Oxygen supplementation during exercise improves leg muscle fatigue in chronic fibrotic interstitial lung disease.

BACKGROUND: Exercise-induced hypoxaemia is a hallmark of chronic fibrotic interstitial lung disease (f-ILD). It remains unclear whether patients' severe hypoxaemia may exaggerate locomotor muscle fatigue and, if so, to what extent oxygen (O2) supplementation can ameliorate these abnormalities. METHODS: Fifteen patients (12 males, 9 with idiopathic pulmonary fibrosis) performed a constant-load (60% peak work rate) cycle test to symptom limitation (Tlim) while breathing medical air. Fifteen age-matched and sex-matched controls cycled up to patients' Tlim. Patients repeated the exercise test on supplemental O2 (42%±7%) for the same duration. Near-infrared spectroscopy assessed vastus lateralis oxyhaemoglobin concentration ((HbO2)). Pre-exercise to postexercise variation in twitch force (∆Tw) induced by femoral nerve magnetic stimulation quantified muscle fatigue. RESULTS: Patients showed severe hypoxaemia (lowest O2 saturation by pulse oximetry=80.0%±7.6%) which was associated with a blunted increase in muscle (HbO2) during exercise vs controls (+1.3±0.3 µmol vs +4.4±0.4 µmol, respectively; p<0.001). Despite exercising at work rates ∼ one-third lower than controls (42±13 W vs 66±13 W), ∆Tw was greater in patients (∆Tw/external work performed by the leg muscles=-0.59±0.21 %/kJ vs -0.25±0.19 %/kJ; p<0.001). Reversal of exertional hypoxaemia with supplemental O2 was associated with a significant increase in muscle (HbO2), leading to a reduced decrease in ∆Tw in patients (-0.33±0.19 %/kJ; p<0.001 vs air). Supplemental O2 significantly improved leg discomfort (p=0.005). CONCLUSION: O2 supplementation during exercise improves leg muscle oxygenation and fatigue in f-ILD. Lessening peripheral muscle fatigue to enhance exercise tolerance is a neglected therapeutic target that deserves clinical attention in this patient population.

Computed tomography machine learning classifier correlates with mortality in interstitial lung disease.

BACKGROUND: A machine learning classifier system, Fibresolve, was designed and validated as an adjunct to non-invasive diagnosis in idiopathic pulmonary fibrosis (IPF). The system uses a deep learning algorithm to analyze chest computed tomography (CT) imaging. We hypothesized that Fibresolve is a useful predictor of mortality in interstitial lung diseases (ILD). METHODS: Fibresolve was previously validated in a multi-site >500-patient dataset. In this analysis, we assessed the usefulness of Fibresolve to predict mortality in a subset of 228 patients with IPF and other ILDs in whom follow up data was available. We applied Cox regression analysis adjusting for the Gender, Age, and Physiology (GAP) score and for other known predictors of mortality in IPF. We also analyzed the role of Fibresolve as tertiles adjusting for GAP stages. RESULTS: During a median follow-up of 2.8 years (range 5 to 3434 days), 89 patients died. After adjusting for GAP score and other mortality risk factors, the Fibresolve score significantly predicted the risk of death (HR: 7.14; 95% CI: 1.31-38.85; p = 0.02) during the follow-up period, as did forced vital capacity and history of lung cancer. After adjusting for GAP stages and other variables, Fibresolve score split into tertiles significantly predicted the risk of death (p = 0.027 for the model; HR 1.37 for 2nd tertile; 95% CI: 0.77-2.42. HR 2.19 for 3rd tertile; 95% CI: 1.22-3.93). CONCLUSIONS: The machine learning classifier Fibresolve demonstrated to be an independent predictor of mortality in ILDs, with prognostic performance equivalent to GAP based solely on CT images.

The Impact of Integrated Palliative Care on Survival in Idiopathic Pulmonary Fibrosis: A Retrospective Multicenter Comparison.

