Students perceive skills learned in pre-clerkship PBL valuable in core clinical rotations.

Purpose: Problem-based learning (PBL) is an instructional method widely used by medical educators that promotes an environment in which students effectively learn the foundational knowledge and skills that are prerequisites for graduation. This study evaluated medical students' perceptions of the helpfulness of skills acquired in PBL to core clerkship rotations.Methods: A 25-item survey was designed to assess students' perceptions of skills learned in PBL that were helpful on core clerkships and transferable to the clinical setting. A random sample of students with at least 8 months of clerkship experience were invited to complete the survey.Results: Of 68 students, 35 (52%) returned questionnaires. Results suggest a clustering of themes based on their perceived value. Skills learned in PBL that students rated most highly as helpful or very helpful during core clinical rotations include: comfort discussing concepts, identifying key information, presentation skills, interpersonal skills, diagnostic thinking, finding information, self-awareness, and organizing information. Other items rated highly included: forming questions, time management, primary literature (engaging with published original research articles), and leadership. The skills acquired in PBL were associated with multiple competency domains.Conclusions: Although conditions of the pre-clerkship curriculum are substantially different from the learning environment of clerkship rotations, skills learned in PBL are perceived as applicable to authentic clinical training.

Scholarship in Teaching: An Approach to Enhancing the Value and Academic Standing of Teaching.

BACKGROUND: In our effort to increase the value and academic standing of teaching, we implemented an initiative focused on scholarship in teaching. Our program was narrowly focused, project-based, peer-reviewed, resource-neutral, and open to all faculty. Faculty members are invited annually to submit a description of their educational projects in keeping with Glassick's criteria. Our purpose was to assess the effects of this award program. METHOD: We reviewed the distribution of applications over a 3-year period and determined the academic departments, academic rank of applicants, and focus of projects. A questionnaire assessed applicants' perceptions of the value of participation, its contribution to promotion and advancement, and its role in subsequent dissemination activities. RESULTS: Slightly fewer than half (60 of 124, 48%) of the applications submitted during 2016 through 2018 were judged by peer review to meet Glassick's criteria for scholarship and received the award. Most applicants were junior faculty, and most applications were from the department of medicine though all departments who taught students in core clinical rotations were represented during the years studied. The projects that were awarded were more likely to be disseminated when compared with those who were not awarded. LESSONS LEARNED: Our scholarship in teaching program seemingly advanced educational scholarship among teaching faculty and provided a way of recognizing projects that advanced educational initiatives. Further efforts are required to promote support from departmental leadership, to enhance faculty participation, and to encourage success through mentoring and assistance in project preparation.

Comparing protein-ligand interactions in solution and single crystals by Raman spectroscopy.

By using a Raman microscope, we show that it is possible to probe the conformational states in protein crystals and crystal fragments under growth conditions (in hanging drops). The flavin cofactor in the enzyme para-hydroxybenzoate hydroxylase can assume two conformations: buried in the protein matrix ("in") or essentially solvent-exposed ("out"). By using Raman difference spectroscopy, we previously have identified characteristic flavin marker bands for the in and out conformers in the solution phase. Now we show that the flavin Raman bands can be used to probe these conformational states in crystals, permitting a comparison between solution and crystal environments. The in or out marker bands are similar for the respective conformers in the crystal and in solution; however, significant differences do exist, showing that the environments for the flavin's isoalloxazine ring are not identical in the two phases. Moreover, the Raman-band widths of the flavin modes are narrower for both in and out conformers in the crystals, indicating that the flavin exists in a more limited range of closely related conformational states in the crystal than in solution. In general, the ability to compare detailed Raman data for complexes in crystals and solution provides a means of bridging crystallographic and solution studies.

Smoking cessation and lung function in mild-to-moderate chronic obstructive pulmonary disease. The Lung Health Study.

