Safety and efficacy of multipotent adult progenitor cells in acute respiratory distress syndrome (MUST-ARDS): a multicentre, randomised, double-blind, placebo-controlled phase 1/2 trial.

PURPOSE: Bone marrow-derived, allogeneic, multipotent adult progenitor cells demonstrated safety and efficacy in preclinical models of acute respiratory distress syndrome (ARDS). METHODS: This phase 1/2 trial evaluated the safety and tolerability of intravenous multipotent adult progenitor cells in patients with moderate-to-severe ARDS in 12 UK and USA centres. Cohorts 1 and 2 were open-label, evaluating acute safety in three subjects receiving 300 or 900 million cells, respectively. Cohort 3 was a randomised, double-blind, placebo-controlled parallel trial infusing 900 million cells (n = 20) or placebo (n = 10) within 96 h of ARDS diagnosis. Primary outcomes were safety and tolerability. Secondary endpoints included clinical outcomes, quality of life (QoL) and plasma biomarkers. RESULTS: No allergic or serious adverse reactions were associated with cell therapy in any cohort. At baseline, the cohort 3 cell group had less severe hypoxia. For cohort 3, 28-day mortality was 25% for cell vs. 45% for placebo recipients. Median 28-day free from intensive care unit (ICU) and ventilator-free days in the cell vs. placebo group were 12.5 (IQR 0,18.5) vs. 4.5 (IQR 0,16.8) and 18.5 (IQR 0,22) vs. 6.5 (IQR 0,18.3), respectively. A prospectively defined severe ARDS subpopulation (PaO2/FiO2 < 150 mmHg (20 kPa); n = 16) showed similar trends in mortality, ICU-free days and ventilator-free days favouring cell therapy. Cell recipients showed greater recovery of QoL through Day 365. CONCLUSIONS: Multipotent adult progenitor cells were safe and well tolerated in ARDS. The clinical outcomes warrant larger trials to evaluate the therapeutic efficacy and optimal patient population.

Impact of macrolide therapy on mortality for patients with severe sepsis due to pneumonia.

Recent studies suggest that macrolides may have beneficial effects for patients at risk for certain infections. The current authors examined the effect of macrolide therapy on 30- and 90-day mortality for patients with severe sepsis caused by pneumonia. A retrospective cohort study was conducted at two tertiary teaching hospitals. Eligible subjects were admitted with a diagnosis of, had chest radiography consistent with, and had a discharge diagnosis of pneumonia and clinical criteria of severe sepsis. Subjects were considered to be on macrolides if they received at least one dose within 48 h of admission. Severe sepsis was present in 237 (30.1%) subjects, out of whom 104 (43.9%) received macrolides. Mortality was 20.3% at 30 days and 24.5% at 90 days. In the multivariable analysis, the use of macrolide was associated with decreased mortality at 30 days (hazard ratio (HR) 0.3, 95% confidence interval (CI) 0.2-0.7) and at 90 days (HR 0.3, 95% CI 0.2-0.6) in patients with severe sepsis and in patients with macrolide-resistant pathogens (HR 0.1, 95% CI 0.02-0.5). Macrolide use was associated with decreased mortality in patients with severe sepsis due to pneumonia and macrolide-resistant pathogens. Confirmatory studies are needed to determine whether macrolide therapy may be protective for patients with sepsis.

Monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia.

