Lung Compliance Research Articles

SCARLET (Supplemental Citicoline Administration to Reduce Lung injury Efficacy Trial): study protocol for a single-site, double-blinded, placebo-controlled, and randomized Phase 1/2 trial of i.v. citicoline (CDP-choline) in hospitalized SARS CoV-2-infected patients with hypoxemic acute respiratory failure

BackgroundThe SARS CoV-2 pandemic has resulted in more than 1.1 million deaths in the USA alone. Therapeutic options for critically ill patients with COVID-19 are limited. Prior studies showed that post-infection treatment of influenza A virus-infected mice with the liponucleotide CDP-choline, which is an essential precursor for de novo phosphatidylcholine synthesis, improved gas exchange and reduced pulmonary inflammation without altering viral replication. In unpublished studies, we found that treatment of SARS CoV-2-infected K18-hACE2-transgenic mice with CDP-choline prevented development of hypoxemia. We hypothesize that administration of citicoline (the pharmaceutical form of CDP-choline) will be safe in hospitalized SARS CoV-2-infected patients with hypoxemic acute respiratory failure (HARF) and that we will obtain preliminary evidence of clinical benefit to support a larger Phase 3 trial using one or more citicoline doses.MethodsWe will conduct a single-site, double-blinded, placebo-controlled, and randomized Phase 1/2 dose-ranging and safety study of Somazina® citicoline solution for injection in consented adults of any sex, gender, age, or ethnicity hospitalized for SARS CoV-2-associated HARF. The trial is named “SCARLET” (Supplemental Citicoline Administration to Reduce Lung injury Efficacy Trial). We hypothesize that SCARLET will show that i.v. citicoline is safe at one or more of three doses (0.5, 2.5, or 5 mg/kg, every 12 h for 5 days) in hospitalized SARS CoV-2-infected patients with HARF (20 per dose) and provide preliminary evidence that i.v. citicoline improves pulmonary outcomes in this population. The primary efficacy outcome will be the SpO2:FiO2 ratio on study day 3. Exploratory outcomes include Sequential Organ Failure Assessment (SOFA) scores, dead space ventilation index, and lung compliance. Citicoline effects on a panel of COVID-relevant lung and blood biomarkers will also be determined.DiscussionCiticoline has many characteristics that would be advantageous to any candidate COVID-19 therapeutic, including safety, low-cost, favorable chemical characteristics, and potentially pathogen-agnostic efficacy. Successful demonstration that citicoline is beneficial in severely ill patients with SARS CoV-2-induced HARF could transform management of severely ill COVID patients.Trial registrationThe trial was registered at www.clinicaltrials.gov on 5/31/2023 (NCT05881135).Trial statusCurrently enrolling.

Bronchoalveolar Lavage and Oleic Acid Two-hit Model for Inducing Acute Respiratory Distress Syndrome in Swine Models.

Acute respiratory distress syndrome (ARDS) is a widespread and often fatal clinical syndrome marked by the acute onset of pulmonary edema and inflammatory-mediated disruptions in alveolar-capillary permeability resulting in impaired gas exchange and tissue oxygenation with subsequent acute respiratory failure that accounts for 10.4% of all intensive care unit admissions worldwide and boasts a mortality rate of 38.5%. The current treatment for ARDS remains largely supportive. This is largely because of the many challenges of achieving a stable and sustainable animal model that recreates the pathophysiology of ARDS experimentally in a controlled setting to allow research to elucidate potential treatments of ARDS moving forward. The bronchoalveolar lavage and oleic acid models are currently the 2 most frequently used experimental models in inducing ARDS in animal models. This study demonstrated that combining them into a "two-hit model" can produce sustained ARDS in swine models per the Horowitz index (PaO2/FiO2 ratio of ≤300 mmHg). Additionally, expected changes in pH, pCO2, lung compliance, cytokines, and tissue histopathology were observed and add to our confidence and reliability that the "two-hit model" produces symptomatic ARDS in a manner very similar to that observed in humans. In conclusion, we demonstrated a viable animal model of human ARDS that is maintained for a prolonged period, suitable for continuous monitoring of the progression, and evaluation of potential future treatments and procedures to reduce patient morbidity and mortality. To carry out this two-hit model, lung injury was induced through a combination of bronchoalveolar lavage and oleic acid administration and the disease process of ARDS is subsequently tracked through clinically relevant parameters such as respiratory mechanics, cytokine response, aretrial blood gas (ABG) changes, and observation of postmortem histopathologic changes. This promising new model has the capacity to successfully replicate human ARDS which is a well-known and notoriously multifactorial pathogenic process to reproduce experimentally for an extended period of time. The "two-hit model" is a viable and appropriate model for the research of novel treatments for ARDS.