Previous studies of lung function in relation to smoking cessation have not adequately quantified the long-term benefit of smoking cessation, nor established the predictive value of characteristics such as airway hyperresponsiveness. In a prospective randomized clinical trial at 10 North American medical centers, we studied 3, 926 smokers with mild-to-moderate airway obstruction (3,818 with analyzable results; mean age at entry, 48.5 yr; 36% women) randomized to one of two smoking cessation groups or to a nonintervention group. We measured lung function annually for 5 yr. Participants who stopped smoking experienced an improvement in FEV(1) in the year after quitting (an average of 47 ml or 2%). The subsequent rate of decline in FEV(1) among sustained quitters was half the rate among continuing smokers, 31 +/- 48 versus 62 +/- 55 ml (mean +/- SD), comparable to that of never-smokers. Predictors of change in lung function included responsiveness to beta-agonist, baseline FEV(1), methacholine reactivity, age, sex, race, and baseline smoking rate. Respiratory symptoms were not predictive of changes in lung function. Smokers with airflow obstruction benefit from quitting despite previous heavy smoking, advanced age, poor baseline lung function, or airway hyperresponsiveness.

Ventilatory-control abnormalities in familial sleep apnea.

The role of ventilatory-control abnormalities in predisposing to familial sleep-disordered breathing (SDB) was assessed in 31 subjects 28 +/- 10 yr of age (mean +/- SD). Subjects with (n = 10) and without SDB (n = 12) were recruited from 13 families having two or more members with SDB. Nine age- and gender-matched controls were recruited from families having no member with SDB. Respiratory responses to eucapnic hypoxia, and ventilatory and occlusion pressure responses to hyperoxic hypercapnia with and without added resistive loads (6.5 cm H2O/L/s), were assessed through rebreathing. Age, FEV1, and FVC did not differ among the groups. Hypoxic responses (delta VE/delta SaO2) were significantly lower among the first-degree relatives of SDB families than among controls (-0.76 +/- 0.47 L/min/% SaO2, and -1.32 +/- 0.92 L/min/% SaO2, respectively, p < 0.05). Respiratory responses to hypercapnia during unloaded conditions were similar among the groups. With resistive loading, inspiratory impedance, as measured through the relationship of mouth occlusion pressure (P100) to inspiratory flow (VT/TI), increased with increasing hypercapnia to a greater extent in members of SDB families than in controls (0.169 +/- 0.054 cm H2O/L/min versus 0.122 +/- 0.051, respectively, p < 0.05). These data suggest that familial SDB may be based partly on a familial abnormality in ventilatory control associated with blunting of the hypoxic ventilatory response. The greater increase in impedance during inspiratory loading in members of affected families also suggests a propensity for dynamic airway narrowing.

Effects of changes in ventilation on respiratory discomfort during isocapnic exercise.

We studied the effects of changes in the level of ventilation on respiratory discomfort during isocapnic exercise. Six subjects exercised at 60 W on a cycle ergometer. They initially breathed 2.5% CO2 in oxygen for 75 breaths. Ventilatory parameters of the last 10 breaths were used as controls. In 7 subsequent test sessions each lasting 2 min alternating with 2 min free breathing periods, subjects tried to achieve a target ventilation ranging from 0.7 to 1.3 times the control with a visual feedback system. End-tidal CO2 was regulated automatically at the control level by changing the inspired CO2. Breathing discomfort was measured at the end of each session using a visual analog scale. Isocapnic constraining of ventilation (0.7 times the control) during exercise significantly increased respiratory discomfort (p < 0.05). Increases in ventilation had no significant effect. These results indicate that respiratory discomfort during exercise is exaggerated when the level of ventilation falls below that spontaneously adopted even when chemical drives are held constant.

Methacholine reactivity predicts changes in lung function over time in smokers with early chronic obstructive pulmonary disease. The Lung Health Study Research Group.

