Sex differences and determinants of anxiety symptoms in patients with COPD initiating pulmonary rehabilitation.

BACKGROUND: Anxiety is common in patients with chronic obstructive pulmonary disease (COPD). However, there is little evidence available regarding gender differences, and severity of dyspnea in relation to anxiety in patients with COPD. AIMS: We examined gender differences and the association of dyspnea with anxiety in a cohort of patients with COPD prior to entering a pulmonary rehabilitation (PR) program. METHOD: We analyzed data from a prospective cohort of COPD patients who attended PR from 2013 to 2019 in Lytham, Lancashire, UK. Patients were aged 40 years or older with a post-bronchodilation forced expiratory volume in 1 s (FEV1) less than 80 % of the predicted normal value and FEV1/FVC (forced vital capacity) ratio less than 0.7. We assessed quality of life (QoL) using the Saint George's Respiratory Questionnaire (SGRQ), anxiety using the Anxiety Inventory for Respiratory disease (AIR), dyspnea using the modified Medical Research Council (mMRC) scale, and exercise capacity using the Incremental Shuttle Walk Test (ISWT). RESULTS: Nine hundred ninety-three patients with COPD (mean age = 71 years, FEV1/FVC = 58 % predicted, 51 % male) entered the PR program. Of these, 348 (35 %) had anxiety symptoms (AIR ≥8); of these 165 (47 %) were male and 183 (53 %) female, (χ2 = 3.33, p = 0.06). On logistic multivariate analysis, the following variables were independently associated with elevated anxiety: younger age (p < 0.001), female sex (p = 0.03), higher SGRQ-total score (p < 0.001) and high FEV1/FVC (p < 0.002). Dyspnea was associated with anxiety r = 0.25, p < 0.001. CONCLUSION: Over a third of COPD patients had clinically relevant anxiety symptoms with a higher prevalence in women than men. Anxiety was associated with younger age, female gender, and impaired QoL. Early recognition and treatment of anxiety in patients with COPD is worthy of consideration for those attending PR, especially women.

Physiological responses to linear treadmill and cycle ergometer exercise in COPD.

Incremental cardiopulmonary exercise testing work rate ideally increases linearly to the subject's tolerance within approximately 10 min. Widely used treadmill protocols often yield shorter exercise times in debilitated patients. We compared a recently described treadmill protocol featuring linear work rate increase, weight adjustments and a priori exercise tolerance estimates with standard cycle and treadmill protocols. We also compared treadmill and cycle responses to examine mechanisms of oxyhaemoglobin desaturation differences. In total, 16 subjects with chronic obstructive pulmonary disease (COPD; mean+/-sd forced expiratory volume in 1 s of 36.5+/-10.9% predicted) performed incremental exercise using cycle, linear treadmill and modified Bruce protocols. Initial linear treadmill speed and grade yielded oxygen uptake (V'(O(2))) similar to cycle unloaded pedalling; Bruce protocol first stage elicited much higher V'(O(2)). Exercise duration was much shorter in Bruce than in cycle or linear treadmill protocols. At peak exercise, greater desaturation was noted in linear treadmill and Bruce protocols compared with cycle (-8.9+/-4.9 versus -8.5+/-4.7 versus -3.7+/-3.3%; p<0.001); at iso-V'(O(2)) values this difference widened as exercise proceeded. Iso-V'(O(2)) desaturation differences were largely related to higher ventilatory response to cycle than to treadmill exercise. The linear incremental treadmill protocol generates responses similar to cycle ergometry in severe COPD. However, cycle ergometry elicits less desaturation than does ambulation, making the linear treadmill protocol advantageous when evaluating COPD patients.

Developing concepts in the pulmonary rehabilitation of COPD.

Randomised trials have demonstrated that pulmonary rehabilitation (PR) can improve dyspnoea, exercise tolerance and health related quality of life. Rehabilitation has traditionally been provided in secondary care to patients with moderate to severe disease. Current concepts are however recommending that it should be delivered in a primary and community care setting for patients with milder disease. There are several opportunities for spreading the word for PR in primary care. One of these is to improve access to PR for all those disabled by their disease by the increase of community schemes and one such scheme being utilised in Canada is reviewed. The essential components of PR include behavior change, patient self-management and prescriptive exercise. In the last decade new strategies have been developed to enhance the effects of exercise training. An overview of these new approaches being an adjunct to exercise training is reviewed. Although the role of exercise training is well established, we are only just beginning to appreciate the importance of behavior change and patient self-management in contributing to improved health and diminished healthcare resource utilisation.