BACKGROUND: Although monotherapy for pneumococcal pneumonia is standard, a survival benefit of combination beta-lactam and macrolide therapy has been suggested. HYPOTHESIS: Initial empirical therapy with a combination of effective antibiotic agents would have a better outcome than a single effective antibiotic agent in patients with bacteremic pneumococcal pneumonia. METHODS: A review of adult bacteremic pneumococcal pneumonia within the Methodist Healthcare System, Memphis, Tenn, between January 1, 1996, and July 31, 2000. Empirical therapy was defined as all antibiotic agents received in the first 24 hours after presentation. On the basis of culture results, empirical therapy was classified as single effective therapy (SET), dual effective therapy (DET), or more than DET (MET). Acute Physiology and Chronic Health Evaluation II (APACHE II)-based predicted mortality, and Pneumonia Severity Index scores were calculated. RESULTS: Of the 225 patients identified, 99 were classified as receiving SET, 102 as receiving DET, and 24 as receiving MET. Compared with the other groups, patients who received MET had statistically significantly more severe pneumonia as measured by the Pneumonia Severity Index score (P =.04) and predicted mortality (P =.03). Mortality within the SET group was significantly higher than within the DET group (P =.02, odds ratio, 3.0 [95% confidence intervals, 1.2-7.6]), even when the DET and MET groups (P =.04) were combined. In a logistic regression model including antibiotic therapy and clinical risk factors for mortality, SET remained an independent predictor of mortality with a predicted mortality-adjusted odds ratio for death of 6.4 (95% confidence intervals, 1.9-21.7). All deaths occurred in patients with a Pneumonia Severity Index score higher than 90, and the predicted mortality-adjusted odds ratio for death with SET in this subgroup was 5.5 (95% confidence intervals, 1.7-17.5). CONCLUSIONS: We found that SET is associated with a significantly greater risk of death than DET. Therefore, monotherapy may be suboptimal for patients with severe bacteremic pneumococcal pneumonia who have Pneumonia Severity Index scores higher than 90.

Legionella and community-acquired pneumonia: a review of current diagnostic tests from a clinician's viewpoint.

Many physicians are unaware of the limitations of the available tests for diagnosing infections with Legionella organisms. Geographic differences in the importance of nonpneumophila Legionella species as pathogens are underrecognized, in part because available diagnostic tests are biased toward the detection of pneumophila serogroup 1. Routine laboratory practices reduce the likelihood of culturing Legionella species from clinical isolates. Failure of seroconversion is common, particularly with nonpneumophila species; even when seroconversion occurs, it may take much longer than 4 weeks. Urinary antigen testing has insufficient sensitivity to affect clinical management in most regions of the United States, as it can reliably detect only L. pneumophila serogroup 1 infections. Polymerase chain reaction-based techniques offer hope of providing highly sensitive, rapid diagnostic tests for all Legionella species, but limitations in the current tests will make validating them difficult.

Incidence of pericardial effusions in acute myocardial infarctions.

To study the incidence of pericardial effusions in the first 72 hours after myocardial infarction, M-mode echocardiograms were performed on 90 of 100 consecutive patients with acute myocardial infarctions. Pericardial effusions were documented in five patients (5.6 percent), four of which resolved without sequelae by the time of discharge. The remaining patient died of presumed myocardial rupture. Pericardial effusions tended to be more common in patients with anterior or anterolateral infarcts and in those who had received intracoronary streptokinase (p less than .10). No patient with postinfarction pericarditis had an effusion.

Comparison of two predictive models for prognosis in critically ill patients in a Veteran's Affairs Medical Center coronary care unit.

STUDY OBJECTIVE: The acute physiologic and chronic health evaluation score has been developed to assess prognosis in critically ill patients. Knaus et al initially determined and validated diagnosis-specific coefficients for prediction of outcome in a group of multidisciplinary ICUs. Teskey et al found different coefficients for cardiac diagnoses in a retrospective analysis of coronary care unit (CCU) only patients. This study compares the actual mortality in a Veteran's Affairs Medical Center (VAMC) CCU with the mortality predicted by the two equations. DESIGN AND SETTING: Data were prospectively collected for patients admitted to the medical CCU at a university-affiliated, tertiary care VAMC. PATIENTS: Patients (n = 338) admitted to the CCU with the diagnoses of coronary artery disease (CAD), myocardial infarction (MI), congestive heart failure (CHF), arrhythmia (Arr), and other cardiac-related diagnoses. RESULTS: The entire CCU population showed no significant differences from either the predictions by Knaus et al and Teskey et al in 1991. However, when specific disease states were analyzed as a whole, significant differences from both prediction models for CAD and MI actual mortality were found. Teskey et al was a better predictor for the Arr and CHF population, while both were equally reliable for other. CONCLUSIONS: Either prediction model is reliable for a CCU population in general. However, diagnosis-specific coefficients of Teskey et al appear to correlate better with actual mortality for this VAMC. Significant outcome differences compared with those predicted may reflect the patient population specific to a VAMC.

