Changes In Pulmonary Mechanics Research Articles

Changes in pulmonary mechanics from supine to prone position measured through esophageal manometry in critically ill patients with COVID-19 severe acute respiratory distress syndrome

ObjectiveTo describe changes in pulmonary mechanics when changing from supine position (SP) to prone position (PP) in mechanically ventilated (MV) patients with Acute Respiratory Distress Syndrome (ARDS) due to severe COVID-19. DesignRetrospective cohort. SettingIntensive Care Unit of the National Institute of Respiratory Diseases (Mexico City). PatientsCOVID-19 patients on MV due to ARDS, with criteria for PP. InterventionMeasurement of pulmonary mechanics in patients on SP to PP, using esophageal manometry. Main variables of interestChanges in lung and thoracic wall mechanics in SP and PP ResultsNineteen patients were included. Changes during first prone positioning were reported. Reductions in lung stress (10.6 vs 7.7, p=0.02), lung strain (0.74 vs 0.57, p=0.02), lung elastance (p=0.01), chest wall elastance (p=0.003) and relation of respiratory system elastances (p=0.001) were observed between patients when changing from SP to PP. No differences were observed in driving pressure (p=0.19) and transpulmonary pressure during inspiration (p=0.70). ConclusionsChanges in pulmonary mechanics were observed when patients were comparing values of supine position with measurements obtained 24h after prone positioning. Esophageal pressure monitoring may facilitate ventilator management despite patient positioning.

508 Retrospective Review of Early Pulmonary Mechanics After Inhalation Injury

Abstract Introduction Management of inhalation injury is largely supportive and consists primarily of mechanical ventilation, bronchodilators, muscarinic receptor antagonists, and inhaled mucolytics and anticoagulants. The purpose of this study is to examine the early changes in pulmonary mechanics after inhalation injury and see if the use of NT affects lung function. Methods Retrospective study was done on Inhalation injury patients over a 12 years period from 01/2009 to 01/2021. Patients’ data collected from their medical records, included patient demographics and outcomes, percentage Total Body Surface Area (TBSA), Carboxyhemoglobin level upon admission, Respiratory Treatments (bronchodilator, Mucolytic and Heparin), Tobramycin treatment, Oxygen requirement, Lung compliance (peak airway pressure & Mean airway Pressure), Mode of Ventilation, total Ventilator Day, and number of Hospital Days. Patients with inhalation injury from 2009-2019 were retrospectively reviewed for treatment of inhalation injury. Univariate analysis and multiple logistic regression were performed using Excel and Stata. Results Of 90 patients with inhalation injury, median age was 53.5 (IQR:31-65) with 30% (n=28) women and median TBSA of 15%(IQR:2-38%). The median length of stay was 21 days (IQR:6-47). Median ventilator days was (8.5, IQR:3-21) and median ICU days was 12 (IQR:3-28). After adjusting for grade of inhalation injury, patients who did not receive NT were 2.7 times as likely to get pneumonia compared to patients who received NT (p=0.037). Initial median carboxyhemoglobin was 3.9 (IQR: 2-9.1). Overall mortality was 21%, but the incidence of death increased with grade of injury The Median Mean Airway Pressures were Day 1: 9.5mmHg, Day 2: 11mmHg, Day 3: 13mmHg, Day 4: 12mmHg The median peak pressures were Day 1; 20mmHg, Day 2: 21mmHg; Day 3: 22.5mmHg; Day 4: 21mmHg Conclusions Patients with inhalation injury are susceptible to Acute Respiratory Distress Syndrome, indicated by a decrease in lung compliance and increase in the patient’s oxygenation support. The lung compliance of these patients being to change resulting in an increase in their Peak Airway Pressure and Mean Airway Pressure within the first 72 hours. Moderate hypoxemia is present in these patients with the progress of the smoke inhalation injury. The usage of NT did not have a direct benefit to the pulmonary mechanics for inhalation injury when used as a prophylactic strategy. Additional research and clinical trials are needed to better understand the effect of inhalation injury on pulmonary mechanics. Applicability of Research to Practice Analysis of pulmonary mechanics in patients with inhalation injury can allow clinicians to better tailor ventilator settings to improve clinical outcomes.