Instantaneous quantification of skeletal muscle activation, power production, and fatigue during cycle ergometry.

A rapid switch from hyperbolic to isokinetic cycling allows the velocity-specific decline in maximal power to be measured, i.e., fatigue. We reasoned that, should the baseline relationship between isokinetic power (Piso) and electromyography (EMG) be reproducible, then contributions to fatigue may be isolated from 1) the decline in muscle activation (muscle activation fatigue); and 2) the decline in Piso at a given activation (muscle fatigue). We hypothesized that the EMG-Piso relationship is linear, velocity dependent, and reliable for instantaneous fatigue assessment at intolerance during and following whole body exercise. Healthy participants (n = 13) completed short (5 s) variable-effort isokinetic bouts at 50, 70, and 100 rpm to characterize baseline EMG-Piso. Repeated ramp incremental exercise tests were terminated with maximal isokinetic cycling (5 s) at 70 rpm. Individual baseline EMG-Piso relationships were linear (r(2) = 0.95 ± 0.04) and velocity dependent (analysis of covariance). Piso at intolerance (two legs, 335 ± 88 W) was ∼45% less than baseline [630 ± 156 W, confidence interval of the difference (CIDifference) 211, 380 W, P < 0.05]. Following intolerance, Piso recovered rapidly (F = 44.1; P < 0.05; η(2) = 0.79): power was reduced (P < 0.05) vs. baseline only at 0-min (CIDifference 80, 201 W) and 1-min recovery (CIDifference 13, 80 W). Activation fatigue and muscle fatigue (one leg) were 97 ± 55 and 60 ± 50 W, respectively. Mean bias ± limits of agreement for reproducibility were as follows: baseline Piso 1 ± 30 W; Piso at 0-min recovery 3 ± 35 W; and EMG at Piso 3 ± 14%. EMG power is linear, velocity dependent, and reproducible. Deviation from this relationship at the limit of tolerance can quantify the "activation" and "muscle" related components of fatigue during cycling.

The effects of supraphysiological doses of testosterone on angry behavior in healthy eugonadal men--a clinical research center study.

UNLABELLED: Anecdotal reports of "roid rage" and violent crimes by androgenic steroid users have brought attention to the relationship between anabolic steroid use and angry outbursts. However, testosterone effects on human aggression remain controversial. Previous studies have been criticized because of the low androgen doses, lack of placebo control or blinding, and inclusion of competitive athletes and those with preexisting psychopathology. To overcome these pitfalls, we used a double-blind, placebo-controlled design, excluded competitive athletes and those with psychiatric disorders, and used 600 mg testosterone enanthate (TE)/week. Forty-three eugonadal men, 19-40 yr, were randomized to 1 of 4 groups: Group I, placebo, no exercise; Group II, TE, no exercise; Group III, placebo, exercise; Group IV, TE plus exercise. Exercise consisted of thrice weekly strength training sessions. The Multi-Dimensional Anger Inventory (MAI), which includes 5 different dimensions of anger (inward anger, outward anger, anger arousal, hostile outlook, and anger eliciting situations), and a Mood Inventory (MI), which includes items related to mood and behavior, were administered to subjects before, during, and after the 10 week intervention. The subject's significant other (spouse, live-in partner, or parent) also answered the same questions about the subject's mood and behavior (Observer Mood Inventory, OMI). No differences were observed between exercising and nonexercising and between placebo and TE treated subjects for any of the 5 subdomains of MAI. Overall there were no significant changes in MI or OMI during the treatment period in any group. CONCLUSION: Supraphysiological doses of testosterone, when administered to normal men in a controlled setting, do not increase angry behavior. These data do not exclude the possibility that still higher doses of multiple steroids might provoke angry behavior in men with preexisting psychopathology.

Testosterone replacement increases fat-free mass and muscle size in hypogonadal men.

