Evidence-based opioid prescribing guidelines after lung resection: a prospective, multicenter analysis.

Background: Opioid prescribing guidelines have significantly decreased overprescribing and post-discharge use after cardiac surgery; however, limited recommendations exist for general thoracic surgery patients, a similarly high-risk population. We examined opioid prescribing and patient-reported use to develop evidence-based, opioid prescribing guidelines after lung cancer resection. Methods: This prospective, statewide, quality improvement study was conducted between January 2020 to March 2021 and included patients undergoing surgical resection of a primary lung cancer across 11 institutions. Patient-reported outcomes at 1-month follow-up were linked with clinical data and Society of Thoracic Surgery (STS) database records to characterize prescribing patterns and post-discharge use. The primary outcome was quantity of opioid used after discharge; secondary outcomes included quantity of opioid prescribed at discharge and patient-reported pain scores. Opioid quantities are reported in number of 5-mg oxycodone tablets (mean ± standard deviation). Results: Of the 602 patients identified, 429 met inclusion criteria. Questionnaire response rate was 65.0%. At discharge, 83.4% of patients were provided a prescription for opioids of mean size 20.5±13.1 pills, while patients reported using 8.2±13.0 pills after discharge (P<0.001), including 43.7% who used none. Those not taking opioids on the calendar day prior to discharge (32.4%) used fewer pills (4.4±8.1 vs. 11.7±14.9, P<0.001). Refill rate was 21.5% for patients provided a prescription at discharge, while 12.5% of patients not prescribed opioids at discharge required a new prescription before follow-up. Pain scores were 2.4±2.5 for incision site and 3.0±2.8 for overall pain (scale 0-10). Conclusions: Patient-reported post-discharge opioid use, surgical approach, and in-hospital opioid use before discharge should be used to inform prescribing recommendations after lung resection.

Implementation and Effectiveness of Opioid Prescribing Guidelines After Hiatal Hernia Repair.

INTRODUCTION: We defined institutional opioid prescribing patterns, established prescribing guidelines, and evaluated the adherence to and effectiveness of these guidelines in association with opioid prescribing after hiatal hernia repair (HHR). METHODS: A retrospective chart review was completed for patients who underwent transthoracic (open) or laparoscopic HHR between January and December 2016. Patient-reported opioid use after surgery was used to establish prescribing recommendations. Guideline efficacy was then evaluated among patients undergoing HHR after implementation (August 2018 to June 2019). Data are reported in oral morphine equivalents (OMEs). RESULTS: The initial cohort included n = 87 patients (35 open; 52 laparoscopic) with a 68% survey response rate. For open repair, median prescription size was 338 mg OME (interquartile range [IQR] 250-420) with patient-reported use of 215 mg OME (IQR 78-308) (P = 0.002). Similarly, median prescription size was 270 mg OME (IQR 200-319) with patient-reported use of 100 mg OME (IQR 4-239) (P < 0.001) for laparoscopic repair. Opioid prescribing guidelines were defined as the 66th percentile of patient-reported opioid use. Postguideline implementation cohort included n = 108 patients (36 open; 72 laparoscopic). Median prescription amount decreased by 54% for open and 43% laparoscopic repair, with no detectable change in the overall refill rate after guideline implementation. Patient education, opioid storage, and disposal practices were also characterized. CONCLUSIONS: Evidence-based opioid prescribing guidelines can be successfully implemented for open and laparoscopic HHR with a high rate of compliance and without an associated increase in opioid refills.

Explanted malignancies after lung transplantation: the University of Michigan experience.

