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Currently available inhaled bronchodilators used as therapy for chronic obstructive pulmonary disease (COPD) necessitate multiple daily dosing. The present study evaluates the long-term safety and efficacy of tiotropium, a new once-daily anticholinergic in COPD. Patients with stable COPD (age 65.2+/-8.7 yrs (mean+/-SD), n=921) were enrolled in two identical randomized double-blind placebo-controlled 1-yr studies. Patients inhaled tiotropium 18 microg or placebo (mean screening forced expiratory volume in one second (FEV1) 1.01 versus 0.99 L, 39.1 and 38.1% of the predicted value) once daily as a dry powder. The primary spirometric outcome was trough FEV1 (i.e. FEV1 prior to dosing). Changes in dyspnoea were measured using the Transition Dyspnea Index, and health status with the disease-specific St. George's Respiratory Questionnaire and the generic Short Form 36. Medication use and adverse events were recorded. Tiotropium provided significantly superior bronchodilation relative to placebo for trough FEV1 response (approximately 12% over baseline) (p<0.01) and mean response during the 3 h following dosing (approximately 22% over baseline) (p<0.001) over the 12-month period. Tiotropium recipients showed less dyspnoea (p<0.001), superior health status scores, and fewer COPD exacerbations and hospitalizations (p<0.05). Adverse events were comparable with placebo, except for dry mouth incidence (tiotropium 16.0% versus placebo 2.7%, p<0.05). Tiotropium is an effective, once-daily bronchodilator that reduces dyspnoea and chronic obstructive pulmonary disease exacerbation frequency and improves health status. This suggests that tiotropium will make an important contribution to chronic obstructive pulmonary disease therapy.

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Noninvasive and invasive tests have been developed and studied for their utility in diagnosing and guiding the treatment of hospital-acquired pneumonia, a condition with an inherently high mortality. Early empiric antibiotic treatment has been shown to reduce mortality, so delaying this treatment until test results are available is not justifiable. Furthermore, tailoring therapy based on results of either noninvasive or invasive tests has not been clearly shown to affect morbidity and mortality. This may be related to quantitative limitations of these tests or possibly to a high false-negative rate in patients who receive early antibiotic treatment and may therefore have suppressed bacterial counts. Results of these tests, however, do influence treatment. It is therefore hoped that they may ultimately provide a rational basis for making therapeutic decisions. In the future, outcomes research should be a part of large-scale clinical trials, and noninvasive and invasive tests should be incorporated into the design in an attempt to provide a better understanding of the value of such tests.

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The value of medical therapy for acute exacerbations of chronic bronchitis generally increases with the severity of the episode. Antibiotics have a definite but limited benefit in severe cases. Systemic corticosteroids are valuable during hospitalization, but not after the patient has been discharged. Once recovery has occurred, pulmonary rehabilitation can improve quality of life.

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Community-acquired pneumonia (CAP) remains a common and serious clinical problem despite the availability of potent antibiotics and aggressive supportive measures. The management of CAP begins with recognition of the likely pathogens causing the illness in the individual patient; identification of several simple clinical clues allows the organization of the broad variety of possible organisms into a more manageable list of likely pathogens. Once the most likely pathogens are identified, then initial antibiotics may be chosen to cover those possibilities. A number of treatment guidelines have been introduced in the past 10 years, most of which share more similarities than differences. We review 2 of the more established guidelines, those published by the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA). We also review the likely modifications of the ATS guidelines and discuss the impact of bacterial resistance on antibiotic choices.

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Pulmonary rehabilitation measures acquired a poor reputation when early studies failed to demonstrate improvements in traditional pulmonary function tests. However, current evidence now indicates that such measures benefit patients with severe chronic obstructive pulmonary disease (COPD). Alleviation of symptoms, improved quality of life, improved nutrition, and decreased health care costs are some of the benefits seen in patients who successfully complete a rehabilitation program. This article reviews the role of a comprehensive rehabilitation program in the continuing care of the patient with severe COPD, the components of such a program, and specific measures to be considered.

