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Purpose: The purpose of this study was to determine the impact of insomnia in Veterans with post-traumatic stress disorder (PTSD) and obstructive sleep apnea (OSA) on health-related outcomes before and after 12 weeks of continuous positive airway pressure (CPAP) treatment., Methods: We conducted a prospective cohort study of Veterans with PTSD and documented apnea hypopnea index (AHI) ≥ 5 with and without clinically significant insomnia as determined by the Insomnia Severity Index (ISI). Health-related outcomes including PTSD checklist (PCL-M), SF-36, and Pittsburgh Sleep Quality Index (PSQI) were assessed at baseline and 12 weeks after initiation of OSA treatment. CPAP adherence was retrieved at each visit., Results: Seventy-two Veterans including 36 with comorbid insomnia and OSA (COMISA) and 36 OSA-only were enrolled. Veterans with COMISA were younger (p = 0.03), had lower BMI (p < 0.001), and were more likely to report depression than those with OSA-only (p = 0.004). Although AHI was higher in the COMISA (p = 0.01), both groups expressed comparable daytime sleepiness (p = 0.16). The COMISA group had no significant change in SF-36 and PSQI after 12 weeks of treatment and used CPAP much less frequently than OSA-only group (p = 0.001)., Conclusions: COMISA in Veterans with PTSD is associated with worse quality of life than those with OSA-only. Insomnia should be assessed in Veterans with PTSD who are not adherent to CPAP treatment.

Study Objectives: Despite the overall improvement in posttraumatic stress disorder (PTSD) symptomatology with continuous positive airway pressure (CPAP) therapy, adherence to CPAP is far worse in veterans with PTSD compared to the general population with obstructive sleep apnea (OSA). The aim of this study was to compare the efficacy, adherence, and preference of CPAP versus mandibular advancement device (MAD) and the effect of these treatments on health outcomes in veterans with PTSD., Methods: Forty-two subjects with PTSD and newly diagnosed OSA by polysomnography were treated in a randomized, crossover trial of 12 weeks with CPAP alternating with MAD separated by a 2-week washout period. The primary outcome was the difference in titration residual apnea-hypopnea index (AHI) between CPAP and MAD. Secondary outcome measures included PTSD Checklist and health-related quality of life (Medical Outcomes Study 36-Item Short Form and Pittsburgh Sleep Quality Index)., Results: Analyses were limited to the 35 subjects (mean age 52.7 ± 11.6 years) who completed the trial, regardless of compliance with their assigned treatment. CPAP was more efficacious in reducing AHI and improving nocturnal oxygenation than MAD ( P < .001 and P = .04, respectively). Both treatments reduced PTSD severity and ameliorated scores of the Medical Outcomes Study Short Form 36 and Pittsburgh Sleep Quality Index, although no differences were detected between the CPAP and MAD arms. The reported adherence to MAD was significantly higher than CPAP ( P < .001), with 58% preferring MAD to CPAP., Conclusions: Although CPAP is more efficacious than MAD at improving sleep apnea, both treatment modalities imparted comparable benefits for veterans with PTSD in relation to PTSD severity and health-related quality of life. MAD offers a viable alternative for veterans with OSA and PTSD who are nonadherent to CPAP., Clinical Trial Registration: Title: A Randomized Cross Over Trial of Two Treatments for Sleep Apnea in Veterans With Post-Traumatic Stress Disorder; URL: https://www.clinicaltrials.gov/ct/show/NCT01569022; Identifier: NCT01569022., (© 2017 American Academy of Sleep Medicine)