The management of patients with an explanted malignancy after lung transplantation is not well understood. We reviewed our institutional experience and outcomes at a single academic medical centre between December 1997 and April 2021 for patients with malignancies of all histologic types identified on explant pathology. Primary lung cancers were reclassified using the 8th Edition TNM staging and the 2021 World Health Organization histologic classification of lung cancers. Of the 733 patients undergoing lung transplantation, 15 (2.05%) were found to have malignancy on the explanted lungs, including 6 (0.82%) primary lung cancers. Four patients were found to have early-stage lung cancers, while 2 patients had advanced-stage IV disease. Survival ranged from 0 to 109 months for the entire cohort with median 23.2 [49.9] months in those with primary lung cancers. There were 2 recurrences following explanted stage I (15 months) and stage IV (53 months) diseases. Other explant pathologies included carcinoid tumourlets in 6 patients, lymphoma in 2 and metastatic leiomyosarcoma in 1. In conclusion, explanted lung malignancies are an infrequent but significant finding on explant pathology. Further data are needed to better characterize and stratify this patient cohort.

Mechano-inflammatory sensitivity of ACE2: Implications for the regional distribution of SARS-CoV-2 injury in the lung.

The coronavirus disease (COVID-19) caused by SARS-CoV-2 can result in severe injury to the lung. Computed tomography images have revealed that the virus preferentially affects the base of the lung, which experiences larger tidal stretches than the apex. We hypothesize that the expression of both the angiotensin converting enzyme-2 (ACE2) receptor for SARS-CoV-2 and the transmembrane serine protease 2 (TMPRSS2) are sensitive to regional cell stretch in the lung. To test this hypothesis, we stretched precision cut lung slices (PCLS) for 12 h with one of the following protocols: 1) unstretched (US); 2) low-stretch (LS), 5% peak-to-peak area strain mimicking the lung base; or 3) high-stretch (HS), the same peak-to-peak area strain superimposed on 10% static area stretch mimicking the lung apex. PCLS were additionally stretched in cigarette smoke extract (CSE) to mimic an acute inflammatory exposure. The expression of ACE2 was higher whereas that of TMPRSS2 was lower in the control samples following LS than HS. CSE-induced inflammation substantially altered the expression of ACE2 with higher levels following HS than LS. These results suggest that ACE2 and TMPRSS2 expression in lung cells is mechanosensitive, which could have implications for the spatial distribution of COVID-19-mediated lung injury and the increased risk for more severe disease in active smokers and patients with COPD.

Breath Hold Facilitates Targeted Deposition of Aerosolized Droplets in a 3D Printed Bifurcating Airway Tree.

The lungs have long been considered a desired route for drug delivery but, there is still a lack of strategies to rationally target delivery sites especially in the presence of heterogeneous airway disease. Furthermore, no standardized system has been proposed to rapidly test different ventilation strategies and how they alter the overall and regional deposition pattern in the airways. In this study, a 3D printed symmetric bifurcating tree model mimicking part of the human airway tree was developed that can be used to quantify the regional deposition patterns of different delivery methodologies. The model is constructed in a novel way that allows for repeated measurements of regional deposition using reusable parts. During ventilation, nebulized ~3-micron-sized fluid droplets were delivered into the model. Regional delivery, quantified by precision weighing individual airways, was highly reproducible. A successful strategy to control regional deposition was achieved by combining an inspiratory wave form with a "breath hold" pause after each inspiration. Specifically, the second generation of the tree was successfully targeted, and deposition was increased by up to four times in generation 2 when compared to a ventilation without the breath hold (p < 0.0001). Breath hold was also demonstrated to facilitate deposition into blocked regions of the model, which mimic airway closure during an asthma that receive no flow during inhalation. Additionally, visualization experiments demonstrated that in the absence of fluid flow, the deposition of 3-micron water droplets is dominated by gravity, which, to our knowledge, has not been confirmed under standard laboratory conditions.

A High-Throughput System for Cyclic Stretching of Precision-Cut Lung Slices During Acute Cigarette Smoke Extract Exposure.