Background: Early and integrated palliative care is recommended for patients with idiopathic pulmonary fibrosis. Unfortunately, palliative care delivery remains poor due to various barriers in practice. This study describes various palliative care delivery models in a real-world cohort of patients with idiopathic pulmonary fibrosis, examines the predictors of survival in this cohort of patients, and explores the impact of palliative care on survival. Design: Charts were reviewed retrospectively and analyzed. The primary outcome was survival during a 4-year follow-up period. Two multivariable models were created to examine the impact of therapeutic strategies including palliative intervention on survival. Results: 298 patients with idiopathic pulmonary fibrosis were enrolled from 3 interstitial lung disease clinics with different palliative care models in Edmonton, Canada; Bristol, UK; and Kingston, Canada. 200 (67%) patients received palliative care and 119 (40%) died during follow up. Primary palliative care models (Edmonton and Bristol) delivered palliative care to 96% and 100% respectively compared 21% in the referral model (Queens). Palliative care [adjusted hazard ratio (aHR) .28 (.12-.65)] along with the use of antifibrotics [aHR .56 (.37-.84)], and body mass index >30 [aHR .47 (.37-.85)] reduced the risk of death in our idiopathic pulmonary fibrosis cohort. Opioid use was associated with worse survival [aHR 2.11 (1.30-23.43)]. Conclusions: Both palliative care and antifibrotic use were associated with survival benefit in this cohort of patients with idiopathic pulmonary fibrosis after adjusting for covariates. The benefit was seen despite differences in disease severity and different palliative care delivery models.

Increased expiratory flows identify early interstitial lung disease.

BACKGROUND: Most interstitial lung diseases (ILDs) manifest with a restrictive ventilatory defect as the common physiologic abnormality. Low carbon monoxide diffusing capacity (Dlco) is considered to be the earliest abnormality on pulmonary function tests (PFTs) in patients with ILD. However, its measurement requires complex and expensive equipment. Our study aimed to assess if high expiratory flows are the earliest PFT abnormality in patients with idiopathic pulmonary fibrosis (IPF) and ILD. METHODS: In a real-world cohort of incident cases with ILD, we identified the initial PFTs on all patients newly diagnosed with ILD at Kingston Health Sciences Center (in Kingston, Ontario, Canada) between 2013 and 2017. The diagnosis of ILD, including IPF, was established as per current guidelines. Among patients with normal forced vital capacity (FVC), total lung capacity (TLC), and Dlco, we assessed the frequency of high expiratory flows defined as forced expiratory volume in 1 s (FEV1)/FVC, FEF25, FEF25-75, FEF75, and peak expiratory flow > 95% confidence limit of normal. We adjusted for emphysema, increased airway resistance, and obesity. RESULTS: We assessed PFTs of 289 patients with ILD; 88 (30%) of them had normal FVC, TLC, and Dlco. Among these, high FEV1/FVC was the most common abnormality in 37% of patients, in 43% of nonobese patients, and in 58% of those with no emphysema and normal airway resistance. Results were similar in the 88 patients with IPF. CONCLUSIONS: High FEV1/FVC could allow identifying patients with ILD/IPF in the earliest stages of their disease with simple spirometry, leading to earlier diagnosis and treatment.

Quantifying leg muscle deoxygenation during incremental cycling in hypoxemic patients with fibrotic interstitial lung disease.

BACKGROUND: Hypoxaemia and cardiocirculatory abnormalities may impair muscle oxygen (O2 ) delivery relative to O2 requirements thereby increasing the rate of O2 extraction during incremental exercise in fibrotic interstitial lung disease (f-ILD). Using changes in deoxyhaemoglobin concentration ([HHb]) by near-infrared spectroscopy (NIRS) as a proxy of O2 extraction, we investigated whether a simplified (double-linear) approach, previously tested in heart failure, would provide useful estimates of muscle deoxygenation in f-ILD. METHODS: A total of 25 patients (23 men, 72 ± 8 years; 20 with idiopathic pulmonary fibrosis, lung diffusing capacity for carbon monoxide = 44 ± 11% predicted) and 12 age- and sex-matched healthy controls performed incremental cycling to symptom limitation. Changes in vastus lateralis [HHb] assessed by NIRS were analysed in relation to work rate (WR) and O2 uptake throughout the exercise. RESULTS: Patients showed lower exercise capacity than controls (e.g., peak WR = 67 ± 18% vs. 105 ± 20% predicted, respectively; p < 0.001). The [HHb] response profile was typically S-shaped, presenting three distinct phases. Exacerbated muscle deoxygenation in patients versus controls was evidenced by: (i) a steeper mid-exercise [HHb]-WR slope (0.30 ± 0.22 vs. 0.11 ± 0.08 µmol/W; p = 0.008) (Phase 2), and (ii) a larger late-exercise increase in [HHb] (p = 0.002) (Phase 3). Steeper [HHb]-WR slope was associated with lower peak WR (r = -0.70) and greater leg discomfort (r = 0.77; p < 0.001) in f-ILD. CONCLUSION: This practical approach to interpreting [HHb] during incremental exercise might prove useful to determine the severity of muscle deoxygenation and the potential effects of interventions thereof in hypoxemic patients with f-ILD.

The relationship between perceived and performance fatigability in severe fibrotic interstitial lung disease: a prospective, cross-sectional study.