Effect of dexmedetomidine on pulmonary function in obese patients undergoing laparoscopic surgery

ObjectiveThis research aimed to ascertain the effect of dexmedetomidine on pulmonary function in obese patients undergoing laparoscopic surgery.MethodsObese patients undergoing laparoscopic surgery under general anesthesia were separated into the control group (group C) and the dexmedetomidine group (group D) (n = 30). Patients in group D were infused with dexmedetomidine (1 μg/kg) intravenously for 10 min and then at a rate of 0.5 mg/kg h until 30 min before the end of the surgery, and those in group C were infused with an equal volume of saline. The surgery time points were divided into: before anesthesia induction (T0), 5 min after intubation (T1), 30 min after pneumoperitoneum (T2), 10 min after pneumoperitoneum release (T3), at the time of extubation (T4), 3 min after extubation (T5), and 24 h after surgery (T6). Arterial blood was collected for blood gas analysis to record arterial partial pressure of oxygen (PaO2) and arterial partial pressure of carbon dioxide (PaCO2). Dynamic lung compliance (Cdyn), oxygenation index (OI), alveolar-arterial oxygen partial pressure difference (A-aDO2), and respiratory index (RI) were calculated. The time of surgery, anesthesia, CO2 pneumoperitoneum, eye-opening, and time from the end of surgery to extubation were recorded. Plasma IL-8 and IL-10 levels were measured from T0 to T6.ResultsThe time of surgery, anesthesia, CO2 pneumoperitoneum, eye-opening, and time from the end of surgery to extubation in group D were not statistically significant when compared with those in group C. Versus at the T1 time point, A-aDO2 and RI were higher and Cdyn and OI were lower in both groups at T2 and T3 time points. Versus group C, group D had higher Cdyn and OI and lower A-aDO2 and RI at T2 and T3 time points. Versus at the T0 time point, at each time point from T1 to T6, IL-8 and IL-10 levels were higher in both groups. Versus group C, group D had lower IL-8 and higher IL-10 levels at each time point from T1 to T6.ConclusionIn obese patients undergoing laparoscopic surgery under general anesthesia, the use of dexmedetomidine can improve the lung compliance and OI of the patients, inhibit the inflammatory response of the lungs of the patients and thus have a certain protective effect on the lung function.

Truss topology optimization for additively manufactured components with respect to structural stiffness and active cooling

This paper focuses on the use of truss topology optimization in the setting, where we aim to design structures with good structural stiffness and heat dissipation properties. Our technique takes advantage of the truss formulation to incorporate a cooling circuit inside the truss, using identified bars as tubes. This approach is closely connected to additive manufacturing, as the inherent complexity of the resulting structures and the inner cooling circuit make conventional techniques impractical or outright impossible. The traveling salesman problem is used as the basis for the optimized cooling path computation by a modified ant colony optimization algorithm, complemented by Dijkstra’s algorithm for finding the shortest path in a graph. The found cooling channels are then taken as inputs to the problem of minimizing static structural compliance, formulated as a semidefinite program. The method is used to solve two example problems, one two-dimensional and a more complex three-dimensional problem.

Transient heat stress protects from severe endothelial damage and dysfunction during prolonged experimental ex-vivo lung perfusion.

The pulmonary endothelium is the primary target of lung ischemia-reperfusion injury leading to primary graft dysfunction after lung transplantation. We hypothesized that treating damaged rat lungs by a transient heat stress during ex-vivo lung perfusion (EVLP) to elicit a pulmonary heat shock response could protect the endothelium from severe reperfusion injury. Rat lungs damaged by 1h warm ischemia were reperfused on an EVLP platform for up to 6h at a constant temperature (T°) of 37°C (EVLP37°C group), or following a transient heat stress (HS) at 41.5°C from 1 to 1.5h of EVLP (EVLPHS group). A group of lungs exposed to 1h EVLP only (pre-heating conditions) was added as control (Baseline group). In a first protocol, we measured lung heat sock protein expression (HSP70, HSP27 and Hsc70) at selected time-points (n=5/group at each time). In a second protocol, we determined (n=5/group) lung weight gain (edema), pulmonary compliance, oxygenation capacity, pulmonary artery pressure (PAP) and vascular resistance (PVR), the expression of PECAM-1 (CD31) and phosphorylation status of Src-kinase and VE-cadherin in lung tissue, as well as the release in perfusate of cytokines (TNFα, IL-1β) and endothelial biomarkers (sPECAM, von Willebrand Factor -vWF-, sE-selectin and sICAM-1). Histological and immunofluorescent studies assessed perivascular edema and formation of 3-nitrotyrosine (a marker of peroxinitrite) in CD31 lung endothelium. HS induced an early (3h) and persisting expression of HSP70 and HSP27, without influencing Hsc70. Lungs from the EVLP37°C group developed massive edema, low compliance and oxygenation, elevated PAP and PVR, substantial release of TNFα, IL-1β, s-PECAM, vWF, E-selectin and s-ICAM, as well as significant Src-kinase activation, VE-cadherin phosphorylation, endothelial 3-NT formation and reduced CD31 expression. In marked contrast, all these alterations were either abrogated or significantly attenuated by HS treatment. The therapeutic application of a transient heat stress during EVLP of damaged rat lungs reduces endothelial permeability, attenuates pulmonary vasoconstriction, prevents src-kinase activation and VE-cadherin phosphorylation, while reducing endothelial peroxinitrite generation and the release of cytokines and endothelial biomarkers. Collectively, these data demonstrate that therapeutic heat stress may represent a promising strategy to protect the lung endothelium from severe reperfusion injury.