Essentials of ventilator graphics

Respiratory function monitoring involves the integration of information such as airway pressures, flow and volume to evaluate changes in pulmonary mechanics. Ventilator graphics are an essential and valuable tool in the care of mechanically ventilated patients. Clinicians responsible for both setting up the ventilators and managing the patients should have a thorough understanding of the different waveforms to be able to recognise mechanical and/or clinical abnormalities. The scalar graphics allow the assessment of each variable (pressure, flow and volume) over time. Despite the ability to customise graphics on modern ventilators, scalars are typically displayed together in the same screen. There are an innumerable number of changes that can be detected in the scalars that may facilitate the management of the mechanical ventilator, and thus optimise the care of the ventilated patient. The loops provide a two-dimensional view of two variables plotted against each other. Understanding how the patient and the ventilator interact must be considered a critical component of the overall assessment of patients undergoing any type of mechanical ventilation since detection and management of asynchrony impacts important clinical outcomes in the ICU.

Local envenomation caused by a bioactive peptide fraction of Bothrops jararaca snake venom induces leukocyte influx in the lung and changes in pulmonary mechanics

The crude venom of the Bothrops jararaca snake (Bj-CV) is a complex mixture of biologically active proteins that includes a variety of peptides in the low molecular weight fraction (Bj-PF). We investigated how an intramuscular injection of Bj-CV (1.2 mg kg−1) and Bj-PF (0.24 mg kg−1) influenced lung mechanics and lung and muscle inflammation in male Swiss mice 15 min, 1, 6, and 24 h after inoculation. Pressure dissipation against lung resistive components (ΔP1) rose significantly from 1 to 24 h after Bj-CV and 6–24 h after Bj-PF inoculation. Both Bj-CV and Bj-PF increased the total pressure variation of the lung (ΔPtot) 24 h after injection. Lung static elastance increased significantly after injection in all time periods investigated by Bj-CV and from 6 to 24 h by Bj-PF. Lung static elastance increased significantly after injection in all time periods investigated by Bj-CV and from 6 to 24 h by Bj-PF. Furthermore, intramuscular inoculation of Bj-CV and Bj-PF resulted in an increase in muscle and pulmonary inflammation, as evidenced by an increase in leukocyte influx when compared to the control group. Finally, both Bj-CV and Bj-PF cause acute lung injury, as shown by pulmonary inflammation and decreased lung mechanics. Furthermore, the fact that Bj-PF produces mechanical alterations in the lungs and muscular inflammation implies that non-enzymatic compounds can cause inflammation.

Impacto da obesidade Grau I na mecânica respiratória durante cirurgia videolaparoscópica: estudo longitudinal prospectivo

Introduction and objectivesThe association pneumoperitoneum and obesity in video laparoscopy can contribute to pulmonary complications, but has not been well defined in specific groups of obese individuals. We assessed the effects of pneumoperitoneum in respiratory mechanics in Grade I obese compared to non‐obese. MethodsProspective study including 20 patients submitted to video laparoscopic cholecystectomy, normal spirometry, divided into non‐obese (BMI ≤ 25kg.m–2) and obese (BMI > 30kg.mg–2), excluding Grade II and III obese. We measured pulmonary ventilation mechanics data before pneumoperitoneum (baseline), and five, fifteen and thirty minutes after peritoneal insufflation, and fifteen minutes after disinflation (final). ResultsMean BMI of non‐obese was 22.72 ± 1.43kg.m–2 and of the obese 31.78 ± 1.09kg.m–2, p < 0.01. Duration of anesthesia and of peritoneal insufflation was similar between groups. Baseline pulmonary compliance (Crs) of the obese (38.3 ± 8.3mL.cm H2O–1) was lower than of the non‐obese (47.4 ± 5.7mL.cm H2O–1), p = 0.01. After insufflation, Crs decreased in both groups and remained even lower in the obese at all moments assessed (GLM p < 0.01). Respiratory system peak pressure and plateau pressure were higher in the obese, albeit variations were similar at moments analyzed (GLM p > 0.05). The same occurred with elastic pressure, higher in the obese at all times (GLM p = 0.04), and resistive pressure showed differences in variations between groups during pneumoperitoneum (GLM p = 0,05). ConclusionsGrade I obese presented more changes in pulmonary mechanics than the non‐obese during video laparoscopies and the fact requires mechanical ventilation‐related care.