Testosterone-induced nitrogen retention in castrated male animals and sex-related differences in the size of the muscles in male and female animals have been cited as evidence that testosterone has anabolic effects. However, the effects of testosterone on body composition and muscle size have not been rigorously studied. The objective of this study was to determine the effects of replacement doses of testosterone on fat-free mass and muscle size in healthy hypogonadal men in the setting of controlled nutritional intake and exercise level. Seven hypogonadal men, 19-47 yr of age, after at least a 12-week washout from previous androgen therapy, were treated for 10 weeks with testosterone enanthate (100 mg/week) by im injections. Body weight, fat-free mass measured by underwater weighing and deuterated water dilution, and muscle size measured by magnetic resonance imaging were assessed before and after treatment. Energy and protein intake were standardized at 35 Cal/kg.day and 1.5 g/kg.day, respectively. Body weight increased significantly from 79.2 +/- 5.6 to 83.7 +/- 5.7 kg after 10 weeks of testosterone replacement therapy (weight gain, 4.5 +/- 0.6 kg; P = 0.0064). Fat-free mass, measured by underwater weighing, increased from 56.0 +/- 2.5 to 60.9 +/- 2.2 kg (change, +5.0 +/- 0.7 kg; P = 0.0004), but percent fat did not significantly change. Similar increases in fat-free mass were observed with the deuterated water method. The cross-sectional area of the triceps arm muscle increased from 2421 +/- 317 to 2721 +/- 239 mm2 (P = 0.045), and that of the quadriceps leg muscle increased from 7173 +/- 464 to 7720 +/- 454 mm2 (P = 0.0427), measured by magnetic resonance imaging. Muscle strength, assessed by one repetition maximum of weight-lifting exercises increased significantly after testosterone treatment. L-[1-13C]Leucine turnover, leucine oxidation, and nonoxidative disappearance of leucine did not significantly change after 10 weeks of treatment. There was no significant change in hemoglobin, hematocrit, creatinine, and transaminase levels. Replacement doses of testosterone increase fat-free mass and muscle size and strength in hypogonadal men. Whether androgen replacement in wasting states characterized by low testosterone levels will have similar anabolic effects remains to be studied.

Principles of exercise training.

Design of exercise programs that are part of pulmonary rehabilitation programs should be founded on an appreciation of the principles of exercise training of healthy subjects. Training produces structural and biochemical changes in the muscles that exercise which increase the ability of the trained muscle to perform aerobic exercise. After training, a given level of heavy exercise engenders lower levels of blood lactate. This is associated with a lower requirement for oxygen uptake, carbon dioxide output, and ventilation. Although the precise mechanism by which training produces changes in the exercising muscles is unknown, characteristics of an effective training program have been defined. Healthy subjects must train for at least 30 min per day, 3 to 5 days per week for 4 to 8 weeks to achieve a physiologic training effect. More controversial is whether a critical training intensity exists. Further, it is not clear which yardstick to apply to quantitate training intensity. Finally, after a training effect has been achieved, regular exercise must be continued or the gains will be lost.

Skeletal muscle function in COPD.

Few effective therapies exist for patients with COPD. Rehabilitative therapy aimed at curing dysfunction of the peripheral muscles may be an appropriate addition to this short list. This review does the following: (1) presents evidence that skeletal muscle dysfunction is present in COPD patients; (2) considers the mechanisms of this dysfunction; (3) describes the role of exercise training in correcting this disorder; and (4) speculates that anabolic hormone supplementation may find a place in COPD therapy. Further research will be necessary to refine these concepts.

Validity of ear oximetry in clinical exercise testing.

Because of suspicion that the ear oximeter might measure the oxyhemoglobin saturation of arterial blood inaccurately during heavy exercise, we made concurrent ear oximetric and blood measurements on 14 consecutive patients with arterial catheters during clinical exercise tests. After correcting for carboxyhemoglobin, the estimated and measured values for the oxyhemoglobin saturation of the blood agreed well, as did resting ear and blood values; however, during heavy exercise, ear oximetric values were falsely elevated in two patients with interstitial pulmonary disease and were falsely depressed in five patients with cardiovascular limitation to exercise. In another patient, ear oximetric values declined during heavy exercise despite mild hyperoxia, suggesting hypoperfusion of the ear. Considering the clinical and physiologic importance of oxyhemoglobin saturation, ear oximetric values during heavy exercise should be cautiously interpreted.