PEEP trial and effect on hemodynamic in cardiogenic shock

Abstract Funding Acknowledgements None. Introduction Congestion is a paramount pathophysiological driver in patients with cardiogenic shock. Almost half of patients admitted due to cardiogenic shock undertake mechanical ventilation although ventilatory parameter, and their potential hemodynamic effect on the hemodynamic and congestion profile are often neglected. Purpose We sought to evaluate the hemodynamic effect of positive end-expiratory pressure (PEEP) titration on patients admitted to intensive care unit for CS. Methods We perform PEEP titration trial on patients undertaking mechanical ventilation for respiratory failure related to CS. The trial consisted in 3 steps of PEEP increase from 5 to 15 cmH2O. For each step arterial saturation, right atrial -RAP- and systemic blood pressure along with heart rate and respiratory mechanics (tidal volume-TV-, dynamic lung compliance- CLdyn, driving- Δ- and plateau pressure- Ppl) were measured. All the measures were taken at end-expiration; RAP trace was analyzed and systolic, mean and diastolic component collected. The final PEEP was decided based on the best matching between saturation, CLdyn and TV. Descriptive and repeated measures with Bonferroni correction were applied as statistical analysis (IBM SPSS 29). Results Twelve patients were included (10 male, 66 ± 7 years old; 8 acute myocardial infarction and 4 acute heart failure). At baseline the mean RAP was 8.44 (± 2.32) ; SBP 106 (IQR 92-112), HR 94 (IQR 88 - 102) Δ and Ppl pressures respectively 7.42 (± 0.79) and 12.08 (± 0.79, ),VT 427(± 65.42) and CLdyn 58.3 (± 7.1). The right atrial pressure (RAP) differed between AMI and AHDF (8.25 ± 2.25 vs 20.25 ± 1.5; p < 0.001), so HR did (113 ± 3.4 versus 96 ± 3.2 betas per minutes; p 0.015). RAP varied consistently during the PEEP trial (either sRAP, dRAP and mRAP- Table and Figure 1). The TV changed signficnatly between the 1st and 3rd step (p 0.004) and the CLdyn varied consistently throughout the 3 steps of the PEEP trial (p <0.001). A significant difference were observed according to aetiology in RAP (AMI Vs ADHF, eman difference 2.4 versus 4.3 mmHg) and in CLdyn (AMI Vs ADHF mean difference 12.31 vs 8 .65, p < 0.01) but not in the other parameters evaluated (p > 0.05). Conclusion This is the first, small, study evaluating the effect of positive pressure ventilation in CS patients according to etiologies. As previously demonstrated PEEP influences the right side hemodynamic by increasing the RAP, although resulting in better CLdyn. The extent of the effect of PEEP increased may be dependent on the underlying aetiology of CS. Considering that the sample size is extremely limited, these results advocate a wider validation. However, the positive pressures induced by the ventilation in patient with CS should be taken in consideration when the comprehensive evaluation of hemodynamic to define congestion profile and phenotype are performed.Table 1.Hemodynamic parametersGraph PEEP vs RAP

Bioinspired Genetic-Algorithm Optimized Ground-Effect Wing Design: Flight Performance Benefits and Aircraft Stability Effects

This paper presents a bioinspired, genetic-algorithm evolutionary process for Ground-Effect vehicle wing design. The study made use of a rapid aerodynamic model generation and results evaluation computational fluid dynamics vortex lattice method software, supervised by a genetic algorithm optimization Python script. The design space for the aircraft wing parametric features drew inspiration from seabirds, under the assumption of their wings being naturally evolved and partially optimized for proximity flight over water surfaces. A case study was based on the A-90 Orlyonok Russian Ekranoplan, where alternative bioinspired wing variations were proposed. The study objective was to investigate the possible increased flight aircraft performance when using bioinspired wings, as well as verify the static and dynamic aircraft stability compliance for Ground-Effect flight. The methodology presented herein along with the study results, provided an incremental step towards advancing Ground-Effect aircraft conceptual designs using computational fluid dynamics.

Relationship of TAPSE Normalized by Right Ventricular Area With Pulmonary Compliance, Exercise Capacity, and Clinical Outcomes.

