Interpretation of treatment changes in 6-minute walk distance in patients with COPD.

There is uncertainty about the interpretation of changes in the 6-min walk distance (6MWD) in chronic obstructive pulmonary disease (COPD) patients and whether the minimal important difference (MID) for this useful outcome measure exists. Data were used from nine trials enrolling a wide spectrum of COPD patients with 6MWD at baseline and follow-up and used to determine threshold values for important changes in 6MWD using three distribution-based methods. Anchor-based methods to determine a MID were also evaluated. Data were included of 460 COPD patients with a mean+/-sd forced expiratory volume in one second (FEV(1)) of 39.2+/-14.1% predicted and 6MWD of 361+/-112 m at baseline. Threshold values for important effects in 6MWD were between 29 and 42 m, respectively, using the empirical rule effect size and the standardised response mean. The threshold value was 35 m (95% confidence interval 30-42 m) based on the standard error of measurement. Correlations of 6MWD with patient-reported anchors were too low to provide meaningful MID estimates. 6-min walk distance should change by approximately 35 m for patients with moderate to severe chronic obstructive pulmonary disease in order to represent an important effect. This corresponds to a 10% change of baseline 6-min walk distance. The low correlations of 6-min walk distance with patient-reported anchors question whether a minimal important difference exists for the 6-min walk distance.

Tuberculosis misclassification among resettled refugees in Buffalo, New York, USA.

BACKGROUND: Discordance in the classification of tuberculosis (TB) disease overseas compared to classification in the United States has been observed among immigrant populations. OBJECTIVE: To examine TB misclassification among recently resettled refugees in Buffalo, NY, between 2005 and 2012. METHODS: Retrospective study of refugees resettled to Buffalo from 2005 to 2012 and evaluated at a refugee/community health center. Centers for Disease Control and Prevention (CDC) Division of Global Migration and Quarantine (DGMQ) Class B1-B3 and American Thoracic Society (ATS) Class 2 (LTBI) cases were abstracted. Independent variables were demographics, countries of origin and refugee camp internment, year of resettlement, purified protein derivative induration, and chest X-ray findings, while CDC DGMQ and ATS classification were dependent variables. Independent samples t-test and analysis of variance were performed. RESULTS: Of 284 charts reviewed, 233 (81.2%) were misclassified. Among 101 cases of LTBI (B1/B2) diagnosed outside the United States, 51 (50.5%) were overdiagnosed. Underdiagnoses occurred among 181/182 refugees (99.5%) originally classified as normal overseas. CONCLUSION: These findings suggest that TB misclassification among recent immigrants remains widespread. Screening procedures both before and after resettlement should be better synchronized. Public health implications range from morbidity and costs of unnecessary treatment to the spread of a highly communicable disease.

Selective paralysis of voluntary but not limbically influenced automatic respiration.

We describe a patient in whom a discrete infarction of the ventral basis pontis caused a complete loss of voluntary respiration, while automatic respiration remained intact. Respiratory excursions, quantified title volumes, and ventilatory response to carbon dioxide were normal, but the patient could not volitionally modify any respiratory parameters. Emotional stimuli producing laughter, crying, or anxiety appropriately modulated automatic respiration. This case established that pathways subserving limbic modulation of automatic respiration descend in the pontine tegmentum and/or lateral portion of the basis pontis spared by this lesion. Furthermore, descending limbic influences on automatic respiration are anatomically and functionally independent of the voluntary respiratory system.

Validity of neural network in sleep apnea.

Clinical assessment of obstructive sleep apnea (OSA) is poor. Overnight polysomnography (OPG) is the standard reference test, but it is expensive and time-consuming. We developed an artificial neural network (ANN) using anthropomorphic measurements and clinical information to predict the apnea-hypopnea index (AHI). All patients completed a questionnaire about sleep symptoms, sleep behavior, and demographic information prior to undergoing OPG. Neck circumference, height, and weight were obtained on presentation to the sleep center. Twelve variables were used as inputs. The output was an estimate of the AHI. The network was trained with a back-propagation algorithm on 189 patients and validated prospectively on 80 additional patients. Data from the derivation group was used to calculate the 95% confidence interval of the estimated AHI. Predictive accuracy at different AHI thresholds was assessed by the c-index, which is equivalent to the area under the receiver operator characteristic curve. The c-index for predicting OSA in the validation set was 0.96 +/- 0.0191 SE, 0.951 +/- 0.0203 SE, and 0.935 +/- 0.0274 SE, using thresholds of > 10, > 15, and > 20/hour respectively. The actual AHI of the 80 patients in the validation data set fell within the 95% confidence limits of the values predicted by the ANN. This study suggests that ANN may be useful as a predictive tool for OSA.

