Towards quantitative perfusion MRI of the lung in COPD: The problem of short-term repeatability.
ABSTRACT: PURPOSE:4D perfusion magnetic resonance imaging (MRI) with intravenous injection of contrast agent allows for a radiation-free assessment of regional lung function. It is therefore a valuable method to monitor response to treatment in patients with chronic obstructive pulmonary disease (COPD). This study was designed to evaluate its potential for monitoring short-term response to hyperoxia in COPD patients. MATERIALS AND METHODS:19 prospectively enrolled COPD patients (median age 66y) underwent paired dynamic contrast-enhanced 4D perfusion MRI within 35min, first breathing 100% oxygen (injection 1, O2) and then room air (injection 2, RA), which was repeated on two consecutive days (day 1 and 2). Post-processing software was employed to calculate mean transit time (MTT), pulmonary blood volume (PBV) and pulmonary blood flow (PBF), based on the indicator dilution theory, for the automatically segmented whole lung and 12 regions of equal volume. RESULTS:Comparing O2 with RA conditions, PBF and PBV were found to be significantly lower at O2, consistently on both days (p<10-8). Comparing day 2 to day 1, MTT was shorter by 0.59±0.63 s (p<10-8), PBF was higher by 22±80 ml/min/100ml (p<3·10-4), and PBV tended to be lower by 0.2±7.2 ml/100ml (p = 0.159) at both, RA and O2, conditions. CONCLUSION:The second injection (RA) yielded higher PBF and PBV, which apparently contradicts the established hypothesis that hyperoxia increases lung perfusion. Quantification of 4D perfusion MRI by current software approaches may thus be limited by residual circulating contrast agent in the short-term and even the next day.
Project description:To compare measurements of regional pulmonary perfused blood volume (PBV) and pulmonary blood flow (PBF) obtained with computed tomography (CT) in two pig models.The institutional animal care and use committee approved all animal studies. CT-derived PBF and PBV were determined in four anesthetized, mechanically ventilated, supine swine by using two methods for creating pulmonary parenchymal perfusion heterogeneity. Two animals were examined after sequentially moving a pulmonary arterial balloon catheter from a distal to a central location, and two others were examined over a range of static airway pressures, which varied the extents of regional PBF. Lung sections were divided into blocks and Pearson correlation coefficients calculated to compare matching regions between the two methods.CT-derived PBF, CT-derived PBV, and their associated coefficients of variation (CV) were closely correlated on a region-by-region basis in both the balloon occlusion (Pearson R = 0.91 and 0.73 for animals 1 and 2, respectively; Pearson R = 0.98 and 0.87 for comparison of normalized mean and CV for animals 1 and 2, respectively) and lung inflation studies (Pearson R = 0.94 and 0.74 for animals 3 and 4, respectively; Pearson R = 0.94 and 0.69 for normalized mean and CV for animals 3 and 4, respectively). When accounting for region-based effects, correlations remained highly significant at the P < .001 level.CT-derived PBV heterogeneity is a suitable surrogate for CT-derived PBF heterogeneity.
Project description:BACKGROUND:Foot perfusion has been recently implemented as a new tool for optimizing outcomes of peripheral endovascular procedures. A custom-made, two-dimensional perfusion digital subtraction angiography (PDSA) algorithm has been implemented to quantify outcomes of endovascular treatment of critical limb ischemia (CLI), assist intra-procedural decision-making, and enhance clinical outcomes. METHODS:The study was approved by the Hospital's Ethics Committee. This prospective, single-center study included seven consecutive patients scheduled to undergo infrapopliteal endovascular treatment of CLI. Perfusion blood volume (PBV), mean transit time (MTT), and perfusion blood flow (PBF) maps were extracted by analyzing time-intensity curves and signal intensity on the perfused vessel mask. Mean values calculated from user-specified regions of interest (ROIs) on perfusion maps were employed to evaluate pre- and post-endovascular treatment condition. Measurements were performed immediately after final PDSA. RESULTS:In total, five patients (aged 54 ± 16?years, mean ± standard deviation) were analyzed, as two patients were excluded due to significant motion artifacts. Post-procedural MTT presented a mean decrease of 19.1% for all patients and increased only in 1 of 5 patients, demonstrating in 4/5 patients an increase in tissue perfusion after revascularization. Overall mean PBF and PBV values were also analogously increased following revascularization (446% and 69.5% mean, respectively) and in the majority of selected ROIs (13/15 and 12/15 ROIs, respectively). CONCLUSIONS:Quantification of infrapopliteal angioplasty outcomes using this newly proposed, custom-made, intra-procedural PDSA algorithm was performed using PBV, MTT, and PBF maps. Further studies are required to determine its role in peripheral endovascular procedures ( ClinicalTrials.gov Identifier: NCT04356092).