Patterns of dissimilarities among instrument models in measuring PO2, PCO2, and pH in blood gas laboratories.

STUDY OBJECTIVES: To ascertain the degree of dissimilarities among blood gas and pH analyzer models of the same and different manufacturers in measurement of PO2, PCO2, and pH using fluorocarbon containing emulsion (FCE) proficiency testing material. DESIGN: Statistically and graphically analyze data from six recent proficiency testing surveys for the 20 more frequently used models of analyzers. SETTING AND PARTICIPANTS: Over a 2-year period, approximately 900 participants from blood gas laboratories in the United States analyzed similar ampules from each of 30 lots. MEASUREMENTS AND RESULTS: Both graphic and statistical comparisons were used to demonstrate differences between manufacturers. For each of the four major manufacturers, comparisons revealed statistically significant differences not only for PO2, but also for PCO2 and pH. Additionally, comparison models within each of the three manufacturers (those with multiple models and > 15 instruments per model represented) disclosed statistically significant dissimilarities among models for each analyte in 115 of 153 model pairings. Previously reported tonometered blood differences among analyzer models for PO2 are qualitatively similar to the differences found in these same models in this FCE study. Model differences are important in research studies and may be clinically important in deciding abnormality, selecting oxygen therapy, or the treatment of patients with respiratory failure or severe respiratory alkalosis. CONCLUSIONS: To minimize the likelihood of misleading clinicians, laboratory directors should consider the degree of dissimilarity among blood gas analyzer models in current use and when changing instrumentation.

Comparison of albuterol to isoproterenol as a bronchodilator for use in pulmonary function testing.

We compared the effectiveness of albuterol with isoproterenol as a bronchodilator for use in pulmonary function testing. A total of 180 patients presenting for routine pulmonary function testing were randomly assigned to receive 5 mg of either albuterol or isoproterenol by compressed air nebulizer. Forced expiratory maneuvers were performed before, 5 min after, and 10 min after bronchodilator administration. The average increase in FEV1 and FVC did not differ between drugs. Also, the fraction of patients achieving a clinically significant bronchodilator response did not differ between drugs. Importantly, there was no significant difference between average 5 and 10 min postbronchodilator values for FEV1 or FVC for either bronchodilator, suggesting that a peak response was reached by 5 min. These results show no advantage of isoproterenol over albuterol in terms of potency or speed of action. Given the well-known cardiovascular side effects of isoproterenol, albuterol is the preferable agent for use in pulmonary function testing.

Effect of altering heart rate on oxygen uptake at exercise onset.

At the onset of exercise, both cardiac output and ventilation increase abruptly. We investigated the hypothesis that a rapid change in cardiac output, as effected by an immediate increase in heart rate at the start of exercise and a decrease in heart rate at the termination of exercise, affects the responses of oxygen uptake. Five patients in whom programmable pacemakers had been previously inserted for complete heart block were studied. Responses in ventilation and gas exchange were recorded breath by breath during studies in which each subject performed 16 transitions between rest and moderate exercise on a cycle ergometer. In a randomized fashion, in half of the transitions, heart rate was accelerated from a low rate to a high rate as exercise began; in the other half, heart rate was held constant at the low rate as exercise began. Oxygen uptake increased by 30 percent in the first 20 seconds of exercise, when heart rate was constrained, while it increased by 70 percent when heart rate was abruptly accelerated. Similarly, smaller changes were observed at the cessation of exercise when the heart rate was constrained, as compared to an abrupt decrease in heart rate. Despite this difference in the responses of oxygen uptake, at the transitions in exercise, the ventilatory responses were indistinguishable. We have demonstrated that ventilation-independent changes in oxygen uptake can be induced at the onset and cessation of exercise. These alterations in oxygen uptake are predictable from differences in blood flow which occur as a consequence of the differences in time course of the heart rate.

A statistical approach for assessment of bronchodilator responsiveness in pulmonary function testing.