Respiratory muscle fatigue and breathing pattern.

The major determinants of VO2 resp and, thus, diaphragmatic endurance are the tension-time index, work rate and lung volume. Changes in breathing pattern that adversely affect any of these factors can impair diaphragmatic endurance. A TTdi above 0.15-0.18 indicates a potentially fatiguing pattern of contraction. However, fatigue may occur at a TTdi below 0.15 if the work rate is sufficiently high or the Pdimax is not measured at the prevailing lung volume. Inspiratory muscle fatigue usually elicits an increase in minute ventilation and respiratory rate and to a lesser degree a reduction in tidal volume. However, fatigue may not always be accompanied by changes in breathing pattern. Furthermore, fatigue may sometimes result in a reduction rather than an increase in motor outflow to the respiratory muscles. Finally, abdominal paradox initially considered to be characteristic clinical sign of inspiratory muscle fatigue appears to be due to increases in respiratory load rather than to muscle fatigue.

Effect of inspiratory muscle fatigue on inspiratory muscle relaxation rates in healthy subjects.

Simple methods to diagnose inspiratory muscle fatigue in the clinical setting would be of considerable benefit. Inspiratory muscle relaxation rates are known to slow following induction of fatigue. Inspiratory muscle relaxation rates have been measured following a short sharp inspiratory effort against an occluded airway (sniffmouth) or through the unoccluded nostrils (sniffnostrils). Relaxation rates in the absence of fatigue are faster when sniffs are performed through the unoccluded nostrils. While both methods have been shown to be capable of detecting inspiratory muscle fatigue, there may be quantitative or qualitative differences between the two techniques in their ability to detect fatigue similar to the differences observed in the fresh state. Accordingly, we measured relaxation rates with the two sniff techniques in five healthy naive male subjects before and after induction of fatigue. Inspiratory muscle fatigue was induced by threshold loading at 80 percent of Pesmax until the subjects were unable to generate the target pressure. For those trials in which sniffnostrils were performed, the maximum relaxation rate from the esophageal pressure curve (MRRes) was significantly decreased following induction of fatigue in nine of ten trials, while the exponential time constant (taues) was significantly increased in all ten trials. In contrast, for those trials in which sniffmouth were performed, the MRRes was significantly decreased following induction of fatigue in only six of ten trials. Similarly, taues was significantly increased following induction of fatigue in only six of ten trials. In addition, the magnitude of change in the MRR or tau following induction of fatigue was quantitatively greater with sniffnostrils compared with sniffmouth. Similar findings were obtained when relaxation rates were measured from the diaphragmatic pressure tracing. In conclusion, changes in relaxation rate following induction of fatigue were quantitatively greater and more consistently observed when sniffs were performed through the unoccluded nostrils rather than against an occluded airway.

Apneustic breathing. A characteristic feature of brainstem compression in achondroplasia?

We have observed apneustic breathing in five patients with achondroplasia. In contrast to experimental models of apneusis, these patients appeared to have intact vagal function and no evidence of pontine disease. However, all our patients displayed clinical, structural, and electrophysiologic features of cervicomedullary compression, a well-recognized complication of achondroplasia. The degree of apneustic breathing was reduced in the majority of our patients following decompressive surgery. Traditional theories on the pathogenesis of apneustic breathing cannot satisfactorily explain the presence of apneustic breathing in our patients. We suggest that cervicomedullary compression may be capable of producing apneustic breathing in the absence of vagal or pneumotaxic center lesions.

Reproducibility of Borg scale measurements of dyspnea during exercise in patients with COPD.

