Aimee M. Layton

Evaluation of Pulmonary Function and Exercise Performance by Cardiopulmonary Exercise Testing Before and After Lung Transplantation

BACKGROUND Detailed description of functional exercise outcomes before and after lung transplantation is lacking. The objective of this study was to describe and compare posttransplant improvement in lung function and peak exercise parameters in patients with advanced lung disease. METHODS The study included 153 patients who underwent lung transplantation over 7 years who had complete cardiopulmonary exercise testing (CPET) and pulmonary function tests (PFTs) before and after lung transplantation. CPET and PFT within 30 months pretransplant and posttransplant were compared. RESULTS Pulmonary function markedly improved posttransplant as FVC increased 67%, maximum voluntary ventilation increased 91%, and FEV(1) increased 136%. However, peak oxygen consumption increased only 19%, peak CO(2) production increased 50%, and peak work increased 78%. Although transplant recipients had a 1.5- to 2.0-fold increase in exercise capacity posttransplant, peak exercise capacity remained at 50% of the predicted normal, suggesting a maximal limitation. Subgroup stratification into quartiles based on pretransplant exercise capacity revealed the greatest exercise benefit to be in the lowest functional pretransplant groups. CONCLUSIONS Lung transplant recipients have an increase in exercise capacity that does not match the improvement in lung function, indicating that poor strength, deconditioning, or other peripheral factors play a significant role in the limitation of exercise benefit posttransplantation. Further elucidation of the mechanisms of exercise limitation may allow for improved exercise outcomes posttransplant.

Sympathetic drive is modulated by central chemoreceptor activation.

To determine the effects of central chemoreceptor stimulation upon sympathetic modulation while minimizing baroreceptor influences, we performed a single-blind, counter-balanced, placebo-controlled trial of a modified hypercapnic/hyperoxic rebreathe protocol stimulus to activate the central chemoreflex. Muscle sympathetic nerve activity (MSNA), heart rate, blood pressure, and ventilation were recorded dynamically as subjects transitioned from a hypocapnia to hypercapnia state. The stages of data recording were defined as hyperventilation (HyV), pre-threshold (PreT) and post-threshold (PostT), with threshold being defined as the point of non-linear deviation in ventilation. The changes in MSNA (-4.2+/-52.4 arbitrary units (AU) vs. 245.0+/-84.0AU) and burst count (-0.1+/-0.7 bursts/segment vs. 2.5+/-1.7 bursts/segment) were significantly different between control and rebreathe for the HyV to PreT step. There was also a significant difference for PreT to PostT for total MSNA (3.9+/-65.4AU vs. 183.7+/-104.2AU). In a hypercapnic/hyperoxic state, the central chemoreceptors modulate sympathetic activity below the chemoreflex threshold independently of the baroreceptors, possibly contributing to basal autonomic/sympathetic tone. Central chemoreceptors also appear to play a significant role in sympathetic modulation after the threshold.

Optoelectronic plethysmography compared to spirometry during maximal exercise

The purpose of this study was to compare simultaneous measurements of tidal volume (Vt) by optoelectronic plethysmography (OEP) and spirometry during a maximal cycling exercise test to quantify possible differences between methods. Vt measured simultaneously by OEP and spirometry was collected during a maximal exercise test in thirty healthy participants. The two methods were compared by linear regression and Bland-Altman analysis at submaximal and maximal exercise. The average difference between the two methods and the mean percentage discrepancy were calculated. Submaximal exercise (SM) and maximal exercise (M) Vt measured by OEP and spirometry had very good correlation, SM R=0.963 (p<0.001), M R=0.982 (p<0.001) and high degree of common variance, SM R(2)=0.928, M R(2)=0.983. Bland-Altman analysis demonstrated that during SM, OEP could measure exercise Vt as much as 0.134 L above and -0.025 L below that of spirometry. OEP could measure exercise Vt as much as 0.188 L above and -0.017 L below that of spirometry. The discrepancy between measurements was -2.0 ± 7.2% at SM and -2.4 ± 3.9% at M. In conclusion, Vt measurements at during exercise by OEP and spirometry are closely correlated and the difference between measurements was insignificant.

