Determinants and functional impacts of diaphragmatic involvement in patients with inclusion body myositis.

BACKGROUND: We evaluated the functional consequences of diaphragm involvement in patients with inclusion body myositis (IBM). METHODS: Ultrasound diaphragm thickening fraction (TFdi), lung function and dyspnea levels were compared between IBM patients and matched controls. Patients with IBM were grouped into "low" and "high" diaphragm activity based on TFdi values (with cutoff value being the lowest observed TFdi in the control group), and clinical characteristics were compared between groups. RESULTS: 20 IBM patients were included. TFdi was significantly lower in patients and correlated with time since symptom onset (rho = 0.74, P < .001). Patients had significantly lower forced vital capacity and higher dyspnea scores than controls. IBM patients with "low" diaphragm activity (n = 9) had lower 6-min walking distance, higher resting and exertional dyspnea and a larger positional decrease in vital capacity (all P ≤ .03) than patients with 'high' activity. Timed Up and Go time and St. George's Respiratory Questionnaire were not different between groups. CONCLUSIONS: Diaphragm involvement in IBM is related to disease duration and has detrimental effects on lung function, dyspnea and exercise capacity. Further studies are required to investigate its potential as a therapeutic target.

Usefulness of Parasternal Intercostal Muscle Ultrasound during Weaning from Mechanical Ventilation.

BACKGROUND: The assessment of diaphragm function with diaphragm ultrasound seems to bring important clinical information to describe diaphragm work and weakness. When the diaphragm is weak, extradiaphragmatic muscles may play an important role, but whether ultrasound can also assess their activity and function is unknown. This study aimed to (1) evaluate the feasibility of measuring the thickening of the parasternal intercostal and investigate the responsiveness of this muscle to assisted ventilation; and (2) evaluate whether a combined evaluation of the parasternal and the diaphragm could predict failure of a spontaneous breathing trial. METHODS: First, an exploratory evaluation of the parasternal in 23 healthy subjects. Second, the responsiveness of parasternal to several pressure support levels were studied in 16 patients. Last, parasternal activity was compared in presence or absence of diaphragm dysfunction (assessed by magnetic stimulation of the phrenic nerves and ultrasound) and in case of success/failure of a spontaneous breathing trial in 54 patients. RESULTS: The parasternal was easily accessible in all patients. The interobserver reproducibility was good (intraclass correlation coefficient, 0.77 (95% CI, 0.53 to 0.89). There was a progressive decrease in parasternal muscle thickening fraction with increasing levels of pressure support (Spearman ρ = -0.61 [95% CI, -0.74 to -0.44]; P < 0.0001) and an inverse correlation between parasternal muscle thickening fraction and the pressure generating capacity of the diaphragm (Spearman ρ = -0.79 [95% CI, -0.87 to -0.66]; P < 0.0001). The parasternal muscle thickening fraction was higher in patients with diaphragm dysfunction: 17% (10 to 25) versus 5% (3 to 8), P < 0.0001. The pressure generating capacity of the diaphragm, the diaphragm thickening fraction and the parasternal thickening fraction similarly predicted failure or the spontaneous breathing trial. CONCLUSIONS: Ultrasound assessment of the parasternal intercostal muscle is feasible in the intensive care unit and provides novel information regarding the respiratory capacity load balance.

ERS statement on respiratory muscle testing at rest and during exercise.