As part of a clinical trial of early intervention in chronic obstructive pulmonary disease (COPD) (the Lung Health Study), 5,733 smokers with mild to moderate airflow obstruction underwent methacholine challenge tests at baseline. All participants were randomized to receive either usual care (no intervention) or special intervention, consisting of intensive smoking cessation counseling and the prescription of a metered-dose inhaler containing either ipratropium bromide or placebo (two inhalations three times daily). For this report, we analyzed the relationship between baseline methacholine reactivity and subsequent change in lung function. Methacholine reactivity was expressed as a logarithmic function of the two-point slope of percent decline in FEV1 over the concentration of methacholine (LMCR). Using a random effects linear model, LMCR was found to be a strong predictor of change in FEV1% predicted, after controlling for baseline lung function, age, sex, baseline smoking history, and changes in smoking status. Significant interactions were found between reactivity and smoking behavior. In the first year, participants who quit smoking showed improvement in FEV1, whereas continuing smokers showed worsening, and between Years 1 and 5, lung function declined to a greater extent in continuing smokers than in sustained quitters. For both time periods, these quitter/smoker differences increased as a function of airway reactivity. These findings indicate that methacholine reactivity is an important predictor of progression of airway obstruction in continuing smokers with early COPD, independent of the baseline level of obstruct.

The association of sudden unexpected infant death with obstructive sleep apnea.

We studied the relationship of sudden unexpected infant death/apparent life-threatening events (ALTE) to obstructive sleep apnea (OSA) in 74 index probands who had either sleep-laboratory-confirmed OSA or a clinical diagnosis of OSA requiring treatment, 62 matched control probands, and their spouses and first- and second-degree relatives. Sleep was monitored in the home overnight, and OSA was defined by respiratory disturbance indices (number of apneas/hypopneas per hour of sleep) corrected for normal increases with age. Information on sudden unexpected infant death/ALTE was obtained by questionnaire and was corroborated. For living relatives, data were obtained by questionnaire, examination, or study (cephalometric radiographs, ventilatory responsiveness to hypercapnia and hypoxia). Eight index families had 10 infants with sudden unexpected infant death/ALTE; two control families had three infants with sudden death (p = 0.11). All told, 91 of the 136 families (index plus control) included members with OSA, and all 10 infant death/ALTE families were among these (versus zero of 45 families with no OSA; p = 0.03). The sudden infant death/ALTE families had a greater frequency of two or more members with OSA (p = 0.06), reported more respiratory disease or allergy, were more frequently brachycephalic (p = 0.05), and had a smaller mean posterior nasal spine-basion distance (p = 0.0001) and ratio of anterior mandibular/anterior maxillary dental height (p < 0.05). Ventilatory responses to hypoxia were reduced in members of families with OSA (p = 0.008), with a trend toward the greatest blunting in subjects from families with OSA plus sudden unexpected infant death/ALTE. Thus, OSA in adults and sudden unexpected infant death/ALTE in their biologic relatives appear to be related. Familial factors influencing this association may include the degree of the predilection for OSA, liability for respiratory illness or allergy, dimensions of the oral-pharyngeal airway, and ventilatory response to hypoxia.

Effects of willful ventilatory control on respiratory sensation during hypercapnia.

Remarkable augmentation of breathing discomfort has been noted when ventilation is constrained to the steady state level during progressive hypercapnia. However, the effect of willful enhancement of ventilation on breathing discomfort remains to be evaluated. The present study examined the effects of moderate willful increases or decreases in ventilation during progressive hypercapnia on breathing discomfort in 12 subjects. There were a total of 5 rebreathing trials. In the first (F1) and the fifth trials the subjects rebreathed freely. In the other trials subjects breathed by tracking a target to achieve hypercapnic ventilatory responses that were the same (HCVR-S), 25% higher (HCVR-H) and 25% lower (HCVR-L) than in the F1 trial. Breathing discomfort was assessed every 30 s by a 150-mm visual analog scale (VAS). The sensational response (dVAS/dPCO2) during HCVR-S [3.8 +/- (SE) 0.8 mm/Torr] was significantly smaller (p < 0.01) than that during the F1 (6.3 +/- 0.8 mm/Torr) trial. HCVR-H resulted in a further decrease in dVAS/dPCO2 to 3.1 +/- 0.7 mm/Torr as compared to HCVR-S (p < 0.05). HCVR-L significantly increased dVAS/dPCO2 to 4.9 +/- 0.7 mm/Torr compared to HCVR-S (p < 0.05). The final free rebreathing ventilatory response was significantly larger than the initial free rebreathing response (2.7 +/- 0.5 as compared to 2.1 +/- 0.4 liters/min/Torr, p < 0.01). However, the sensational response did not change (6.3 +/- 0.8 vs. 5.8 +/- 0.7 mm/Torr). These rebreathing studies indicate that willful control of respiration decreases respiratory sensation even at comparable levels of ventilation. In particular, moderate willful increases in ventilation produce an ameliorating effect on the sensation of breathing discomfort.