OBJECTIVE: Because published criteria for bronchodilator responsiveness are based on population variability and compare only the single best measures before and after intervention, we hypothesized that the variability of the FEV1 and FEV3 of each patient would better determine that patient's responsiveness. DESIGN AND INTERVENTIONS: Five 3-s forced expiratory maneuvers were used for each of 3 sequential portions of the study: baseline, after nebulized saline solution, and after nebulized albuterol. SETTING: Clinical pulmonary function laboratory in a county/university teaching hospital. PATIENTS: Fifty consecutive adult patients with obstruction referred for routine testing and thought to be able to complete the study. (The primary diagnoses were found to be equally divided between asthma, bronchitis, and emphysema; equal numbers had very severe, severe, moderate, mild, or minimal obstruction.) MEASUREMENTS AND RESULTS: The primary finding was that 36 patients were found to be responders (consistent and statistically significant FEV1 and FEV3 improvement after albuterol). The 14 identified as nonresponders would have been so categorized by all other published criteria. For assessing responsiveness, we found FEV3 measures preferable to vital capacity measures, because the latter depends on the duration of the maneuver. CONCLUSIONS: The percentage of responders identified is higher than recognized by any other published criteria. Most criteria would not have identified the responders with very severe or minimal airways obstruction.

Contribution of the respiratory muscles to the lactic acidosis of heavy exercise in COPD.

Patients with COPD usually are limited in their exercise tolerance by a limited ventilatory capacity. Lactic acidosis induced by exercise increases the stress on the ventilatory system due to CO2 generated by bicarbonate buffering and hydrogen ion stimulation. Patients with COPD are often observed to increase blood lactate levels at low levels of exercise. We wished to determine whether patients with COPD who experience lactic acidosis do so because of respiratory muscle production of lactate. Eight patients with moderate to severe COPD (FEV1 = 43.5 +/- 11.6% predicted) and 5 healthy subjects performed 10 min of moderate constant work rate exercise either breathing spontaneously or volitionally increasing their ventilation for 5 min to approximate the peak minute ventilation seen during incremental exercise. During volitional increased ventilation, 3% CO2 was added to the inspirate to prevent alkalosis and hypocapnia. In neither the healthy subjects nor the COPD group was the end-exercise lactate level significantly higher during volitional ventilation increase than during spontaneous ventilation. Further, in the COPD patients, the blood lactate levels during volitional ventilation increase were much lower than during maximal exercise (averaging 2.4 vs 5.3 mmol/L) despite similar ventilation levels (averaging 50 and 53 L/min). We conclude that it is unlikely that the respiratory muscles have an important influence on the blood lactate level elevation seen during maximal exercise in COPD patients.

Inaccuracy of noninvasive estimates of VD/VT in clinical exercise testing.

To evaluate the accuracy of noninvasive estimates of VD/VT in clinical exercise testing, we compared measurements of standard VD/VT with estimates based either on end-tidal CO2 (VD/VTET) or a published estimate of arterial PCO2 (VD/VTest) at peak exercise in 68 patients. Using regression analysis, we identified highly significant differences (p < 0.001) between each method and VD/VTstand across a broad range of observed VD/VT. Assuming a normal exercise VD/VT < or = 0.30, estimate methods were specific but were insensitive (50 percent for VD/VTET and 57 percent for VD/VTest) for identifying patients with abnormal gas exchange during exercise. Separate analysis of subgroups based on resting pulmonary function did not identify any group for which either method was acceptable. Our analysis showed that errors in estimating PaCO2, which are amplified by the Bohr equation when calculating VD/VT, are responsible for the inaccuracies of each noninvasive method. We conclude that noninvasive estimates of PaCO2 cannot replace measured arterial PCO2 for calculation of VD/VT during exercise.

Application of systolic time intervals to acute cardiomyopathy with echovirous 2.

The occurrence of echovirus type 2 myocarditis in an adult is reported. Myocarditis was substantiated by abnormal electrocardiograms. More important, a prolonged course and severe functional impairment was quantitatively assessed by serial systolic time intervals, even after the ECGs became normal. The patient also had meningitis, hemiparesis, and convulsions. Viral isolation was from the spinal fluid.

Metabolic acidosis during exercise in patients with chronic obstructive pulmonary disease. Use of the V-slope method for anaerobic threshold determination.

