Sabrina S. Wilkie

Genotype‐guided drug prescribing: a systematic review and meta‐analysis of randomized control trials

Aim Adverse drug events lead to increased morbidity, mortality and health care costs. Pharmacogenetic testing that guides drug prescribing has the potential to reduced adverse drug events and increase drug effectiveness. Our aim was to quantify the clinical effectiveness of genotype-guided prescribing. Methods Three electronic databases were searched from January 1980 through December 2013. Studies were eligible if they were RCTs comparing genotype-guided prescribing with non-genetic informed prescribing, reported drug specific adverse drug events and clinical effectiveness outcomes. Two reviewers independently screened titles and abstracts, extracted data and assessed study quality. Meta-analyses of specific outcomes were conducted where data allowed. Results Fifteen studies, involving 5688 patients and 19 drugs, met the inclusion and exclusion criteria. Eight studies had statistically significant results for their primary outcome in favour of genotype-guided prescribing. Nine studies evaluated genotype-guided warfarin dosing. Analysis of percentage of time in therapeutic international normalized ratio range (1952 individuals) showed a statistically significant benefit in favour of genotype-guided warfarin dosing (mean difference = 6.67; 95% CI 1.34, 12.0, I2 = 80%). There was a statistically significant reduction in numbers of warfarin-related minor bleeding, major bleeding and thromboembolisms associated with genotype guided warfarin dosing, relative risk 0.57 (95% CI 0.33, 0.99; I2 = 60%). It was not possible to meta-analyze genotype-guided dosing for other drugs. Of the six non-warfarin genotype-guided trials, two demonstrated a statistically significant benefit for their primary outcome, odds ratio 0.03 (95% CI 0.00, 0.62, P < 0.001) for abacavir. Conclusions There is evidence of improved clinical effectiveness associated with genotype-guided warfarin dosing.

Effects of hyperoxia on dyspnoea and exercise endurance in fibrotic interstitial lung disease

Dyspnoea is a major source of distress and is the hallmark symptom of patients with interstitial lung disease (ILD). Supplemental oxygen may alleviate dyspnoea by attenuating arterial oxygen desaturation, increasing oxygen delivery and reducing the drive to breathe; however, previous studies show conflicting results on the effectiveness of supplemental oxygen on dyspnoea and exercise performance in ILD [1–6]. Methodological factors in these studies likely led to underestimation of the potential magnitude of improvement, including an insufficient fraction of inspired oxygen (FIO2) and/or the use of self-paced walking tests and incremental cycle tests rather than constant-load exercise protocols [3–8]. Dyspnoea was also either not evaluated or only evaluated at peak exercise [1, 3–6], which is insensitive to change compared to more clinically relevant submaximal exercise [8]. Finally, some studies were retrospective and did not include a blinded room-air exercise trial, making it difficult to rule out the potential placebo effect [4, 5]. The purpose of this study was to determine the effects of hyperoxia on exercise endurance as well as the intensity and qualitative dimensions of exertional dyspnoea in patients with fibrotic ILD. Hyperoxia significantly improves exertional dyspnoea and exercise tolerance in patients with fibrotic ILD http://ow.ly/WbHf309VwcM

Cardiorespiratory and sensory responses to exercise in adults with mild cystic fibrosis.

The purpose of this study was to evaluate cardiorespiratory fitness and reasons for exercise curtailment in a contemporary adult cystic fibrosis (CF) cohort with mild lung disease. Adults with mild CF (n = 19, forced expiratory volume in 1 s = 95 ± 17% predicted) were age-, sex-, ethnicity-, and body mass index-matched to healthy controls (n = 19) and underwent a detailed cardiopulmonary cycle exercise test. While CF subjects had a reduced peak oxygen uptake compared with controls, the values were normal when expressed as %predicted in 14/19 (74%) of subjects. Both groups demonstrated a normal cardiovascular limitation to exercise and stopped exercise primarily because of leg fatigue. Despite not being exercise-limited by respiratory factors, there was some evidence of ventilatory abnormalities as patients with mild CF had increased end-inspiratory lung volumes and reached an inflection/plateau in tidal volume relative to minute ventilation at lower exercise intensities compared with controls. Subjects with CF were not more likely to demonstrate expiratory flow limitation compared with controls and did not have evidence of dynamic hyperinflation during exercise. Despite increased end-inspiratory lung volumes and an earlier tidal volume inflection/plateau, CF subjects did not experience higher levels of dyspnea. In an exploratory analysis, a significant inverse correlation was observed between sweat chloride and peak work rate. Adult CF subjects with relatively well preserved spirometry have normal exercise performance relative to reference values and are primarily limited by nonrespiratory factors. However, ventilatory abnormalities were detected even in this mild CF cohort and should be evaluated in future therapeutic trials focused on disease-modifying therapies in mild CF.

