Interhospital ECMO Transport: Regional Focus.

Utilization of extracorporeal membrane oxygenation (ECMO) has increased dramatically over the last decade. Despite this trend, many medical centers have limited, if any, access to this technology or the resources necessary to manage these complex patients. In an effort to improve the current infrastructure of regional ECMO care, ECMO centers of excellence have an obligation to partner with facilities within their communities and regions to increase access to this potentially life-saving technology. While the need for this infrastructure is widely acknowledged in the ECMO community, few reports describe the actual mechanisms by which a successful interfacility transport program can operate. As such, the purpose of this document is to describe the elements of and methods for providing safe and efficient mobile ECMO services from the perspective of an experienced, high-volume tertiary ECMO center of excellence in the Southeastern United States.

Using hyperpolarized 129Xe MRI to quantify regional gas transfer in idiopathic pulmonary fibrosis.

BACKGROUND: Assessing functional impairment, therapeutic response and disease progression in patients with idiopathic pulmonary fibrosis (IPF) continues to be challenging. Hyperpolarized 129Xe MRI can address this gap through its unique capability to image gas transfer three-dimensionally from airspaces to interstitial barrier tissues to red blood cells (RBCs). This must be validated by testing the degree to which it correlates with pulmonary function tests (PFTs) and CT scores, and its spatial distribution reflects known physiology and patterns of disease. METHODS: 13 healthy individuals (33.6±15.7 years) and 12 patients with IPF (66.0±6.4 years) underwent 129Xe MRI to generate three-dimensional quantitative maps depicting the 129Xe ventilation distribution, its uptake in interstitial barrier tissues and its transfer to RBCs. For each map, mean values were correlated with PFTs and CT fibrosis scores, and their patterns were tested for the ability to depict functional gravitational gradients in healthy lung and to detect the known basal and peripheral predominance of disease in IPF. RESULTS: 129Xe MRI depicted functional impairment in patients with IPF, whose mean barrier uptake increased by 188% compared with the healthy reference population. 129Xe MRI metrics correlated poorly and insignificantly with CT fibrosis scores but strongly with PFTs. Barrier uptake and RBC transfer both correlated significantly with diffusing capacity of the lungs for carbon monoxide (r=-0.75, p<0.01 and r=0.72, p<0.01), while their ratio (RBC/barrier) correlated most strongly (r=0.94, p<0.01). RBC transfer exhibited significant anterior-posterior gravitational gradients in healthy volunteers, but not in IPF, where it was significantly impaired in the basal (p=0.02) and subpleural (p<0.01) lung. CONCLUSIONS: Hyperpolarized129Xe MRI is a rapid and well-tolerated exam that provides region-specific quantification of interstitial barrier thickness and RBC transfer efficiency. With further development, it could become a robust tool for measuring disease progression and therapeutic response in patients with IPF, sensitively and non-invasively.

Quantitative analysis of hyperpolarized 129 Xe gas transfer MRI.

PURPOSE: Hyperpolarized 129 Xe magnetic resonance imaging (MRI) using Dixon-based decomposition enables single-breath imaging of 129 Xe in the airspaces, interstitial barrier tissues, and red blood cells (RBCs). However, methods to quantitatively visualize information from these images of pulmonary gas transfer are lacking. Here, we introduce a novel method to transform these data into quantitative maps of pulmonary ventilation, and 129 Xe gas transfer to barrier and RBC compartments. METHODS: A total of 13 healthy subjects and 12 idiopathic pulmonary fibrosis (IPF) subjects underwent thoracic 1 H MRI and hyperpolarized 129 Xe MRI with one-point Dixon decomposition to obtain images of 129 Xe in airspaces, barrier and red blood cells (RBCs). 129 Xe images were processed into quantitative binning maps of all three compartments using thresholds based on the mean and standard deviations of distributions derived from the healthy reference cohort. Binning maps were analyzed to derive quantitative measures of ventilation, barrier uptake, and RBC transfer. This method was also used to illustrate different ventilation and gas transfer patterns in a patient with emphysema and one with pulmonary arterial hypertension (PAH). RESULTS: In the healthy reference cohort, the mean normalized signals were 0.51 ± 0.19 for ventilation, 4.9 ± 1.5 x 10-3 for barrier uptake and 2.6 ± 1.0 × 10-3 for RBC (transfer). In IPF patients, ventilation was similarly homogenous to healthy subjects, although shifted toward slightly lower values (0.43 ± 0.19). However, mean barrier uptake in IPF patients was nearly 2× higher than in healthy subjects, with 47% of voxels classified as high, compared to 3% in healthy controls. Moreover, in IPF, RBC transfer was reduced, mainly in the basal lung with 41% of voxels classified as low. In healthy volunteers, only 15% of RBC transfer was classified as low and these voxels were typically in the anterior, gravitationally nondependent lung. CONCLUSIONS: This study demonstrates a straightforward means to generate semiquantitative binning maps depicting 129 Xe ventilation and gas transfer to barrier and RBC compartments. These initial results suggest that the method could be valuable for characterizing both normal physiology and pathophysiology associated with a wide range of pulmonary disorders.