While tricuspid annular plane systolic excursion (TAPSE) captures the predominant longitudinal motion of the right ventricle (RV), it does not account for ventricular morphology and radial motion changes in various forms of pulmonary hypertension. This study aims to account for both longitudinal and radial motions by dividing TAPSE by RV area and to assess its clinical significance. We performed a retrospective analysis of 71 subjects with New York Heart Association class II to III dyspnea who underwent echocardiogram and invasive cardiopulmonary exercise testing (which defined 4 hemodynamic groups: control, isolated postcapillary pulmonary hypertension, combined postcapillary pulmonary hypertension, and pulmonary arterial hypertension). On the echocardiogram, TAPSE was divided by RV area in diastole (TAPSE/RVA-D) and systole (TAPSE/RVA-S). Analyses included correlations (Pearson and linear regression), receiver operating characteristic, and survival curves. On linear regression analysis, TAPSE/RVA metrics (versus TAPSE) had a stronger correlation with pulmonary artery compliance (r=0.48-0.54 versus 0.38) and peak VO2 percentage predicted (0.23-0.30 versus 0.18). Based on the receiver operating characteristic analysis, pulmonary artery compliance ≥3 mL/mm Hg was identified by TAPSE/RVA-D with an under the curve (AUC) of 0.79 (optimal cutoff ≥1.1) and by TAPSE/RVA-S with an AUC of 0.83 (optimal cutoff ≥1.5), but by TAPSE with only an AUC of 0.67. Similarly, to identify peak VO2 <50% predicted, AUC of 0.66 for TAPSE/RVA-D and AUC of 0.65 for TAPSE/RVA-S. Death or cardiovascular hospitalization at 12 months was associated with TAPSE/RVA-D ≥1.1 (HR, 0.38 [95% CI, 0.11-0.56]) and TAPSE/RVA-S ≥1.5 (HR, 0.44 [95% CI, 0.16-0.78]), while TAPSE was not associated with adverse outcomes (HR, 0.99 [95% CI, 0.53-1.94]). Among 31 subjects with available cardiac magnetic resonance imaging, RV ejection fraction was better correlated with novel metrics (TAPSE/RVA-D r=0.378 and TAPSE/RVA-S r=0.328) than TAPSE (r=0.082). In a broad cohort with suspected pulmonary hypertension, TAPSE divided by RV area was superior to TAPSE alone in correlations with pulmonary compliance and exercise capacity. As a prognostic marker of right heart function, TAPSE/RVA-D <1.1 and TAPSE/RVA-S <1.5 predicted adverse cardiovascular outcomes.

Allometric scaling of the parameters characterizing venous return surface in the generalized framework of circulatory equilibrium

Study objective: In the generalized framework of circulatory equilibrium (GCE), the integrated cardiac output (CO) curve characterizes the pumping abilities of the left and right hearts, whereas the venous return (VR) surface characterizes the preloading properties of the systemic and pulmonary circuits. Equilibrium CO (= VR), left (PLA) and right (PRA) atrial pressures are predicted from the intersection between the CO curve and VR surface. In VR surface, VR is theoretically related with stressed blood volume (V), PLA and PRA as: VR =V/W − Gs × PRA − Gp × PLA, where Gs and Gp is a ratio of systemic (Cs) and pulmonary (Cp) vascular compliance to W (time constant of the systemic and pulmonary circuits), respectively. However, there was a concern whether the standard parameters can be applicable to animals with different body size including human. The objective of this study is to experimentally investigate whether an allometric scaling of the parameters (Gs, Gp, W, Cs, Cp) of the VR surface is feasible. Hypothesis: Kleiber’s law indicates that an animal's metabolic rate scales to the 3⁄4 power of the animal's body weight (BW). Based on this, we hypothesize that Cs and Cp may be proportionate to BW, W may be proportionate to BW1/4. Hence, Gs and Gp may be proportionate to BW3/4. Methodology: Seven mongrel dogs (BW 26±2.8 kg) and 4 beagles (BW 9±0.5 kg) were anesthetized, and their left and right hearts were replaced by dual mechanical pumps. While V was kept constant, by controlling the speed of the fluid pumps, VR (ml/min), PLA and PRA (mmHg) were changed variably over a wide range to obtain six sets of VR, PLA and PRA. After the change of a known amount of V (4 mL/kg), six sets of VR, PLA and PRA were obtained in a similar manner. Using 12 sets of VR, PLA and PRA, we obtained Gs, Gp, W, Cs, and Cp using regression analysis in each animal. Finally, we analyzed relations between BW and all these parameters using regression analysis over the 11 animals. Data: Gs (r2=0.73, p value for independent variable piv&lt;0.01; p value for intercept, pi=0.57) and Gp (r2=0.81, piv&lt;0.01, pi=0.64) were proportionate to BW3/4. Cs (r2=0.37, piv=0.027, pi=0.40) and Cp (r2=0.61, piv&lt;0.01, pi=0.48) were proportionate to BW. However, W (r2=-0.11, piv=0.90, pi=0.17) was not associated with BW1/4. Summary of results: All parameters characterizing VR surface except for W were significantly associated with BW. W did not show a significant association with BW, potentially due to the low variations of BW. Conclusions: Allometric scaling of VR surface may be feasible and effective in future clinical application of GCE. NTT Research, Inc. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Vertical vibration of a rigid disc over a transversely isotropic and layered poroelastic half-space