Project description:Surfactant therapy has become the standard of care for preterm infants with respiratory distress syndrome. Preclinical studies have reported the therapeutic benefits of mesenchymal stem cells (MSCs) in experimental bronchopulmonary dysplasia. This study investigated the effects of a surfactant on the in vitro viability and in vivo function of human MSCs.The viability, phenotype, and mitochondrial membrane potential (MMP) of MSCs were assessed through flow cytometry. The in vivo function was assessed after intratracheal injection of human MSCs (1 × 105 cells) diluted in 30 μl of normal saline (NS), 10 μl of a surfactant diluted in 20 μl of NS, and 10 μl of a surfactant and MSCs (1 × 105 cells) diluted in 20 μl of NS in newborn rats on postnatal day 5. The pups were reared in room air (RA) or an oxygen-enriched atmosphere (85% O2) from postnatal days 1 to 14; eight study groups were examined: RA + NS, RA + MSCs, RA + surfactant, RA + surfactant + MSCs, O2 + NS, O2 + MSCs, O2 + surfactant, and O2 + surfactant + MSCs. The lungs were excised for histological and cytokine analysis on postnatal day 14.Compared with the controls, surfactant-treated MSCs showed significantly reduced viability and MMP after exposure to 1:1 and 1:2 of surfactant:MSCs for 15 and 60 minutes. All human MSC samples exhibited similar percentages of CD markers, regardless of surfactant exposure. The rats reared in hyperoxia and treated with NS exhibited a significantly higher mean linear intercept (MLI) than did those reared in RA and treated with NS, MSCs, surfactant, or surfactant + MSCs. Treatment with MSCs, surfactant, or surfactant + MSCs significantly reduced the hyperoxia-induced increase in MLI. The O2 + surfactant + MSCs group exhibited a significantly higher MLI than did the O2 + MSCs group. Furthermore, treatment with MSCs and MSCs + surfactant significantly reduced the hyperoxia-induced increase in apoptotic cells.Combination therapy involving a surfactant and MSCs does not exert additive effects on lung development in hyperoxia-induced lung injury.
Project description:Cerebrovascular reactivity (CVR)-weighted blood-oxygenation-level-dependent magnetic resonance imaging (BOLD-MRI) experiments are frequently used in conjunction with hyperoxia. Owing to complex interactions between hyperoxia and hypercapnia, quantitative effects of these gas mixtures on BOLD responses, blood and tissue R2*, and blood oxygenation are incompletely understood. Here we performed BOLD imaging (3?T; TE/TR=35/2,000?ms; spatial resolution=3 × 3 × 3.5?mm(3)) in healthy volunteers (n=12; age=29±4.1 years) breathing (i) room air (RA), (ii) normocapnic-hyperoxia (95% O2/5% N2, HO), (iii) hypercapnic-normoxia (5% CO2/21% O2/74% N2, HC-NO), and (iv) hypercapnic-hyperoxia (5% CO2/95% O2, HC-HO). For HC-HO, experiments were performed with separate RA and HO baselines to control for changes in O2. T2-relaxation-under-spin-tagging MRI was used to calculate basal venous oxygenation. Signal changes were quantified and established hemodynamic models were applied to quantify vasoactive blood oxygenation, blood-water R2*, and tissue-water R2*. In the cortex, fractional BOLD changes (stimulus/baseline) were HO/RA=0.011±0.007; HC-NO/RA=0.014±0.004; HC-HO/HO=0.020±0.008; and HC-HO/RA=0.035±0.010; for the measured basal venous oxygenation level of 0.632, this led to venous blood oxygenation levels of 0.660 (HO), 0.665 (HC-NO), and 0.712 (HC-HO). Interleaving a HC-HO stimulus with HO baseline provided a smaller but significantly elevated BOLD response compared with a HC-NO stimulus. Results provide an outline for how blood oxygenation differs for several gas stimuli and provides quantitative information on how hypercapnic BOLD CVR and R2* are altered during hyperoxia.
