Joseph Milic-Emili’s research while affiliated with McGill University and other places

Background: Forced expiratory volume 1 second (FEV1) has traditionally been used as a readily available marker of health in adult cystic fibrosis (CF). However, due to the obstructive nature of this disease, it is possible that lung hyperinflation could be more closely related to disease severity than is FEV1. The purpose of this study was to determine if hyperinflation is more closely associated with quality of life, functional status, and pulmonary exacerbations than FEV1 in patients with CF. Methods: Sixty-eight adult patients with CF were evaluated in this retrospective study. We used IC and functional residual capacity (FRC) and their ratios to total lung capacity (TLC) as measures of lung hyperinflation. We used bivariate correlations and backwards regression analysis to assess possible associations between FEV1, lung hyperinflation, and measures of disease severity including questionnaire based quality of life, pulmonary exacerbation frequency, and mortality. The respiratory component of the Cystic Fibrosis Questionnaire–Revised (CRQ-R-Respiratory) was used as a measure of quality of life. Results: Both FEV1 and IC were negatively correlated with pulmonary exacerbations over a 3 year period (p = 0.004, r2 = 0.127; p Conclusions: FEV1 and lung hyperinflation-as measured by IC and FRC/TLC-are both associated with pulmonary exacerbation frequency. This suggests that chronic dynamic hyperinflation contributes significantly to disease severity in adult cystic fibrosis.

Background While the effects of postural change on arterial oxygenation have been well documented in normal subjects, and attributed to the relationship of closing volume (CV) to the tidal volume, in liver cirrhosis such postural changes have been evaluated mainly in a rare, peculiar clinical end-stage condition which is characterized by increased dyspnea shifting from supine to upright position ("platypnea"). The latter is associated with worsening of PaO2 ("orthodeoxia"). Our study was undertaken to evaluate the effects of postural change on arterial oxygenation in patients affected by mild/moderate liver cirrhosis. Methods We studied pulmonary function tests and arterial blood gases in sitting and supine position in 22 consecutive, biopsy-proved, mild/moderate liver cirrhosis, non-smokers patients, and 22 matched non-smokers control subjects. Results Recumbency elicited a decrease of PaO2 (Δ(sup-sit)PaO2) in 19 out of 22 controls and in all but one cirrhotics. The magnitude of this postural change was significantly (p= 0.04) greater in cirrhotics (9.6±5.3%) compared to controls (6.7±3.7%). In the subset of cirrhotics older than 60 yrs and with PaO2 greater than 80 mmHg in sitting position, the Δ(sup-sit)PaO2 in recumbency further increased to 12±5.8 mmHg, significantly (p= 0.014) greater than in same subgroup of controls (7.1±3.8 mmHg). Conclusions In mild/moderate liver cirrhosis the postural variations in PaO2 follow the normal trends, but are of greater magnitude probably as a consequence of hypoventilated units of lung for postural and disease-linked tidal airway closure, resulting in more pronounced recumbent hypoxemia ("clinodeoxia").

Background: Respiratory symptoms are usually underestimated in patients with chronic kidney disease undergoing maintenance hemodialysis. Therefore, we set out to investigate the prevalence of patients chronic dyspnea and the relationship of the symptom to lung function indices. Methods: Twenty-five clinically stable hemodialysis patients were included. The mMRC dyspnea scale was applied before and after hemodialysis. Spirometry, single breath nitrogen test, arterial blood gases, static maximum inspiratory (P(imax)) and expiratory (P(emax)) muscle pressures, and mouth occlusion pressure (P 0.1) were also measured. Results: Despite normal spirometry, all patients (100%) reported mild to moderate degree of chronic dyspnea pre which was reduced after hemodialysis. The sole predictor of (Δ) mMRC was the (Δ) P 0.1 (r = 0.71, P < 0.001). The P(imax) was reduced before and correlated with the duration of hemodialysis (r = 0.614, P < 0.001), whilst after the session it was significantly increased (P < 0.001). Finally (Δ) weight was correlated with the (Δ) P(imax) %pred (r = 0.533, P = 0,006) and with the (Δ) CV (%pred) (r = 0.65, P < 0.001). Conclusion: We conclude that dyspnea is the major symptom among the CKD patients that improves after hemodialysis. The neuromechanical dissociation observed probably is one of the major pathophysiologic mechanisms of dyspnea.