Exercise ventilatory kinematics in endurance trained and untrained men and women

To determine how increased ventilatory demand impacts ventilatory kinematics, we compared the total chest wall volume variations (V(CW)) of male and female endurance-trained athletes (ET) to untrained individuals (UT) during exercise. We hypothesized that training and gender would have an effect on V(CW) and kinematics at maximal exercise. Gender and training significantly influenced chest wall kinematics. Female ET did not change chest wall end-expiratory volume (V(CW,ee)) or pulmonary ribcage (V(RCp,ee)) with exercise, while female UT significantly decreased V(CW,ee) and V(RCp,ee) with exercise (p<0.05). Female ET significantly increased pulmonary ribcage end-inspiratory volume (V(RCp,ei)) with exercise (p<0.05), while female UT did not change V(RCp,ei) with exercise. Male ET significantly increased V(RCp,ei) with exercise (p<0.05); male UT did not. Men and women had significantly different variation of V(CW) (p<0.05). Women demonstrated the greatest variation of V(CW) in the pulmonary ribcage compartment (V(RCp)). Men had even volumes variation of the V(RCp) and the abdomen (V(Ab)). In conclusion, gender and training had a significant impact on ventilatory kinematics.

An assessment of pulmonary function testing and ventilatory kinematics by optoelectronic plethysmography

New advances in computer processing and imaging have allowed the development of innovative techniques to assess lung function. A promising methodology is optoelectronic plethysmography (OEP). OEP evaluates ventilatory kinematics through the use of infrared imaging. Markers are placed, and images read on the chest, back and abdomen of subjects. Currently, this system is used mainly in research settings, but in the future may have broad applicability to patient populations such as very young children, patients with neuromuscular disease and patients who cannot be tested with classical spirometry testing. This paper presents the history and development of OEP, along with a summary of the OEP methodology, a discussion of research findings and results to date, as well as application and limitations.

The effect of lung volume reduction surgery on chronotropic incompetence

BACKGROUND Chronotropic incompetence (CI) is a marker of poor prognosis in patients with COPD. Treatments that improve pulmonary function and exercise capacity may affect CI. Objectives are to evaluate CI before and after lung volume reduction surgery (LVRS) and determine if changes in CI are associated with changes in pulmonary function and exercise capacity. METHODS We performed a retrospective review of 75 patients who underwent LVRS and who had complete cardiopulmonary exercise testing and concurrent pulmonary function tests two months before and about 6 months after surgery. Additionally we evaluated 28 control patients that were randomized to medical treatment as part of the National Emphysema Treatment Trial at our center. We studied CI using the percent of predicted heart rate reserve=(heart rate peak-heart rate rest)/((208-0.7×age)-heart rate rest)×100, before and after surgery and compared it to the control group. RESULTS Mean percent of predicted heart rate reserve improved from 41% to 50% (p-value <0.001) after LVRS, while the control group did not change. The mean forced vital capacity and expiratory volume in 1s, peak oxygen consumption, carbon dioxide production, ventilation, tidal volume and maximal workload all improved in the surgery group, while the controls did not improve. CONCLUSIONS CI improves after LVRS in a population of patients with COPD. CI improvements are associated with the increases in pulmonary function and exercise capacity. This improvement is seen in a domain of known cardiopulmonary impairment prior to surgery that improves as a positive response to the therapy of LVRS.

Non-invasive measurement of abnormal ventilatory mechanics in amyotrophic lateral sclerosis

In this study we investigated non‐invasive, effort‐independent measurement of ventilatory mechanics in patients with amyotrophic lateral sclerosis (ALS).

Update in Exercise Testing

Clinical exercise testing expands from field tests such as six-minute walk testing, time up and go testing, and shuttle walk testing, to lab tests such as cardiopulmonary exercise testing (CPET). Although these tests have been utilized in the clinical setting for nearly half a decade, the populations and uses for these tests are continually expanding. All of the exercise tests discussed have increased utilization in predicting postoperative outcomes; however, the six-minute walk test, timed up and go test, and shuttle walk test appear to have increased utility in populations with neurological and cognitive limitations; whereas the primary utility of CPET is in populations with cardiac and pulmonary disease.

Quantification of Improvements in Static and Dynamic Ventilatory Measures Following Lung Volume Reduction Surgery for Severe COPD