A novel semi-analytical method is proposed for solving the vertical vibration of a rigid disc over a transversely isotropic and layered poroelastic half-space. The fundamental solutions in the layered poroelastic half-space under a vertical patch load on the surface are solved in terms of the newly developed Fourier-Bessel series (FBS) system of vector functions and the unconditionally stable dual-variable and position method. The expansion coefficients in FBS system are discrete, as such the computational efficiency is greatly improved and the accuracy is better than the commonly used integral-transform methods. By virtue of the superposition method, the Green’s function due to vertical ring load is derived in the transform domain. By making use of the integral least-square scheme, the densities of a series of ring loads discretized within the disc area are determined. Finally, the dynamic vertical compliance is derived via the balance between the external applied force and the induced total contact traction. After verifying the reliability of the developed solution, selected numerical examples are presented to investigate the influence of material properties and excitation frequency on the forced vibration of the rigid disc.

Essential Roles of Mitochondrial Reactive Oxygen Species Signaling in Airway Smooth Muscle from Mice following Nicotine, Pyoverdine, and their Co-exposure Authors: Subika Khatoon, Ed Wilson Santos, Yun-Min Zheng, Yong-Xiao Wang Corresponding Author: Yong-Xiao Wang, wangy@amc.edu

Consumption of nicotine, a major active component of cigarettes or e-cigarette smoke, is a global health problem, causing a myriad of life-threatening diseases. Pseudomonas aeruginosa is a common cause of lung infections and often exacerbate nicotine-associated lung diseases. However, the underlying cellular and molecular mechanisms remain poorly understood. In this study, we aim to address these important questions by performing a series of experiments. establish a clinical threshold of Pseudomonas Aeruginosa Infection in a COPD animal model and determine the underlying molecular mechanisms underlying the mitochondrial dysfunctions in Airway Smooth Muscle Cells (ASMCs). Utilizing in vitro and in vivo models, our data revealed that mice following inhalation of nicotine showed increased lung resistance, decreased lung compliance, and elevated airway resistance in vivo. In support, nicotine caused airway hyperresponsiveness in isolated mouse tracheal and bronchial smooth muscles. We also found that reactive oxygen species (ROS) production was largely increased in isolated mitochondria from mice after nicotine inhalation. Application of pyoverdine, a primary active component of Pseudomonas aeruginosa, produced a similar effect on ROS production in isolated mouse airway smooth muscle (ASM) mitochondria. Furthermore, mice co-exposed to nicotine inhalation and pyoverdine had a higher increase in ROS production in isolated ASM mitochondria compared with mice following nicotine or pyoverdine exposure alone. In conclusion, our findings for the first time demonstrate mitochondrial ROS signaling plays essential roles in airway dysfunctions following nicotine, pyoverdine, and their co-exposure and may also offer new strategies to treat lung diseases induced by nicotine inhalation and/or Pseudomonas aeruginosa. Funding: This work was supported by the NIH (R01HL122865, R03AG070784, and R01HL108232, to Yong-Xiao Wang). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sildenafil Versus Placebo for Early Pulmonary Vascular Disease in Scleroderma (SEPVADIS): protocol for a randomized controlled trial

BackgroundPulmonary hypertension (PH) is a leading cause of death in patients with systemic sclerosis (SSc). An important component of SSc patient management is early detection and treatment of PH. Recently the threshold for the diagnosis of PH has been lowered to a mean pulmonary artery pressure (mPAP) threshold of > 20 mmHg on right heart catheterization (RHC). However, it is unknown if PH-specific therapy is beneficial in SSc patients with mildly elevated pressure (SSc-MEP, mPAP 21–24 mmHg).MethodsThe SEPVADIS trial is a randomized, double-blind, placebo-controlled phase 2 trial of sildenafil in SSc-MEP patients with a target enrollment of 30 patients from two academic sites in the United States. The primary outcome is change in six-minute walk distance after 16 weeks of treatment. Secondary endpoints include change in pulmonary arterial compliance by RHC and right ventricular function by cardiac magnetic resonance imaging at 16 weeks. Echocardiography, serum N-terminal probrain natriuretic peptide, and health-related quality of life is being measured at 16 and 52 weeks.DiscussionThe SEPVADIS trial will be the first randomized study of sildenafil in SSc-MEP patients. The results of this trial will be used to inform a phase 3 study to investigate the efficacy of treating patients with mild elevations in mPAP.Trial registrationClinicalTrials.gov Identifier NCT04797286.