Objectives: Previous retrospective studies have shown that continuous positive airway pressure (CPAP) exerts salutary effect on post-traumatic stress disorder (PTSD) symptoms and nightmare distress. The relative magnitude of therapeutic benefits from CPAP and the strength of associations between duration of CPAP use and PTSD symptomatology are unknown., Methods: A prospective cohort design involving 47 combat veterans with PTSD and documented obstructive sleep apnea (OSA) by overnight polysomnography. Epworth Sleepiness Scale (ESS) score, PTSD checklist-Military (PCL-M), Nightmare Distress Questionnaire (NDQ), and Nightmare Frequency Questionnaire (NFQ) were administered at baseline and 3 months after CPAP therapy. Objective adherence was assessed at the 3-month follow-up., Results: Twenty-two veterans with mild-to-moderate PTSD (PCL-M score 17-59) and 18 with severe-to-very-severe PTSD (PCL-M score 60-85) completed the study. There was a dose-dependent response of PCL-M to duration of CPAP usage (r = 0.45; p = 0.003). Veterans with severe-to-very-severe PTSD had a larger improvement in PTSD symptoms (d = 0.65; p = 0.004) compared with those with mild-to-moderate PTSD (d = 0.47; p = 0.04). CPAP usage was the only significant predictor of overall subjective improvement in PTSD symptoms (OR 10.5; p = 0.01). Significant changes in NDQ and NFQ scores following 3 months of treatment were observed in veterans adherent to CPAP, but the correlations with duration of CPAP use were not statistically significant (r = 0.24; p = 0.13 and r = 0.13; p = 0.4, respectively)., Conclusions: Improvement of PTSD symptoms in veterans with OSA was more pronounced with prolonged use of CPAP. Adherence to treatment was linked to abatement in nightmare distress and frequency. Future investigation of multimodal treatment, including behavioral intervention combined with CPAP, is warranted., (Published by Elsevier B.V.)

Purpose: This study aims to compare treatment response and adherence rate to positive airway pressure (PAP) in patients with opioid-related central sleep apnea (O-CSA) and idiopathic central sleep apnea (I-CSA)., Methods: We performed a retrospective chart over a 5-year period performed at a VA sleep center. Continuous PAP (CPAP) was prescribed initially for all participants. For those nonresponders (apnea hypopnea index (AHI) of >10/h), bi-level PAP (BiPAP) or adaptive servoventilation (ASV) was instituted upon provider's discretion. Adherence to therapy was checked with the built-in meter., Results: Thirty-four patients with O-CSA and 61 with I-CSA were included in the analysis. The two groups were comparable with respect to age, body mass index (BMI), Epworth Sleepiness Scale, and burden of comorbidities. The mean daily equivalent dose of morphine in the O-CSA was 168 mg (range 30-1,217 mg). In the O-CSA group, 24% of PAP-naïve patients responded to CPAP compared to 38% in the I-CSA group. BiPAP and ASV were comparable in eliminating central events in both O-CSA (66 versus 60 %) and I-CSA (93 versus 90%), respectively. Eight patients (24%) with O-CSA and six patients (10%) with I-CSA were considered nonresponders. The adherence rate was 48 and 24% in the I-CSA group compared to 23 and 18% in the O-CSA group at 3 and 12 months following initiation of effective treatment (p = 0.04 and p = 0.6)., Conclusions: The presence of O-CSA does not preclude an adequate response to CPAP. Adherence rate to PAP was poor in both the O-CSA and I-CSA groups. Further studies are needed to define optimal adherence rate and long-term benefits of PAP in CSA.

Background: Patients with the combination of chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), known as the "overlap syndrome," have a substantially greater risk of morbidity and mortality compared to those with either COPD or OSA alone. The study's objective was to report on the long-term outcome of hypercapnic (PaCO2 ≥ 45 mmHg) and normocapnic patients with the overlap syndrome treated with continuous positive airway pressure (CPAP)., Methods: A nonconcurrent cohort of consecutive patients with the overlap syndrome was followed for a median duration of 71 months (range 1-100) at a VA sleep center. All patients were managed according to the prevailing recommendations of both diseases. The end point of the study was all-cause mortality., Results: Of the 271 patients identified, 104 were hypercapnic (PaCO2 = 51.6 ± 4.3 mmHg). Both normocapnic and hypercapnic patients had comparable apnea-hypopnea indexes (AHI) (29.2 ± 23.8 and 35.2 ± 29.2/h, respectively; p = 0.07) and similar adherence rates to CPAP (43 and 42 %, respectively, p = 0.9). Survival analysis revealed that hypercapnic patients who were adherent to CPAP had reduced mortality compared to nonadherent hypercapnic patients (p = 0.04). In contrast, the cumulative mortality rate for normocapnic patients was not significantly different between the adherent and the nonadherent group (p = 0.42). In multivariate analysis, the comorbidity index was the only independent predictor of mortality in normocapnic patients with the overlap syndrome [hazard ratio (HR) 1.68; p < 0.001] while CPAP adherence was associated with improved survival (HR 0.65; p = 0.04)., Conclusions: CPAP mitigates the excess risk of mortality in hypercapnic patients but not in normocapnic patients with the overlap syndrome.

