Persistency of Pseudomonas aeruginosa in sputum cultures and clinical outcomes in adult patients with cystic fibrosis.

Our objective was to describe the natural history of infection with transmissible and unique strains of P. aeruginosa (PA) in adult CF patients and to determine if clearance of PA from sputum was associated with an improvement in clinical status. This was a 3-year prospective cohort study of adult patients with CF. Sputum was collected at baseline and annually. Rate of decline of FEV1, BMI, exacerbation rate, and time to death or transplant were compared between patients who cleared PA versus those in whom PA was persistent. A total of 373 patients were included in the study, 75% were infected with PA at baseline; 24% were infected with transmissible strains and 51% with unique strains. Patients infected with unique strains were more likely to clear PA from their sputum over 3 years compared to those infected with transmissible strains (19% vs 10%, P=0.05). Declines in FEV1 and rates of pulmonary exacerbations, deaths, or lung transplants were not different between patients who cleared PA compared to those who remained persistently infected. No clinical benefit was identified in patients who cleared PA from sputum compared to those who remained persistently infected.

Confirmation of asthma in an era of overdiagnosis.

It was recently shown that 30% of adults with a physician diagnosis of asthma did not have asthma when objectively assessed using a four-step algorithm involving serial spirometry, bronchial challenge testing and subsequent tapering of asthma medications. The objective of the present study was to determine how many steps in the algorithm were required in order to confirm asthma, and whether any patient-related variables were associated with earlier asthma confirmation. A total of 540 subjects with a previous physician diagnosis of asthma were randomly recruited from the community. The number of subjects confirmed with asthma at each study visit was calculated. Regression analysis was used to determine variables associated with earlier asthma confirmation. Of the 499 subjects who completed the diagnostic algorithm, 346 (69%) had asthma confirmed and 150 (30%) had asthma excluded. Of subjects in whom asthma was confirmed, including those using regular asthma controlling medications, >90% were confirmed with only one or two study visits, by either pre- and post-bronchodilator spirometry or a single bronchial challenge test. Only 46 (9%) out of 499 subjects required tapering of asthma medications and repeated bronchial challenge tests for exclusion or confirmation of asthma. Lower forced expiratory volume in 1 s and younger age were associated with earlier asthma confirmation. For the majority with a previous physician diagnosis of asthma, only pre- and post-bronchodilator spirometry and a single methacholine challenge test are required in order to confirm asthma.

Cost effectiveness of therapy with combinations of long acting bronchodilators and inhaled steroids for treatment of COPD.

BACKGROUND: Little is known about the combination of different medications in chronic obstructive pulmonary disease (COPD). This study determined the cost effectiveness of adding salmeterol (S) or fluticasone/salmeterol (FS) to tiotropium (T) for COPD. METHODS: This concurrent, prospective, economic analysis was based on costs and health outcomes from a 52 week randomised study comparing: (1) T 18 microg once daily + placebo twice daily (TP group); (2) T 18 microg once daily + S 25 microg/puff, 2 puffs twice daily (TS group); and (3) T 18 microg once daily + FS 250/25 microg/puff, 2 puffs twice daily (TFS group). The incremental cost effectiveness ratios (ICERs) were defined as incremental cost per exacerbation avoided, and per additional quality adjusted life year (QALY) between treatments. A combination of imputation and bootstrapping was used to quantify uncertainty, and extensive sensitivity analyses were performed. RESULTS: The average patient in the TP group generated CAN$2678 in direct medical costs compared with $2801 (TS group) and $4042 (TFS group). The TS strategy was dominated by TP and TFS. Compared with TP, the TFS strategy resulted in ICERs of $6510 per exacerbation avoided, and $243,180 per QALY gained. In those with severe COPD, TS resulted in equal exacerbation rates and slightly lower costs compared with TP. CONCLUSIONS: TFS had significantly better quality of life and fewer hospitalisations than patients treated with TP but these improvements in health outcomes were associated with increased costs. Neither TFS nor TS are economically attractive alternatives compared with monotherapy with T.

Methodological issues in therapeutic trials of COPD.

The recent Towards a Revolution in COPD Health (TORCH) randomised trial replicated the findings of previous trials in chronic obstructive pulmonary disease (COPD) on the apparent effectiveness of inhaled corticosteroids (ICS) in reducing exacerbation rates, but not so for mortality. In the present article, the authors review methodological issues in the TORCH and previous trials, such as patients already receiving ICS before randomisation and the absence of follow-up after study drug discontinuation, using data from two trials. First, among previous ICS users in the Canadian Optimal Therapy of COPD Trial, the hazard ratio of the first exacerbation with ICS relative to bronchodilators was 0.71 (95% confidence interval (CI) 0.53-0.96), while among those not using ICS prior to randomisation, it was 1.11 (95% CI 0.69-1.79). Secondly, the rate ratio of exacerbations with ICS was 0.78 (95% CI 0.61-0.99) prior to drug discontinuation during follow-up and 1.23 (95% CI 0.78-1.95) thereafter. Finally, a 2x2 factorial analysis of the TORCH data found a rate ratio of mortality for the salmeterol component to be 0.83 (95% CI 0.74-0.95), while for the fluticasone component it was 1.00 (95% CI 0.89-1.13). In conclusion, after proper consideration of the various methodological shortcomings in the design and analysis of randomised trials, the effectiveness of inhaled corticosteroids in treating chronic obstructive pulmonary disease remains doubtful, while the benefit observed with combination therapy may be due exclusively to the beneficial effects of the long-acting bronchodilator alone.