Assessing respiratory mechanics and muscle function is critical for both clinical practice and research purposes. Several methodological developments over the past two decades have enhanced our understanding of respiratory muscle function and responses to interventions across the spectrum of health and disease. They are especially useful in diagnosing, phenotyping and assessing treatment efficacy in patients with respiratory symptoms and neuromuscular diseases. Considerable research has been undertaken over the past 17 years, since the publication of the previous American Thoracic Society (ATS)/European Respiratory Society (ERS) statement on respiratory muscle testing in 2002. Key advances have been made in the field of mechanics of breathing, respiratory muscle neurophysiology (electromyography, electroencephalography and transcranial magnetic stimulation) and on respiratory muscle imaging (ultrasound, optoelectronic plethysmography and structured light plethysmography). Accordingly, this ERS task force reviewed the field of respiratory muscle testing in health and disease, with particular reference to data obtained since the previous ATS/ERS statement. It summarises the most recent scientific and methodological developments regarding respiratory mechanics and respiratory muscle assessment by addressing the validity, precision, reproducibility, prognostic value and responsiveness to interventions of various methods. A particular emphasis is placed on assessment during exercise, which is a useful condition to stress the respiratory system.

Respective contribution of intensive care unit-acquired limb muscle and severe diaphragm weakness on weaning outcome and mortality: a post hoc analysis of two cohorts.

BACKGROUND: Intensive care unit (ICU)-acquired weakness (ICU-AW) and ICU-acquired diaphragm dysfunction (ICU-DD) occur frequently in mechanically ventilated (MV) patients. It is unknown whether they have different risk factors and different impacts on outcome. This study was designed to (1) describe the respective risk factors associated with ICU-AW and severe ICU-DD and (2) evaluate the respective impact of ICU-AW and severe ICU-DD on outcome. METHODS: Post hoc analysis of two prospective cohort studies conducted in two ICUs. In patients mechanically ventilated for at least 24 h undergoing a first spontaneous breathing trial, severe ICU-DD was defined as diaphragm twitch pressure < 7 cmH2O and ICU-AW was defined as Medical Research Council Score < 48. RESULTS: One hundred sixteen patients were assessed. Factors independently associated with severe ICU-DD were age, longer duration of MV, and exposure to sufentanil, and those factors associated with ICU-AW were longer duration of MV and exposure to norepinephrine. Severe ICU-DD (OR 3.56, p = 0.008), but not ICU-AW, was independently associated with weaning failure (59%). ICU-AW (OR 4.30, p = 0.033), but not severe ICU-DD, was associated with ICU mortality. Weaning failure and mortality rate were higher in patients with both severe ICU-DD and ICU-AW (86% and 39%, respectively) than in patients with either severe ICU-DD (64% and 0%) or ICU-AW (63% and 13%). CONCLUSION: Severe ICU-DD and ICU-AW have different risk factors and different impacts on weaning failure and mortality. The impact of the combination of ICU-DD and ICU-AW is more pronounced than their individual impact.

Coexistence and Impact of Limb Muscle and Diaphragm Weakness at Time of Liberation from Mechanical Ventilation in Medical Intensive Care Unit Patients.

RATIONALE: Intensive care unit (ICU)- and mechanical ventilation (MV)-acquired limb muscle and diaphragm dysfunction may both be associated with longer length of stay and worse outcome. Whether they are two aspects of the same entity or have a different prevalence and prognostic impact remains unclear. OBJECTIVES: To quantify the prevalence and coexistence of these two forms of ICU-acquired weakness and their impact on outcome. METHODS: In patients undergoing a first spontaneous breathing trial after at least 24 hours of MV, diaphragm dysfunction was evaluated using twitch tracheal pressure in response to bilateral anterior magnetic phrenic nerve stimulation (a pressure <11 cm H2O defined dysfunction) and ultrasonography (thickening fraction [TFdi] and excursion). Limb muscle weakness was defined as a Medical Research Council (MRC) score less than 48. MEASUREMENTS AND MAIN RESULTS: Seventy-six patients were assessed at their first spontaneous breathing trial: 63% had diaphragm dysfunction, 34% had limb muscle weakness, and 21% had both. There was a significant but weak correlation between MRC score and twitch pressure (ρ = 0.26; P = 0.03) and TFdi (ρ = 0.28; P = 0.01), respectively. Low twitch pressure (odds ratio, 0.60; 95% confidence interval, 0.45-0.79; P < 0.001) and TFdi (odds ratio, 0.84; 95% confidence interval, 0.76-0.92; P < 0.001) were independently associated with weaning failure, but the MRC score was not. Diaphragm dysfunction was associated with higher ICU and hospital mortality, and limb muscle weakness was associated with longer duration of MV and hospital stay. CONCLUSIONS: Diaphragm dysfunction is twice as frequent as limb muscle weakness and has a direct negative impact on weaning outcome. The two types of muscle weakness have only limited overlap.