Objective: To systematically review the various modalities of positive airway pressure (PAP) in the treatment of opioid-related central sleep apnea (CSA)., Design: Systematic review., Interventions: MEDLINE, the Cochrane Library, and EMBASE were screened through March 2013 to identify articles which investigated treatment of opioid related CSA with PAP. Eligible articles were identified in a staged process and were assessed by two investigators independently. The methodological quality of the reporting of eligible articles was assessed using a set of questions addressing both general and statistical methodologies., Results: Five articles met the inclusion criteria for a total of 127 patients. All patients had been on opioids for at least 6 months. The dose ranged from 10 mg to 450 mg daily of morphine equivalent dose. Continuous positive airway pressure (CPAP) was proven mostly ineffective in reducing central apneic events. Bi-level positive airway pressure (BiPAP) with and without supplemental oxygen achieved elimination of central apneas in 62 percent of patients. Adaptive servo ventilation (ASV) yielded conflicting results with 58 percent of participants attaining a central apnea index <10 per hour. The presence of ataxic breathing predicted poor response to PAP., Conclusions: The available evidence on the efficacy of PAP in opioid-related CSA is inconclusive. With the increasing use of opioids, further studies are needed to assess optimal PAP therapy and predictors of success in this group of patients.

Background: Obstructive sleep apnea (OSA) has been linked to chronic inflammation and cardiovascular diseases. Considerable evidence suggests that innate immune defense mechanisms might interact with proinflammatory pathways and contribute to atherogenesis. We hypothesized that the classical pathogen recognition receptors of the innate immune response, Toll-like receptors, are involved in modulating the inflammatory response in OSA., Methods: Expression of TLR2 and TLR4 on circulating monocytes from 29 subjects with documented OSA and 18 controls were compared with the use of flow cytometry and reverse transcription-polymerase chain reaction at baseline and after 8 weeks of continuous positive airway pressure (CPAP)., Results: There was a significant increase in both TLR2 and TLR4 surface expression and mRNA levels on monocytes after adjustment for age, body mass index, and waist-to-hip ratio. This was paralleled by enhanced nuclear factor-κB nuclear binding and an increased release of IL-6, INF-γ, and TNF-α in OSA versus control subjects. Following 8 weeks of treatment, continuous positive airway pressure downregulated TLR2 and TLR4 expression and abrogated the release of inflammatory cytokines., Conclusion: OSA is associated with enhanced expression and signaling events downstream of TLR2 and TLR4 in circulating monocytes. These observations are mitigated by CPAP therapy, which suggest that TLR2 and TLR4 activation may be involved as a signaling mechanism in immune-mediated progression of atherosclerosis in OSA.

Purpose: Clinical and epidemiologic investigations suggest a strong association between obesity and obstructive sleep apnea (OSA). The purpose of this study is to evaluate the currently available literature reporting on the effectiveness of dietary weight loss in treating OSA among obese patients., Methods: Relevant studies were identified by computerized searches of PubMed, EMBASE, CINAHL, Web of Science, and The Cochrane Central Register of Controlled Trials through September 2011 as well as the reference lists of all obtained articles. Information on study design, patient characteristics, pre- and post-dietary weight loss measures of OSA and body mass index (BMI), and study quality was obtained. Data were extracted by two independent analysts. Weighted averages using a random-effects model are reported with 95 % confidence intervals., Results: Nine articles representing 577 patients were selected. Dietary weight loss program resulted in a pooled mean BMI reduction of 4.8 kg/m(2) (95 % confidence interval [CI] 3.8-5.9). The random-effects pooled apnea hypopnea (AHI) indices at pre- and post-dietary intervention were 52.5 (range 10.0-91.0) and 28.3 events/h (range 5.4-64.5), respectively (p < 0.001). Compared to control, the weighted mean difference of AHI was decreased by -14.3 events/h (95 % CI -23.5 to -5.1; p = 0.002) in favor of the dietary weight loss programs., Conclusions: Dietary weight loss programs are effective in reducing the severity of OSA but not adequate in relieving all respiratory events. Weight reduction programs should be considered as adjunct rather than curative therapy.