The purpose of this study was to evaluate the moderate term (5 weeks) reproducibility of Borg scale ratings of the effort to breathe (Borge) and the degree of discomfort evoked by breathing (Borgd) in patients with COPD during exercise. Six subjects with moderately severe COPD (FEV1, 1.42 +/- 0.50 L) underwent progressive incremental exercise (15 W/min) on a cycle ergometer to a symptom-limited maximum every week for 6 weeks (first week used as practice session). Minute ventilation (VE), oxygen consumption (VO2), and Borg ratings were obtained every minute during exercise. Borge and Borgd were highly correlated in each subject (r = 0.99 +/- 0.01). Borg scores were not significantly different across study days during both maximal and submaximal exercise. The within-subject coefficient of variation (CV) for Borge during maximal exercise was 13.9 +/- 9.0% (range, 6 to 31%) which was not significantly different from that observed for the physiological indices: 8.2 +/- 4.1% (range, 4 to 15%) for VE and 5.2 +/- 3.4% (range, 1 to 10%) for VO2. In contrast, at 66% of the maximum workload, the within-subject CV for Borge was 25.0 +/- 13.6% (range, 12 to 50%) which was significantly greater than that observed for the physiologic indices: 5.8 +/- 2.0% (range, 3 to 9%) for VE and 4.6 +/- 1.1% (range, 3 to 6%) for VO2. In every subject, Borge was linearly correlated with VE, VO2, and workload. However, within an individual subject, the slope of these relationships varied between trials; within-subject CV for the slope of the Borge/VE relationship was 20.2 +/- 8.0% (range, 12 to 32%). In conclusion, during incremental exercise Borg ratings of dyspnea are not as reproducible as physiologic indices in patients with COPD.

Effect of nebulized lidocaine on ventilatory response to CO2 in healthy subjects.

Partial vagal blockade produced by inhalation of a local anesthetic aerosol has enhanced CO2 responsiveness in some studies but not in others. The effect of inhaled local anesthetic may depend on the amount of drug depositing in the central airways, i.e., the degree of airway anesthesia. We examined the ventilatory response to CO2 rebreathing in 11 healthy subjects before and after inhalation of 4% lidocaine and a normal saline control solution. Lidocaine and control solutions were aerosolized via two different nebulizers: one produced particles with a mass median aerodynamic diameter of 5.28 microns, and the other produced particles with a mass median aerodynamic diameter of 1.76 microns. The ventilatory response to CO2 was not affected by the control solution. In contrast, the ventilatory response to CO2 was significantly increased after aerosolized lidocaine when administered via the moderate-particle-size nebulizer (2.13 +/- 0.66 vs. 1.83 +/- 0.54 l.min-1.Torr-1 during control, P = 0.01) but not via the small-particle-size nebulizer (1.96 +/- 0.82 vs. 1.94 +/- 0.84 l.min-1.Torr-1 during control, P = NS). The increase in ventilation was achieved predominantly by an increase in frequency (P = 0.01) while tidal volume was unchanged. In conclusion, airway receptors accessible to inhaled local anesthetic play a role in the control of breathing during CO2 rebreathing. Previous negative studies may be due to differences in nebulizer technique, affecting the amount of drug depositing within the central airways.

Effect of respiratory muscle fatigue on subsequent exercise performance.

The purpose of this study was to determine whether induction of inspiratory muscle fatigue might impair subsequent exercise performance. Ten healthy subjects cycled to volitional exhaustion at 90% of their maximal capacity. Oxygen consumption, breathing pattern, and a visual analogue scale for respiratory effort were measured. Exercise was performed on three separate occasions, once immediately after induction of fatigue, whereas the other two episodes served as controls. Fatigue was achieved by having the subjects breathe against an inspiratory threshold load while generating 80% of their predetermined maximal mouth pressure until they could no longer reach the target pressure. After induction of fatigue, exercise time was reduced compared with control, 238 +/- 69 vs. 311 +/- 96 (SD) s (P less than 0.001). During the last minute of exercise, oxygen consumption and heart rate were lower after induction of fatigue than during control, 2,234 +/- 472 vs. 2,533 +/- 548 ml/min (P less than 0.002) and 167 +/- 15 vs. 177 +/- 12 beats/min (P less than 0.002). At exercise isotime, minutes ventilation and the visual analogue scale for respiratory effort were larger after induction of fatigue than during control. In addition, at exercise isotime, relative tachypnea was observed after induction of fatigue. We conclude that induction of inspiratory muscle fatigue can impair subsequent performance of high-intensity exercise and alter the pattern of breathing during such exercise.

Effect of inspiratory muscle fatigue on breathing pattern during inspiratory resistive loading.