The impact of blood cultures on antibiotic therapy in pneumococcal pneumonia.

INTRODUCTION: The cost-effectiveness of blood cultures in community-acquired pneumonia (CAP) has been questioned. Although penicillin-resistant Streptococcus pneumoniae is an increasing problem, penicillin therapy, where appropriate, reduces cost and may reduce antibiotic resistance. Blood cultures, however, can only reduce cost if physicians are prepared to alter therapy based on the results. We reviewed our experience to determine how often physicians changed management based on blood culture results positive for S pneumoniae. METHODS: Retrospective chart review was performed of all CAP admissions between January 1996 and December 1998 with blood culture results positive for S pneumoniae. RESULTS: Seventy-four patients out of 1,805 patients admitted with CAP during this period had pneumococcemia. Penicillin resistance was identified in 15 cases (20.3%; high grade in 4 cases) with cephalosporin resistance in 4 of these cases (1 high grade). Fifty-one patients had initial empiric therapy with a third-generation cephalosporin, and 58 patients had empiric coverage of atypical organisms; no patient received empiric penicillin therapy. Blood culture results altered management in 31 patients (41.9%), but in only 2 cases was this due to antibiotic resistance. Fifty-one patients without penicillin allergy grew penicillin-sensitive pneumococci; only 11 patients (21.6%) were changed to penicillin therapy. Thirteen of 35 patients (37.1%) who were given an additional antibiotic for atypical coverage had this antibiotic ceased. CONCLUSION: Despite evidence of penicillin-sensitive pneumococcal CAP, physicians were reluctant to narrow antibiotic therapy, potentially adding to treatment cost and reducing the impact of blood culture results on management. The impact of penicillin resistance was reduced by the usual empiric choice of a third-generation cephalosporin. While positive blood culture results can clearly be useful in the management of patients with CAP, their cost-effectiveness needs to be assessed in prospective clinical trials.

Ventilator-associated pneumonia due to Pseudomonas aeruginosa.

OBJECTIVE: Ventilator-associated pneumonia (VAP) caused by Pseudomonas aeruginosa has been associated with higher case fatality rates than VAP caused by other bacterial etiologies. The causes of this excess mortality are unclear. DESIGN: Retrospective review of 38 consecutive ventilated patients with Pseudomonas pneumonia, documented by highly reliable methods. Charts of five additional patients were unavailable for review. SETTING: Medical ICUs of a university-affiliated Veterans Affairs Medical Center and a university-affiliated municipal hospital. MEASUREMENTS: Prospectively collected hospital admission acute physiologic and chronic health examination (APACHE) II scores and cause of ICU admission. Retrospectively calculated organ failure and APACHE scores, VAP score. Clinical and microbiologic variables. Antibiotic treatment and outcome. Direct cause of death by standard definitions. RESULTS: Overall mortality was 69% (26/38), significantly higher than the APACHE II predicted mortality of 42.6% (p=0.037). At least 38% (10/26) of deaths were directly attributable to Pseudomonas VAP. Multivariate analysis of factors associated with death found infectious cause for ICU admission (odds ratio [OR]=8.67; 95% confidence interval [CI], 0.86 to 85.94) and number of organ dysfunctions on the day of diagnosis (OR=1.73, 95% CI, 1.02 to 2.92) were significant. Septic shock from Pseudomonas VAP, septic shock from subsequent infection, and multiple organ dysfunction syndrome were the most common immediate causes of death. Mortality increased linearly with increasing APACHE III score on the day of diagnosis. Of initial antibiotic regimens, 67% (26/36) were considered failures. Persistent pneumonia occurred in 35% of patients while recurrent pneumonia was unusual (1/38). CONCLUSIONS: Development of Pseudomonas pneumonia results in a mortality rate in excess of that due to the presenting illness. The attributable mortality determined by several means appears to approach 40%. The excess mortality appears to be related to the host defense response to the pneumonia rather than any characteristic of the pneumonia. Even standard antibiotic regimens fail frequently and do not prevent the excess mortality. Since at least 38% of deaths can be directly attributable to the Pseudomonas pneumonia, improvement in therapy is needed.