Ultrasound evaluation of diaphragm function in mechanically ventilated patients: comparison to phrenic stimulation and prognostic implications.

RATIONALE: In intensive care unit (ICU) patients, diaphragm dysfunction is associated with adverse clinical outcomes. Ultrasound measurements of diaphragm thickness, excursion (EXdi) and thickening fraction (TFdi) are putative estimators of diaphragm function, but have never been compared with phrenic nerve stimulation. Our aim was to describe the relationship between these variables and diaphragm function evaluated using the change in endotracheal pressure after phrenic nerve stimulation (Ptr,stim), and to compare their prognostic value. METHODS: Between November 2014 and June 2015, Ptr,stim and ultrasound variables were measured in mechanically ventilated patients <24 hours after intubation ('initiation of mechanical ventilation (MV)', under assist-control ventilation, ACV) and at the time of switch to pressure support ventilation ('switch to PSV'), and compared using Spearman's correlation and receiver operating characteristic curve analysis. Diaphragm dysfunction was defined as Ptr,stim <11 cm H2O. RESULTS: 112 patients were included. At initiation of MV, Ptr,stim was not correlated to diaphragm thickness (p=0.28), EXdi (p=0.66) or TFdi (p=0.80). At switch to PSV, TFdi and EXdi were respectively very strongly and moderately correlated to Ptr,stim, (r=0.87, p<0.001 and 0.45, p=0.001), but diaphragm thickness was not (p=0.45). A TFdi <29% could reliably identify diaphragm dysfunction (sensitivity and specificity of 85% and 88%), but diaphragm thickness and EXdi could not. This value was associated with increased duration of ICU stay and MV, and mortality. CONCLUSIONS: Under ACV, diaphragm thickness, EXdi and TFdi were uncorrelated to Ptr,stim. Under PSV, TFdi was strongly correlated to diaphragm strength and both were predictors of remaining length of MV and ICU and hospital death.

SPECT/CT to quantify early small airway disease and its relationship to clinical symptoms in smokers with normal lung function: a pilot study.

Introduction: Smokers frequently display respiratory symptoms despite the fact that their pulmonary function tests (PFTs) can be normal. Quantitative lung ventilation single-photon emission computed tomography (SPECT/CT) can provide a quantification of lung ventilatory homogeneity and could prove useful as an early marker of airway disease in smokers. We measured the effects of smoking on regional ventilation distribution in subjects with normal lung function and evaluated whether ventilation distribution in these subjects is related to lung function tests results and clinical symptoms. Methods: Subjects without any history of respiratory disease were prospectively recruited and separated in two groups: active smokers (AS: ≥10 cigarettes/day and history of ≥15 pack-years) and never smokers (NS: lifetime exposure of <5 cigarettes). All subjects performed PFTs (which had to be normal, defined as z-score values of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, total lung capacity (TLC) residual volume and diffusion capacity (DLCO) all falling between -1.65 and +1.65) and underwent SPECT/CT with Technegas, which generated subject- specific ventilation heterogeneity maps. The area under the compensated coefficient of variation (CV) density curve for CV values > 40%, (AUC-CV40%) was used as the measure of ventilation heterogeneity. Results: 30 subjects were recruited (15 per group). Subjects in the AS group displayed higher dyspnea levels (1 [1-2] vs. 0 [0-1] units on mMRC scale, p < 0.001). AUC- CV40% was significantly higher in the AS group (0.386 ± 0.106 vs. 0.293 ± 0.069, p = 0.004). AUC-CV40% was significantly correlated to FEV1 (rho = -0.47, p = 0.009), DLCO (rho = -0.49, p = 0.006), CAT score (rho = 0.55, p = 0.002) and mMRC score (rho = 0.54, p = 0.002). Subjects with mMRC >0 had higher AUC-CV40% values than those without dyspnea (0.289 ± 0.071 vs. 0.378 ± 0.102, p = 0.006), while FEV1 and DLCO were not different between those groups. ROC analyses showed that the AUC for AUC-CV40% in identifying subjects with mMRC score >0 was 0.78 (95%CI 0.61-0.95, p = 0.009), which was significantly higher than that of FEV1 and DLCO. Discussion: In smokers with normal lung function, ventilatory inhomogeneities can be quantified using SPECT/CT. AUC-CV40% values are related to lung function decline and to respiratory symptomatology, suggesting a potential role for this marker in the evaluation of symptomatic smokers.

