Dennis Jensen

Lung Hyperinflation and Its Reversibility in Patients with Airway Obstruction of Varying Severity

ABSTRACT The natural history of lung hyperinflation in patients with airway obstruction is unknown. In particular, little information exists about the extent of air trapping and its reversibility to bronchodilator therapy in those with mild airway obstruction. We completed a retrospective analysis of data from individuals with airway obstruction who attended our pulmonary function laboratory and had plethysmographic lung volume measurements pre- and post-bronchodilator (salbutamol). COPD was likely the predominant diagnosis but patients with asthma may have been included. We studied 2,265 subjects (61% male), age 65 ± 9 years (mean ± SD) with a post-bronchodilator FEV1/FVC <0.70. We examined relationships between indices of airway obstruction and lung hyperinflation, and measured responses to bronchodilation across subgroups stratified by GOLD criteria. In GOLD stage I, vital capacity (VC) and inspiratory capacity (IC) were in the normal range; pre-bronchodilator residual volume (RV), functional residual capacity (FRC) and specific airway resistance were increased to 135%, 119% and 250% of predicted, respectively. For the group as a whole, RV and FRC increased exponentially as FEV1 decreased, while VC and IC decreased linearly. Regardless of baseline FEV1, the most consistent improvement following bronchodilation was RV reduction, in terms of magnitude and responder rate. In conclusion, increases (above normal) in airway resistance and plethysmographic lung volumes were found in those with only minor airway obstruction. Indices of lung hyperinflation increased exponentially as airway obstruction worsened. Those with the greatest resting lung hyperinflation showed the largest bronchodilator-induced volume deflation effects. Reduced air trapping was the predominant response to acute bronchodilation across severity subgroups.

Phasic menstrual cycle effects on the control of breathing in healthy women

This study examined the effects of menstrual cycle phase on ventilatory control. Fourteen eumenorrheic women were studied in the early follicular (FP; 1-6 days) and mid-luteal (LP; 20-24 days) phase of the menstrual cycle. Blood for the determination of arterial PCO(2) (PaCO(2)) , plasma strong ion difference ([SID]), progesterone ([P(4)]), and 17beta-estradiol ([E(2)]) concentrations were obtained at rest. Subjects performed a CO(2) rebreathing procedure that included prior hyperventilation and maintenance of iso-oxia to evaluate central and peripheral chemoreflex, and nonchemoreflex drives to breathe. Resting PaCO(2) and [SID] were lower; minute ventilation (V (E)), [P(4)] and [E(2)] were higher in the LP versus FP. Within the LP, significant correlations were observed for PaCO(2) with [P(4)], [E(2)] and [SID]. Menstrual cycle phase had no effect on the threshold or sensitivity of the central and/or peripheral ventilatory chemoreflex response to CO(2). Both (V (E)) and the ventilatory response to hypocapnia (representing nonchemoreflex drives to breathe) were approximately 1L/min greater in the LP versus FP accounting for the reduction in PaCO(2) . These data support the hypothesis that phasic menstrual cycle changes in PaCO(2) may be due, at least in part, to the stimulatory effects of [P(4)], [E(2)] and [SID] on ventilatory drive.

Mechanisms of dyspnoea relief and improved exercise endurance after furosemide inhalation in COPD