Measuring diffusion limitation with a perfusion-limited gas--hyperpolarized 129Xe gas-transfer spectroscopy in patients with idiopathic pulmonary fibrosis.

Although xenon is classically taught to be a "perfusion-limited" gas, (129)Xe in its hyperpolarized (HP) form, when detected by magnetic resonance (MR), can probe diffusion limitation. Inhaled HP (129)Xe diffuses across the pulmonary blood-gas barrier, and, depending on its tissue environment, shifts its resonant frequency relative to the gas-phase reference (0 ppm) by 198 ppm in tissue/plasma barrier and 217 ppm in red blood cells (RBCs). In this work, we hypothesized that in patients with idiopathic pulmonary fibrosis (IPF), the ratio of (129)Xe spectroscopic signal in the RBCs vs. barrier would diminish as diffusion-limitation delayed replenishment of (129)Xe magnetization in RBCs. To test this hypothesis, (129)Xe spectra were acquired in 6 IPF subjects as well as 11 healthy volunteers to establish a normal range. The RBC:barrier ratio was 0.55 ± 0.13 in healthy volunteers but was 3.3-fold lower in IPF subjects (0.16 ± 0.03, P = 0.0002). This was caused by a 52% reduction in the RBC signal (P = 0.02) and a 58% increase in the barrier signal (P = 0.01). Furthermore, the RBC:barrier ratio strongly correlated with lung diffusing capacity for carbon monoxide (DLCO) (r = 0.89, P < 0.0001). It exhibited a moderate interscan variability (8.25%), and in healthy volunteers it decreased with greater lung inflation (r = -0.78, P = 0.005). This spectroscopic technique provides a noninvasive, global probe of diffusion limitation and gas-transfer impairment and forms the basis for developing 3D MR imaging of gas exchange.

Type 2 alveolar cells are stem cells in adult lung.

Gas exchange in the lung occurs within alveoli, air-filled sacs composed of type 2 and type 1 epithelial cells (AEC2s and AEC1s), capillaries, and various resident mesenchymal cells. Here, we use a combination of in vivo clonal lineage analysis, different injury/repair systems, and in vitro culture of purified cell populations to obtain new information about the contribution of AEC2s to alveolar maintenance and repair. Genetic lineage-tracing experiments showed that surfactant protein C-positive (SFTPC-positive) AEC2s self renew and differentiate over about a year, consistent with the population containing long-term alveolar stem cells. Moreover, if many AEC2s were specifically ablated, high-resolution imaging of intact lungs showed that individual survivors undergo rapid clonal expansion and daughter cell dispersal. Individual lineage-labeled AEC2s placed into 3D culture gave rise to self-renewing "alveolospheres," which contained both AEC2s and cells expressing multiple AEC1 markers, including HOPX, a new marker for AEC1s. Growth and differentiation of the alveolospheres occurred most readily when cocultured with primary PDGFRα⁺ lung stromal cells. This population included lipofibroblasts that normally reside close to AEC2s and may therefore contribute to a stem cell niche in the murine lung. Results suggest that a similar dynamic exists between AEC2s and mesenchymal cells in the human lung.

Building and maintaining the epithelium of the lung.

Airspaces of the lung are lined by an epithelium whose cellular composition changes along the proximal-to-distal axis to meet local functional needs for mucociliary clearance, hydration, host defense, and gas exchange. Advances in cell isolation, in vitro culture techniques, and genetic manipulation of animal models have increased our understanding of the development and maintenance of the pulmonary epithelium. This review discusses basic cellular mechanisms that regulate establishment of the conducting airway and gas exchange systems as well as the functional maintenance of the epithelium during postnatal life.

Airway epithelial progenitors are region specific and show differential responses to bleomycin-induced lung injury.

Mechanisms that regulate regional epithelial cell diversity and pathologic remodeling in airways are poorly understood. We hypothesized that regional differences in cell composition and injury-related tissue remodeling result from the type and composition of local progenitors. We used surface markers and the spatial expression pattern of an SFTPC-GFP transgene to subset epithelial progenitors by airway region. Green fluorescent protein (GFP) expression ranged from undetectable to high in a proximal-to-distal gradient. GFP(hi) cells were subdivided by CD24 staining into alveolar (CD24(neg)) and conducting airway (CD24(low)) populations. This allowed for the segregation of three types of progenitors displaying distinct clonal behavior in vitro. GFP(neg) and GFP(low) progenitors both yielded lumen containing colonies but displayed transcriptomes reflective of pseudostratified and distal conducting airways, respectively. CD24(low)GFP(hi) progenitors were present in an overlapping distribution with GFP(low) progenitors in distal airways, yet expressed lower levels of Sox2 and expanded in culture to yield undifferentiated self-renewing progeny. Colony-forming ability was reduced for each progenitor cell type after in vivo bleomycin exposure, but only CD24(low) GFP(hi) progenitors showed robust expansion during tissue remodeling. These data reveal intrinsic differences in the properties of regional progenitors and suggest that their unique responses to tissue damage drive local tissue remodeling.