Patients with chronic obstructive pulmonary disease (COPD) usually have limited exercise tolerance owing to low ventilatory capacity. Because metabolic acidosis induced by exercise increases ventilatory drive, decreasing the hydrogen ion stimulus may improve exercise capacity. However, in those with mechanical limitation to ventilation or chemoreceptor insensitivity, identifying metabolic acidosis may be difficult using gas exchange methods that depend on the ventilatory response to the acidosis. We compared a modification of a gas exchange method (V-slope) for determining the lactate (anaerobic) threshold (AT), which is independent of ventilatory response with a method using the change in blood standard bicarbonate (HCO3-) level in COPD and normal subjects during cycle incremental exercise. In 43 normal subjects, the VO2 at which metabolic acidosis was identified using the two method correlated (r = 0.75), although mean values differed. In 22 patients with moderately severe to severe COPD, eight who had a change in standard HCO3- less than 2.0 mEq/L between rest and 2 min of recovery from exercise (group 1) were contrasted with 14 whose blood standard HCO3- fell by greater than 2.5 mEq/L (group 2). Mean VC was higher and FEV1/VC was lower in group 2, but mean FEV1, maximal voluntary ventilation, and diffusing capacity for carbon monoxide were not different. The degree of obstruction did not correlate strongly with the degree of exercise metabolic acidosis. The AT determined by the V-slope method was compared with that from standard HCO3-; good correlation between these methods was found (r = 0.98), although mean values were different. The V-slope method predicted metabolic acidosis in 10/14 who had a fall in HCO3- more than 2.5 mEq/L. A significant proportion of patients with COPD seem to develop metabolic acidosis during exercise. The V-slope gas exchange method may be useful in selecting those patients with COPD who develop exercise metabolic acidosis and might therefore benefit from exercise training.

The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week multicenter trial. The US Tiotropium Study Group.

STUDY OBJECTIVE: To compare the bronchodilator efficacy and safety of tiotropium and placebo. DESIGN: A 3-month, randomized, double-blind, placebo-controlled, multicenter trial. SETTING: Outpatient. PATIENTS: Four hundred seventy patients with stable COPD (mean FEV(1) = 38.6% predicted). INTERVENTIONS: Tiotropium 18 microg (N = 279) or placebo (N = 191) given once daily via a lactose-based dry-powder inhaler device. MEASUREMENTS AND RESULTS: Spirometry was evaluated on days 1, 8, 50, and 92. Data were expressed as the mean trough (ie, before morning dose; 23 to 24 h after previous dose) and average response observed in the 3 h after the dose was received. Tiotropium produced significant improvement in trough FEV(1) and FVC, averaging 12% greater than baseline on day 8; these improvements were maintained on days 50 and 92. The average postdose FEV(1) was 16% greater than baseline on day 1 and 20% greater than baseline on day 92; FVC was 17% greater than baseline on day 1 and 19% greater than baseline on day 92. Tiotropium was significantly more effective than placebo in both trough and average FEV(1) and FVC response (p < 0.001). These spirometric effects were corroborated by significant improvements in daily morning and evening peak expiratory flow rate, as well as a reduction in "as-needed" albuterol use. Symptoms of wheezing and shortness of breath were significantly less in patients receiving tiotropium, and the physician global assessment noted overall improvements with those treated with tiotropium relative to placebo. The most common reported adverse event after tiotropium was dry mouth (9.3% vs 1.6% relative to placebo; p < 0.05). CONCLUSIONS: These data demonstrate that tiotropium is a safe and effective once-daily anticholinergic bronchodilator and should prove useful as first-line maintenance therapy in COPD.

Acid-base regulation during exercise and recovery in humans.

Arterial pH, PCO2, standard bicarbonate, lactate, and ventilation were measured with a high sampling density during rest, exercise, and recovery in normal subjects performing upright cycle ergometer exercise. Three 6-min constant-work exercise tests (moderate, heavy, and very heavy) were performed by each subject. We found a small respiratory acidosis during the moderate-intensity exercise and an early respiratory acidosis followed by a metabolic acidosis for the heavy- and very-heavy-intensity exercise. During recovery, arterial pH rapidly returned to the preexercise value for the moderate-intensity work. However, arterial pH decreased further during the first 2 min of recovery for the heavy- and very-heavy-intensity work, before a slower return toward the resting values. We conclude that arterial acidosis is the consistent arterial pH reaction for moderate-, heavy-, and very-heavy-intensity cycle ergometer exercise in humans and that this acidosis is blunted but not eliminated by the ventilatory response. During recovery, the return to resting arterial pH and PCO2 and standard bicarbonate appears to be determined by the rate of lactate decline.