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BACKGROUND: Despite the availability of potent antibiotics and intensive care, mortality rates from septic shock are 40-70%. We assessed the safety and efficacy of murine monoclonal antibody to human tumour necrosis factor alpha (TNF alpha MAb) in the treatment of septic shock. METHODS: In a randomised, multicentre, double-blind, placebo-controlled clinical trial in 105 hospitals in the USA and Canada, we randomly assigned 1879 patients a single infusion of 7.5 mg/kg TNF alpha MAb (n=949) or placebo (0.25% human serum albumin n=930). Our main outcome measurement was the rate of all-cause mortality at 28 days. FINDINGS: 382 (40.3%) of 948 patients who received TNF alpha MAb and 398 (42.8%) of 930 who received placebo had died at 28 days (95% CI -0.02 to 0.07, p=0.27). We found no association between therapy with TNF alpha MAb and increased rapidity in reversal of initial shock or prevention of subsequent shock. Similarly, baseline plasma interleukin-6 concentrations of more than 1000 pg/mL or detectable circulating TNF concentrations were not associated with improvement in survival after TNF alpha MAb therapy. Coagulopathy but not other organ or system failures, was significantly decreased in the TNF alpha MAb group compared with placebo (day 7, p<0.001; day 28, p=0.005). Serious adverse events were reported in 55.2% of patients given placebo and 54.1% in the TNF alpha MAb group. INTERPRETATION: We did not find an improvement in survival after septic shock with TNF alpha MAb. Therapy not solely dependent on TNF alpha blockade may be required to improve survival.

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Community-acquired pneumonia (CAP) remains a major cause of morbidity and mortality in the United States. The ideal of a simple diagnostic evaluation yielding a specific etiologic diagnosis allowing directed antimicrobial therapy remains elusive. Empiric therapy is justified as initial management, as the specific bacteriological etiology of most cases of CAP is usually unknown, and delaying therapy while attempting to find a diagnosis may be injurious to the patient. Guidelines have been developed to assist in the recognition and evaluation of CAP based on age and underlying medical illness as predictors of outcome. While these criteria are by no means perfect and cannot be applied to every individual, they offer a rational approach to the initial management of the patient.

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The intrapulmonary pharmacokinetics of oral azithromycin were studied in 25 healthy volunteers, each of whom received an initial dose of 500 mg and then 250 mg once daily for four additional doses. Bronchoscopy, bronchoalveolar lavage, and venipuncture were performed 4, 28, 76, 124, 172, 244, 340, and 508 h after the first dose was administered. Azithromycin concentrations in epithelial lining fluid (ELF), alveolar macrophages, peripheral blood monocytes, and serum were measured by high-performance liquid chromatography. Azithromycin was extensively concentrated in cells and ELF. Drug concentrations in AMs (peak mean +/- standard deviation, 464 +/- 65 micrograms/ml) exceeded 80 micrograms/ml up to 508 h (21 days) following the first dose, while concentrations in PBMs (peak, 124 +/- 28 micrograms/ml) exceeded 20 micrograms/ml up to 340 h (14 days). Azithromycin concentrations in ELF peaked at 124 h (3.12 +/- 0.93 micrograms/ml) and were detectable up to 172 h (7 days), when they were 20 times the concurrent serum concentrations. Although the clinical significance of antibiotic concentrations in these compartments is nuclear, the sustained lung tissue penetration and extensive phagocytic accumulation demonstrated in this study support the proven efficacy of azithromycin administered on a 5-day dosage schedule in the treatment of extracellular or intracellular pulmonary infections.

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In response to the current emphasis on health maintenance and disease prevention, the authors developed a comprehensive education program in which sophomore medical students interview a standardized patient about breast problems and risk factors, receive one-on-one instruction from the standardized patient during the clinical breast examination, and practice recommendations for screening and instruction in breast self-examination. In this pilot study sophomore students who underwent the comprehensive education program were compared with students who received the traditional, didactic instruction and practiced on plastic breast models. The students who received the didactic instruction had mean scores on a multiple-choice knowledge-base pretest and posttest of 54.6% and 76.8%, respectively. The students who participated in the comprehensive education program had mean pretest and posttest scores of 51.2% and 78.5%, respectively. All students participated in a practical test of the clinical breast examination during an objective structured clinical examination. The students who had received the didactic instruction scored 69.9% (mean), compared with 84.1% for the students who had had the comprehensive education program. The comprehensive breast education program teaches medical students about risk factors, screening recommendations, and clinical breast examination more effectively than do traditional didactic methods.

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