Objective: Previous reports have supported the concept that messenger ribonucleic acid (mRNA) concentrations for cytochrome P450 (CYP) enzymes in peripheral blood mononuclear cells may be predictive of systemic enzyme activity. We investigated whether changes in mRNA expression for CYP1A2,CYP2C19, CYP2D6 and CYP3A4 in peripheral blood lymphocytes (PBLs) may serve as surrogate markers for changes in CYP enzyme activity following the administration of rifampin., Methods: On day 1 and day 9 of the study, 12 healthy volunteers were administered caffeine 100 mg, debrisoquine 10 mg and omeprazole 40 mg orally, along with midazolam 0.025 mg/kg intravenously. Blood samples and urine were collected for 8 h after drug administration. The subjects took rifampin 300 mg (n = 6) or 600 mg (n = 6) daily on days 2-8. Total RNA was isolated from PBLs on day 1 and day 9, and mRNA expression for the CYP enzymes and hGAPDH were determined by means of quantitative, real-time, reverse-transcriptase polymerase chain reaction. CYP1A2 activity was estimated by calculating the plasma paraxanthine to caffeine AUC ratio (caffeine metabolic ratio; CMR), CYP2C19 activity by the 2-h omeprazole hydroxylation index (HI), CYP2D6 activity by the urinary debrisoquine recovery ratio (DBRR) and CYP3A4 activity by midazolam clearance., Results: Median midazolam clearance (0.362 to 0.740 l/kg/h), omeprazole HI (0.752 to 0.214), CMR (0.365 to 0.450) and DBRR (0.406 to 0.479) all changed significantly following rifampin, consistent with the expected enzyme induction. CYP1A2,CYP2D6 and CYP3A4 mRNA content were measurable in all samples. CYP2C19 mRNA was inconsistently detectable. There were no significant correlations between changes in enzyme activity and mRNA expression by Spearman's rank order correlation., Conclusion: The results do not support the use of mRNA expression assays for CYP1A2, CYP2C19, CYP2D6 and CYP3A4 enzymes in PBLs as surrogates for quantifying changes in systemic enzyme activity in the setting of enzyme induction.

Objective: To evaluate the plasma concentration versus time profile of omeprazole following the administration of a compounded transdermal gel formulation in healthy volunteers., Design: Single-dose transdermal pharmacokinetic (PK) study including a comparison with historical data from an oral PK study., Setting: Academic clinical research center., Participants: Eight healthy volunteers between 18 and 50 years of age., Interventions: Omeprazole gel 40 mg (0.8 mL) was applied to the ventral surface of the forearm covering an area of 7 x 15 cm without an occlusive dressing. Blood samples were collected just before application and then at 1, 2, 3, 4, 6, and 8 hours. Plasma concentrations of omeprazole were determined using a validated liquid chromatography tandem mass spectrometry method., Main Outcome Measures: PK parameters (maximal plasma concentration [C(max)], the time of C(max), [T(max)], the area under the omeprazole concentration versus time curve from 0 to 8 hours, the elimination rate constant, and the half-life of the elimination phase) following transdermal administration, compared with historical controls who had received an oral omeprazole 40 mg dose during a previous study., Results: Of the eight volunteers, five had undetectable plasma omeprazole concentrations throughout the 8-hour study, precluding a complete PK analysis. For the three volunteers with detectable plasma omeprazole concentrations, the values ranged from 0.204 to 0.552 ng/mL. Including values of 0 for the patients with undetectable levels, the mean (+/- SD) C(max) was 0.153 +/- 0.241 ng/mL, and the T(max) in patients with detectable levels occurred at approximately 6 hours. The plasma concentrations following transdermal administration were approximately 1,000-fold lower than those observed with oral dosing., Conclusion: Transdermal absorption from a single dose of the omeprazole gel formulation used in this study was poor. This transdermal gel formulation is clearly not bioequivalent to the oral capsule.