Model of respiratory sensation and wilful control of ventilation.

A mathematical model has been developed that includes sensations of breathlessness and a dynamic CO2 respiratory controller. Breathing sensations, which are represented as a discomfort index, are assumed to depend on arterial PCO2 level, automatic and wilful motor commands and mechanoreceptor feedback. Wilful control is assumed to arise from cortical centres of the brain and is independent of the reflex control system. The bulbopontine respiratory controller produces the automatic motor command, which is determined by chemical and mechanical feedback. Simulations demonstrate how the controller output and breathing sensations change when wilful motor commands disturb spontaneous breathing. Simulations include isocapnic hyper- and hypoventilation and deliberate hypoventilation during CO2 rebreathing. Simulations are compared with experimental data from human subjects. Simulations predict that the discomfort index intensifies when ventilation is either voluntarily raised or lowered from the optimal level; and discomfort is greater when ventilation is lowered than when it is raised at a given level of PCO2. The simulated results agree with those obtained experimentally. The simulations suggest that respiratory drive integration may depend not only on the direct effects of chemical and mechanical feedback, but also on the perceptual consequences of these stimuli.

Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study.

OBJECTIVE: To determine whether a program incorporating smoking intervention and use of an inhaled bronchodilator can slow the rate of decline in forced expiratory volume in 1 second (FEV1) in smokers aged 35 to 60 years who have mild obstructive pulmonary disease. DESIGN: Randomized clinical trial. Participants randomized with equal probability to one of the following groups: (1) smoking intervention plus bronchodilator, (2) smoking intervention plus placebo, or (3) no intervention. SETTING: Ten clinical centers in the United States and Canada. PARTICIPANTS: A total of 5887 male and female smokers, aged 35 to 60 years, with spirometric signs of early chronic obstructive pulmonary disease. INTERVENTIONS: Smoking intervention: intensive 12-session smoking cessation program combining behavior modification and use of nicotine gum, with continuing 5-year maintenance program to minimize relapse. Bronchodilator: ipratropium bromide prescribed three times daily (two puffs per time) from a metered-dose inhaler. MAIN OUTCOME MEASURES: Rate of change and cumulative change in FEV1 over a 5-year period. RESULTS: Participants in the two smoking intervention groups showed significantly smaller declines in FEV1 than did those in the control group. Most of this difference occurred during the first year following entry into the study and was attributable to smoking cessation, with those who achieved sustained smoking cessation experiencing the largest benefit. The small noncumulative benefit associated with use of the active bronchodilator vanished after the bronchodilator was discontinued at the end of the study. CONCLUSIONS: An aggressive smoking intervention program significantly reduces the age-related decline in FEV1 in middle-aged smokers with mild airways obstruction. Use of an inhaled anticholinergic bronchodilator results in a relatively small improvement in FEV1 that appears to be reversed after the drug is discontinued. Use of the bronchodilator did not influence the long-term decline of FEV1.

Gender difference in airway hyperresponsiveness in smokers with mild COPD. The Lung Health Study.

Methacholine bronchoprovocation challenge testing was successfully completed in 5,662 participants (3,556 men and 2,106 women) at the time they were randomized into the Lung Health Study, a multicenter trial designed to evaluate early intervention in chronic obstructive pulmonary disease (COPD). All participants were smokers between the ages of 35 and 60 yr who had mild COPD. The male:female prevalence of a positive challenge (PC20FEV1) was 25%:48% and 63%:87% at a PC20FEV1 of < or = 5 mg/ml (AHR5) and < or = 25 mg/ml (AHR25), respectively. This analysis explores these marked gender differences in airway hyperresponsiveness (AHR). Relative risks (RR) for predictors of AHR and the 95% confidence intervals (95% CI) were estimated using semiparametric Cox proportional-hazards models. The initial model controlled for age, gender, smoking history, height, and weight. The RR (95% CI) for female gender was 1.75 (1.60, 1.92). When the measured baseline FEV1 was added to the model as a surrogate for airway caliber, the RR for female gender decreased to 1.06 (0.96, 1.18). Thus, in this population of middle-aged smokers with mild COPD, the high prevalence of AHR appears to be associated with a decrease in airway caliber. The higher prevalence of AHR noted in women is due to their having a smaller airway caliber than their male counterparts.

