Jacob Herrmann

Multifrequency Oscillatory Ventilation in the Premature Lung: Effects on Gas Exchange, Mechanics, and Ventilation Distribution.

Background:Despite the theoretical benefits of high-frequency oscillatory ventilation (HFOV) in preterm infants, systematic reviews of randomized clinical trials do not confirm improved outcomes. The authors hypothesized that oscillating a premature lung with multiple frequencies simultaneously would improve gas exchange compared with traditional single-frequency oscillatory ventilation (SFOV). The goal of this study was to develop a novel method for HFOV, termed “multifrequency oscillatory ventilation” (MFOV), which relies on a broadband flow waveform more suitable for the heterogeneous mechanics of the immature lung. Methods:Thirteen intubated preterm lambs were randomly assigned to either SFOV or MFOV for 1 h, followed by crossover to the alternative regimen for 1 h. The SFOV waveform consisted of a pure sinusoidal flow at 5 Hz, whereas the customized MFOV waveform consisted of a 5-Hz fundamental with additional energy at 10 and 15 Hz. Per standardized protocol, mean pressure at airway opening () and inspired oxygen fraction were adjusted as needed, and root mean square of the delivered oscillatory volume waveform (Vrms) was adjusted at 15-min intervals. A ventilatory cost function for SFOV and MFOV was defined as , where Wt denotes body weight. Results:Averaged over all time points, MFOV resulted in significantly lower VC (246.9 ± 6.0 vs. 363.5 ± 15.9 ml2 mmHg kg−1) and (12.8 ± 0.3 vs. 14.1 ± 0.5 cm H2O) compared with SFOV, suggesting more efficient gas exchange and enhanced lung recruitment at lower mean airway pressures. Conclusion:Oscillation with simultaneous multiple frequencies may be a more efficient ventilator modality in premature lungs compared with traditional single-frequency HFOV.

Regional gas transport in the heterogeneous lung during oscillatory ventilation

Regional ventilation in the injured lung is heterogeneous and frequency dependent, making it difficult to predict how an oscillatory flow waveform at a specified frequency will be distributed throughout the periphery. To predict the impact of mechanical heterogeneity on regional ventilation distribution and gas transport, we developed a computational model of distributed gas flow and CO2 elimination during oscillatory ventilation from 0.1 to 30 Hz. The model consists of a three-dimensional airway network of a canine lung, with heterogeneous parenchymal tissues to mimic effects of gravity and injury. Model CO2 elimination during single frequency oscillation was validated against previously published experimental data (Venegas JG, Hales CA, Strieder DJ, J Appl Physiol 60: 1025-1030, 1986). Simulations of gas transport demonstrated a critical transition in flow distribution at the resonant frequency, where the reactive components of mechanical impedance due to airway inertia and parenchymal elastance were equal. For frequencies above resonance, the distribution of ventilation became spatially clustered and frequency dependent. These results highlight the importance of oscillatory frequency in managing the regional distribution of ventilation and gas exchange in the heterogeneous lung.

Respiratory System Mechanics During Low Versus High Positive End-Expiratory Pressure in Open Abdominal Surgery: A Substudy of PROVHILO Randomized Controlled Trial.