Heliox breathing equally influences respiratory mechanics and cycling performance in trained males and females

In this study we tested the hypothesis that inspiring a low-density gas mixture (helium-oxygen; HeO2) would minimize mechanical ventilatory constraints and preferentially increase exercise performance in females relative to males. Trained male (n = 11, 31 yr) and female (n = 10, 26 yr) cyclists performed an incremental cycle test to exhaustion to determine maximal aerobic capacity (V̇o2max; male = 61, female = 56 ml·kg(-1)·min(-1)). A randomized, single-blinded crossover design was used for two experimental days where subjects completed a 5-km cycling time trial breathing humidified compressed room air or HeO2 (21% O2:balance He). Subjects were instrumented with an esophageal balloon for the assessment of respiratory mechanics. During the time trial, we assessed the ability of HeO2 to alleviate mechanical ventilatory constraints in three ways: 1) expiratory flow limitation, 2) utilization of ventilatory capacity, and 3) the work of breathing. We found that HeO2 significantly reduced the work of breathing, increased the size of the maximal flow-volume envelope, and reduced the fractional utilization of the maximal ventilatory capacity equally between men and women. The primary finding of this study was that inspiring HeO2 was associated with a statistically significant performance improvement of 0.7% (3.2 s) for males and 1.5% (8.1 s) for females (P < 0.05); however, there were no sex differences with respect to improvement in time trial performance (P > 0.05). Our results suggest that the extent of sex-based differences in airway anatomy, work of breathing, and expiratory flow limitation is not great enough to differentially affect whole body exercise performance.

Effects of inspiratory muscle training on respiratory muscle electromyography and dyspnea during exercise in healthy men

Inspiratory muscle training (IMT) has consistently been shown to reduce exertional dyspnea in health and disease; however, the physiological mechanisms remain poorly understood. A growing body of literature suggests that dyspnea intensity can be explained largely by an awareness of increased neural respiratory drive, as measured indirectly using diaphragmatic electromyography (EMGdi). Accordingly, we sought to determine whether improvements in dyspnea following IMT can be explained by decreases in inspiratory muscle electromyography (EMG) activity. Twenty-five young, healthy, recreationally active men completed a detailed familiarization visit followed by two maximal incremental cycle exercise tests separated by 5 wk of randomly assigned pressure threshold IMT or sham control (SC) training. The IMT group (n = 12) performed 30 inspiratory efforts twice daily against a 30-repetition maximum intensity. The SC group (n = 13) performed a daily bout of 60 inspiratory efforts against 10% maximal inspiratory pressure (MIP), with no weekly adjustments. Dyspnea intensity was measured throughout exercise using the modified 0-10 Borg scale. Sternocleidomastoid and scalene EMG was measured using surface electrodes, whereas EMGdi was measured using a multipair esophageal electrode catheter. IMT significantly improved MIP (pre: -138 ± 45 vs. post: -160 ± 43 cmH2O, P < 0.01), whereas the SC intervention did not. Dyspnea was significantly reduced at the highest equivalent work rate (pre: 7.6 ± 2.5 vs. post: 6.8 ± 2.9 Borg units, P < 0.05), but not in the SC group, with no between-group interaction effects. There were no significant differences in respiratory muscle EMG during exercise in either group. Improvements in dyspnea intensity ratings following IMT in healthy humans cannot be explained by changes in the electrical activity of the inspiratory muscles.NEW & NOTEWORTHY Exertional dyspnea intensity is thought to reflect an increased awareness of neural respiratory drive, which is measured indirectly using diaphragmatic electromyography (EMGdi). We examined the effects of inspiratory muscle training (IMT) on dyspnea, EMGdi, and EMG of accessory inspiratory muscles. IMT significantly reduced submaximal dyspnea intensity ratings but did not change EMG of any inspiratory muscles. Improvements in exertional dyspnea following IMT may be the result of nonphysiological factors or physiological adaptations unrelated to neural respiratory drive.

Cardiorespiratory and sensory responses to exercise in well-controlled asthmatics

Abstract Objectives: The purpose of this study was to evaluate detailed ventilatory, cardiovascular and sensory responses to cycle exercise in sedentary patients with well-controlled asthma and healthy controls. Methods: Subjects included sedentary patients meeting criteria for well-controlled asthma (n = 14), and healthy age- and activity-matched controls (n = 14). Visit 1 included screening for eligibility, medical history, anthropometrics, physical activity assessment, and pre- and post-bronchodilator spirometry. Visit 2 included spirometry and a symptom limited incremental cycle exercise test. Detailed ventilatory, cardiovascular and sensory responses were measured at rest and throughout exercise. Results: Asthmatics and controls were well matched for age, body mass index and physical activity levels. Baseline forced expiratory volume in 1 second (FEV1) was similar between asthmatics and controls (98 ± 10 versus 95 ± 9% predicted, respectively, p > 0.05). No significant differences were observed between asthmatics and controls for maximal oxygen uptake (31.8 ± 5.6 versus 30.6 ± 5.9 ml/kg/min, respectively, p > 0.05) and power output (134 ± 35 versus 144 ± 32 W, respectively, p > 0.05). Minute ventilation (VE) relative to maximum voluntary ventilation (VE/MVV) was similar between groups at maximal exercise with no subjects showing evidence of ventilatory limitation. Asthmatics and controls achieved similar age-predicted maximum heart rates (92 ± 7 versus 93 ± 8% predicted, respectively, p > 0.05). Ratings of perceived breathing discomfort and leg fatigue were not different between groups throughout exercise. Conclusions: The results of this study indicate that sedentary patients with well-controlled asthma have preserved sensory and cardiorespiratory responses to exercise with no evidence of exercise impairment or ventilatory limitation.