The purpose of this study was to determine whether induction of either inspiratory muscle fatigue (expt 1) or diaphragmatic fatigue (expt 2) would alter the breathing pattern response to large inspiratory resistive loads. In particular, we wondered whether induction of fatigue would result in rapid shallow breathing during inspiratory resistive loading. The breathing pattern during inspiratory resistive loading was measured for 5 min in the absence of fatigue (control) and immediately after induction of either inspiratory muscle fatigue or diaphragmatic fatigue. Data were separately analyzed for the 1st and 5th min of resistive loading to distinguish between immediate and sustained effects. Fatigue was achieved by having the subjects breathe against an inspiratory threshold load while generating a predetermined fraction of either the maximal mouth pressure or maximal transdiaphragmatic pressure until they could no longer reach the target pressure. Compared with control, there were no significant alterations in breathing pattern after induction of fatigue during either the 1st or 5th min of resistive loading, regardless of whether fatigue was induced in the majority of the inspiratory muscles or just in the diaphragm. We conclude that the development of inspiratory muscle fatigue does not alter the breathing pattern response to large inspiratory resistive loads.

Accuracy of the respiratory inductive plethysmograph during loaded breathing.

Indirect methods of measuring ventilation, such as the respiratory inductive plethysmograph (RIP), operate on the assumption that the respiratory system possesses two degrees of freedom of motion: the rib cage and abdomen. Accurate measurements have been obtained in many patients with pulmonary disease who possess additional degrees of freedom. Since calibration and validation of the RIP was carried out during quiet breathing in these patients, the amount of asynchronous or paradoxic breathing was presumably similar during the calibration and validation runs. Conversely, accuracy might be lost if following the initial calibration procedure the magnitude of chest wall distortion increased during subsequent validation runs. We calibrated the RIP during quiet breathing and examined its accuracy while subsequently breathing against resistive loads that required the generation of 20-80% of the subject's maximum inspiratory mouth pressure (Pmmax). We compared the relative accuracy of three commonly employed calibration methods: isovolume technique, least-squares technique, and single position loop-area technique. Up to 60% of Pmmax, 89% of the RIP values with the least-squares technique were within +/- 10% of simultaneous spirometric (SP) measurements and 100% were within +/- 20% of SP, compared with 63 and 91%, respectively, for the loop-area technique and 19 and 54%, respectively, for the isovolume technique. At 70 and 80% of Pmmax accuracy deteriorated. Accuracy of respiratory timing was judged in terms of fractional inspiratory time (TI/TT).(ABSTRACT TRUNCATED AT 250 WORDS)

Variability of resting respiratory drive and timing in healthy subjects.

Studies of breathing pattern have focused primarily on changes in the mean values of the breathing pattern components, whereas there has been minimal investigation of breath-to-breath variability, which should provide information on the constancy with which respiration is controlled. In this study we examined the variability of breathing pattern both on a breath-to-breath and day-to-day basis by calculating the coefficient of variation (i.e., the standard deviation expressed as a percentage of the mean). By examining breath-to-breath data, we found that the coefficients of variation of tidal volume (VT) and fractional inspiratory time (TI/TT, an index of timing) obtained with an inductive plethysmograph and spirometer were within 1% of each other. Examination of breath-to-breath variability in breathing pattern over a 15-min period in 65 subjects revealed large coefficients of variation, indicating the need to base calculations on a relatively large number of breaths. Less breath-to-breath variability was observed in respiratory frequency [f, 20.8 +/- 11.5% (SD)] and TI/TT (17.9 +/- 6.5%) than in VT (33 +/- 14.9%) and mean inspiratory flow (VT/TI, an index of drive; 31.6 +/- 12.6%; P less than 0.0001). Older subjects (60-81 yr) displayed greater breath-to-breath variability than young subjects (21-50 yr). Use of a mouthpiece did not affect the degree of variability.(ABSTRACT TRUNCATED AT 250 WORDS)

The utility of neural network in the diagnosis of Cheyne-Stokes respiration.

The aim of this study was to design a diagnostic model to identify patients with Cheyne-Stokes respiration (CSR-CSA) based on indices of oximetric spectral analysis. A retrospective analysis of oximetric recordings of 213 sleep studies conducted over a one-year period at a Veterans Affairs medical facility was performed. A probabilistic neural network (PNN) was developed from salient features of the oximetric spectral analysis, desaturation events and the delta index. A fivefold cross-validation was used to assess the accuracy of the neural network in identifying CSR-CSA. When compared to overnight polysomnography, the PNN achieved a sensitivity of 100% (95% confidence interval [CI] 85%-100%) and a specificity of 99% (95% 97%-100%) with a corresponding area under the curve of 99% (95% CI 99%-100%). When combined with overnight pulse oximetry, PNN offers an accurate and easily applicable tool to detect CSR-CSA.