Project description:T1 maps have been shown to yield useful diagnostic information on lung function in patients with chronic obstructive pulmonary disease (COPD) and asthma, both for native T1 and ?T1, the relative reduction while breathing pure oxygen. As parameter quantification is particularly interesting for longitudinal studies, the purpose of this work was both to examine the reproducibility of lung T1 mapping and to compare T1 found in COPD and asthma patients using IRSnapShotFLASH embedded in a full MRI protocol. 12 asthma and 12 COPD patients (site 1) and further 15 COPD patients (site 2) were examined on two consecutive days. In each patient, T1 maps were acquired in 8 single breath-hold slices, breathing first room air, then pure oxygen. Maps were partitioned into 12 regions each to calculate average values. In asthma patients, the average T1,RA = 1206ms (room air) was reduced to T1,O2 = 1141ms under oxygen conditions (?T1 = 5.3%, p < 5?10-4), while in COPD patients both native T1,RA = 1125ms was significantly shorter (p < 10-3) and the relative reduction to T1,O2 = 1081ms on average ?T1 = 4.2%(p < 10-5). On the second day, with T1,RA = 1186ms in asthma and T1,RA = 1097ms in COPD, observed values were slightly shorter on average in all patient groups. ?T1 reduction was the least repeatable parameter and varied from day to day by up to 23% in individual asthma and 30% in COPD patients. While for both patient groups T1 was below the values reported for healthy subjects, the T1 and ?T1 found in asthmatics lies between that of the COPD group and reported values for healthy subjects, suggesting a higher blood volume fraction and better ventilation. However, it could be demonstrated that lung T1 quantification is subject to notable inter-examination variability, which here can be attributed both to remaining contrast agent from the previous day and the increased dependency of lung T1 on perfusion and thus current lung state.
Project description:Bronchopulmonary dysplasia (BPD) is characterized by arrested alveolar development and complicated by pulmonary hypertension (PH). NO promotes alveolar growth. Inhaled NO (iNO) ameliorates the BPD phenotype in experimental models and in some premature infants. Arginosuccinate synthetase (ASS) and arginosuccinate lyase (ASL) convert L-citrulline to L-arginine; L-citrulline is regenerated during NO synthesis from L-arginine. Plasma levels of these NO precursors are low in PH. We hypothesized that L-citrulline prevents experimental O2-induced BPD in newborn rats. Rat pups were assigned from birth through postnatal day (P) 14 to room air (RA), RA + L-citrulline, 95% hyperoxia (BPD model), and 95%O2 + L-citrulline. Rat pups exposed to hyperoxia had fewer and enlarged air spaces and decreased capillary density, mimicking human BPD. This was associated with decreased plasma L-arginine and L-citrulline concentrations on P7. L-citrulline treatment significantly increased plasma L-arginine and L-citrulline concentrations and increased ASL protein expression in hyperoxia. L-citrulline preserved alveolar and vascular growth in O2-exposed pups and decreased pulmonary arterial medial wall thickness (MWT) and right ventricular hypertrophy (RVH). Increased lung arginase (ARG) activity in O2-exposed pups was reversed by L-citrulline treatment. L-citrulline supplementation prevents hyperoxia-induced lung injury and PH in newborn rats. L-citrulline may represent a novel therapeutic alternative to iNO for prevention of BPD.
Project description:Hyperoxia therapy is often required to treat newborns with respiratory disorders. Prolonged hyperoxia exposure increases oxidative stress and arrests alveolar development in newborn rats. Tn antigen is N-acetylgalactosamine residue that is one of the most remarkable tumor-associated carbohydrate antigens. Tn immunization increases the serum anti-Tn antibody titers and attenuates hyperoxia-induced lung injury in adult mice. We hypothesized that maternal Tn immunizations would attenuate hyperoxia-induced lung injury through the suppression of oxidative stress in neonatal rats. Female Sprague-Dawley rats (6 weeks old) were intraperitoneally immunized five times with Tn (50 ?g/dose) or carrier protein at biweekly intervals on 8, 6, 4, 2, and 0 weeks before the day of delivery. The pups were reared in room air (RA) or 2 weeks of 85% O2, creating the four study groups: carrier protein + RA, Tn vaccine + RA, carrier protein + O2, and Tn vaccine + O2. The lungs were excised for oxidative stress, cytokine, vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) expression, and histological analysis on postnatal day 14. Blood was withdrawn from dams and rat pups to check anti-Tn antibody using western blot. We observed that neonatal hyperoxia exposure reduced the body weight, increased 8-hydroxy-2-deoxyguanosine (8-OHdG) expression and lung cytokine (interleukin-4), increased mean linear intercept (MLI) values, and decreased vascular density and VEGF and PDGF-B expressions. By contrast, Tn immunization increased maternal and neonatal serum anti-Tn antibody titers on postnatal day 14, reduced MLI, and increased vascular density and VEGF and PDGF-B expressions to normoxic levels. Furthermore, the alleviation of lung injury was accompanied by a reduction in lung cytokine and 8-OHdG expression. Therefore, we propose that maternal Tn immunization attenuates hyperoxia-induced lung injury in neonatal rats through the suppression of oxidative stress and inflammation.