RATIONALE: Precision-cut lung slices (PCLSs) are a valuable tool in studying tissue responses to an acute exposure; however, cyclic stretching may be necessary to recapitulate physiologic, tidal breathing conditions. OBJECTIVES: To develop a multi-well stretcher and characterize the PCLS response following acute exposure to cigarette smoke extract (CSE). METHODS: A 12-well stretching device was designed, built, and calibrated. PCLS were obtained from male Sprague-Dawley rats (N = 10) and assigned to one of three groups: 0% (unstretched), 5% peak-to-peak amplitude (low-stretch), and 5% peak-to-peak amplitude superimposed on 10% static stretch (high-stretch). Lung slices were cyclically stretched for 12 h with or without CSE in the media. Levels of Interleukin-1ß (IL-1ß), matrix metalloproteinase (MMP)-1 and its tissue inhibitor (TIMP1), and membrane type-MMP (MT1-MMP) were assessed via western blot from tissue homogenate. RESULTS: The stretcher system produced nearly identical normal Lagrangian strains (E xx and E yy , p > 0.999) with negligible shear strain (E xy < 0.0005) and low intra-well variability 0.127 ± 0.073%. CSE dose response curve was well characterized by a four-parameter logistic model (R 2 = 0.893), yielding an IC50 value of 0.018 cig/mL. Cyclic stretching for 12 h did not decrease PCLS viability. Two-way ANOVA detected a significant interaction between CSE and stretch pattern for IL-1ß (p = 0.017), MMP-1, TIMP1, and MT1-MMP (p < 0.001). CONCLUSION: This platform is capable of high-throughput testing of an acute exposure under tightly-regulated, cyclic stretching conditions. We conclude that the acute mechano-inflammatory response to CSE exhibits complex, stretch-dependence in the PCLS.

CT Imaging-Based Low-Attenuation Super Clusters in Three Dimensions and the Progression of Emphysema.

BACKGROUND: Distributions of low-attenuation areas in two-dimensional (2-D) CT lung slices are used to quantify parenchymal destruction in patients with COPD. However, these segmental approaches are limited and may not reflect the true three-dimensional (3-D) tissue processes that drive emphysematous changes in the lung. The goal of this study was to instead evaluate distributions of 3-D low-attenuation volumes, which we hypothesized would follow a power law distribution and provide a more complete assessment of the mechanisms underlying disease progression. METHODS: CT scans and pulmonary function test results were acquired from an observational database for N = 12 patients with COPD and N = 12 control patients. The data set included baseline and two annual follow-up evaluations in patients with COPD. Three-dimensional representations of the lungs were reconstructed from 2-D axial CT slices, with low-attenuation volumes identified as contiguous voxels < -960 Hounsfield units. RESULTS: Low-attenuation sizes generally followed a power law distribution, with the exception of large, individual outliers termed "super clusters," which deviated from the expected distribution. Super cluster volume was correlated with disease severity (% total low attenuation, ρ = 0.950) and clinical measures of lung function including FEV1 (ρ = -0.849) and diffusing capacity of the lung for carbon monoxide Dlco (ρ = -0.874). To interpret these results, we developed a personalized computational model of super cluster emergence. Simulations indicated disease progression was more likely to occur near existing emphysematous regions, giving rise to a biomechanical, force-induced mechanism of super cluster growth. CONCLUSIONS: Low-attenuation super clusters are defining, quantitative features of parenchymal destruction that dominate disease progression, particularly in advanced COPD.

Topographic distribution of idiopathic pulmonary fibrosis: a hybrid physics- and agent-based model.

OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by excessive deposition of collagen and associated stiffening of lung tissue. While it is known that inflammation and dysfunction of fibroblasts are involved in disease development, it remains poorly understood how cells and their microenvironment interact to produce a characteristic subpleural pattern of high and low tissue density variations, called honeycombing, on CT images of patients with IPF. Since the pleura is stiffer than the parenchyma, we hypothesized that local stiffness of the underlying extracellular matrix can influence fibroblast activation and consequently the deposition of collagen, which in turn influences tissue stiffness in a positive feedback loop. APPROACH: We tested this hypothesis by developing a hybrid physics-based/agent-based computational model in which aberrant fibroblast activation is induced when cells migrate on stiff tissue. This activation then feeds back on itself via the altered mechanical environment that it creates by depositing collagen. MAIN RESULTS: The model produces power law distributions of both low- and high-attenuation area clusters and predicts the development of honeycombing only when mechanical rupture is allowed to take place in highly strained normal tissue surrounded by stiff fibrotic tissue. These predictions compare well with histologic data computed from CT images of patients with IPF. SIGNIFICANCE: We conclude that the clinical manifestation of subpleural honeycombing in IPF may result from fibroblasts entering into a positive feedback loop induced by the abnormally high tissue stiffness near the pleura.

Targeted Versus 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 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 .

A microfluidic chamber-based approach to map the shear moduli of vascular cells and other soft materials.

There is growing interest in quantifying vascular cell and tissue stiffness. Most measurement approaches, however, are incapable of assessing stiffness in the presence of physiological flows. We developed a microfluidic approach which allows measurement of shear modulus (G) during flow. The design included a chamber with glass windows allowing imaging with upright or inverted microscopes. Flow was controlled gravitationally to push culture media through the chamber. Fluorescent beads were conjugated to the sample surface and imaged before and during flow. Bead displacements were calculated from images and G was computed as the ratio of imposed shear stress to measured shear strain. Fluid-structure simulations showed that shear stress on the surface did not depend on sample stiffness. Our approach was verified by measuring the moduli of polyacrylamide gels of known stiffness. In human pulmonary microvascular endothelial cells, G was 20.4 ± 12 Pa and decreased by 20% and 22% with increasing shear stress and inhibition of non-muscle myosin II motors, respectively. The G showed a larger intra- than inter-cellular variability and it was mostly determined by the cytosol. Our shear modulus microscopy can thus map the spatial distribution of G of soft materials including gels, cells and tissues while allowing the visualization of microscopic structures such as the cytoskeleleton.

Predicting Structure-Function Relations and Survival following Surgical and Bronchoscopic Lung Volume Reduction Treatment of Emphysema.

Lung volume reduction surgery (LVRS) and bronchoscopic lung volume reduction (bLVR) are palliative treatments aimed at reducing hyperinflation in advanced emphysema. Previous work has evaluated functional improvements and survival advantage for these techniques, although their effects on the micromechanical environment in the lung have yet to be determined. Here, we introduce a computational model to simulate a force-based destruction of elastic networks representing emphysema progression, which we use to track the response to lung volume reduction via LVRS and bLVR. We find that (1) LVRS efficacy can be predicted based on pre-surgical network structure; (2) macroscopic functional improvements following bLVR are related to microscopic changes in mechanical force heterogeneity; and (3) both techniques improve aspects of survival and quality of life influenced by lung compliance, albeit while accelerating disease progression. Our model predictions yield unique insights into the microscopic origins underlying emphysema progression before and after lung volume reduction.

Comparison of pneumotachography and anemometery for flow measurement during mechanical ventilation with volatile anesthetics.