To investigate the prevalence of chronic dyspnea and its relationship to respiratory muscle function in end-stage liver disease. Sixty-eight consecutive, ambulatory, Caucasian patients with end-stage liver disease, candidates for liver transplantation, were referred for preoperative respiratory function assessment. Forty of these (29 men) were included in this preliminary study after applying strict inclusion and exclusion criteria. Seventeen of 40 patients (42%) had ascites, but none of them was cachectic. Fifteen of 40 patients (38%) had a history of hepatic encephalopathy, though none of them was symptomatic at study time. All patients with a known history and/or presence of co-morbidities were excluded. Chronic dyspnea was rated according to the modified medical research council (mMRC) 6-point scale. Liver disease severity was assessed according to the Model for end-stage liver disease (MELD). Routine lung function tests, maximum static expiratory (Pemax) and inspiratory (Pimax) mouth pressures were measured. Respiratory muscle strength (RMS) was calculated from Pimax and Pemax values. In addition, arterial blood gases and pattern of breathing (VE: minute ventilation; VT: tidal volume; VT/TI: mean inspiratory flow; TI: duration of inspiration) were measured. Thirty-five (88%) of 40 patients aged (mean ± SD) 52 ± 10 years reported various degrees of chronic dyspnea (mMRC), ranging from 0 to 4, with a mean value of 2.0 ± 1.2. MELD score was 14 ± 6. Pemax, percent of predicted (%pred) was 105 ± 35, Pimax, %pred was 90 ± 29, and RMS, %pred was 97 ± 30. These pressures were below the normal limits in 12 (30%), 15 (38%), and 14 (35%) patients, respectively. Furthermore, comparing the subgroups of ascites to non-ascites patients, all respiratory muscle indices measured were found significantly decreased in ascites patients. Patients with ascites also had a significantly worse MELD score compared to non-ascites ones (P = 0.006). Significant correlations were found between chronic dyspnea and respiratory muscle function indices in all patients. Specifically, mMRC score was significantly correlated with Pemax, Pimax, and RMS (r = -0.53, P < 0.001; r = -0.42, P < 0.01; r = -0.51, P < 0.001, respectively). These correlations were substantially closer in the non-ascites subgroup (r = -0.82, P < 0.0001; r = -0.61, P < 0.01; r = -0.79, P < 0.0001, respectively) compared to all patients. Similar results were found for the relationship between mMRC vs MELD score, and MELD score vs respiratory muscle strength indices. In all patients the sole predictor of mMRC score was RMS (r = -0.51, P < 0.001). In the subgroup of patients without ascites this relationship becomes closer (r = -0.79, P < 0.001), whilst this relationship breaks down in the subgroup of patients with ascites. The disappearance of such a correlation may be due to the fact that ascites acts as a "confounding" factor. PaCO2 (4.4 ± 0.5 kPa) was increased, whereas pH (7.49 ± 0.04) was decreased in 26 (65%) and 34 (85%) patients, respectively. PaO2 (12.3 ± 0.04 kPa) was within normal limits. VE (11.5 ± 3.5 L/min), VT (0.735 ± 0.287 L), and VT/TI (0.449±0.129 L/s) were increased signifying hyperventilation in both subgroups of patients. VT/TI was significantly higher in patients with ascites than without ascites. Significant correlations, albeit weak, were found for PaCO2 with VE and VT/TI (r = -0.44, P < 0.01; r = -0.41, P < 0.01, respectively). The prevalence of chronic dyspnea is 88% in end-stage liver disease. The mMRC score closely correlates with respiratory muscle strength.

Objective: To identify the nature of the changes of respiratory mechanics in patients with middle cervical spinal cord injury (SCI) and their correlation with posture. Design: Clinical trial. Setting: Acute SCI unit. Participants: Patients with SCI (N=34) at C4-5 level studied within 6 months of injury. Interventions: Patients were assessed by the negative expiratory pressure test, maximal static respiratory pressure test, and standard spirometry. Main outcome measures: The following respiratory variables were recorded in both the semirecumbent and supine positions: (1) tidal expiratory flow limitation (TEFL); (2) airway resistances; (3) mouth occlusion pressure developed 0.1 seconds after occluded inspiration at functional residual capacity (P(0.1)); (4) maximal static inspiratory pressure (MIP) and maximal static expiratory pressure (MEP); and (5) spirometric data. Results: TEFL was detected in 32% of the patients in the supine position and in 9% in the semirecumbent position. Airway resistances and P(0.1) were much higher compared with normative values, while MIP and MEP were markedly reduced. The ratio of forced expiratory volume in 1 second to forced vital capacity was less than 70%, while the other spirometric data were reduced up to 30% of predicted values. Conclusions: Patients with middle cervical SCI can develop TEFL. The presence of TEFL, associated with increased airway resistance, could increase the work of breathing in the presence of a reduced capacity of the respiratory muscles to respond to the increased load. The semirecumbent position and the use of continuous positive airway pressure can be helpful to (1) reduce the extent of TEFL and avoid the opening/closure of the small airways; (2) decrease airway resistance; and (3) maintain the expiratory flow as high as possible, which aids in the removal of secretions.