Counting, analysing and reporting exacerbations of COPD in randomised controlled trials.

BACKGROUND: Clinical trials measure exacerbations of chronic obstructive pulmonary disease (COPD) inconsistently. A study was undertaken to determine if different methods for ascertaining and analysing COPD exacerbations lead to biased estimates of treatment effects. METHODS: Information on the methods used to count, analyse and report COPD exacerbation rates was abstracted from clinical trials of long-acting bronchodilators or long-acting bronchodilator/inhaled steroid combination products published between 2000 and 2006. Data from the Canadian Optimal Therapy of COPD Trial was used to illustrate how different analytical approaches can affect the estimate of exacerbation rates and their confidence intervals. RESULTS: 22 trials (17,156 patients) met the inclusion criteria and were reviewed. None of the trials adjudicated exacerbations or determined independence of events. 14/22 studies (64%) introduced selection bias by not analysing outcome data for subjects who prematurely stopped study medications. Only 31% of trials used time-weighted analyses to calculate the mean number of exacerbations/patient-year and only 15% accounted for between-subject variation. In the Canadian Optimal Therapy of COPD Trial the rate ratio for exacerbations/patient-year was 0.85 when all data were included in a time-weighted analysis, but was overestimated as 0.79 when data for those who prematurely stopped study medications were excluded and was further overestimated as 0.46 when a time-weighted analysis was not conducted; p values ranged from 0.03 to 0.24 depending on how exacerbations were determined and analysed. CONCLUSIONS: Clinical trials have used widely different methods to define and analyse COPD exacerbations and this can lead to biased estimates of treatment effects. Future trials should strive to include blinded adjudication and assessment of the independence of exacerbation events, and trials should report time-weighted intention-to-treat analyses with adjustments for between-subject variation in COPD exacerbations.

Sex differences in the clinical presentation and management of airflow obstruction.

The aim of the present study was to explore differences in the clinical expression, clinical diagnoses and management of airway diseases in a primary-care setting. Patients aged >or=35 yrs who had ever smoked were enrolled when they presented for any reason to one of eight rural primary-care practices. Respiratory symptom questionnaires and spirometry were administered. In total, 1,034 patients had acceptable and reproducible spirometry, of whom 550 (53%) were males and 484 (47%) were females. Males smoked more than females (41.2 versus 29.2 pack-yrs) respectively, and were more likely to have a pre-bronchodilator forced expiratory volume in one second/forced vital capacity <0.70 at 22.4 versus 11.8%, respectively. However, more females than males reported breathlessness (51.0 versus 42.8%, respectively), a prior diagnosis compatible with airflow obstruction and taking respiratory medications (23.4 versus 14.9%, respectively). In conclusion, the current results suggest that females are more likely than males to report breathlessness and be prescribed respiratory medications independent of differences in the severity of airflow obstruction.

Predictors of pulmonary exacerbations in patients with cystic fibrosis infected with multi-resistant bacteria.

BACKGROUND: This study examined characteristics of adult and adolescent patients with cystic fibrosis (CF) to determine factors associated with an increased risk of pulmonary exacerbations. METHODS: 249 patients with CF infected with multidrug resistant bacteria were recruited and prospectively followed for up to 4.5 years until they experienced a pulmonary exacerbation severe enough to require intravenous antibiotics. Multivariable regression analyses were used to compare the characteristics of patients who experienced an exacerbation with those who did not. RESULTS: 124 of the 249 patients (50%) developed a pulmonary exacerbation during the first year and 154 (62%) experienced an exacerbation during the 4.5 year study period. Factors predictive of exacerbations in a multivariable survival model were younger age (OR 0.98, 95% CI 0.96 to 0.99), female sex (OR 1.45, 95% CI 1.07 to 1.95), lower forced expiratory volume in 1 second (FEV(1)) (OR 0.98, 95% CI 0.97 to 0.99), and a previous history of multiple pulmonary exacerbations (OR 3.16, 95% CI 1.93 to 5.17). Chronic use of inhaled corticosteroids was associated with an increased risk of exacerbation (OR 1.92, 95% CI 1.00 to 3.71) during the first study year. CONCLUSIONS: Patients who experience pulmonary exacerbations are more likely to be younger, female, using inhaled steroids, have a lower FEV(1), and a history of multiple previous exacerbations. It is hoped that knowledge of these risk factors will allow better identification and closer monitoring of patients who are at high risk of exacerbations.

Sputum versus bronchoscopy for diagnosis of Pseudomonas aeruginosa biofilms in cystic fibrosis.