A randomised trial to evaluate the self-administered standardised chronic respiratory questionnaire.

The original chronic respiratory questionnaire (CRQ), one of the most widely used measures of health-related quality of life (HRQL) in chronic respiratory disease (CRD), is traditionally interviewer administered (IA) and includes an individualised dyspnoea domain. The present authors studied the impact of self-administered (SA) and standardised dyspnoea questions on CRQ measurement properties. In a factorial design multicentre trial, 177 patients with CRD (mean age 67.7 yrs; mean forced expiratory volume in one second per cent predicted 44.6%) were randomised to CRQ-IA (n = 86) or CRQ-SA (n = 91), and to initially complete the standardised or individualised items before and after respiratory rehabilitation. While maintaining validity, the CRQ-SA proved more responsive to changes in HRQL than the CRQ-IA in all domains. Compared with the standardised dyspnoea domain, the individualised dyspnoea domain indicated greater responsiveness. The correlations of baseline scores and change scores with other HRQL instruments indicated good validity of the CRQ-SA. In conclusion, self-administration and standardisation of the chronic respiratory questionnaire maintains validity and responsiveness relative to the interviewer-administered chronic respiratory questionnaire. These results challenge the assumption that interviewer-administered questionnaires are superior to self-administered questionnaires in older patients with chronic respiratory disease.

Effect of respiratory muscle fatigue on breathing pattern during incremental exercise.

We examined the breathing pattern during incremental exercise before and after induction of inspiratory muscle fatigue. Our aim was to determine whether induction of fatigue alters the ventilatory response to exercise and in particular whether such changes are most apparent at high levels of exercise when minute ventilation and thus inspiratory load are greatest. A group of 10 healthy subjects was studied on a cycle ergometer. Fatigue was achieved by having the subject breathe against an inspiratory threshold load that required the subject to generate 80% of the predetermined maximal mouth pressure to initiate airflow. Breathing pattern, oxygen consumption (VO2), mouth occlusion pressure (P0.1), and a visual analog scale (VAS) for respiratory effort were obtained for 3 min at rest and at 25, 50, 75, and 100% of the subject's maximal work load (Wmax) as determined by preliminary testing. Exercise was performed on two separate occasions, once immediately after induction of fatigue and the other as a control. Induction of fatigue had no effect on resting breathing and only minimal effects at the lower work loads (25 and 50% Wmax). At the higher work loads (75 and 100% Wmax) induction of fatigue significantly altered the pattern of breathing during exercise. At 75% of Wmax the respiratory frequency (f) increased from 22.5 +/- 4.4 (SD) during control to 27.0 +/- 6.7 breaths/min (p less than 0.02) following induction of fatigue; tidal volume was not significantly altered, 2.15 +/- 0.65 versus 2.24 +/- 0.74 L during control. The increase in f was due to reductions in both inspiratory and expiratory time because fractional inspiratory time remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of alterations in mental activity on the breathing pattern in healthy subjects.

The overall output from the respiratory centers is regulated by an automatic metabolic control system in the brainstem and by higher neural centers under direct voluntary control. An understanding of the constancy with which respiration is controlled can be obtained by measuring the breath-to-breath variability in breathing pattern. We hypothesized that different forms of mental activity would alter the variability of breathing pattern. To test this hypothesis, we measured breathing pattern on a breath-by-breath basis during resting wakefulness and during four conditions of altered mental activity. Measurements were obtained with a calibrated respiratory inductive plethysmograph, and variability was assessed by calculations of the coefficients of variation. We also examined the effect of the altered states of mental activity on the mean values of the breathing pattern components. We found that noxious stimulation increased the variability of all the breathing pattern indices, audiovisual stimulation tended to increase the variability of tidal volume (VT), and mental arithmetic had no effect. In addition, the variability of breathing pattern was increased during rapid eye movement sleep and decreased during Stage IV sleep. The variability of VT and expiratory time were greater than that of inspiratory time (TI) across the different states of mental activity. Significant correlations were observed between VT and TI and between VT and frequency (f) during Stage IV sleep. With regards to the mean values, mental arithmetic, audiovisual stimulation, and noxious stimulation all increased minute ventilation and mean inspiratory flow.(ABSTRACT TRUNCATED AT 250 WORDS)