Effect of chest wall vibration on dyspnea in patients with chronic respiratory disease.

The effect of chest wall vibration on dyspnea at rest was investigated in 15 patients with severe chronic respiratory diseases. The magnitude of their baseline dyspnea was 17.9 +/- SE 3.3 mm on a 150-mm visual analog scale. One hundred hertz out-of-phase vibration (OPV; inspiratory intercostal muscles vibrated during expiration and expiratory intercostal muscles vibrated during inspiration) increased dyspnea an average of 21.9 +/- SE 7.8 mm (p < 0.05). One hundred hertz in-phase vibration (IPV; inspiratory intercostal muscles vibrated during inspiration and expiratory intercostal muscles vibrated during expiration) decreased dyspnea an average of 6.9 +/- SE 2.8 mm (p < 0.05). Changes in the respiratory pattern and arterial blood gas determinations elicited by 5-min IPV were investigated in eight of the 15 patients. Tidal volume was significantly increased in all eight of these patients. Respiratory frequency was decreased in seven patients and increased in one. Functional residual capacity, measured before and during the application of IPV for a period of about 10 breaths, was increased in one patient and decreased in the remaining seven. PaCO2 decreased by 1.3 +/- 1.0 mm Hg (p < 0.05), from 49.6 +/- 8.4 mm Hg; PaO2 increased by 3.4 +/- 2.3 mm Hg (p < 0.05), from 67.7 +/- 12.7 mm Hg. The results indicate that in-phase chest wall vibration decreased pathologic dyspnea in patients with chronic respiratory disease and suggest that the effects on respiratory sensation are mediated by afferent information from chest wall respiratory muscles to supraspinal centers.

Perceptual contributions to optimization of breathing.

Besides regulating the energetic cost of breathing, optimization of breathing may involve the alleviation of an uncomfortable breathing sensation. In this article, we consider perceptual contributions to the optimization of breathing. Just as the cost function proposed by Poon depends on ventilation and arterial PCO2 so does the sense of dyspnea. Consequently, we examined the relationship between breathing discomfort and Poon's cost function. Based on our model and psychophysical studies, it appears that breathing discomfort, which can integrate chemical and mechanical inputs to the respiratory controller, may not operate simply as an estimate of a cost function. We explain how our reflex control model can dynamically minimize a cost function such as Poon's. Also, we consider the influence of willful adjustments of ventilation on breathing discomfort. From this we infer that ventilatory optimization may emerge from automatic reflexes and behavioral responses that involve excitatory chemical and inhibitory neuromechanical feedbacks.

The lung health study: airway responsiveness to inhaled methacholine in smokers with mild to moderate airflow limitation. The Lung Health Study Research Group.

As part of a multicenter clinical trial (Lung Health Study), methacholine inhalation challenge testing was performed in 5,877 current cigarette smokers, ages 35 to 59 yr (mean 48.5 +/- 6.8 yr), with borderline to moderate airflow limitation (FEV1/FVC ratio 63.0 +/- 5.5). The test was successfully completed in 96.4% of subjects, of whom 63% were male and 95.9% were white. Symptomatic reactions to methacholine were rarely severe enough to require evaluation by a trial physician. Nonspecific airways hyperresponsiveness (AHR) was defined as a greater than or equal to 20% decline in FEV1 from the post-diluent control value after inhalation of less than or equal to 25 mg/ml methacholine. AHR was noted in a significantly higher percentage of women (85.1%) than men (58.9%). Moreover, nearly twice as many women as men (46.6 and 23.9%, respectively) responded to less than or equal to 5 mg/ml of methacholine. In both men and women, baseline degree of airways obstruction and clinical center were strongly associated with AHR (p less than 0.001), whereas age was not. Additional associations with AHR were analyzed in men and women separately using logistic regression after adjustment for baseline lung function, age, and center-to-center differences. In men, AHR was significantly related to symptoms of wheeze, chronic cough and/or sputum, and a history of asthma or hay fever (p less than 0.004), but not to current or lifetime tobacco use. By contrast, among women, AHR was not significantly associated with chronic cough and/or phlegm (p greater than 0.05) or a past history of asthma or hay fever (p greater than 0.1) and was only weakly related to wheeze and current asthma (p = 0.04), as well as to cigarette pack-years (p = 0.044). These results indicate that most continuing smokers with functional evidence of early chronic obstructive pulmonary disease have nonspecific AHR that is strongly related to gender and baseline lung function and, to a lesser extent, to respiratory symptoms. The reason for the striking effect of gender on AHR in early chronic obstructive pulmonary disease is unclear but cannot be attributed to male-female differences in age, cigarette use, presence of asthma, or baseline degree of airflow obstruction.