The Synthetic Surfactant CHF5633 Restores Lung Function and Lung Architecture in Severe Acute Respiratory Distress Syndrome in Adult Rabbits

PurposeAcute respiratory distress syndrome (ARDS) is a major cause of hypoxemic respiratory failure in adults. In ARDS extensive inflammation and leakage of fluid into the alveoli lead to dysregulation of pulmonary surfactant metabolism and function. Altered surfactant synthesis, secretion, and breakdown contribute to the clinical features of decreased lung compliance and alveolar collapse. Lung function in ARDS could potentially be restored with surfactant replacement therapy, and synthetic surfactants with modified peptide analogues may better withstand inactivation in ARDS alveoli than natural surfactants.MethodsThis study aimed to investigate the activity in vitro and the bolus effect (200 mg phospholipids/kg) of synthetic surfactant CHF5633 with analogues of SP‐B and SP‐C, or natural surfactant Poractant alfa (Curosurf®, both preparations Chiesi Farmaceutici S.p.A.) in a severe ARDS model (the ratio of partial pressure arterial oxygen and fraction of inspired oxygen, P/F ratio ≤ 13.3 kPa) induced by hydrochloric acid instillation followed by injurious ventilation in adult New Zealand rabbits. The animals were ventilated for 4 h after surfactant treatment and the respiratory parameters, histological appearance of lung parenchyma and levels of inflammation, oxidative stress, surfactant dysfunction, and endothelial damage were evaluated.ResultsBoth surfactant preparations yielded comparable improvements in lung function parameters, reductions in lung injury score, pro-inflammatory cytokines levels, and lung edema formation compared to untreated controls.ConclusionsThis study indicates that surfactant replacement therapy with CHF5633 improves lung function and lung architecture, and attenuates inflammation in severe ARDS in adult rabbits similarly to Poractant alfa. Clinical trials have so far not yielded conclusive results, but exogenous surfactant may be a valid supportive treatment for patients with ARDS given its anti-inflammatory and lung-protective effects.

Restoration of Pulmonary Compliance after Laparoscopic Gynecologic Surgery Using a Recruitment Maneuver.

This study aimed to investigate the hypothesis that an alveolar recruitment maneuver can restore lung compliance to initial values after laparoscopic gynecological surgery. A total of 31 patients who underwent laparoscopic gynecological surgery were enrolled. Protective mechanical ventilation was applied, and the radial artery was catheterized in all patients. An alveolar recruitment maneuver (incremental and decremental positive end-expiratory pressure) was applied ten minutes after the release of pneumoperitoneum. The respiratory mechanics and blood gas results were recorded at eight different time points: after induction of anesthesia (T1), in the lithotomy position (T2), in the Trendelenburg position (T3), 10 and 90 min after insufflation of carbon dioxide (T4 and T5), in the supine position (T6), after desufflation (T7), and 10 min after an alveolar recruitment maneuver at the end of surgery (T8). Pneumoperitoneum and the Trendelenburg position caused a decline of 15 units in compliance (T7 vs. T1; p < 0.05) compared to baseline. After the alveolar recruitment maneuver, compliance increased by 17.5% compared with the mean value of compliance at time T1 (T8 vs. T1; p < 0.05). The recruitment maneuver had favorable results in patients with low initial compliance (41.5 mL/cmH2O, IQR: 9.75 mL/cmH2O), high Body Mass Index 30.32 kg/m2 (IQR: 1.05 kg/m2), and high initial plateau airway pressure (16.5 cmH2O, IQR: 0.75 cmH2O). Lung compliance does not return to initial values after performing laparoscopic gynecological procedures. However, after the release of pneumoperitoneum, an alveolar recruitment maneuver is beneficial as it improves compliance and gas exchange.

The Effect of Recruitment Maneuver on Static Lung Compliance in Patients Undergoing General Anesthesia for Laparoscopic Cholecystectomy: A Single-Centre Prospective Clinical Intervention Study.