Respiratory muscle strength and endurance is reduced in patients with congestive heart failure, making these patients susceptible to diaphragmatic fatigue during exercise. In order to determine whether or not contractile fatigue of the diaphragm occurs in patients with congestive heart failure following intense exercise, twitch transdiaphragmatic pressures (twitch Ptdi) were measured during unpotentiated and potentiated cervical magnetic stimulation (CMS) of the phrenic nerves before and at intervals after cycle endurance exercise. Ten patients aged 65.7+/-6.0 yrs (mean+/-SD) with an ejection fraction of 31.2+/-9.8% performed a constant-load symptom-limited exercise test at 60% of their peak work capacity. Twitch Ptdi at baseline were 15.9+/-6.3 cmH2O (unpotentiated CMS) and 28.8+/-10.7 cmH2O (potentiated CMS) and at 10 min postexercise were 16.4+/-4.7 cmH2O (unpotentiated CMS) and 27.6+/-10.1 cmH2O (potentiated CMS). One patient demonstrated a sustained fall in twitch Ptdi of > or = 15%, considered potentially indicative of diaphragmatic fatigue. Contractile diaphragmatic fatigue is uncommon in untrained patients with congestive heart failure following high-intensity constant-workload cycle exercise. Therefore, diaphragmatic fatigue is an unlikely cause of exercise-limitation during activities of daily living in heart failure patients.

We have recently shown that patients with chronic obstructive pulmonary disease (COPD) develop contractile fatigue of their quadriceps muscle following endurance exercise. Pulmonary rehabilitation can produce physiological adaptations in patients with COPD. We hypothesized that if pulmonary rehabilitation induces physiological adaptations in the exercising muscle, it should become more fatigue resistant. Twenty one patients with COPD, mean age 69.9 +/- 1.9 yr, FEV(1) 45 +/- 4% predicted, participated in an 8-wk outpatient, supervised pulmonary rehabilitation exercise program. Quadriceps contractile fatigue was detected by a fall in quadriceps twitch force postexercise. Twitch force was measured during magnetic stimulation of the femoral nerve. Because potentiated twitches may be more sensitive at detecting fatigue, both unpotentiated (TwQu) and potentiated (TwQp) twitches were obtained before and 10, 30, and 60 min after constant load cycle exercise. Prerehabilitation, during constant load exercise, patients exercised at 37 +/- 4 W for 11.2 +/- 1.8 min. Prerehabilitation, TwQu fell significantly postexercise down to a minimum value of 82.5 +/- 3.1% of the baseline preexercise value (p < 0.001). Similarly, prerehabilitation, TwQp fell significantly postexercise down to a minimum value of 73.9 +/- 3.9% of baseline (p < 0.001). Postrehabilitation, for the same intensity and duration of exercise, TwQu was not significantly different from baseline at any time postexercise. Postrehabilitation, TwQp fell significantly postexercise but the fall in TwQp with exercise was significantly less postrehabilitation compared with prerehabilitation (p < 0.001). In conclusion, pulmonary rehabilitation resulted in increased fatigue resistance of the quadriceps muscle in patients with COPD.