The diagnostic utility of the antibody-coated bacteria test in intubated patients.

PURPOSE: Pilot study to determine if the presence of antibody-coated bacteria (ACB) in sputum specimens obtained from endotracheal tube suctioning would aid in the diagnosis of lower respiratory tract infection (LRTI). PATIENTS AND METHODS: All endotracheally intubated and mechanically ventilated patients for a two-month period were recruited for study. The diagnosis of LRTI was based on a clinical suspicion sufficient enough to start or change antibiotic therapy. Specimens were obtained by blind endotracheal tube suctioning. After processing, sputum smears were stained with fluorescein-labelled antibody to the Fc portion of IgG, IgM, and IgA. More than five fluorescein-labelled bacteria per oil immersion field were considered positive smears. RESULTS: Seventy-one specimens were obtained from 36 patients. Eighteen specimens were positive in 12 patients, all of whom had LRTI. No specimen was positive in patients not diagnosed as having LRTI. The ACB test was positive in 12 of 25 patients with LRTI. Patients with LRTI but negative ACB were more likely to have received prior antibiotic therapy (p less than 0.001). ACB was positive prior to the clinical diagnosis of LRTI in seven of nine patients (av 4.1 days, range 2-6 days) and converted to negative in three specimens obtained seven or more days after starting appropriate antibiotics, while in three specimens it remained positive three-six days post treatment initiation. CONCLUSIONS: The ACB test appears to be highly specific for the presence of LRTI in intubated patients. Sensitivity of the test may be adversely affected by prior antibiotic therapy. A positive ACB test may predict the subsequent development of LRTI. Further study is warranted.

The radiologic diagnosis of autopsy-proven ventilator-associated pneumonia.

An abnormal chest roentgenogram is essential for the diagnosis of ventilator-associated pneumonia. The diagnostic accuracy of various roentgenographic signs of pneumonia has not been assessed previously in the portable anteroposterior roentgenograms obtained in ventilated patients. Seven roentgenographic signs (air bronchograms, alveolar infiltrates, silhouette sign, cavities, fissure abutment, atelectasis, and asymmetric infiltrates superimposed on diffuse bilateral infiltrates) were evaluated for their accuracy in predicting pneumonia alone, in combination with other signs, or in combination with clinical parameters. The last roentgenogram prior to autopsy of 69 ventilated patients was interpreted by three reviewers and the above signs were correlated with autopsy evidence of pneumonia. Pneumonia was present in 24 (35 percent) of the 69 autopsies. No roentgenographic sign had a diagnostic efficiency of greater than 68 percent. By stepwise logistic regression, the presence of air bronchograms was the only roentgenographic sign that correlated with pneumonia in the total group, correctly predicting 64 percent of pneumonias. In patients without adult respiratory distress syndrome (ARDS), the presence of air bronchograms or alveolar infiltrates correlated with pneumonia, while in patients with ARDS, no roentgenographic sign and only the clinical parameter of purulent sputum correlated with pneumonia. Only a minority (7/22) of worsening alveolar infiltrates in all groups were due to pneumonia and were often confused with ARDS. Alveolar hemorrhage occurred with a surprising frequency (38 percent of autopsies), including 13/45 (29 percent) patients without pneumonia. Alveolar hemorrhage was associated with 29 percent of multiple air bronchograms and 30 percent of bilateral alveolar infiltrates in patients without pneumonia. We conclude that in intubated patients with diffuse bilateral roentgenographic infiltrates, no roentgenographic sign correlates well with pneumonia. No clinical parameter added to the accuracy of either an alveolar infiltrate or an air bronchogram in patients without diffuse infiltrates. Pulmonary hemorrhage and/or infarction are frequent autopsy findings in intubated patients and may be confused radiologically with pneumonia.