Impact of Grade I obesity on respiratory mechanics during video laparoscopic surgery

Introduction and objectivesThe association pneumoperitoneum and obesity in video laparoscopy can contribute to pulmonary complications, but has not been well defined in specific groups of obese individuals. We assessed the effects of pneumoperitoneum in respiratory mechanics in Grade I obese compared to non-obese. MethodsProspective study including 20 patients submitted to video laparoscopic cholecystectomy, normal spirometry, divided into non-obese (BMI ≤ 25 kg.m-2) and obese (BMI > 30 kg.mg-2), excluding Grade II and III obese. We measured pulmonary ventilation mechanics data before pneumoperitoneum (baseline), and five, fifteen and thirty minutes after peritoneal insufflation, and fifteen minutes after disinflation (final). Results: Mean BMI of non-obese was 22.72 ± 1.43 kg.m-2 and of the obese 31.78 ± 1.09 kg.m-2, p < 0.01. Duration of anesthesia and of peritoneal insufflation was similar between groups. Baseline pulmonary compliance (Crs) of the obese (38.3 ± 8.3 mL.cm H2O-1) was lower than of the non-obese (47.4 ± 5.7 mL.cm H2O-1), p = 0.01. After insufflation, Crs decreased in both groups and remained even lower in the obese at all moments assessed (GLM p < 0.01). Respiratory system peak pressure and plateau pressure were higher in the obese, albeit variations were similar at moments analyzed (GLM p > 0.05). The same occurred with elastic pressure, higher in the obese at all times (GLM p = 0.04), and resistive pressure showed differences in variations between groups during pneumoperitoneum (GLM p = 0,05). ConclusionsGrade I obese presented more changes in pulmonary mechanics than the non-obese during video laparoscopies and the fact requires mechanical ventilation-related care.

Ventilation strategies in transition from neonatal respiratory distress to chronic lung disease

Despite the advance in neonatal care over the past few decades, preventing preterm infants with respiratory distress syndrome progress to bronchopulmonary dysplasia remained challenging. In this review, we will discuss the respiratory support strategies in preterm infants with RDS evolving into BPD based on the changes in pulmonary mechanics and pathophysiology as well as currently available evidence.

Comparing the effects and compliance between volume-assured and pressure support non-invasive ventilation in patients with chronic respiratory failure.

Standard bi-level non-invasive ventilation with fixed-level pressure support (PS) delivery may not maintain ventilation during the changes in pulmonary mechanics that occur throughout day and night, so average volume-assured pressure support (AVAPS) modes that target a preset volume by adjustment of PS may be effective. Our meta-analysis wants to compare AVAPS and pressure support non-invasive ventilation (PS-NIV) regarding arterial blood gases (ABGs), sleep efficiency and compliance. Relevant publications indexed in PubMed, Cochrane Library, Embase, Web of Science, Wanfang Data, China National Knowledge Infrastructure and VIPI were identified. Appropriate articles identified from the reference lists of the above searches were also reviewed. We included randomized controlled trials involved the use of AVAPS and PS-NIV ventilation for chronic respiratory failure. Each included study weighted mean differences, and 95% confidence intervals (CI) were calculated for continuous outcomes. Statistical heterogeneity was assessed using the I2 value≤50% were considered as no statistical heterogeneity and used fixed effects model. Otherwise, a random effects model was used. Eight trials were eligible. No significant difference was observed between AVAPS and PS-NIV groups to compare PaCO2 (OR -0.97, CI-2.54-0.61, P=0.23) and PaO2 (OR -1.81, CI-4.29-0.67, P=0.15) in ABGs. There was no significant difference between the two groups with sleep efficiency (OR -3.31, CI-7.58-0.95, P=0.13) and visual analog scale (OR 0.32, CI-6.97-7.61, P=0.93). The evidence shows there is no significant difference in clinical outcomes when comparing AVAPS and PS-NIV used for chronic respiratory failure patients.

INOS Inhibition Reduces Lung Mechanical Alterations and Remodeling Induced by Particulate Matter in Mice.

Background. The epidemiologic association between pulmonary exposure to ambient particulate matter (PM) and acute lung damage is well known. However, the mechanism involved in the effects of repeated exposures of PM in the lung injury is poorly documented. This study tested the hypotheses that chronic nasal instillation of residual oil fly ash (ROFA) induced not only distal lung and airway inflammation but also remodeling. In addition, we evaluated the effects of inducible nitric oxide inhibition in these responses. For this purpose, airway and lung parenchyma were evaluated by quantitative analysis of collagen and elastic fibers, immunohistochemistry for macrophages, neutrophils, inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS), and alveolar septa 8-iso prostaglandin F2α (8-iso-PGF-2α) detection. Anesthetized in vivo (airway resistance, elastance, H, G, and Raw) respiratory mechanics were also analyzed. C57BL6 mice received daily 60ul of ROFA (intranasal) for five (ROFA-5d) or fifteen days (ROFA-15d). Controls have received saline (SAL). Part of the animals has received 1400W (SAL+1400W and ROFA-15d+1400W), an iNOS inhibitor, for four days before the end of the protocol. A marked neutrophil and macrophage infiltration and an increase in the iNOS, nNOS, and 8-iso-PGF2 α expression was observed in peribronchiolar and alveolar wall both in ROFA-5d and in ROFA-15d groups. There was an increment of the collagen and elastic fibers in alveolar and airway walls in ROFA-15d group. The iNOS inhibition reduced all alterations induced by ROFA, except for the 8-iso-PGF2 α expression. In conclusion, repeated particulate matter exposures induce extracellular matrix remodeling of airway and alveolar walls, which could contribute to the pulmonary mechanical changes observed. The mechanism involved is, at least, dependent on the inducible nitric oxide activation.