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Exertional dyspnea is the most prominent and disabling feature in idiopathic pulmonary fibrosis (IPF). The Medical Research Chronic (MRC) chronic dyspnea score as well as physiological measurements obtained during cardiopulmonary exercise testing (CPET) and the 6-minute walk test (6MWT) are shown to provide information on the severity and survival of disease. We prospectively recruited IPF patients and examined the relationship between the MRC score and either CPET or 6MWT parameters known to reflect physiologic derangements limiting exercise capacity in IPF patients Twenty-five patients with IPF were included in the study. Significant correlations were found between the MRC score and the distance (r = -.781, p < 0.001), the SPO2 at the initiation and the end (r = -.542, p = 0.005 and r = -.713, p < 0.001 respectively) and the desaturation index (r = .634, p = 0.001) for the 6MWT; the MRC score and VO2 peak/kg (r = -.731, p < 0.001), SPO2 at peak exercise (r = -. 682, p < 0.001), VE/VCO2 slope (r = .731, p < 0.001), VE/VCO2 at AT (r = .630, p = 0.002) and the Borg scale at peak exercise (r = .50, p = 0.01) for the CPET. In multiple logistic regression analysis, the only variable independently related to the MRC is the distance walked at the 6MWT. In this population of IPF patients a good correlation was found between the MRC chronic dyspnoea score and physiological parameters obtained during maximal and submaximal exercise testing known to reflect ventilatory impairment and exercise limitation as well as disease severity and survival. This finding is described for the first time in the literature in this group of patients as far as we know and could explain why a simple chronic dyspnea score provides reliable prognostic information on IPF.

In normal animals, cyclic airway closure and reopening during prolonged mechanical ventilation at low lung volumes causes histological damage of small airways, characterized by epithelial sloughing and lesion and/or rupture of alveolar-bronchiolar attachments, with a concurrent increase in airway resistance that persists after restoration of physiological end-expiratory lung volume. Peripheral airway injury should be therefore expected to occur when the closing capacity exceeds the functional residual capacity and tidal airway closure is regularly present during spontaneous breathing. On these basis, it is proposed that in smokers the transition from peripheral airway disease to chronic obstructive pulmonary disease is characterized by three sequential stages: Stage I, during which the closing capacity eventually exceeds the functional residual capacity, i.e. airway closure and reopening occur cyclically with breathing; Stage II, during which tidal expiratory flow limitation is eventually exhibited; and Stage III, during which dynamic hyperinflation progressively increases leading to dyspnea and exercise limitation. In this perspective, it is tidal airway closure and, probably, tidal expiratory flow limitation that promote peripheral airway injury, accelerate the abnormalities of lung function, and may determine which smoker is destined to develop chronic obstructive pulmonary disease.

Imaging studies have shown that general anesthesia in children results in atelectasis. Lung recruitment total lung capacity (TLC) maneuvers plus positive end-expiratory pressure (PEEP) are effective in preventing atelectasis. However, physiological changes in children during general anesthesia have not been elucidated. In eight anesthetized and mechanically ventilated children (median age: 3.5 years; range: 2.3-6.5), we measured static respiratory system elastance (E(st)), flow resistance (R(int)), and elastance and resistance components resulting from tissue viscoelasticity (deltaE and deltaR, respectively) using the constant inflow, end-inspiratory occlusion method preceded by TLC maneuvers, both with zero PEEP (ZEEP) and PEEP (5 cm H2O) for comparison. With constant inspiratory flow V(I) and ZEEP, increases in end-inspiratory lung volume above relaxation volume (tidal volume, V(T)) from 8 to 20 mL x kg(-1) resulted in decreases in E(st) from 1.06 to 0.82 cm H2O x mL(-1) x kg, deltaE from 0.16 to 0.09, and R(int) from 0.13 to 0.11 cm H2O x mL(-1) x s x kg, whereas deltaR increased from 0.08 to 0.12 (P < 0.05). Similar relationships were found with PEEP. Increases in V(I) (8 to 26 mL x s(-1) x kg) with constant V(T) and ZEEP resulted in decreases in E(st) from 1.09 to 0.9 and deltaR from 0.17 to 0.06 (P < 0.01), whereas deltaE and R(int) did not change. There was a similar flow and volume dependence of elastance and resistance with PEEP. The observed steady decreases in E(st) with increasing V(T) (up to 16 mL/kg with PEEP) indicate marked reductions in end-expiratory relaxation volume (functional residual capacity) even with PEEP. Similarity in results with ZEEP and PEEP suggests that TLC-maneuvers and O2-N2 ventilation prevented airway closure throughout the study.