Management of bacterial pneumonia in ventilated patients. Protected bronchoalveolar lavage as a diagnostic tool.

We conducted a prospective study to determine the effectiveness of protected bronchoalveolar lavage (PBAL) in diagnosing pneumonia in ventilated patients and the usefulness of bronchoscopic data in treating ventilated patients. Entrance criteria were (1) fever and a new or progressive infiltrate on chest roentgenogram with either leukocytosis or a macroscopically purulent tracheal aspirate, and (2) no antibiotic therapy for at least 48 h before bronchoscopy. Twenty-five ventilated patients met entrance criteria for the study and completed the protocol. PBAL was effective in retrieving distal airway secretions with a minimal degree of contamination as indicated by a specificity and a negative predictive value of 100 percent. Bacterial isolates grew in all patients with pneumonia at a concentration greater than or equal to 100,000 cfu/ml, with a median growth of 500,000 cfu/ml. The presence of a two-log difference between the highest quantitative culture count in patients without pneumonia and the lowest quantitative culture count in patients with pneumonia allowed a clearer determination of a patient's status, with regard to pneumonia, compared with the significant overlap in unprotected BAL. Gram and Giemsa stains of the PBAL were positive in all patients with pneumonia and negative in those without pneumonia. All but one patient with pneumonia received narrow-spectrum antibiotic therapy. All patients without infection had no antibiotic administered. Clinical and roentgenographic criteria could not discriminate between patients with and without pneumonia, confirming the findings of previous investigations. The results of microscopic and culture analyses of the PBAL effluent proved useful in directing antibiotic treatment in patients with pneumonia and in avoiding unnecessary antibiotic use in those patients without pneumonia.

Noninvasive face mask mechanical ventilation in patients with acute hypercapnic respiratory failure.

Mechanically assisted intermittent positive-pressure ventilation effectively provides ventilatory support in patients with respiratory failure but it requires placing an artificial airway. We have previously reported our successful experience delivering mechanical ventilation via a face mask (FMMV) rather than with an endotracheal tube in a pilot study of patients with acute respiratory failure. The present investigation evaluated an additional 18 patients with hypercapnic respiratory failure to determine the efficacy of FMMV in a more homogeneous group and to determine factors predicting its success. FMMV was successful in avoiding intubation in 13 of the 18 patients. A significant initial improvement in PCO2 (greater than 16 percent decrease) and in pH (from less than 7.30 to greater than 7.30) predicted success. The five patients who failed on FMMV required endotracheal intubation because of inability to improve gas exchange (three patients), apnea due to sedatives (one patient), and management of secretions (one patient). FMMV was generally well accepted with only two patients withdrawn because of intolerance of the mask. The mean duration of FMMV was 25 h. Complications were seen in only two patients (11 percent): aspiration (one patient) and mild skin necrosis (one patient). Seven patients entered the study by meeting entrance criteria after an unsuccessful extubation attempt and therefore received both forms of mechanical ventilation. All but one patient avoided reintubation, and the face mask proved to be as effective as the endotracheal tube as a conduit for delivering the mechanical tidal volume and improving gas exchange. Our findings indicate that FMMV is a viable option for short-term (one to four days) ventilatory support of patients with hypercapnic respiratory failure and insufficiency.

Fibroproliferative phase of ARDS. Clinical findings and effects of corticosteroids.