Myositis with prominent B-cell aggregates causing shrinking lung syndrome in systemic lupus erythematosus: a case report.

BACKGROUND: Shrinking lung syndrome (SLS) is a rare manifestation of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and diaphragmatic weakness in a dyspneic patient. Chest wall dysfunction secondary to pleuritis is the most commonly proposed cause. In this case report, we highlight a new potential mechanism of SLS in SLE, namely diaphragmatic weakness associated with myositis with CD20 positive B-cell aggregates. CASE PRESENTATION: A 51-year-old Caucasian woman was diagnosed with SLE and secondary Sjögren's syndrome based on a history of pleuritis, constrictive pericarditis, polyarthritis, photosensitivity, alopecia, oral ulcers, xerophthalmia and xerostomia. Serologies were significant for positive antinuclear antibodies, anti-SSA, lupus anticoagulant and anti-cardiolopin. Blood work revealed a low C3 and C4, lymphopenia and thrombocytopenia. She was treated with with low-dose prednisone and remained in remission with oral hydroxychloroquine. Seven years later, she developed mild proximal muscle weakness and exertional dyspnea. Pulmonary function testing revealed a restrictive pattern with small lung volumes. Pulmonary imaging showed elevation of the right hemidiaphragm without evidence of interstitial lung disease. Diaphragmatic ultrasound was suggestive of profound diaphragmatic weakness and dysfunction. Based on these findings, a diagnosis of SLS was made. Her proximal muscle weakness was investigated, and creatine kinase (CK) levels were normal. Electromyography revealed fibrillation potentials in the biceps, iliopsoas, cervical and thoracic paraspinal muscles, and complex repetitive discharges in cervical paraspinal muscles. Biceps muscle biopsy revealed dense endomysial lymphocytic aggregates rich in CD20 positive B cells, perimysial fragmentation with plasma cell-rich perivascular infiltrates, diffuse sarcolemmal upregulation of class I MHC, perifascicular upregulation of class II MHC, and focal sarcolemmal deposition of C5b-9. Treatment with prednisone 15 mg/day and oral mycophenolate mofetil 2 g/day was initiated. Shortness of breath and proximal muscle weakness improved significantly. CONCLUSION: Diaphragmatic weakness was the inaugural manifestation of myositis in this patient with SLE. The spectrum of myologic manifestations of myositis with prominent CD20 positive B-cell aggregates in SLE now includes normal CK levels and diaphragmatic involvement, in association with SLS.

Predictive value of positional change in vital capacity to identify diaphragm dysfunction.