Background: This study examined the effects of inhaled furosemide on the ventilatory and perceptual response to high-intensity constant-load cycle exercise in chronic obstructive pulmonary disease (COPD). Methods: In a randomised, double-blind, placebo-controlled, crossover study, 20 patients with COPD (mean (SD) forced expiratory volume in 1 s 45 (15)% predicted) received either nebulised furosemide 40 mg or placebo on two separate days. Thirty minutes after each treatment, patients performed pulmonary function tests and a symptom-limited cycle exercise test at 75% of their maximum incremental work rate. Changes in spirometry, plethysmographic lung volumes, dynamic operating lung volumes, ventilation, breathing pattern, cardiovascular function, dyspnoea intensity and exercise endurance time were compared between treatments. Results: Compared with placebo, treatment with furosemide resulted in a mean (SD) decrease in dyspnoea intensity at the highest equivalent exercise time (ie, isotime for each patient) of 0.9 (1.0) Borg units (p<0.01) and an increase in exercise endurance time of 1.65 (0.63) min (p<0.05). These improvements were associated with increases in dynamic inspiratory capacity, tidal volume and mean tidal expiratory flow rates at isotime (p<0.01). The eight patients whose exercise endurance time improved by >1 min had greater changes in operating lung volumes (p<0.05), submaximal oxygen pulse (p<0.05) and oxygen uptake (p = 0.05) than those in whom exercise endurance time did not improve. Conclusion: Alleviation of exertional dyspnoea after single-dose furosemide inhalation in COPD is multifactorial but improvements in dynamic ventilatory mechanics are contributory in some individuals.

Pulmonary Gas Exchange Abnormalities in Mild Chronic Obstructive Pulmonary Disease. Implications for Dyspnea and Exercise Intolerance.

RATIONALE Several studies in mild chronic obstructive pulmonary disease (COPD) have shown a higher than normal ventilatory equivalent for carbon dioxide ([Formula: see text]e/[Formula: see text]co2) during exercise. Our objective was to examine pulmonary gas exchange abnormalities and the mechanisms of high [Formula: see text]e/[Formula: see text]co2 in mild COPD and its impact on dyspnea and exercise intolerance. METHODS Twenty-two subjects (11 patients with GOLD [Global Initiative for Chronic Obstructive Lung Disease] grade 1B COPD, 11 age-matched healthy control subjects) undertook physiological testing and a symptom-limited incremental cycle exercise test with arterial blood gas collection. MEASUREMENTS AND MAIN RESULTS Patients (post-bronchodilator FEV1: 94 ± 10% predicted; mean ± SD) had evidence of peripheral airway dysfunction and reduced peak oxygen uptake compared with control subjects (80 ± 18 vs. 113 ± 24% predicted; P<0.05). Arterial blood gases were within the normal range and effective alveolar ventilation was not significantly different from control subjects throughout exercise. The alveolar-arterial O2 tension gradient was elevated at rest and throughout exercise in COPD (P<0.05). [Formula: see text]e/[Formula: see text]co2, dead space to tidal volume ratio (Vd/Vt), and arterial to end-tidal CO2 difference were all higher (P<0.05) in patients with COPD than in control subjects during exercise. In patients with COPD versus control subjects, there was significant dynamic hyperinflation and greater tidal volume constraints (P<0.05). Standardized dyspnea intensity ratings were also higher (P<0.05) in patients with COPD versus control subjects in association with higher ventilatory requirements. Within all subjects, Vd/Vt correlated with the [Formula: see text]e/[Formula: see text]co2 ratio during submaximal exercise (r=0.780, P<0.001). CONCLUSIONS High Vd/Vt was the most consistent gas exchange abnormality in smokers with only mild spirometric abnormalities. Compensatory increases in minute ventilation during exercise maintained alveolar ventilation and arterial blood gas homeostasis but at the expense of earlier dynamic mechanical constraints, greater dyspnea, and exercise intolerance in mild COPD.

Sex differences in exertional dyspnea in patients with mild COPD: Physiological mechanisms

The purpose of this study was to evaluate the physiological basis for sex-differences in exercise-induced dyspnea in patients with mild COPD. We compared operating lung volumes, breathing pattern and dyspnea during incremental cycling in 32 men (FEV(1)=86±10% predicted) and women (FEV(1)=86±12% predicted) with mild COPD and 32 age-matched controls. There were no sex differences in dyspnea in the control group at any work-rate or ventilation (V(E)). Women with COPD had significantly greater dyspnea than men at 60 and 80 W. At 80 W, dyspnea ratings were 5.7±2.3 and 3.3±2.5 Borg units (P<0.05) and the V(E) to maximal ventilatory capacity ratio was 72% and 55% in women and men, respectively (P<0.05). Comparable increases in dynamic hyperinflation were seen in both male and female COPD groups at symptom limitation but women reached tidal volume constraints at a lower work rate and V(E) than men. Superimposing mild COPD on the normal aging effects had greater sensory consequences in women because of their naturally reduced ventilatory reserve.