Most patients with adult respiratory distress syndrome (ARDS) survive the initial insult which caused respiratory failure only to succumb later to sepsis caused by nosocomial pneumonia or to pulmonary fibrosis. Clinical criteria and analysis of the tracheal aspirate are notoriously inadequate for establishing a diagnosis of ventilator-associated pneumonia. We implemented a comprehensive diagnostic protocol to determine the cause of sepsis in ARDS patients who had been ventilated for more than three days and who had no bronchoscopic evidence of pneumonia. Nine patients with late ARDS who had fever (89 percent), leukocytosis (89 percent), a new localized infiltrate (78 percent), purulent tracheal secretions (89 percent), low systemic vascular resistance (50 percent), and marked uptake of gallium in the lungs (100 percent) had no source of infection identified. Open-lung biopsy specimens from seven patients showed the fibroproliferative phase of diffuse alveolar damage and confirmed absence of pneumonia. Treatment with prolonged high doses of corticosteroids was associated with a marked and rapid improvement in lung injury score (p less than 0.003 at five days). Our findings indicate that the fibroproliferative process occurring in the lungs of patients with late ARDS gives rise to clinical manifestations identical to those of pneumonia and is potentially responsive to steroid treatment.

Causes of fever and pulmonary densities in patients with clinical manifestations of ventilator-associated pneumonia.

BACKGROUND: Ventilator-associated pneumonia, a leading cause of sepsis in patients with acute respiratory failure, is difficult to distinguish clinically from other processes affecting patients receiving mechanical ventilation. We conducted a prospective study of patients with suspected ventilator-associated pneumonia to identify the causes of fever and densities on chest radiographs and to evaluate the diagnostic yield and efficiency of tests used alone and in combination. METHODS: The 50 patients entered into the study underwent a systematic diagnostic protocol designed to identify all potential causes of fever and pulmonary densities. Diagnoses responsible for fever were established by strict diagnostic criteria for 45 of the 50 patients. The prevalence of specific conditions and diagnostic yield of individual tests were used to formulate a simplified diagnostic protocol. RESULTS: The diagnostic protocol identified 78 causes of fever (median 2 per patient). Infections were the leading causes of fever and pulmonary densities. Of the 45 patients with fever, 37 had one or more infections identified (67 sources). Most infections (84 percent) were one of four types:pneumonia, sinusitis, catheter-related infection, or urinary tract infection. Ventilator-associated pneumonia occurred in only 42 percent. All but nine infections (87 percent) were directly or indirectly related to insertion of a catheter or a tube. Concomitant infections were frequent (62 percent), particularly in patients with sinusitis (100 percent), catheter-related infections (93 percent), and pneumonia (74 percent). Of concomitant infections, 60 percent were caused by a different pathogen. Noninfectious causes of fever were more common in the 22 patients with adult respiratory distress syndrome. Histologically proved pulmonary fibroproliferation was the only cause of fever in 25 percent of patients with adult respiratory distress syndrome. Radiographic densities were caused by an infection in only 20 patients (19 pneumonia, 1 empyema). In more than 50 percent of the 25 patients without adult respiratory distress syndrome, congestive heart failure, and atelectasis were the sole causes of pulmonary densities, and fever always originated from an extrapulmonary site of infection. Used in combination, bronchoscopy with protected sampling, computed tomographic scan of the sinuses, and cultures of maxillary sinus aspirate, central intravenous or arterial lines, urine, and blood identified 58 of the 78 sources of fever (74 percent). CONCLUSIONS: The observations in this study document the complex nature of acute respiratory failure and fever and underscore the need for accuracy in diagnosis. The frequent occurrence of multiple infectious and noninfectious processes justifies a systematic search for source of fever, using a comprehensive diagnostic protocol. A simplified diagnostic protocol was devised based on the diagnostic value of individual tests.

Corticosteroid rescue treatment of progressive fibroproliferation in late ARDS. Patterns of response and predictors of outcome.