BACKGROUND: In the 2014 PROtective Ventilation using HIgh versus LOw positive end-expiratory pressure (PROVHILO) trial, intraoperative low tidal volume ventilation with high positive end-expiratory pressure (PEEP = 12 cm H2O) and lung recruitment maneuvers did not decrease postoperative pulmonary complications when compared to low PEEP (0–2 cm H2O) approach without recruitment breaths. However, effects of intraoperative PEEP on lung compliance remain poorly understood. We hypothesized that higher PEEP leads to a dominance of intratidal overdistension, whereas lower PEEP results in intratidal recruitment/derecruitment (R/D). To test our hypothesis, we used the volume-dependent elastance index %E2, a respiratory parameter that allows for noninvasive and radiation-free assessment of dominant overdistension and intratidal R/D. We compared the incidence of intratidal R/D, linear expansion, and overdistension by means of %E2 in a subset of the PROVHILO cohort. METHODS: In 36 patients from 2 participating centers of the PROVHILO trial, we calculated respiratory system elastance (E), resistance (R), and %E2, a surrogate parameter for intratidal overdistension (%E2 > 30%) and R/D (%E2 < 0%). To test the main hypothesis, we compared the incidence of intratidal overdistension (primary end point) and R/D in higher and lower PEEP groups, as measured by %E2. RESULTS: E was increased in the lower compared to higher PEEP group (18.6 [16…22] vs 13.4 [11.0…17.0] cm H2O·L−1; P < .01). %E2 was reduced in the lower PEEP group compared to higher PEEP (−15.4 [−28.0…6.5] vs 6.2 [−0.8…14.0] %; P < .05). Intratidal R/D was increased in the lower PEEP group (61% vs 22%; P = .037). The incidence of intratidal overdistension did not differ significantly between groups (6%). CONCLUSIONS: During mechanical ventilation with protective tidal volumes in patients undergoing open abdominal surgery, lung recruitment followed by PEEP of 12 cm H2O decreased the incidence of intratidal R/D and did not worsen overdistension, when compared to PEEP ⩽2 cm H2O.

Frequency-Selective Computed Tomography: Applications During Periodic Thoracic Motion

We seek to use computed tomography (CT) to characterize regional lung parenchymal deformation during high-frequency and multi-frequency oscillatory ventilation. Periodic motion of thoracic structures results in artifacts of CT images obtained by standard reconstruction algorithms, especially for frequencies exceeding that of the X-ray source rotation. In this paper, we propose an acquisition and reconstruction technique for high-resolution imaging of the thorax during periodic motion. Our technique relies on phase-binning projections according to the frequency of subject motion relative to the scanner rotation, prior to volumetric reconstruction. The mathematical theory and limitations of the proposed technique are presented, and then validated in a simulated phantom as well as a living porcine subject during oscillatory ventilation. The 4-D image sequences obtained using this frequency-selective reconstruction technique yielded high-spatio-temporal resolution of the thorax during periodic motion. We conclude that the frequency-based selection of CT projections is ideal for characterizing dynamic deformations of thoracic structures that are ordinarily obscured by motion artifact using conventional reconstruction techniques.

Transfer Learning for Segmentation of Injured Lungs Using Coarse-to-Fine Convolutional Neural Networks.

Deep learning using convolutional neural networks (ConvNets) achieves high accuracy across many computer vision tasks, with the ability to learn multi-scale features and generalize across a variety of input data. In this work, we propose a deep learning framework that utilizes a coarse-to-fine cascade of 3D ConvNet models for segmentation of lung structures obtained from computed tomographic (CT) images. Deep learning requires a large number of training datasets, which may be challenging in medical imaging, especially for rare diseases. In the present study, transfer learning is utilized for lung segmentation of CT scans in large animal models of the acute respiratory distress syndrome (ARDS) using only 13 subjects. The method was quantitatively evaluated on a human dataset, consisting of 395 3D CT scans from 153 subjects, and an animal dataset consisting of 148 3D CT images from 5 porcine subjects. The human dataset achieved an average Jacaard index of 0.99, and an average symmetric surface distance (ASSD) of 0.29 mm. The animal dataset had an average Jacaard index of 0.94, and an ASSD of 0.99 mm.

Targeted vs. Continuous Delivery of Volatile Anesthetics During Cholinergic Bronchoconstriction

Volatile anesthetics have been shown to reduce lung resistance through dilation of constricted airways. In this study, we hypothesized that diffusion of inhaled anesthetics from airway lumen to smooth muscle would yield significant bronchodilation in vivo, and systemic recirculation would not be necessary to reduce lung resistance (RL) and elastance (EL) during sustained bronchoconstriction. To test this hypothesis, we designed a delivery system for precise timing of inhaled volatile anesthetics during the course of a positive pressure breath. We compared changes in RL, EL, and anatomic dead space (VD) in canines (N = 5) during pharmacologically induced bronchoconstriction with intravenous methacholine, and following treatments with: (1) targeted anesthetic delivery to VD and (2) continuous anesthetic delivery throughout inspiration. Both sevoflurane and isoflurane were used during each delivery regimen. Compared to continuous delivery, targeted delivery resulted in significantly lower doses of delivered anesthetic and decreased end-expiratory concentrations. However, we did not detect significant reductions in RL or EL for either anesthetic delivery regimen. This lack of response may have resulted from an insufficient dose of the anesthetic to cause bronchodilation, or from the preferential distribution of air flow with inhaled anesthetic delivery to less constricted, unobstructed regions of the lung, thereby enhancing airway heterogeneity and increasing apparent RL and EL.