Inhaled Fentanyl Citrate Improves Exercise Endurance During High-Intensity Constant Work Rate Cycle Exercise in Chronic Obstructive Pulmonary Disease

CONTEXT Activity limitation and dyspnea are the dominant symptoms of chronic obstructive pulmonary disease (COPD). Traditionally, efforts to alleviate these symptoms have focused on improving ventilatory mechanics, reducing ventilatory demand, or both of these in combination. Nevertheless, many patients with COPD remain incapacitated by dyspnea and exercise intolerance despite optimal therapy. OBJECTIVES To determine the effect of single-dose inhalation of nebulized fentanyl citrate (a μ-opioid agonist drug) on exercise tolerance and dyspnea in COPD. METHODS In a randomized, double-blind, placebo-controlled, crossover study, 12 stable patients with COPD (mean ± standard error of the mean post-β(2)-agonist forced expiratory volume in one second [FEV(1)] and FEV(1) to forced vital capacity ratio of 69% ± 4% predicted and 49% ± 3%, respectively) received either nebulized fentanyl citrate (50 mcg) or placebo on two separate days. After each treatment, patients performed pulmonary function tests and a symptom-limited constant work rate cycle exercise test at 75% of their maximum incremental work rate. RESULTS There were no significant postdose differences in spirometric parameters or plethysmographic lung volumes. Neither the intensity nor the unpleasantness of perceived dyspnea was, on average, significantly different at isotime (5.0 ± 0.6 minutes) or at peak exercise after treatment with fentanyl citrate vs. placebo. Compared with placebo, fentanyl citrate was associated with 1) increased exercise endurance time by 1.30 ± 0.43 minutes or 25% ± 8% (P=0.01); 2) small but consistent increases in dynamic inspiratory capacity by ∼0.10 L at isotime and at peak exercise (both P≤0.03); and 3) no concomitant change in ventilatory demand, breathing pattern, pulmonary gas exchange, and/or cardiometabolic function during exercise. The mean rate of increase in dyspnea intensity (1.2 ± 0.3 vs. 2.9 ± 0.8 Borg units/minute, P=0.03) and unpleasantness ratings (0.5 ± 0.2 vs. 2.9 ± 1.3 Borg units/minute, P=0.06) between isotime and peak exercise was less after treatment with fentanyl citrate vs. placebo. CONCLUSION Single-dose inhalation of fentanyl citrate was associated with significant and potentially clinically important improvements in exercise tolerance in COPD. These improvements were accompanied by a delay in the onset of intolerable dyspnea during exercise near the limits of tolerance.

Physiological mechanisms of hyperventilation during human pregnancy

This study examined the role of pregnancy-induced changes in wakefulness (or non-chemoreflex) and central chemoreflex drives to breathe, acid-base balance and female sex hormones in the hyperventilation of human pregnancy. Thirty-five healthy women were studied in the third trimester (TM(3); 36.3+/-1.0 weeks gestation; mean+/-S.D.) and again 20.2+/-7.8 weeks post-partum (PP). An iso-oxic hyperoxic rebreathing procedure was used to evaluate wakefulness and central chemoreflex drives to breathe. At rest, arterialized venous blood was obtained for the estimation of arterial PCO(2) (PaCO(2)) and [H(+)]. Blood for the determination of plasma strong ion difference ([SID]), albumin ([Alb]), as well as serum progesterone ([P(4)]) and 17beta-estradiol ([E(2)]) concentrations was also obtained at rest. Wakefulness and central chemoreflex drives to breathe, [P(4)] and [E(2)], ventilation and V CO(2) increased, whereas PaCO(2) and the central chemoreflex ventilatory recruitment threshold for PCO(2) (VRTCO(2)) decreased from PP to TM(3) (all p<0.01). The reductions in PaCO(2) were not related to the increases in [P(4)] and [E(2)]. The alkalinizing effects of reductions in PaCO(2) and [Alb] were partly offset by the acidifying effects of a reduced [SID], such that arterial [H(+)] was still reduced in TM(3) vs. PP (all p<0.001). A mathematical model of ventilatory control demonstrated that pregnancy-induced changes in wakefulness and central chemoreflex drives to breathe, acid-base balance, V CO(2) and cerebral blood flow account for the reductions in PaCO(2), [H(+)] and VRTCO(2). This is the first study to demonstrate that the hyperventilation and attendant hypocapnia/alkalosis of human pregnancy results from a complex interaction of pregnancy-induced changes in wakefulness and central chemoreflex drives to breathe, acid-base balance, metabolic rate and cerebral blood flow.

