Miu Lam

Changes in lung hyperinflation, dyspnea, and exercise endurance are important outcomes in assessing therapeutic responses in chronic obstructive pulmonary disease (COPD). Therefore, we studied the reproducibility of Borg dyspnea ratings, inspiratory capacity (IC; to monitor lung hyperinflation), and endurance time during constant-load symptom-limited cycle exercise in 29 patients with COPD (FEV1 = 40 +/- 2% predicted; mean +/- SEM). Responsiveness was also studied by determining the acute effects of nebulized 500 micrograms ipratropium bromide (IB) or saline placebo (P) on these measurements. During each of four visits conducted over an 8-wk period, spirometry and exercise testing were performed before and 1 h after receiving IB or P (randomized, double-blinded). Highly reproducible measurements included: endurance time (intraclass correlation R = 0.77, p < 0.0001); Borg ratings and IC at rest, at a standardized exercise time (STD), and at peak exercise (R > 0.6, p < 0.0001); and slopes of Borg ratings over time, oxygen consumption (V O2), and ventilation (R > 0.6, p < 0.0001). Responsiveness was confirmed by finding a significant drug effect for: change (Delta) in endurance time (p = 0.0001); DeltaBorgSTD and DeltaBorg-time slopes (p < 0.05); and DeltaIC at rest, at STD, and at peak exercise (p = 0.0001). With all completed visits, DeltaBorgSTD correlated better with DeltaICSTD than any other resting or exercise parameter (n = 115, r = -0.35, p < 0.001). We concluded that Borg dyspnea ratings, and measurements of IC and endurance time during submaximal cycle exercise testing are highly reproducible and responsive to change in severe COPD.

BACKGROUND: Controlled clinical trials of health care interventions are either explanatory or pragmatic. Explanatory trials test whether an intervention is efficacious; that is, whether it can have a beneficial effect in an ideal situation. Pragmatic trials measure effectiveness; they measure the degree of beneficial effect in real clinical practice. In pragmatic trials, a balance between external validity (generalizability of the results) and internal validity (reliability or accuracy of the results) needs to be achieved. The explanatory trial seeks to maximize the internal validity by assuring rigorous control of all variables other than the intervention. The pragmatic trial seeks to maximize external validity to ensure that the results can be generalized. However the danger of pragmatic trials is that internal validity may be overly compromised in the effort to ensure generalizability. We are conducting two pragmatic randomized controlled trials on interventions in the management of hypertension in primary care. We describe the design of the trials and the steps taken to deal with the competing demands of external and internal validity. DISCUSSION: External validity is maximized by having few exclusion criteria and by allowing flexibility in the interpretation of the intervention and in management decisions. Internal validity is maximized by decreasing contamination bias through cluster randomization, and decreasing observer and assessment bias, in these non-blinded trials, through baseline data collection prior to randomization, automating the outcomes assessment with 24 hour ambulatory blood pressure monitors, and blinding the data analysis. SUMMARY: Clinical trials conducted in community practices present investigators with difficult methodological choices related to maintaining a balance between internal validity (reliability of the results) and external validity (generalizability). The attempt to achieve methodological purity can result in clinically meaningless results, while attempting to achieve full generalizability can result in invalid and unreliable results. Achieving a creative tension between the two is crucial.

We wished to determine which resting spirometric parameters best reflect improvements in exercise tolerance and exertional dyspnea in response to acute high-dose anticholinergic therapy in advanced COPD. We studied 29 patients with stable COPD (FEV(1) = 40 +/- 2% predicted [%pred]; mean +/- SEM) and moderate to severe chronic dyspnea. In a double-blind placebo-controlled cross-over study, patients performed spirometry and symptom-limited constant-load cycle exercise before and 1 h after receiving 500 micrograms of nebulized ipratropium bromide (IB) or saline placebo. There were no significant changes in spirometry, exercise endurance, or exertional dyspnea after receiving placebo. In response to IB (n = 58): FEV(1), FVC, and inspiratory capacity (IC) increased by 7 +/- 1%pred, 10 +/- 1%pred, and 14 +/- 2%pred, respectively (p < 0.001), with no change in the FEV(1)/FVC ratio. After receiving IB, exercise endurance time (Tlim) increased by 32 +/- 9% (p < 0.001) and slopes of Borg dyspnea ratings over time decreased by 11 +/- 6% (p < 0.05). Percent change (%Delta) in Tlim correlated best with DeltaIC%pred (p = 0.020) and change in inspiratory reserve volume (DeltaTLC%pred) (p = 0.014), but not with DeltaFVC%pred, DeltaPEFR%pred, or DeltaFEV(1)%pred. Change in Borg dyspnea ratings at isotime near end exercise also correlated with DeltaIC%pred (p = 0.04), but not with any other resting parameter. Changes in spirometric measurements are generally poor predictors of clinical improvement in response to bronchodilators in COPD. Of the available parameters, increased IC, which is an index of reduced resting lung hyperinflation, best reflected the improvements in exercise endurance and dyspnea after IB. IC should be used in conjunction with FEV(1) when evaluating therapeutic responses in COPD.