The purpose of this study was to determine whether quadriceps or diaphragmatic fatigue or both occur after high-intensity cycle exercise to exhaustion in healthy elderly persons. Ten relatively sedentary male subjects aged 68.3 +/- 1.4 yr (mean +/- SE) (range: 60 to 75 yr) exercised at 65% to 75% of their predetermined maximal work capacity to the limits of tolerance on two separate days. On one occasion, quadriceps twitch force (Q(tw)) was measured during magnetic stimulation of the femoral nerve. On the other occasion, twitch transdiaphragmatic pressure (Pdi(tw)) was measured during bilateral stimulation of the phrenic nerves. Because potentiated twitches may be more sensitive for detecting fatigue, both unpotentiated and potentiated (obtained 5 s after a 5-s maximum voluntary muscle contraction) twitches were measured before and at 10, 30, and 60 min after exercise. During constant-load exercise, subjects exercised at 75 +/- 7 W for 21.9 +/- 1.8 min during the quadriceps studies, and for 17.7 +/- 1.9 min during the diaphragm studies. Peak V O(2) was 1.58 +/- 0.08 L/min during both studies. Pdi(tw) (unpotentiated and potentiated) was not significantly different from baseline at any time after exercise. Unpotentiated Q(tw) was significantly decreased after exercise, to 64.0 +/- 6.3% of the baseline value at 10 min after exercise (p < 0.0003), and remained significantly decreased at 30 min after exercise. Potentiated Q(tw) was also significantly decreased after exercise, to 63.5 +/- 2.7% of the baseline value at 10 min after exercise (p < 0.0001), and remained significantly decreased at 30 and 60 min after exercise. In conclusion, high-intensity cycle exercise to exhaustion results in significant contractile fatigue of the quadriceps muscle but not of the diaphragm in healthy, relatively sedentary, elderly subjects.

Patients with COPD have derangements in respiratory mechanics that may cause them to stop exercising before the exercising limb muscles reach their functional limits. However, because lung disease makes activity unpleasant, patients with chronic obstructive pulmonary disease (COPD) often adapt a sedentary lifestyle leading to progressive deconditioning. Deconditioning will lead to progressive deterioration in limb muscle function, which could adversely affect exercise capacity. The purpose of this study was to determine whether fatigue of the quadriceps muscle occurs after high intensity cycle exercise to the limits of tolerance in patients with moderate to severe COPD. Nineteen male patients with COPD (FEV(1) 1.54 +/- 0. 12 L; 42 +/- 3% predicted) exercised at 60 to 70% of their predetermined maximal work capacity until exhaustion. The femoral nerve was supramaximally stimulated with a figure-of-eight magnetic coil, and quadriceps twitch force (TwQ) was measured before and at 10, 30, and 60 min postexercise. Patients exercised at 53.7 +/- 4.1 watts for 10.4 +/- 1.4 min. Peak V O(2) was 1.24 +/- 0.08 L/min (51. 3 +/- 3.6% predicted). TwQ fell significantly postexercise; 79.2 +/- 5.4% of baseline value at 10 min postexercise (p < 0.005), 75.7 +/- 4.8% at 30 min postexercise (p < 0.001), and 84.0 +/- 5.0% at 60 min postexercise (p < 0.005). Acceptable M-waves from the quadriceps muscle (not obscured by stimulus artifact) were obtained in six subjects. M-wave amplitude was unchanged from baseline at all times postexercise indicating that the fall in TwQ was due to contractile fatigue and not to transmission failure. In conclusion, contractile fatigue of the quadriceps muscle occurs after high intensity cycle exercise to the limits of tolerance in patients with COPD.

Patients with chronic obstructive pulmonary disease (COPD) are at a mechanical disadvantage and should be predisposed to the development of diaphragmatic fatigue when the ventilatory system is stressed by exercise. The purpose of this study was to determine whether patients with moderately severe COPD develop contractile fatigue of the diaphragm after cycle exercise to the limits of tolerance. Twelve male patients with COPD, age 61.4 +/- 3.0 yr, participated. Their forced expiratory volume in 1 s (FEV(1)) was 1.79 +/- 0.14 L, 49.6 +/- 3.4% of predicted. Patients cycled at 60-70% of their predetermined maximal work capacity until they had to stop because of intolerable symptoms. Twitch transdiaphragmatic pressure (Pdi,tw) was measured during cervical magnetic stimulation before and 10, 30, and 60 min after exercise. A persistent fall in Pdi,tw postexercise of >/= 10% was considered potentially indicative of contractile fatigue of the diaphragm. Patients cycled for 10.2 +/- 2.0 min at a workload of 59.9 +/- 4.3 W. Patients exercised maximally relative to their capacity reaching a peak oxygen consumption (V O(2)) of 108.1 +/- 2.8% of the peak V O(2) obtained during a preliminary maximal incremental exercise test. Pdi,tw was not significantly different from baseline at any time postexercise. Pdi,tw was 19.9 +/- 1.6 cm H(2)O at baseline, 19.6 +/- 2.0 cm H(2)O at 10 min postexercise, 18. 6 +/- 2.0 cm H(2)O at 30 min postexercise, and 19.5 +/- 1.7 cm H(2)O at 60 min postexercise. In the individual patients, two of the patients had a persistent >/= 10% fall in Pdi,tw postexercise, potentially indicative of contractile fatigue of the diaphragm. In conclusion, the majority of patients with moderately severe COPD do not develop contractile fatigue of the diaphragm after high-intensity constant workload cycle exercise to the limits of tolerance.