Sex differences in respiratory muscle activation patterns during high-intensity exercise in healthy humans

Although women experience greater ventilatory constraints and have a higher work of breathing during exercise, they are less susceptible to diaphragm fatigue compared to men. The mechanisms for diaphragmatic fatigue resistance in women is unknown but may be related to sex differences in respiratory muscle recruitment. Accordingly, the purpose of this study was to determine if electromyography (EMG) of the diaphragm (EMGdi) and extra-diaphragmatic inspiratory muscles differ between sexes during exercise. Forty subjects (21M:19F) completed a constant load cycling test at 85% of maximum work rate until exhaustion, while instrumented with an oesophageal electrode catheter to measure EMGdi and surface electrodes to measure EMG of the sternocleidomastoid (EMGscm) and scalene (EMGsca) muscles. No sex difference in EMGdi was observed at any measurement time. However, EMGscm and EMGsca were higher throughout all submaximal exercise times in women (p<0.01). These results suggest greater reliance on the extra-diaphragmatic inspiratory muscles in women relative to men, which may serve as a strategy to minimize diaphragmatic fatigue.

Physiological mechanisms of dyspnea relief following ivacaftor in cystic fibrosis: a case report.

Ivacaftor is a novel oral pharmacologic agent that specifically targets the genetic defect of cystic fibrosis (CF) by augmenting chloride conductance through the CF transmembrane regulator (CFTR) protein. For individuals with CF and at least one copy of the G551D gating mutation, improvements in sweat chloride, nutritional parameters, lung function, respiratory symptoms, and exercise tolerance (i.e., 6-min walk distance) are attained within 2 weeks of initiating ivacaftor. However, there are no reports detailing the physiological and sensory implications of these improvements and their underlying mechanisms. We performed detailed cardiopulmonary exercise testing pre- and post-initiation of ivacaftor in a 27-year old male with CF (CFTR genotype F508del/G551D) and chronic airflow obstruction (FEV1/FVC=0.44). An improvement of FEV1 (by 16%) following ivacaftor was accompanied by clinically significant improvements in exercise capacity (by 14%) and exertional dyspnea (by up to 5 Borg scale units). These improvements were attributable, at least in part, to favorable alterations in the ventilatory response to exercise, including improvements in breathing patterns (e.g., increased tidal volume and reduced breathing frequency) and dynamic operating lung volumes (e.g., increased inspiratory reserve volume and inspiratory capacity) and decreases in dynamic mechanical ventilatory constraints.

Neurophysiological mechanisms of exertional dyspnoea in fibrotic interstitial lung disease

Our understanding of the mechanisms of dyspnoea in fibrotic interstitial lung disease (ILD) is incomplete. The aims of this study were two-fold: 1) to determine whether dyspnoea intensity is better predicted by neural respiratory drive (NRD) or neuromechanical uncoupling (NMU) of the respiratory system in fibrotic ILD, and 2) to examine the effect of breathing 60% oxygen on NRD, NMU and dyspnoea ratings. Fourteen patients with fibrotic ILD were included. Visit 1 comprised a familiarisation incremental cycle exercise test, Visit 2 comprised a normoxic incremental cycling test to address Aim 1, and Visits 3 and 4 consisted of constant-load cycling while breathing room air or 60% oxygen to address Aim 2. Diaphragmatic electromyography (EMGdi) was used as a surrogate of NRD. NMU was calculated as the ratio between EMGdi (%max) and tidal volume (%vital capacity). On adjusted analysis, NMU and its constituents were all significantly associated with dyspnoea ratings during incremental cycling, with EMGdi having the strongest correlation. The between-treatment change in dyspnoea ratings during constant load cycling was only correlated with change in exercise endurance time and NMU. Dyspnoea more strongly reflected the level of EMGdi than NMU in fibrotic ILD. However, the improvement in dyspnoea with 60% oxygen was better predicted by improvements in NMU. Neural respiratory drive is a strong independent predictor of dyspnoea in patients with fibrotic ILD http://ow.ly/MXjd30hcabH