Pulmonary fibroproliferation (PFP) is directly or indirectly the leading cause of death in patients with late ARDS. We previously reported our experience using intravenous corticosteroids (IVC) in 8 patients with late ARDS and now have expanded our observation to a total of 25 patients with severe fibroproliferation (mean lung injury score [LIS] 3) and progressive respiratory failure (RF). Thirteen patients had open-lung biopsy before treatment. Patients were started on IVC treatment (IVCT) an average of 15 +/- 7.5 days into mechanical ventilation (MV). Significant physiologic improvement (SPI) to IVCT was defined as a reduction in LIS of greater than 1 point or an increase in PaO2:FIO2 ratio of greater than 100. We observed three patterns of response: rapid responders (RR) had an SPI by day 7 (n = 15); delayed responders (DR) had an SPI by day 14 (n = 6); nonresponders (NR) were without SPI by day 14 (n = 4). Overall the following significant mean changes were seen within 7 days of IVCT: LIS from 3 to 2 (p = 0.001), PaO2:FIO2 from 162 to 234 (p = 0.0004), PEEP from 11 to 6.8 cm H2O (p = 0.001), chest radiograph score from 3.8 to 3.0 (p = 0.009), and VE from 16 to 13.6 L/min (p = 0.01). Development of pneumonia was related to the pattern of response. Surveillance bronchoscopy was effective in identifying pneumonia in eight afebrile patients. Nineteen of 25 (76 percent) patients survived the ICU admission. Comparisons were made between survivors (S) and nonsurvivors (NS) and among the three groups of responders. At the time ARDS developed, no physiologic or demographic variable could discriminate between S and NS. At the time of IVCT, only liver failure was more frequent in nonsurvivors (p = 0.035). Histologic findings at open-lung biopsy and pattern of physiologic response clearly predicted outcome. The presence of preserved alveolar architecture (p = 0.045), myxoid type fibrosis (p = 0.045), coexistent intraluminal bronchiolar fibrosis (p = 0.0045), and lack of arteriolar subintimal fibroproliferation (p = 0.045) separated S from NS. ICU survival rate was 86 percent in responders and 25 percent in nonresponders (p = 0.03). Only one death resulted from refractory respiratory failure.

Airflow limitation is underrecognized in well-functioning older people.

OBJECTIVES: Dyspnea is a common symptom in older people. A reduced forced expiratory volume in 1 second (FEV1) is associated with a higher mortality rate from cardiovascular and respiratory disease, and increased admissions to hospitals. Underrecognized or undertreated airflow limitation may exacerbate the problem. The purpose of this study was to assess the prevalence and treatment of airflow limitation in a cohort of well-functioning older people. DESIGN: Cross-sectional study. SETTING: Baseline of a clinical-epidemiological study of incident functional limitation. PARTICIPANTS: Participants attended the baseline examination of the Health, Aging, and Body Composition study, a prospective cohort study of 3,075 well-functioning subjects age 70 to 79. MEASUREMENTS: Demographic and clinical data were collected by interview. Spirometry was performed unless contraindicated and repeated until three acceptable sets of flow-volume loops were obtained. Patients on bronchodilator medications had spirometry performed posttherapy. Blinded readers assessed the flow-volume loops, and inadequate tests were omitted from analysis. Airflow limitation was defined as a reduced forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) as determined by age-, sex-, and race-normalized values. Severity of airflow limitation was defined by American Thoracic Society criteria. RESULTS: Two thousand four hundred eighty-five subjects (80.8%) had assessable spirometry and data on treatment and diagnosis (1,265 men, 1,220 women). The mean age was 73.6 years. Two hundred sixty-two subjects (10.5%) had airflow limitation; 43 (16.4%) of these never smoked. Only 37.4% of participants with airflow limitation and 55.6% of participants with severe airflow limitation reported a diagnosis of lung disease. Only 20.5% of subjects with at least moderate airflow limitation had used a bronchodilator in the previous 2 weeks. CONCLUSION: Despite their good functional status, airflow limitation was present, and underrecognized, in a considerable proportion of our older population. The low bronchodilator use suggests a significant reservoir of untreated disease. Physicians caring for older people need to be more vigilant for both the presence, and the need for treatment, of airflow limitation.

Controversies in the diagnosis of ventilator-acquired pneumonia.