This study suggests that interventions geared to improve peripheral factors of performance fatigability during exercise in interstitial lung disease may prove valuable to decrease patients' perceived fatigability, since both seem closely related https://bit.ly/3lpIUPs.

Beyond the Lungs: O 2 Supplementation Improves Cerebral Oxygenation and Fatigue during Exercise in Interstitial Lung Disease.

PURPOSE: Cerebral hypoxia may exacerbate the perception of fatigue. We previously demonstrated that exercise-related hypoxemia, a hallmark of fibrotic interstitial lung disease ( f -ILD), dose dependently impairs cerebral oxygenation in these patients. It is unknown whether normalizing cerebral oxygenation with O 2 supplementation would be associated with positive changes in a relevant patient-centered outcome during exercise in f -ILD, such as improved perceived fatigue. METHODS: Fourteen patients (12 males, 72 ± 8 yr, 8 with idiopathic pulmonary fibrosis, lung diffusing capacity for carbon monoxide = 44% ± 13% predicted) performed a constant-load (60% peak work rate) cycle test to symptom limitation (Tlim) breathing medical air. Fourteen controls cycled up to Tlim of an age- and sex-matched patient. Patients repeated the test on supplemental O 2 (fraction of inspired O 2 = 0.41 ± 0.08) for the same duration. Near-infrared spectroscopy and the rating-of-fatigue (ROF) scale assessed prefrontal cortex oxygenation and perceived fatigue, respectively. RESULTS: Patients showed severe exertional hypoxemia (Tlim O 2 saturation by pulse oximetry = 80% ± 8%); they had poorer cerebral oxygenation (e.g., oxy-deoxyhemoglobin difference [HbDiff] = -3.5 ± 4.7 [range = -17.6 to +1.9] vs +1.9 ± 1.7 µmol from rest) and greater fatigue (ROF = 6.2 ± 2.0 vs 2.6 ± 2.3) versus controls under air ( P < 0.001). Reversal of exertional hypoxemia with supplemental O 2 led to improved HbDiff (+1.7 ± 2.4 µmol from rest; no longer differing from controls) and lower ROF scores (3.7 ± 1.2, P < 0.001 vs air) in patients. There was a significant correlation between O 2 -induced changes in HbDiff and ROF scores throughout exercise in f -ILD ( rrepeated-measures correlation = -0.51, P < 0.001). CONCLUSIONS: Supplemental O 2 improved cerebral oxygenation during exercise in f -ILD, which was moderately associated with lower ratings of perceived fatigue. Reversing cerebral hypoxia with O 2 supplementation may thus have positive effects on patients' disablement beyond those expected from lower ventilation and dyspnea in this patient population.

Physiological underpinnings of exertional dyspnoea in mild fibrosing interstitial lung disease.

The functional disturbances driving "out-of-proportion" dyspnoea in patients with fibrosing interstitial lung disease (f-ILD) showing only mild restrictive abnormalities remain poorly understood. Eighteen patients (10 with idiopathic pulmonary fibrosis) showing preserved spirometry and mildly reduced total lung capacity (≥70% predicted) and 18 controls underwent an incremental cardiopulmonary exercise test with measurements of operating lung volumes and Borg dyspnoea scores. Patients' lower exercise tolerance was associated with higher ventilation (V̇E)/carbon dioxide (V̇CO2) compared with controls (V̇E/V̇CO2 nadir=35 ± 3 versus 29 ± 2; p < 0.001). Patients showed higher tidal volume/inspiratory capacity and lower inspiratory reserve volume at a given exercise intensity, reporting higher dyspnoea scores as a function of both work rate and V̇E. Steeper dyspnoea-work rate slopes were associated with lower lung diffusing capacity, higher V̇E/V̇CO2, and lower peak O2 uptake (p < 0.05). Heightened ventilatory demands in the setting of progressively lower capacity for tidal volume expansion on exertion largely explain higher-than-expected dyspnoea in f-ILD patients with largely preserved dynamic and "static" lung volumes at rest.

Systemic Determinants of Exercise Intolerance in Patients With Fibrotic Interstitial Lung Disease and Severely Impaired DLCO.