RATIONALE: Sitting-to-supine fall in vital capacity (ΔVC) can be used to help identify diaphragm dysfunction (DD), but its optimal predictive threshold value is uncertain. Our aim was to evaluate the diagnostic performance of ΔVC in identifying the presence of unilateral or bilateral DD. METHODS: Patients referred to the diaphragm dysfunction clinic of our center (2017-2018) were included. All subjects had lung function testing (including measurement of ΔVC) and an ultrasound assessment of diaphragm thickening fraction (TFdi). Unilateral DD was defined as a single hemidiaphragm with TFdi ≤30 % and bilateral DD as a mean TFdi value of both hemidiaphragms ≤30 %. Clinical and physiological characteristics were compared across groups, and sensitivity/specificity analyses of ΔVC to identify DD were performed. RESULTS: 84 patients were included (31 unilateral DD, 17 bilateral DD and 36 without significant DD). DD groups had similar age, gender and BMI (all p > 0.05), but patients with bilateral DD had lower FVC, FEV1, MIP, TLC, ΔVC and more frequent orthopnea than patients with unilateral DD (all p < 0.05). There was a significant correlation between TFdi and ΔVC (rho=-0.56, p < 0.001). The optimal ΔVC value to identify bilateral DD was ≤-15 % [AUC 0.97 (95 %CI 0.89-1.00), p < 0.001, with sensitivity and specificity of 100 % and 89 %, respectively]. No single threshold of ΔVC could accurately predict unilateral DD [AUC 0.58 (95 %CI 0.45-0.72), p = 0.24]. CONCLUSION: ΔVC performs poorly in identifying patients with unilateral DD. However, a ΔVC value ≤-15 % is strongly associated with the presence of bilateral DD. These findings should be taken into account when using ΔVC in the evaluation of patients with suspected DD.

Ultrasound-Derived Diaphragm Contractile Reserve as a Marker of Clinical Status in Patients With Cystic Fibrosis.

Introduction: In patients with cystic fibrosis (CF), the monitoring of respiratory muscle activity using electromyography can provide information on the demand-to-capacity ratio of the respiratory system and act as a clinical marker of disease activity, but this technique is not adapted to routine clinical care. Ultrasonography of the diaphragm could provide an alternative, simpler and more widely available alternative allowing the real-time assessment of the diaphragm contractile reserve (DCR), but its relationship with recognized markers of disease severity and clinical outcomes are currently unknown. Methods: Stable patients with CF were prospectively recruited. Diaphragm ultrasound was performed and compared to forced expiratory volume in 1 s (FEV1), residual volume (RV), handgrip strength, fat-free mass index (FFMI), serum vitamin levels, dyspnea levels and rate of acute exacerbation (AE). Diaphragm activity was reported as DCR (the ratio of tidal-to-maximal thickening fractions, representing the remaining diaphragm contractility available after tidal inspiration) and TFmax (representing maximal diaphragm contractile strength). Inter-observer reliability of the measurement of DCR was evaluated using intra-class correlation analysis. Results: 110 patients were included [61 males, median (interquartile range), age 31 (27-38) years, FEV1 66 (46-82)% predicted]. DCR was significantly correlated to FEV1 (rho = 0.46, p < 0.001), RV (rho = -0.46, p < 0.001), FFMI (rho = 0.41, p < 0.001), and handgrip strength (rho = 0.22, p = 0.02), but TFmax was not. In a multiple linear regression analysis, both RV and FFMI were independent predictors of DCR. DCR, but not TFmax, was statistically lower in patients with > 2 exacerbations/year (56 ± 25 vs. 71 ± 17%, p = 0.001) and significantly lower with higher dyspnea levels. A ROC analysis showed that DCR performed better than FEV1 (mean difference in AUROC 0.09, p = 0.04), RV (mean difference in AUROC 0.11, p = 0.03), and TFmax at identifying patients with an mMRC score > 2. Inter-observer reliability of DCR was high (ICC = 0.89, 95% CI 0.84-0.92, p < 0.001). Conclusion: In patients with CF, DCR is a reliable and non-invasive marker of disease severity that is related to respiratory and extra-pulmonary manifestations of the disease and to clinical outcomes. Future studies investigating the use of DCR as a longitudinal marker of disease progression, response to interventions or target for therapy would further validate its translation into clinical practice.