Respiratory muscle power and lung function in healthy obese Sudanese medical students

There is an increasing prevalence of obesity worldwide (Body Mass Index equals or above 30kg/m2). Obesity may cause changes in pulmonary mechanics, as measured by spirometric values: mild reduction in vital capacity and proportionate reduction in Forced Expiratory volume in the first second (FEV1) depending upon the age, type of body fat distribution and severity of obesity. Changes in respiratory muscle strength in healthy obese individuals have not been widely investigated. The aim of this study is to assess the effect of obesity on respiratory muscle strength and pulmonary function in healthy obese subjects. A cross sectional study was carried out at National Ribat University, Faculty of Medicine, among ninety-five healthy male and female medical students aged 17-25 years (52 obese with BMI equals or above 30kg/m2, 43 non-obese with BMI&lt; 0.05). These results were also found to be consistent in female subjects. Significant negative correlation was also observed between % fat and lung function parameters (FVC, FEV1). Increased strengthening of respiratory muscles in healthy obese adults (as measured by elevated MEP and MIP) might be a compensatory effect to bring lung function to comparable values of the non- obese. Percent of body fat could be a good predictor for decline in lung function in obese individuals.

Plant Proteinase Inhibitor BbCI Modulates Lung Inflammatory Responses and Mechanic and Remodeling Alterations Induced by Elastase in Mice.

Background. Proteinases play a key role in emphysema. Bauhinia bauhinioides cruzipain inhibitor (BbCI) is a serine-cysteine proteinase inhibitor. We evaluated BbCI treatment in elastase-induced pulmonary alterations. Methods. C57BL/6 mice received intratracheal elastase (ELA group) or saline (SAL group). One group of mice was treated with BbCI (days 1, 15, and 21 after elastase instillation, ELABC group). Controls received saline and BbCI (SALBC group). After 28 days, we evaluated respiratory mechanics, exhaled nitric oxide, and bronchoalveolar lavage fluid. In lung tissue we measured airspace enlargement, quantified neutrophils, TNFα-, MMP-9-, MMP-12-, TIMP-1-, iNOS-, and eNOS-positive cells, 8-iso-PGF2α, collagen, and elastic fibers in alveolar septa and airways. MUC-5-positive cells were quantified only in airways. Results. BbCI reduced elastase-induced changes in pulmonary mechanics, airspace enlargement and elastase-induced increases in total cells, and neutrophils in BALF. BbCI reduced macrophages and neutrophils positive cells in alveolar septa and neutrophils and TNFα-positive cells in airways. BbCI attenuated elastic and collagen fibers, MMP-9- and MMP-12-positive cells, and isoprostane and iNOS-positive cells in alveolar septa and airways. BbCI reduced MUC5ac-positive cells in airways. Conclusions. BbCI improved lung mechanics and reduced lung inflammation and airspace enlargement and increased oxidative stress levels induced by elastase. BbCI may have therapeutic potential in chronic obstructive pulmonary disease.

Pulmonary Function at Hospital Discharge in Preterm Infants Randomized to a Single Rescue Course of Antenatal Steroids

To compare the pulmonary function, measured at birth and at hospital discharge, of infants whose mothers had been randomized to a single rescue course of antenatal steroids versus those whose mothers had been randomized to placebo. This study involved follow-up at hospital discharge of subjects of a randomized, double-blinded trial. In the original trial, pregnant women at ≥14 days after their initial course of antenatal steroids and <34 weeks' gestation were randomized to rescue antenatal steroids (44 mothers, 56 infants) or placebo (41 mothers, 57 infants). Passive respiratory compliance (Crs), passive respiratory resistance, and functional residual capacity were measured in all infants at birth and again at discharge to evaluate changes in pulmonary mechanics over time. Statistical analyses were based on intention to treat. We previously reported that compared with infants in the placebo group, infants in the rescue antenatal steroids group had a higher mean Crs value measured within 72 hours of birth (1.21 vs 1.01 mL/cm H2O/kg; P < .05). Here we show that the Crs benefit in the antenatal steroids group was sustained until discharge. Infants in the placebo group demonstrated improvement in Crs such that by discharge, there was no difference in mean Crs between the rescue antenatal steroids and placebo groups (1.18 vs 1.22 mL/cm H2O/kg). Rescue antenatal steroids significantly increased Crs measured within 72 hours of birth, and this increase was sustained until hospital discharge. Preterm infants in the placebo group demonstrated a decreased initial Crs compared with the rescue antenatal steroids group, but achieved a comparable Crs by the time of discharge. ClinicalTrials.gov: NCT00669383.