Rationale: This study quantitatively measured the effects of lung volume reduction surgery (LVRS) on spirometry, static and dynamic lung and chest wall volume subdivision mechanics, and cardiopulmonary exercise measures. Methods: Patients with severe COPD (mean FEV1 = 23 ± 6% predicted) undergoing LVRS evaluation were recruited. Spirometry, plethysmography and exercise capacity were obtained within 6 months pre-LVRS and again within 12 months post- LVRS. Ventilatory mechanics were quantified using stationary optoelectronic plethysmography (OEP) during spontaneous tidal breathing and during maximum voluntary ventilation (MVV). Statistical significance was set at P< 0.05. Results:Ten consecutive patients met criteria for LVRS (5 females, 5 males, age: 62±6yrs). Post -LVRS (mean follow up 7 months ± 2 months), the group showed significant improvements in dyspnea scores (pre 4±1 versus post 2 ± 2), peak exercise workload (pre 37± 21 watts versus post 50 ± 27watts ), heart rate (pre 109±19 beats per minutes [bpm] versus post 118±19 bpm), duty cycle (pre 30.8 ± 3.8% versus post 38.0 ± 5.7%), and spirometric measurements (forced expiratory volume in 1 second [FEV1] pre 23 ± 6% versus post 32 ± 13%, total lung capacity / residual lung volume pre 50 ± 8 versus 50 ± 11) . Six to 12 month changes in OEP measurements were observed in an increased percent contribution of the abdomen compartment during tidal breathing (41.2±6.2% versus 44.3±8.9%, P=0.03) and in percent contribution of the pulmonary ribcage compartment during MVV (34.5±10.3 versus 44.9±11.1%, P=0.02). Significant improvements in dynamic hyperinflation during MVV occurred, demonstrated by decreases rather than increases in end expiratory volume (EEV) in the pulmonary ribcage (pre 207.0 ± 288.2 ml versus post -85.0 ± 255.9 ml) and abdominal ribcage compartments (pre 229.1 ± 182.4 ml versus post -17.0 ± 136.2 ml) during the maneuver. Conclusions: Post-LVRS, patients with severe COPD demonstrate significant favorable changes in ventilatory mechanics, during tidal and maximal voluntary breathing. Future work is necessary to determine if these findings are clinically relevant, and extend to other environments such as exercise.