Parenchymal strain heterogeneity during oscillatory ventilation: why two frequencies are better than one

High-frequency oscillatory ventilation (HFOV) relies on low tidal volumes cycled at supraphysiological rates, producing fundamentally different mechanisms for gas transport and exchange compared with conventional mechanical ventilation. Despite the appeal of using low tidal volumes to mitigate the risks of ventilator-induced lung injury, HFOV has not improved mortality for most clinical indications. This may be due to nonuniform and frequency-dependent distribution of flow throughout the lung. The goal of this study was to compare parenchymal strain heterogeneity during eucapnic HFOV when using oscillatory waveforms that consisted of either a single discrete frequency or two simultaneous frequencies. We utilized a three-dimensional, anatomically structured canine lung model for simulating frequency-dependent ventilation distribution. Gas transport was simulated via direct alveolar ventilation, advective mixing at bifurcations, turbulent and oscillatory dispersion, and molecular diffusion. Volume amplitudes at each oscillatory frequency were iteratively optimized to attain eucapnia. Ventilation using single-frequency HFOV demonstrated increasing heterogeneity of acinar flow and CO2 elimination with frequency for frequencies greater than the resonant frequency. For certain pairs of frequencies, a linear combination of the two corresponding ventilation distributions yielded reduced acinar strain heterogeneity compared with either frequency alone. Our model demonstrates that superposition of two simultaneous oscillatory frequencies can achieve more uniform ventilation distribution, and therefore lessen the potential for ventilator-induced lung injury, compared with traditional single-frequency HFOV. NEW & NOTEWORTHY In this study, we simulated oscillatory ventilation with multiple simultaneous frequencies using a computational lung model that includes distributed flow and gas transport. A mechanism of benefit was identified by which ventilation with two simultaneous frequencies results in reduced acinar strain heterogeneity compared with either frequency alone. This finding suggests the possibility of tuning the spectral content of ventilator waveforms according to patient-specific mechanical heterogeneity.

Extracellular Matrix Presentation Modulates Vascular Smooth Muscle Cell Mechanotransduction

The development of atherosclerotic lesions involves phenotypic changes among resident vascular smooth muscle cells (VSMCs) that often contribute to inflammation at the site of injury and are correlated with stiffening of the vessel wall. Studies have shown that there are major alterations in extracellular matrix (ECM) composition and mechanical properties during atherosclerosis that likely contribute to VSMC pathology, yet precisely how such changes lead to regulation of VSMC behavior remains poorly understood. In this study, we used substrates with tunable mechanics to investigate the combined influence of ECM stiffness and composition on VSMC adhesion, spreading, proliferation, and traction force generation. To model the stiffening ECM, we synthesized 25kPa and 135kPa polyacrylamide substrates functionalized with equal mass quantities of fibronectin, laminin, type I collagen, or a combination of fibronectin and laminin. On fibronectin and collagen substrates, we observed that increasing stiffness stimulates VSMC adhesion, spreading, and proliferation, whereas on laminin substrates, the effect is reversed, with 135kPa substrates supporting 35% less attachment (p<0.05), 25% smaller cell area (p<0.05), and 10% less proliferation than 25kPa substrates. We also examined attachment on gels containing varying ratios of fibronectin and laminin, and found that cell number on 135kPa versus 25kPa substrates was a direct function of the proportion of each ligand, i.e., gels with more fibronectin supported higher attachment at 135kPa, while gels with more laminin supported higher attachment at 25kPa. We then quantified single cell traction forces on 10kPa substrates containing fibronectin or laminin and found that total force per area on laminin was 55% less than on fibronectin (p<0.05). Collectively, our results demonstrate that VSMC response to substrate stiffness is critically dependent on ligand biochemistry, and have broad implications for the study of VSMC physiology and mechanotransduction in other cell types.