BACKGROUND: The precise mechanisms driving poor exercise tolerance in patients with fibrotic interstitial lung diseases (fibrotic ILDs) showing a severe impairment in single-breath lung diffusing capacity for carbon monoxide (DLCO < 40% predicted) are not fully understood. Rather than only reflecting impaired O2 transfer, a severely impaired DLCO may signal deranged integrative physiologic adjustments to exercise that jointly increase the burden of exertional symptoms in fibrotic ILD. METHODS: Sixty-seven subjects (46 with idiopathic pulmonary fibrosis, 24 showing DLCO < 40%) and 22 controls underwent pulmonary function tests and an incremental cardiopulmonary exercise test with serial measurements of operating lung volumes and 0-10 Borg dyspnea and leg discomfort scores. RESULTS: Subjects from the DLCO < 40% group showed lower spirometric values, more severe restriction, and lower alveolar volume and transfer coefficient compared to controls and participants with less impaired DLCO (P < .05). Peak work rate was ∼45% (vs controls) and ∼20% (vs DLCO > 40%) lower in the former group, being associated with lower (and flatter) O2 pulse, an earlier lactate (anaerobic) threshold, heightened submaximal ventilation, and lower SpO2 . Moreover, critically high inspiratory constrains were reached at lower exercise intensities in the DLCO < 40% group (P < .05). In association with the greatest leg discomfort scores, they reported the highest dyspnea scores at a given work rate. Between-group differences lessened or disappeared when dyspnea intensity was related to indexes of increased demand-capacity imbalance, that is, decreasing submaximal, dynamic ventilatory reserve, and inspiratory reserve volume/total lung capacity (P > .05). CONCLUSIONS: A severely reduced DLCO in fibrotic ILD signals multiple interconnected derangements (cardiovascular impairment, an early shift to anaerobic metabolism, excess ventilation, inspiratory constraints, and hypoxemia) that ultimately lead to limiting respiratory (dyspnea) and peripheral (leg discomfort) symptoms. DLCO < 40%, therefore, might help in clinical decision-making to indicate the patient with fibrotic ILD who might derive particular benefit from pharmacologic and non-pharmacologic interventions aimed at lessening these systemic abnormalities.

Fine crackles on chest auscultation in the early diagnosis of idiopathic pulmonary fibrosis: a prospective cohort study.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease (ILD) with a poor prognosis. Early diagnosis and treatment of IPF may increase lifespan and preserve quality of life. Chest CT is the best test to diagnose IPF, but it is expensive and impractical as a screening test. Fine crackles on chest auscultation may be the only best to screen for IPF. METHODS: We prospectively assessed the presence and type of crackles on chest auscultation in all patients referred to the ILD Clinic at the Kingston Health Sciences Center in Ontario, Canada. Clinicians with varying levels of experience recorded the presence of fine crackles, coarse crackles or both independently and unaware of the final diagnosis. We applied multinomial logistic regression to adjust for ILD severity and factors that could affect the identification of crackles. RESULTS: We evaluated 290 patients referred to the ILD Clinic. On initial presentation, 93% of patients with IPF and 73% of patients with non-IPF ILD had fine crackles on auscultation. In patients with IPF, fine crackles were more common than cough (86%), dyspnoea (80%), low diffusing capacity (87%), total lung capacity (57%) and forced vital capacity (50%). There was 90% observer agreement in identifying fine crackles at a subsequent visit. In multiple regression analysis, the identification of fine crackles was unaffected by lung function, symptoms, emphysema, chronic obstructive pulmonary disease, obesity or clinician experience (p>0.05). CONCLUSIONS: Fine crackles on chest auscultation are a sensitive and robust screening tool that can lead to early diagnosis and treatment of patients with IPF.

Influence of exertional hypoxemia on cerebral oxygenation in fibrotic interstitial lung disease.

It is unknown whether hypoxemia, a hallmark of fibrotic interstitial lung disease (f-ILD), may impair cerebral oxygenation during exercise in these patients. Twenty-seven patients [23 males, 72 ± 8 years, lung diffusing capacity for carbon monoxide (DLCO) = 44 ± 11 % predicted] and 12 controls performed an incremental bicycle test. Prefrontal oxygenation [tissue saturation index (TSI)] was assessed by near-infrared spectroscopy. Patients showed lower arterial O2 saturation (SpO2) and larger fall in cerebral TSI during exercise vs controls (p < 0.05). However, changes (Δ) from rest to peak-exercise in SpO2 (-2.2 % to -26.9 %) and TSI (1.4 % to -16.6 %) varied substantially among patients. In the 16 patients showing significant cerebral deoxygenation (Δ TSI ≥ 4% based on controls), SpO2 decreased more (-12.6 ± 6.7 % vs -5.7 ± 2.8 %, p = 0.001) and peak O2 uptake was lower (68.3 ± 19.2 % vs 87.8 ± 24.8 % predicted, p = 0.03) vs their 11 counterparts. In association with DLCO and forced vital capacity, Δ cerebral TSI independently predicted peak O2 uptake on multivariable regression analysis (R2 = 0.54). Exertional hypoxemia impairs cerebral oxygenation in a dose-dependent fashion in f-ILD. Future studies are warranted to investigate whether this potentially reversible abnormality play a contributory role in limiting exercise tolerance in these patients.