Background and Objectives: The aim of this study was to examine whether the use of an alveolar recruitment maneuver (RM) leads to a significant increase in static lung compliance (Cstat) and an improvement in gas exchange in patients undergoing laparoscopic cholecystectomy. Material and Methods: A clinical prospective intervention study was conducted. Patients were divided into two groups according to their body mass index (BMI): normal-weight (group I) and pre-obese and obese grade I (group II). Lung mechanics were monitored (Cstat, dynamic compliance-Cdin, peak pressure-Ppeak, plateau pressure-Pplat, driving pressure-DP) alongside gas exchange, and hemodynamic changes (heart rate-HR, mean arterial pressure-MAP) at six time points: T1 (induction of anesthesia), T2 (formation of pneumoperitoneum), T3 (RM with a PEEP of 5 cm H2O), T4 (RM with a PEEP of 7 cm H2O), T5 (desufflation), and T6 (RM at the end). The RM was performed by increasing the peak pressure by +5 cm of H2O at an equal inspiration-to-expiration ratio (I/E = 1:1) and applying a PEEP of 5 and 7 cm of H2O. Results: Out of 96 patients, 33 belonged to group I and 63 to group II. An increase in Cstat values occurred after all three RMs. At each time point, the Cstat value was measured higher in group I than in group II. A higher increase in Cstat was observed in group II after the second and third RM. Cstat values were higher at the end of the surgical procedure compared to values after the induction of anesthesia. The RM led to a significant increase in PaO2 in both groups without changes in HR or MAP. Conclusions: During laparoscopic cholecystectomy, the application of RM leads to a significant increase in Cstat and an improvement in gas exchange. The prevention of atelectasis during anesthesia should be initiated immediately after the induction of anesthesia, using protective mechanical ventilation and RM.

Prognostic role of haemodynamics at follow-up in patients with pulmonary arterial hypertension: a challenge to current European Society of Cardiology/European Respiratory Society risk tools.

Haemodynamic variables like right atrial pressure (RAP), cardiac index (CI), stroke volume index (SVI) and mixed venous oxygen saturation (S vO2 ) predict survival in patients with pulmonary arterial hypertension (PAH). However, there is the need to identify further prognostic haemodynamic parameters as well as to redefine their role in PAH risk stratification compared to current risk tools and non-invasive parameters. This cohort study includes treatment-naïve patients assessed at baseline and after first-line PAH therapy with clinical, functional, exercise, laboratory and haemodynamic evaluations. Using a stepwise multivariate Cox regression analysis, independent prognostic haemodynamic parameters were identified and stratified according to cut-offs already defined in the European Society of Cardiology (ESC)/European Respiratory Society (ERS) risk table or defined based on the highest Chi-squared of the log-rank test. Their discriminatory power was tested for all-cause death and a combined end-point of death, hospitalisation and need of treatment escalation. 794 patients with PAH were enrolled. At first follow-up, RAP and pulmonary artery elastance were independently associated with death. Because of high correlations between haemodynamic parameters, different multivariable analyses were done identifying six other variables (pulmonary arterial compliance, cardiac efficiency, pulmonary vascular resistance, S vO2 , CI and SVI). Haemodynamic parameters were of no added prognostic value compared to ESC/ERS risk tools for the all-cause death end-point but they showed additional value to non-invasive parameters for the combined end-point and, when taken alone, had a discriminatory capacity comparable to ESC/ERS risk tools. Haemodynamics' discriminative ability for clinical worsening is comparable to current ESC/ERS risk tools and is of added value to non-invasive parameters.

Contribution of electrical impedance tomography to personalize positive end-expiratory pressure under ECCO2R

Extracorporeal Carbon Dioxide Removal (ECCO2R) is used in acute respiratory distress syndrome (ARDS) patients to facilitate lung-protective ventilatory strategies. Electrical Impedance Tomography (EIT) allows individual, non-invasive, real-time, bedside, radiation-free imaging of the lungs, providing global and regional dynamic lung analyses. To provide new insights for future ECCO2R research in ARDS, we propose a potential application of EIT to personalize End-Expiratory Pressure (PEEP) following each reduction in tidal volume (VT), as demonstrated in an illustrative case. A 72-year-old male with COVID-19 was admitted to the ICU for moderate ARDS. Monitoring with EIT was started to determine the optimal PEEP value (PEEPEIT), defined as the intersection of the collapse and overdistention curves, after each reduction in VT during ECCO2R. The identified PEEPEIT values were notably low (< 10 cmH2O). The decrease in VT associated with PEEPEIT levels resulted in improved lung compliance, reduced driving pressure and a more uniform ventilation pattern. Despite current Randomized Controlled Trials showing that ultra-protective ventilation with ECCO2R does not improve survival, the applicability of universal ultra-protective ventilation settings for all patients remains a subject of debate. Inappropriately set PEEP levels can lead to alveolar collapse or overdistension, potentially negating the benefits of VT reduction. EIT facilitates real-time monitoring of derecruitment associated with VT reduction, guiding physicians in determining the optimal PEEP value after each decrease in tidal volume. This original description of using EIT under ECCO2R to adjust PEEP at a level compromising between recruitability and overdistention could be a crucial element for future research on ECCO2R.

Is EIT-guided positive end-expiratory pressure titration for optimizing PEEP in ARDS the white elephant in the room? A systematic review with meta-analysis and trial sequential analysis.

