was found in another [20]. We examined factors associated with ventilator-associated pneumonia. We explored baseline and time-dependent characteristics, including measures of illness severity, factors relating to mechanical ventilation, variables in the gastropulmonary route of infection, and drug exposure. Methods Patients We used a multicenter national database of 1200 patients who received mechanical ventilation for 48 hours or more and were enrolled from October 1992 to May 1996 in a double-blind, concealed, randomized trial of sucralfate compared with ranitidine to determine rates of ventilator-associated pneumonia and gastrointestinal bleeding [22]. Patients were followed until death, discharge, or clinical suspicion of ventilator-associated pneumonia as determined by the attending intensivist. Bronchoalveolar lavage or protected specimen brush was indicated for patients with a clinical suspicion of ventilator-associated pneumonia. A diagnosis of ventilator-associated pneumonia was considered only in patients who were receiving mechanical ventilation or who stopped receiving ventilation for less than 48 hours. In the absence of a reference standard for diagnosing pneumonia in critically ill patients [23, 24], each patient's clinical, laboratory, and radiographic data were independently reviewed by one of four pairs of adjudicators blinded to treatment group. The readers in each adjudication pair decided on the presence or absence of ventilator-associated pneumonia, resolving any disagreement through discussion. Consensus was achieved on all cases. The adjudicated outcome was used for the primary analysis [177 cases]. However, each case of pneumonia was classified according to four additional definitions: 1) the bedside clinician's diagnosis [233 cases]; 2) the modified Centers for Disease Control and Prevention criteria [25], which require a new radiographic infiltrate persistent for 48 hours or more plus a body temperature greater than 38.5 C or less than 35.0 C, a leukocyte count of more than 10 cells 109/L or less than 3 cells 109/L, purulent sputum or change in character of sputum, or isolation of pathogenic bacteria from an endotracheal aspirate [211 cases]; 3) a Clinical Pulmonary Infection score of 7 or more [26] [194 cases]; or 4) a positive culture from bronchoalveolar lavage (>104 colony-forming units/mL) or protected specimen brush (<103 colony-forming units/mL) (97 cases). Statistical Analysis We expressed continuous variables as the mean (SD) or as the median and interquartile range if their distribution was skewed. We used the Student t-test to compare continuous variables and the chi-square test to compare proportions. All statistical tests were two-tailed. We performed a forward stepwise Cox proportional-hazards regression analysis to evaluate potential risk factors for ventilator-associated pneumonia. The Cox model assesses the effect of each risk factor on the hazard rate of ventilator-associated pneumonia over time, adjusted for other factors in the model and allowing for censoring because of death or discharge. The hazard function in the Cox model can be used to estimate the event rate per day over the duration of stay in the intensive care unit. Independent variables recorded at baseline included age; sex; primary diagnosis; medical or surgical status; hospital admission in the fall or winter compared with spring or summer; location before admission to the intensive care unit; treatment center; Acute Physiology and Chronic Health Evaluation II score; Acute Physiology score; Multiple Organ Dysfunction score [27]; Glasgow Coma Scale score; and chronic comorbid conditions, such as alcoholism, a smoking history of 10 or more pack-years, asthma, bronchiectasis, pulmonary fibrosis, cancer, and HIV infection; organ transplantation; and recent corticosteroid therapy or chemotherapy. Additional independent variables evaluated daily throughout the intensive care unit stay were classified as illness severity measures (daily Multiple Organ Dysfunction score and change in Multiple Organ Dysfunction score from baseline), ventilation variables (mechanical ventilation, change or reinsertion of endotracheal tube, discontinuation and reinstitution of mechanical ventilation, and tracheostomy), nutritional variables (nasoenteral nutrition, gastrostomy feeding, jejunostomy feeding, enteral nutrition through any route, central parenteral nutrition, peripheral parenteral nutrition, and insulin requirement of more than 15 U/d), witnessed aspiration, and drug exposure (stress-ulcer prophylaxis with ranitidine or sucralfate, paralytic agents, and antibiotics). The Multiple Organ Dysfunction Score combines measures of physiologic dysfunction in six domains: the cardiovascular system (heart rate x right atrial pressure/mean arterial pressure), pulmonary system (Pao 2:Fio 2 ratio), the renal system (serum creatinine concentration), the hepatic system (serum bilirubin level), the hematologic system (platelet count), and the central nervous system (Glasgow Coma Scale score) [25]. These continuous variables are constructed in 5 categories so that 0 represents normal function and 4 reflects marked physiologic derangement and is associated with a mortality rate greater than 50%. Composite scores provide a quantitative measure of global physiologic dysfunction at a discrete point in the intensive care unit stay. For individual domains, either the raw data or their score provides a measure of dysfunction in the system of interest. Variables that were associated with ventilator-associated pneumonia in the univariable analysis and had a P value less than 0.10 were entered into a multivariable regression analysis. Factors were considered significant if the P value was less than 0.05 in the multivariable analysis. We calculated risk ratios and 95% CIs for all significant predictors of ventilator-associated pneumonia in the multivariable analysis using all five definitions. We tested for all pairwise interactions between significant risk factors in the multivariable model. We also tested for interactions between predictors in the multivariable model and factors that were significant in the univariable analysis. Finally, we investigated the possibility that the effects of risk factors may vary over the duration of stay in the intensive care unit; this was done by using a nonproportional Cox model testing the interaction of each variable in the final model with time. For example, we hypothesized that the influence of antibiotics on ventilator-associated pneumonia may vary over time. Time was considered both a continuous variable and a discretized variable by using 3-day and 5-day intervals. We did not consider antibiotics administered 24 hours before the diagnosis of ventilator-associated pneumonia, so that drugs prescribed in response to early ventilator-associated pneumonia would be excluded [28]. Role of Study Sponsor Our funding sources had no role in the acquisition, analysis, or interpretation of data or in the submission of this report. Results Of the 1200 patients enrolled in this study, 186 were excluded (85 were discharged, 71 died, and 30 had pneumonia in the first 48 hours), leaving 1014 patients ventilated for 48 hours or more who were free of pneumonia at admission to the intensive care unit. Of these patients, 177 (17.5%) developed ventilator-associated pneumonia 9.0 5.9 days after admission (median, 7 days [interquartile range, 5 to 10 days]). The characteristics of patients with and without ventilator-associated pneumonia are shown in Table 1. The total duration of mechanical ventilation among patients with ventilator-associated pneumonia was 19.3 16.0 days (median, 15 days [interquartile range, 9 to 23 days]) compared with 10.2 10.5 days (median, 7 days [interquartile range, 4 to 11 days]) in other patients (P < 0.001). Among the 177 patients with ventilator-associated pneumonia, 131 (74.0%) had bronchoscopic testing with bronchoalveolar lavage or protected specimen brush. Patients in the following admitting diagnostic categories