The purpose of this study was to determine whether diaphragmatic fatigue occurs after high-intensity constant-load whole-body exercise to volitional exhaustion. Ten sedentary subjects with a maximal oxygen uptake of 2.52 +/- 0.47 L/min were studied. Subjects exercised on a bicycle ergometer at 80% of their maximal working capacity until volitional exhaustion. Minute ventilation during the last minute of exercise was 89.9 +/- 13.6 L/min, which represented 50 +/- 6% of the subjects' 12-s maximal voluntary ventilation. During the last minute of exercise, mean inspiratory esophageal pressure was 18.1 +/- 5.3 cm H2O, which represented only 15 +/- 4% of the subjects' maximal static inspiratory pressure. Bilateral transcutaneous supramaximal phrenic nerve stimulation was performed before and 10, 30, 45 and 60 min after exercise. Twitch diaphragmatic pressure (twitch Pdi) was significantly decreased after exercise in seven of the 10 subjects. For the group as a whole, twitch Pdi fell from 28.9 +/- 3.7 cm H2O during control to 23.9 +/- 5.1 cm H2O at 10 min after exercise (p < 0.005). The fall in twitch Pdi was due to a significant decrease in twitch esophageal pressure from 19.6 +/- 4.3 cm H2O during control to 15.5 +/- 4.9 cm H2O (p < 0.001). Twitch gastric pressure was not significantly different: 8.7 +/- 4.0 cm H2O, compared with 9.2 +/- 3.8 cm H2O during control. Twitch Pdi recovered to 93 +/- 7% of control values at 60 min after exercise. The fall in twitch Pdi after exercise indicates that diaphragmatic fatigue can occur following heavy endurance exercise in sedentary healthy persons.

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.

The purpose of this study was to evaluate the reproducibility of visual analog scale ratings of the effort to breathe (VASe) and the degree of discomfort evoked by breathing (VASd) in patients with chronic obstructive pulmonary disease (COPD) during exercise. Six subjects with moderately severe COPD (FEV1 = 1.12 +/- 0.29 L, FEV1/FVC = 44 +/- 4%) underwent progressive incremental exercise testing to a symptom-limited maximum every week for 8 wk. VASe and VASd were highly correlated in each subject (r = 0.99 +/- 0.01). The slope of the VASd/VASe relationship for all trials in all subjects was not significantly different from 1, indicating that our subjects were rating a common sensation with the two scales. VASe at maximal exercise was reproducible in every subject; the within-subject coefficient of variation (CV) was 6% (range, 2 to 10%) and compared favorably with physiologic indices: 7% (range, 3 to 12%) for oxygen consumption and 10% (range, 5 to 16%) for minute ventilation (VI). In contrast, submaximal VAS ratings were highly variable. At 66% of the maximal work load, the within-subject CV for VASe was 21% (range, 11 to 28%) compared with 6% (range, 4 to 7%) for VO2 (p less than 0.003) and 10% (range, 5 to 16%) for VI (p less than 0.01). VASe correlated linearly with VI and VO2 in all subjects in all trials. However, within an individual subject the slope and position of these relationships varied widely between trials.(ABSTRACT TRUNCATED AT 250 WORDS)