Electrical Impedance Tomography (EIT) is a novel real-time lung imaging technology for personalized ventilation adjustments, indicating promising results in animals and humans. The present study aimed to assess its clinical utility for improved ventilation and oxygenation compared to traditional protocols. Comprehensive electronic database screening was done until 30th November, 2023. Randomized controlled trials,controlled clinical trials, comparative cohort studies, and assessments of EIT-guided PEEP titration and conventional methods in adult ARDS patients regarding outcome, ventilatory parameters, and P/F ratio were included. Our search retrieved five controlled cohort studies and two RCTs with 515 patients and overall reduced risk of mortality [RR = 0.68; 95% CI: 0.49 to 0.95; I2 = 0%], better dynamic compliance [MD = 3.46; 95% CI: 1.59 to 5.34; I2 = 0%] with no significant difference in PaO2/FiO2 ratio [MD = 6.5; 95%CI -13.86 to 26.76; I2 = 74%]. The required information size except PaO2/FiO2 was achieved for a power of 95% based on the 50% reduction in risk of mortality, 10% improved compliance as the cumulative Z-score of the said outcomes crossed the alpha spending boundary and did not dip below the inner wedge of futility. EIT-guided individualized PEEP titration is a novel modality; further well-designed studies are needed to substantiate its utility.

Multi-scale concurrent topology optimization of cellular structures with multiple microstructures for minimizing dynamic response in the time domain

This paper proposes a concurrent topology optimization method for optimizing the structures that are periodically filled with multiple microstructures excited by dynamic response in the time domain. At the macroscale, different microstructures are considered as different materials. To generate the various distribution of different microstructures, a multi-material interpolation approach based on the Solid Isotropic Material with Penalization (SIMP) is integrated. At the microscale, the energy-based homogenization method (EBHM) is employed to determine the macroscopic effective properties of the microstructures. All macroscale elements with identical material are represented by a distinct microstructure. For the proportional damping model, the HHT-α is implemented as a time integration technique to obtain the dynamic response of multi-scale and assumed multi-material structures. The objective function of the topology optimization problem is to minimize the mean dynamic compliance. Combined differentiate-then-discretize method with the adjoint variable method, the sensitivity analysis applies the gradient-based Zhang-Paulino-Ramos Jr. (ZPR) algorithm or Method of Moving Asymptotes (MMA) to update the design variables under multiple constraints in the time and space-discretized system. The proposed approach is numerically performed through 2D and 3D examples to demonstrate its effectiveness.

Positive Vasoreactivity Testing in Pulmonary Arterial Hypertension: Therapeutic Consequences, Treatment Patterns, and Outcomes in the Modern Management Era.

Among patients with pulmonary arterial hypertension (PAH), acute vasoreactivity testing during right heart catheterization may identify acute vasoresponders, for whom treatment with high-dose calcium channel blockers (CCBs) is recommended. However, long-term outcomes in the current era remain largely unknown. We sought to evaluate the implications of acute vasoreactivity response for long-term response to CCBs and other outcomes. Patients diagnosed with PAH between January 1999 and December 2018 at 15 pulmonary hypertension centers were included and analyzed retrospectively. In accordance with current guidelines, acute vasoreactivity response was defined by a decrease of mean pulmonary artery pressure by ≥10 mm Hg to reach <40 mm Hg, without a decrease in cardiac output. Long-term response to CCBs was defined as alive with unchanged initial CCB therapy with or without other initial PAH therapy and World Health Organization functional class I/II and/or low European Society of Cardiology/European Respiratory Society risk status at 12 months after initiation of CCBs. Patients were followed for up to 5 years; clinical measures, outcome, and subsequent treatment patterns were captured. Of 3702 patients undergoing right heart catheterization for PAH diagnosis, 2051 had idiopathic, heritable, or drug-induced PAH, of whom 1904 (92.8%) underwent acute vasoreactivity testing. A total of 162 patients fulfilled acute vasoreactivity response criteria and received an initial CCB alone (n=123) or in combination with another PAH therapy (n=39). The median follow-up time was 60.0 months (interquartile range, 30.8-60.0), during which overall survival was 86.7%. At 12 months, 53.2% remained on CCB monotherapy, 14.7% on initial CCB plus another initial PAH therapy, and the remaining patients had the CCB withdrawn and/or PAH therapy added. CCB long-term response was found in 54.3% of patients. Five-year survival was 98.5% in long-term responders versus 73.0% in nonresponders. In addition to established vasodilator responder criteria, pulmonary artery compliance at acute vasoreactivity testing, low risk status and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels at early follow-up correlated with long-term response and predicted survival. Our data display heterogeneity within the group of vasoresponders, with a large subset failing to show a sustained satisfactory clinical response to CCBs. This highlights the necessity for comprehensive reassessment during early follow-up. The use of pulmonary artery compliance in addition to current measures may better identify those likely to have a good long-term response.