The present authors hypothesised that bronchoscopy with protected specimen brush may sample biofilm-forming bacteria adherent to the airway wall, whereas traditional sputum collection may not. Pseudomonas aeruginosa obtained from sputum, bronchoalveolar lavage and protected brush, taken from the right upper lung bronchus of 12 adult patients with cystic fibrosis, were compared. Retrieved bacteria were genotyped, and grown in planktonic cultures and as biofilms, and susceptibilities to individual antibiotics and to antibiotic combinations were determined. Bacterial cultures obtained using bronchoscopy did not yield any new strains of bacteria that were not also found in sputum. A total of 10 patients (83%) had a single strain of P. aeruginosa found using sputum, bronchoalveolar lavage and protected brush techniques, and two patients (17%) had two strains recovered in sputum, but only one strain was recovered using bronchoscopic techniques. Susceptibility to single antibiotics and to antibiotic combinations were not different between planktonically or biofilm-grown bacteria derived from sputum, as compared to those obtained by bronchoalveolar lavage and protected brush. In conclusion, sputum collection provides as much information as bronchoscopy for characterising the genotype and antibiotic susceptibility of chronic Pseudomonas aeruginosa infection in patients with stable cystic fibrosis.

The Canadian C-spine rule for radiography in alert and stable trauma patients.

CONTEXT: High levels of variation and inefficiency exist in current clinical practice regarding use of cervical spine (C-spine) radiography in alert and stable trauma patients. OBJECTIVE: To derive a clinical decision rule that is highly sensitive for detecting acute C-spine injury and will allow emergency department (ED) physicians to be more selective in use of radiography in alert and stable trauma patients. DESIGN: Prospective cohort study conducted from October 1996 to April 1999, in which physicians evaluated patients for 20 standardized clinical findings prior to radiography. In some cases, a second physician performed independent interobserver assessments. SETTING: Ten EDs in large Canadian community and university hospitals. PATIENTS: Convenience sample of 8924 adults (mean age, 37 years) who presented to the ED with blunt trauma to the head/neck, stable vital signs, and a Glasgow Coma Scale score of 15. MAIN OUTCOME MEASURE: Clinically important C-spine injury, evaluated by plain radiography, computed tomography, and a structured follow-up telephone interview. The clinical decision rule was derived using the kappa coefficient, logistic regression analysis, and chi(2) recursive partitioning techniques. RESULTS: Among the study sample, 151 (1.7%) had important C-spine injury. The resultant model and final Canadian C-Spine Rule comprises 3 main questions: (1) is there any high-risk factor present that mandates radiography (ie, age >/=65 years, dangerous mechanism, or paresthesias in extremities)? (2) is there any low-risk factor present that allows safe assessment of range of motion (ie, simple rear-end motor vehicle collision, sitting position in ED, ambulatory at any time since injury, delayed onset of neck pain, or absence of midline C-spine tenderness)? and (3) is the patient able to actively rotate neck 45 degrees to the left and right? By cross-validation, this rule had 100% sensitivity (95% confidence interval [CI], 98%-100%) and 42.5% specificity (95% CI, 40%-44%) for identifying 151 clinically important C-spine injuries. The potential radiography ordering rate would be 58.2%. CONCLUSION: We have derived the Canadian C-Spine Rule, a highly sensitive decision rule for use of C-spine radiography in alert and stable trauma patients. If prospectively validated in other cohorts, this rule has the potential to significantly reduce practice variation and inefficiency in ED use of C-spine radiography.

Vasopressin versus epinephrine for inhospital cardiac arrest: a randomised controlled trial.

BACKGROUND: Survival rates for cardiac arrest patients, both in and out of hospital, are poor. Results of a previous study suggest better outcomes for patients treated with vasopressin than for those given epinephrine, in the out-of-hospital setting. Our aim was to compare the effectiveness and safety of these drugs for the treatment of in-patient cardiac arrest. METHODS: We did a triple-blind randomised trial in the emergency departments, critical care units, and wards of three Canadian teaching hospitals. We assigned adults who had cardiac arrest and required drug therapy to receive one dose of vasopressin 40 U or epinephrine 1 mg intravenously, as the initial vasopressor. Patients who failed to respond to the study intervention were given epinephrine as a rescue medication. The primary outcomes were survival to hospital discharge, survival to 1 h, and neurological function. Preplanned subgroup assessments included patients with myocardial ischaemia or infarction, initial cardiac rhythm, and age. FINDINGS: We assigned 104 patients to vasopressin and 96 to epinephrine. For patients receiving vasopressin or epinephrine survival did not differ for hospital discharge (12 [12%] vs 13 [14%], respectively; p50.67; 95% CI for absolute increase in survival 211.8% to 7.8%) or for 1 h survival (40 [39%] vs 34 [35%]; p50.66; 210.9% to 17.0%); survivors had closely similar median mini-mental state examination scores (36 [range 19-38] vs 35 [20-40]; p50.75) and median cerebral performance category scores (1 vs 1). INTERPRETATION: We failed to detect any survival advantage for vasopressin over epinephrine. We cannot recommend the routine use of vasopressin for inhospital cardiac arrest patients, and disagree with American Heart Association guidelines, which recommend vasopressin as alternative therapy for cardiac arrest.