Ventilatory Mechanics in Endurance Athletes

VENTILATORY MECHANICS IN ENDURANCE ATHLETES Aimee Marie Layton The lungs were once thought to be over-built for exercise. However, upon further research, endurance athletes have been found to reach their maximum ventilation, demonstrating an insufficiency of the lungs to accommodate the demands of highly demanding endurance sport. This knowledge has inspired researchers to look further into the exercise ventilatory responses and, in doing so, researchers discovered that the adaptations of the pulmonary system to endurance training are still not well understood. Potential reasons for this lack of knowledge may be methodological measurement limitations, as ventilatory mechanics have been measured classically either invasively or by breathing maneuvers. These measurements are difficult to perform during high intensity exercise and in large groups of athletes. However, recent innovations in motion analysis technology have allowed for ventilatory mechanics to be measured during high intensity exercise, potentially allowing for further insight into how high intensity endurance training impacts ventilatory mechanics. The purpose of this study is to describe normal ventilatory mechanics during exercise in endurance trained and healthy untrained individuals, explore potential gender differences during exercise and investigate the impact of flow limitation during exercise on ventilatory mechanics, using a motion analysis system that allows researchers to obtain information on chest wall volume changes and chest wall compartmental interactions during high intensity exercise. This motion analysis system is called Optoelectronic Plethysmography (OEP). This dissertation is comprised of an introduction to the work and the 3 projects that comprise the dissertation along with an appendix, which includes a complete literature review. The three projects are as follows (1) an introduction to motion analysis as a tool in measuring ventilatory mechanics, (2) research determining the differences in the ventilatory mechanics in endurance athletes and healthy controls from rest to maximal exercise and (3) the differences in ventilatory mechanics between endurance trained women who demonstrate expiratory flow limitation during high intensity exercise versus endurance trained women who do not. Project 1: Optoelectronic Plethysmography (OEP) is a motion analysis tool that can be used to define exercise ventilatory mechanics by analyzing chest wall movements and calculating volume changes. By analyzing breathing mechanics by motion analysis rather than traditional breathing maneuvers, individual components of the chest wall can be analyzed and changes in volume throughout the chest wall can be assessed without altering the individual’s natural breathing pattern. This review presents the history and development of OEP technology, along with a summary of the methods used and a discussion of findings to date, giving insight into exercise ventilatory mechanics never investigated before. Project 2: Differences between the ventilatory mechanics of endurance athletes and non athletes using motion analysis have not yet been described. To determine how increased ventilatory demand impacts ventilatory kinematics, we compared the total chest wall volume variations (VCW) of 18 male and female endurance-trained athletes (ET) to 14 untrained individuals (UT) during exercise. We hypothesized that training and gender would have an effect on VCW and kinematics at maximal exercise. Gender and training significantly influenced chest wall kinematics. Female ET did not change chest wall end-expiratory volume (VCW,ee) or pulmonary ribcage end-expiratory volume (VRCp,ee) with exercise, while female UT significantly decreased VCW,ee and VRCp,ee with exercise (p<0.05). Female ET significantly increased pulmonary ribcage end-inspiratory volume (VRCp,ei) with exercise (p<0.05), while female UT did not change VRCp,ei with exercise. Male ET significantly increased VRCp,ei with exercise (p<0.05); male UT did not. Men and women had significantly different VCW (p <0.05). Women demonstrated the greatest variation of VCW in the pulmonary ribcage compartment (VRCp). Men had similar volumes in the VRCp and the abdomen (VAb). In conclusion, gender and training had a significant association with ventilatory kinematics. Project 3: Research has found potential limitations of the airways to accommodate the large tidal volumes generated during high intensity exercise. This airway limitation has been defined as expiratory flow limitation (EFL) observed during high intensity exercise in a large percentage of healthy women. Because of endurance athletes’ ability to exercise at high intensities for prolonged periods of time and produce greater than average tidal volumes, female endurance athletes may be particularly susceptible to EFL and the impact EFL may have on performance. The purpose of this last chapter was to investigate the ventilatory mechanics and exercise capacity parameters of female endurance athletes with and without EFL. Female competitive cyclists participated in two days of testing; day one consisted of a maximal aerobic capacity test ( o2max test) with spirometry and day two involved chest wall motion analysis testing during two steady state exercise tests. Baseline flow volume loops were performed prior to exercise and repeated post exercise. During exercise participants performed flow volume loops at minutes 4, 6, 8 and last 30 seconds of exercise. EFL was considered present when the exercise flow volume loop surpassed the baseline flow volume loop. To quantify the degree of flow limitation when comparing the peak exercise flow volume loop to the baseline flow volume loop, we calculated the percent flow volume loop reserve (%FVL reserve). Two levels of submaximal constant-load exercise bouts (at 60% and 85% maximal watts) were employed to investigate if EFL impacted ventilatory mechanics differently at different intensities. Optoelectronic plethysmography (OEP) was employed to measure VT from the pulmonary ribcage (VRCp), abdominal ribcage (VRCa) and the abdomen (VAb), as well as to measure end-expiratory volume chest wall volume (EEV) to calculate potential dynamic hyperinflation. Comparison of participants with and without EFL was made using an ANOVA or Kruskal-Wallis test (p≤0.05). Predictors of %FVL reserve were explored with a multiple linear regression. Two participants were not included in the data analysis due to the presence of asthma (one at rest, one exercise induced) as determined by spirometry during day one testing. Out of the other 28 participants, 6 participants had definite EFL (DEFL) demonstrated by overlapping of the peak exercise flow volume loop with the pre and post exercise flow volume loop, 5 had borderline EFL (BEFL) demonstrated by an overlapping of only the pre exercise flow volume loop and 17 had no EFL (NEFL) demonstrated by no overlapping of the pre or post flow volume loops. All participants had within normal limits of the percent predicted normal reference values in resting forced expiratory volume in 1 second (FEV1), forced mid expiratory flow rates (FEF25-75L/sec), forced vital capacity (FVC) and FEV1/FVC ratio. DEFL and BEFL participants’ had a significantly lower FEV1/FVC ratio compared to NEFL (p=0.003), DEFL had significantly lower FEF25-75% predicted normal reference values before and after exercise compared to NEFL (p=0.004). There were no differences in the exercise capacity values between groups. During the day two steady state tests, there was a significant interaction effect between groups and exercise intensity in the %VRCa (p=0.045) and % VAb (p=0.049). End-tidal carbon dioxide pressure, FEF25-75%, history of self reported excessive mucus with exercise and % VRCp during the 85% constant load test explained 71.6% of the variability in %FVL reserve in our regression model (p=0.002). Independent predictors of %FVL reserve were: end-tidal carbon dioxide pressure (p=0.033), FEF25-75% (p=0.010) and history of excessive mucus with exercise (0.014). In conclusion, female endurance athletes demonstrating EFL had normal but significantly different FeV1/FVC ratio and significantly different abdominal ribcage and abdomen percent contribution with increased exercise intensity, but similar exercise capacities compared to the female endurance athletes with no EFL. Also, independent predictors of %FVL reserve were found to be FEF25-75%, history of mucus production with exercise and end-tidal carbon dioxide level at peak exercise. This dissertation has provided further insight into the ventilatory mechanics of endurance athletes and how potential airway limitation can impact high intensity exercise. Further research can seek to better understand if the differences in ventilatory mechanics between endurance athletes with EFL and no EFL allow for preservation of exercise capacity in the presence of airway limitation.