The appropriate investigation of patients with suspected VAP is controversial. Because it is unlikely that any new diagnostic technique will become available in the near future with better performance characteristics than those currently available, physicians need to tailor their diagnostic approach depending on individual patients and clinical scenarios. The most crucial factor in deciding which diagnostic approach to take is the influence that any test result would have on management. If preliminary screening tests, including Gram stain, are used to determine whether to start antibiotic therapy, invasive diagnostic techniques have an advantage over ETA. Quantitative cultures of respiratory specimens have a higher specificity than qualitative cultures and should be used if there is any possibility that a negative culture result would result in the discontinuation of antibiotic therapy. Physicians are caught between the need to treat VAP promptly with appropriate antibiotics and the undeniable problems of multidrug-resistant bacteria and their association with inappropriate antibiotic use. When clinically possible, a diagnostic strategy should be chosen that maximizes the possibility of limiting broad-spectrum antibiotic use. To give physicians greater comfort in the ability to withhold or discontinue antibiotics safely, further research is needed into the appropriate diagnostic strategies in different clinical settings that make this possible. The studies by Fagon et al and Singh et al are important steps in this direction.

Ventilator-associated pneumonia. Failure to respond to antibiotic therapy.

VAP is clearly associated with an increased mortality, principally because of virulent pathogens such as P. aeruginosa. Part of the increased mortality may be due to inadequacies of antibiotic therapy. Apparent failure of antibiotic therapy has many causes; some are related to deficiencies of the antibiotic therapy, but others are unrelated. Antibiotic failure can be the result of persistence of the original causative organism because of resistance, inadequate local antibiotic levels, anatomic limitations, or to the development of superinfection, either pneumonia or extrapulmonary. Factors probably unrelated to the adequacy of antibiotic regimens include misdiagnosis of the source of infection or causative organism, SIRS associated with the VAP, and the immunocompetency of the host. The pattern of apparent failure can assist in determination of the cause. Four typical patterns are rapid early progression; persistent pneumonia; initial improvement followed by deterioration; and slow, progressive improvement. The deficiencies of tracheal aspirate cultures and portable chest radiographs make determination of the cause of apparent failure difficult by these methods. Therefore, more accurate but invasive or expensive tests are usually required to avoid spiraling empirical antibiotic therapy. Quantitative bronchoscopic cultures and chest CT scans are most likely to lead to an accurate evaluation and appropriate antibiotic changes.

Ventilator-associated pneumonia caused by Pseudomonas infection.

So far, P. aeruginosa has matched each new therapeutic advance with an antibiotic resistance or toxin move of its own. The result has been a persistently high mortality rate for Pseudomonas pneumonia, which is unacceptable. Further research to define aspects of the organism important in infection and to determine more effective treatment and prevention strategies are clearly needed.

Pharmacoeconomics of pneumonia.

Because diagnosis and treatment are so intimately linked, the pharmacoeconomics of treatment of ventilator-associated pneumonia (VAP) is impossible to discuss without discussing the cost-effectiveness of VAP diagnosis. The cost of VAP treatment is more complex than simply drug acquisition and administration costs. The critical factor in cost-effective therapy is the avoidance of inappropriate or ineffective therapy. The second most important benefit of a more accurate diagnostic strategy, such as the use of quantitative cultures, is the ability either to stop or to withhold antibiotics if the quantitative culture is negative. Therefore, the benefit of any diagnostic strategy must be evaluated principally from the aspect of these resultant changes in management. Reassurance or concern about an alternative site of infection or cause of fever will also add to the benefit or cost of more accurate diagnosis of VAP. The baseline antibiotic treatment strategy of the specific intensive care unit (ICU) will determine, to a large degree, the cost of antibiotics and the efficacy of empiric regimens. In the final analysis, pharmacy costs and cost of diagnostic testing for VAP must be based on outcome analysis, including comparison of the more expensive aspects of care, such as mortality, length of mechanical ventilation, and length of ICU stay.