Objective To determine the extent to which postpyloric feeding reduces gastroesophageal regurgitation and pulmonary microaspiration in critically ill patients. Design Randomized trial. Setting A medical/surgical intensive care unit at a tertiary care hospital. Participants Intensive care unit patients were expected to remain ventilated >72 hrs. We excluded patients with esophageal, gastric, or small bowel surgery in the last week and patients with overt or clinically significant gastrointestinal bleeding. We studied 33 patients; 42.4% were female, mean age (sd) was 59.2 (± 16.8) yrs, and mean Acute Physiology and Chronic Health Evaluation II score was 22.5 (7.8). Interventions Patients were randomized to gastric or postpyloric enteral feeds. Technetium 99-sulphur colloid was added to the feeds for 6 hrs of each of the first 3 days on study. Measurements and Results We sampled the oropharynx and trachea hourly for the 6 hrs per day that patients received radioisotope-labeled enteral feeds, and the level of radioactivity in these specimens was measured. We defined an episode of gastroesophageal regurgitation and microaspiration as an increase in radioactivity >100 counts per minute/g. Patients fed into the stomach had more episodes of gastroesophageal regurgitation (39.8% vs. 24.9%, p = .04) and trended toward more microaspiration (7.5% vs. 3.9%, p = .22) compared with patients fed beyond the pylorus. When the logarithmic mean of the radioactivity count was compared across groups, there was a trend toward an increase in gastroesophageal regurgitation (3.7 vs. 2.9 counts/g, p = .22) and a trend toward increased microaspiration (1.9 vs. 1.4 counts/g, p = .09) in patients fed into the stomach. Patients who had gastroesophageal regurgitation were much more likely to aspirate than patients who did not have gastroesophageal regurgitation (odds ratio: 3.2; 95% confidence interval: 1.36, 7.77). Conclusions Feeding beyond the pylorus is associated with a significant reduction in gastroesophageal regurgitation and a trend toward less microaspiration.

BACKGROUND: Authorities advocate that resistance and aerobic exercise are essential for reducing risk factors for chronic disease and disability in older adults. However, the incremental effects of combined resistance and aerobic exercise compared with either modality alone on risk factors for disease and disability is generally unknown. METHODS: Participants were 136 sedentary, abdominally obese older men and women recruited from September 30, 2002, through November 15, 2006, at Queen's University. Participants were randomized to 1 of the following 4 groups for 6 months: resistance exercise, aerobic exercise, resistance and aerobic exercise (combined exercise), or nonexercise control. Primary outcomes were analyzed by an intent-to-treat model and included changes in insulin resistance by hyperinsulinemic-euglycemic clamp and functional limitation using the average change in 4 tests combined (average z score). RESULTS: After controlling for age, sex, and baseline value, insulin resistance improved compared with controls in the aerobic exercise and the combined exercise groups but not in the resistance exercise group. Improvement (mean [SE]) in the combined exercise group was greater than in the resistance exercise group (9.2 [1.3] vs 1.8 [1.3] mg/mL/microIU per kilogram of skeletal muscle per minute x100 [P < .001]) but not in the aerobic exercise group (9.2 [1.3] vs 6.5 [1.3] mg/mL/microIU per kilogram of skeletal muscle per minute x100 [P = .46]). Functional limitation improved significantly in all groups compared with the control group. Improvement in the combined exercise group was greater than in the aerobic exercise group (0.5 [0.1] vs -0.0 [0.1]; standard units, z score [P = .003]) but not in the resistance exercise group. Improvement in the resistance exercise group was not different from the aerobic exercise group. CONCLUSION: The combination of resistance and aerobic exercise was the optimal exercise strategy for simultaneous reduction in insulin resistance and functional limitation in previously sedentary, abdominally obese older adults. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00520858.