Project description:INTRODUCTION:Hypoxemia and hyperoxia may occur after surgery with potential related complications. The FreeO2 PostOp trial is a prospective, multicentre, randomised controlled trial that evaluates the clinical impact of automated O2 administration versus conventional O2 therapy after major abdominal or thoracic surgeries. The study is powered to demonstrate benefits of automated oxygen titration and weaning in term of oxygenation, which is an important surrogate for complications after such interventions. METHODS AND ANALYSIS:After extubation, patients are randomly assigned to the Standard (manual O2 administration) or FreeO2 group (automated closed-loop O2 administration). Stratification is performed for the study centre and a medical history of chronic obstructive pulmonary disease (COPD). Primary outcome is the percentage of time spent in the target zone of oxygen saturation, during a 3-day time frame. In both groups, patients will benefit from continuous oximetry recordings. The target zone of oxygen saturation is SpO2=88%-92% for patients with COPD and 92%-96% for patients without COPD. Secondary outcomes are the nursing workload assessed by the number of manual O2 flow adjustments, the time spent with severe desaturation (SpO2 <85%) and hyperoxia area (SpO2 >98%), the time spent in a hyperoxia area (SpO2 >98%), the VO2, the duration of oxygen administration during hospitalisation, the frequency of use of mechanical ventilation (invasive or non-invasive), the duration of the postrecovery room stay, the hospitalisation length of stay and the survival rate. ETHICS AND DISSEMINATION:The FreeO2 PostOp study is conducted in accordance with the declaration of Helsinki and was registered on 11 September 2015 (http://www.clinicaltrials.gov). First patient inclusion was performed on 14 January 2016. The results of the study will be presented at academic conferences and submitted to peer-reviewed journals. TRIAL REGISTRATION NUMBER:NCT02546830.
Project description:Introduction:Patients with COPD have increased respiratory loads and altered blood gases, both of which affect vascular function and sympathetic activity. Sleep, particularly rapid eye movement (REM) sleep, is known to exacerbate hypoxia and respiratory loads. Therefore, we hypothesize that nasal high flow (NHF), which lowers ventilatory loads, reduces sympathetic activity during sleep and that this effect depends on COPD severity. Methods:We performed full polysomnography in COPD patients (n=17; FEV1, 1.6±0.6 L) and in matched controls (n=8). Participants received room air (RA) at baseline and single night treatment with O2 (2 L/min) and NHF (20 L/min) in a random order. Finger pulse wave amplitude (PWA), a measure of vascular sympathetic tone, was assessed by photoplethysmography. Autonomic activation (AA) events were defined as PWA attenuation ?30% and indexed per hour for sleep stages (AA index [AAI]) at RA, NHF, and O2). Results:In COPD, sleep apnea improved following O2 (REM-apnea hypopnea index [AHI] with RA, O2, and NHF: 18.6±20.9, 12.7±18.1, and 14.4±19.8, respectively; P=0.04 for O2 and P=0.06 for NHF). REM-AAI was reduced only following NHF in COPD patients (AAI-RA, 21.5±18.4 n/h and AAI-NHF, 9.9±6.8 n/h, P=0.02) without changes following O2 (NHF-O2 difference, P=0.01). REM-AAI reduction was associated with lung function expressed as FEV1 and FVC (FEV1: r=-0.59, P=0.001; FEV1/FVC: r=-0.52 and P=0.007). Conclusion:NHF but not elevated oxygenation reduces peripheral vascular sympathetic activity in COPD patients during REM sleep. Sympathetic off-loading by NHF, possibly related to improved breathing mechanics, showed a strong association with COPD severity.
Project description:Altered functions of the lung epithelial surface likely contribute to the respiratory morbidities in infants with bronchopulmonary dysplasia (BPD). Infants with BPD exhibit decreased expressions of secretoglobins (SCGBs), including Clara cell secretory protein (CCSP). Expression of lung SCGB and annexin A1 (ANXA1) is persistently altered in CCSP knockout mice suggesting that CCSP indirectly influences innate immune responses. The present studies tested the hypothesis that neonatal hyperoxic exposure induces deficits in CCSP expression that are associated with persistent alterations in lung SCGB and ANXA1 expression. Newborn C3H/HeN mice were exposed to room air (RA) or 85% O2 from birth and were sacrificed at 14?d or returned to RA for 14?d. Neonatal hyperoxia followed by RA recovery was associated with decreased lung CCSP and SCGB3A1 protein but not mRNA expression. Hyperoxia-induced alterations in the charge characteristics of ANXA1 were unchanged by RA recovery and were associated with elevated lung macrophage numbers. These findings support a model in which hyperoxia-induced alterations in Clara cell function influence lung innate immune function through effects on immunomodulatory proteins. Studies to determine the mechanism(s) by which CCSP alterations affect SCGBs, ANXA1, and innate immune responses in BPD are warranted.