Sensation and control of breathing: a dynamic model.

A dynamic model of the CO2 respiratory control system is proposed, which can provide a qualitative basis for predicting breathing sensations. The discomfort index, which represents breathing sensations, is assumed to be composed of two sources: the arterial CO2 level and the respiratory motor command. The respiratory controller receives inhibitory neuromechanical and excitatory CO2 signals from the plant. The CO2 signal is enhanced by exercise stimuli. This dynamic multiplicative-type controller is used in simulations of key experiments: exercise and CO2 rebreathing with and without resistive loading. The dynamics of the discomfort index, the respiratory motor command, ventilation, and arterial CO2 concentration conform to the experimental data. The perceptual sensitivity to CO2 relative to respiratory effort is significantly correlated with the slope of hypercapnic ventilatory response. This result shows a clear linkage between ventilatory response and breathing sensations. Although it is shown that the automatic controller effectively minimizes the discomfort index for perturbations about an operating point under certain conditions, the discomfort index itself does not seem to be an underlying control principle of the proposed automatic controller model. Rather, breathing sensations may influence ventilatory responses by modifying the output of the automatic controller.

Effects of changes in inspiratory muscle strength on the sensation of respiratory force.

The sensation of respiratory muscle force was compared in seven normal subjects before and after inspiratory muscle strength training. Subjects performed 20 sustained maximal inspiratory maneuvers daily for 6-18 wk. Maximal inspiratory pressures (MIP) increased from 124 +/- 10 to 187 +/- 9 (SE) cmH2O (P less than 0.005). Exponents of the power function relationships between mouth pressure (Pm) and the intensity of the sensation of force, corrected for inspiratory duration, during magnitude scaling of resistive and elastic ventilatory loads were the same before and after training (P greater than 0.05). However, absolute sensation intensity (S) during resistive and elastic loading was reduced significantly after strength training but returned toward baseline levels greater than or equal to 8 wk after the cessation of training when the MIP had fallen to 150 +/- 5 cmH2O. The absolute S at a given Pm during ventilatory loading changed inversely with changes in MIP (P less than 0.001). Furthermore the relationship between absolute S and Pm expressed as a proportion of the MIP (Pm/MIP) was constant over testing periods. These results suggest that the sensation of respiratory muscle force reflects the proportion of the maximum force utilized in breathing and may be based on the level of respiratory motor command signals.

Effect of norepinephrine on diaphragm contractility and blood flow.