Volatile anesthetics alter the physical properties of inhaled gases, such as density and viscosity. We hypothesized that the use of these agents during mechanical ventilation would yield systematic biases in estimates of flow ([Formula: see text]) and tidal volume (V T) for two commonly used flowmeters: the pneumotachograph (PNT), which measures a differential pressure across a calibrated resistive element, and the hot-wire anemometer (HWA), which operates based on convective heat transfer from a current-carrying wire to a flowing gas. We measured [Formula: see text] during ventilation of a spring-loaded mechanical test lung, using both the PNT and HWA placed in series at the airway opening. Delivered V T was estimated from the numerically-integrated [Formula: see text]. Measurements were acquired under baseline conditions with room air, and during ventilation with increasing concentrations of isoflurane, sevoflurane, and desflurane. We also evaluated a simple compensation technique for HWA flow, which accounted for changes in gas mixture density. We found that discrepancies in estimated V T between the PNT and HWA occurred during ventilation with isoflurane (6.3 ± 3.0%), sevoflurane (10.0 ± 7.3%), and desflurane (25.8 ± 17.2%) compared to baseline conditions. The magnitude of these discrepancies increased with anesthetic concentration. A simple compensation factor based on density reduced observed differences between the flowmeters, regardless of the anesthetic or concentration. These data indicate that the choice and concentration of anesthetic agents are primary factors for differences in estimated V T between the PNT and HWA. Such discrepancies may be compensated by accounting for alterations in gas density.

Design of a Novel Equi-Biaxial Stretcher for Live Cellular and Subcellular Imaging.

Cells in the body experience various mechanical stimuli that are often essential to proper cell function. In order to study the effects of mechanical stretch on cell function, several devices have been built to deliver cyclic stretch to cells; however, they are generally not practical for live cell imaging. We introduce a novel device that allows for live cell imaging, using either an upright or inverted microscope, during the delivery of cyclic stretch, which can vary in amplitude and frequency. The device delivers equi-biaxial strain to cells seeded on an elastic membrane via indentation of the membrane. Membrane area strain was calibrated to indenter depth and the device showed repeatable and accurate delivery of strain at the scale of individual cells. At the whole cell level, changes in intracellular calcium were measured at different membrane area strains, and showed an amplitude-dependent response. At the subcellular level, the mitochondrial network was imaged at increasing membrane area strains to demonstrate that stretch can lead to mitochondrial fission in lung fibroblasts. The device is a useful tool for studying transient as well as long-term mechanotransduction as it allows for simultaneous stretching and imaging of live cells in the presence of various chemical stimuli.

Volatile Anesthetics and the Treatment of Severe Bronchospasm: A Concept of Targeted Delivery.

Status asthmaticus (SA) is a severe, refractory form of asthma that can result in rapid respiratory deterioration and death. Treatment of SA with inhaled anesthetics is a potentially life-saving therapy, but remarkably few data are available about its mechanism of action or optimal administration. In this paper, we will review the clinical use of inhaled anesthetics for treatment of SA, the potential mechanisms by which they dilate constricted airways, and the side effects associated with their administration. We will also introduce the concept of 'targeted' delivery of these agents to the conducting airways, a process which may maximize their therapeutic effects while minimizing associated systemic side effects. Such a delivery regimen has the potential to define a rapidly translatable treatment paradigm for this life-threatening disorder.

Progressive structural and biomechanical changes in elastin degraded aorta.

Aortic aneurysm is an important clinical condition characterized by common structural changes such as the degradation of elastin, loss of smooth muscle cells, and increased deposition of fibrillary collagen. With the goal of investigating the relationship between the mechanical behavior and the structural/biochemical composition of an artery, this study used a simple chemical degradation model of aneurysm and investigated the progressive changes in mechanical properties. Porcine thoracic aortas were digested in a mild solution of purified elastase (5 U/mL) for 6, 12, 24, 48, and 96 h. Initial size measurements show that disruption of the elastin structure leads to increased artery dilation in the absence of periodic loading. The mechanical properties of the digested arteries, measured with a biaxial tensile testing device, progress through four distinct stages termed (1) initial-softening, (2) elastomer-like, (3) extensible-but-stiff, and (4) collagen-scaffold-like. While stages 1, 3, and 4 are expected as a result of elastin degradation, the S-shaped stress versus strain behavior of the aorta resulting from enzyme digestion has not been reported previously. Our results suggest that gradual changes in the structure of elastin in the artery can lead to a progression through different mechanical properties and thus reveal the potential existence of an important transition stage that could contribute to artery dilation during aneurysm formation.