Respiratory function and the obesity paradox.

Purpose of reviewObese individuals have impaired respiratory function relative to their normal-weight counterparts. Despite these negative effects, obesity is paradoxically associated with better survival in individuals with chronic obstructive pulmonary disease (COPD). The purpose of this review is to describe this ‘obesity paradox’, to discuss the effects of obesity on respiratory function, and to speculate as to whether obesity-related alterations in respiratory mechanics can influence the natural history of COPD. Recent findingsGiven the known negative effects of obesity on respiratory physiology, it is reasonable to predict that obese COPD patients would be more likely to experience greater dyspnea and exercise intolerance relative to COPD patients of normal weight. However, recent evidence suggests that obese COPD patients have similar or better dyspnea scores during exercise and do not have diminished exercise capacity. These observations may be attributable to the fact that obese COPD patients have reduced operating lung volumes and higher inspiratory capacity to total lung capacity ratios than their lean COPD counterparts. SummaryObese patients with COPD do not appear to be at a disadvantage during exercise relative to lean COPD patients. Obesity may be associated with improved survival in COPD but specific mechanisms for this paradox remain to be elucidated.

Chemical and mechanical adaptations of the respiratory system at rest and during exercise in human pregnancy

Human pregnancy is characterized by significant increases in ventilatory drive both at rest and during exercise. The increased ventilation and attendant hypocapnia of pregnancy has been attributed primarily to the stimulatory effects of female sex hormones (progesterone and estrogen) on central and peripheral chemoreflex drives to breathe. However, recent research from our laboratory suggests that hormone-mediated increases in neural (or non-chemoreflex) drives to breathe may contribute importantly to the hyperventilation of pregnancy. This review challenges traditional views of ventilatory control, and outlines an alternative hypothesis of the control of breathing during human pregnancy that is currently being tested in our laboratory. Conventional wisdom suggests that pregnancy-induced increases in central respiratory motor output command in combination with progressive thoraco-abdominal distortion may compromise the normal mechanical response of the respiratory system to exercise, increase the perception of exertional breathlessness, and curtail aerobic exercise performance in otherwise healthy pregnant women. The majority of available evidence suggests, however, that neither pregnancy nor advancing gestation are associated with reduced aerobic working capacity or increased breathlessness at any given work rate or ventilation during exhaustive weight-supported exercise.

Physiological mechanisms of sex differences in exertional dyspnoea: role of neural respiratory motor drive

What is the central question of this study? Does the combination of a higher neural respiratory drive and greater dynamic mechanical ventilatory constraints during exercise in healthy women versus men form the mechanistic basis of sex differences in activity‐related dyspnoea? What is the main finding and its importance? Sex differences in activity‐related dyspnoea in health primarily reflected the awareness of a higher neural respiratory drive needed to achieve any given ventilation during exercise in the setting of relatively greater dynamic mechanical ventilatory constraints in women. These findings may have implications for our understanding of the mechanisms of sex differences in exertional dyspnoea in variants of health (e.g. the elderly) and in patients with cardiorespiratory disease.