Recent studies have shown that diaphragm fatigue can be reversed by mechanical augmentation of phrenic arterial flow. The purpose of the present experiment was to determine whether it was possible to pharmacologically augment diaphragm blood flow and reverse fatigue by the administration of norepinephrine. Four groups of studies were performed, all employing our previously described in situ isometric canine diaphragm strip preparation (Supinski et al., J. Appl. Physiol. 60: 1789-1796, 1986). Group I studies examined the effects of norepinephrine on the contractility of the nonfatigued diaphragm in normotensive dogs, group II studies examined the effects of this drug on the contractility of the fatigued diaphragm in normotensive animals, and group III studies examined the effect of this drug on the contractility of the fatigued diaphragm in hypotensive animals. Group IV studies examined the effect of norepinephrine in normotensive animals in which the phrenic artery was cannulated and pump perfused at constant flow. Fatigue was induced in group II, III, and IV studies by rhythmically stimulating the diaphragm via intramuscular electrodes. Norepinephrine had no effect on the contractility of the nonfatigued diaphragm (group I). In normotensive (group II) and hypotensive animals (group III), norepinephrine elicited dramatic increases in arterial blood pressure and phrenic arterial flow and produced a significant upshift in the force-frequency curve of the fatigued diaphragm. However, when phrenic flow was held constant (group IV experiments), norepinephrine failed to augment the contractility of the fatigued diaphragm. These results indicate that 1) norepinephrine can increase phrenic blood flow and augment the contractility of the fatigued diaphragm in both normotensive and hypotensive conditions and 2) this effect of norepinephrine to partially reverse fatigue is secondary to its action to augment diaphragmatic blood flow.

Effects of changes in level and pattern of breathing on the sensation of dyspnea.

Breathing during hypercapnia is determined by reflex mechanisms but may also be influenced by respiratory sensations. The present study examined the effects of voluntary changes in level and pattern of breathing on the sensation of dyspnea at a constant level of chemical drive. Studies were carried out in 15 normal male subjects during steady-state hypercapnia at an end-tidal PCO2 of 50 Torr. The intensity of dyspnea was rated on a Borg category scale. In one experiment (n = 8), the level of ventilation was increased or decreased from the spontaneously adopted level (Vspont). In another experiment (n = 9), the minute ventilation was maintained at the level spontaneously adopted at PCO2 of 50 Torr and breathing frequency was increased or decreased from the spontaneously adopted level (fspont) with reciprocal changes in tidal volume. The intensity of dyspnea (expressed as percentage of the spontaneous breathing level) correlated with ventilation (% Vspont) negatively at levels below Vspont (r = -0.70, P less than 0.001) and positively above Vspont (r = 0.80, P less than 0.001). At a constant level of ventilation, the intensity of dyspnea correlated with breathing frequency (% fspont) negatively at levels below fspont (r = -0.69, P less than 0.001) and positively at levels above fspont (r = 0.75, P less than 0.001). These results indicate that dyspnea intensifies when the level or pattern of breathing is voluntarily changed from the spontaneously adopted level. This is consistent with the possibility that ventilatory responses to changes in chemical drive may be regulated in part to minimize the sensations of respiratory effort and discomfort.

Effects of expiratory resistive loading on the sensation of dyspnea.

To determine whether an increase in expiratory motor output accentuates the sensation of dyspnea (difficulty in breathing), the following experiments were undertaken. Ten normal subjects, in a series of 2-min trials, breathed freely (level I) or maintained a target tidal volume equal to (level II) or twice the control (level III) at a breathing frequency of 15/min (similar to the control frequency) with an inspiratory load, an expiratory load, and without loads under hyperoxic normocapnia. In tests at levels II and III, end-expiratory lung volume was maintained at functional residual capacity. A linear resistance of 25 cmH2O.1(-1).s was used for both inspiratory and expiratory loading; peak mouth pressure (Pm) was measured, and the intensity of dyspnea (psi) was assessed with a visual analog scale. The sensation of dyspnea increased significantly with the magnitude of expiratory Pm during expiratory loading (level II: Pm = 9.4 +/- 1.5 (SE) cmH2O, psi = 1.26 +/- 0.35; level III: Pm = 20.3 +/- 2.8 cmH2O, psi = 2.22 +/- 0.48) and with inspiratory Pm during inspiratory loading (level II: Pm = 9.7 +/- 1.2 cmH2O, psi = 1.35 +/- 0.38; level III: Pm = 23.9 +/- 3.0 cmH2O, psi = 2.69 +/- 0.60). However, at each level of breathing, neither the intensity of dyspnea nor the magnitude of peak Pm during loading was different between inspiratory and expiratory loading. The augmentation of dyspnea during expiratory loading was not explained simply by increases in inspiratory activity. The results indicate that heightened expiratory as well as inspiratory motor output causes comparable increases in the sensation of difficulty in breathing.