Effects of positive end-expiratory pressure and 30% inspired oxygen on pulmonary mechanics and atelectasis in cats undergoing non-bronchoscopic bronchoalveolar lavage.

Objectives The objective of this study was to determine if modification of inspired oxygen concentration or positive end-expiratory pressure (PEEP) would alter bronchoalveolar lavage (BAL)-induced changes in pulmonary mechanics or atelectasis, as measured using ventilator-acquired pulmonary mechanics and thoracic CT. Methods Six experimentally asthmatic cats underwent anesthesia and non-bronchoscopic BAL, each under four randomized treatment conditions: 100% oxygen, zero PEEP; 30% oxygen, zero PEEP; 100% oxygen, PEEP 2 cmH2O; and 30% oxygen, PEEP 2 cmH2O. Pulse oximetry was used to estimate oxygen saturation (SpO2). Ventilator-acquired pulmonary mechanics and thoracic CT scans were collected prior to BAL and at 1, 5 and 15 mins post-BAL. Results While receiving 100% oxygen, no cat had SpO2 <91%. Some cats receiving 30% oxygen had decreased saturation immediately post-BAL (mean ± SD 70.8 ± 31%), but 6/8 of these had SpO2 >90% by 1 min later. There was a significant increase in airway resistance and a decrease in lung compliance following BAL, but there was no significant difference between treatment groups. Cats receiving no PEEP and 30% oxygen conserved better aeration of the lung parenchyma in BAL-sampled areas than those receiving no PEEP and 100% oxygen. Conclusions and relevance Alterations in pulmonary mechanics or atelectasis may not be reflected by SpO2 following BAL. The use of 30% inspired oxygen concentration failed to show any significant improvement in pulmonary mechanics but did diminish atelectasis. In some cats, it was also associated with desaturation of hemoglobin. The use of PEEP in this study did not show any effect on our outcome parameters. Further studies using higher PEEP (5-10 cmH2O) and intermediate inspired oxygen concentration (40-60%) are warranted to determine if they would confer clinical benefit in cats undergoing diagnostic BAL.

G141(P) Monitoring respiratory function parameters in ventilated infants during inter-hospital emergency neonatal transport

Introduction Volume targeted ventilation (VTV) has been shown to decrease the incidence of hypocarbia, air leaks, bronchopulmonary dysplasia (BPD), intraventricular haemorrhage (IVH) and periventricular leukomlacia (PVL). As a result it has now become the predominant mode of ventilation in the NICU. Within the setting of a UK neonatal transport service, ventilation is more commonly non-triggered pressure limited and time cycled. End tidal Carbondioxide (ETCO) monitoring is used as a surrogate marker of ventilation and minute volume and has demonstrable effectiveness. There is a paucity of data however evaluating the use of additional respiratory function parameters, particularly tidal volume and tube leak during inter-hospital emergency neonatal transport. Aim We aimed to assess current use of supplementary respiratory function monitoring within a UK neonatal transport setting. Methods We carried out a telephonic survey of all UK neonatal transport teams to ascertain current practice with regards to monitoring of the following respiratory function parameters in ventilated infants during emergency neonatal transport: PIP, PEEP, MAP, minute volumes, flow, tidal volumes, ETCO and leaks around the ETT. Method of carbon dioxide monitoring was also recorded. Results 21/22 (95%) of UK neonatal transport teams responded to the survey. Currently, during inter-hospital neonatal transport, 9/21(42%) teams monitor tidal volumes and 8/21(38%) teams monitor delivered airway pressures, flow, minute volumes and leaks around ETT. 18/21(85%) teams use ETCO monitoring. Of these, 14/18(77%) use side stream/micro stream and 4/18(23%) use mainstream ETCO monitoring. Conclusions Our survey shows that currently, mechanical ventilation is mainly assessed using heart rate, respiratory rate, oxygen saturations, blood gas, chest rise, auscultation and ETCO monitoring. Hypocapnia is a well-known complication of mechanical ventilation and rates vary significantly between UK neonatal transport teams. Although the vast majority of teams use ETCO monitoring only 40% of services are using a measure of tidal volume. Continuous monitoring of ventilator parameters in an emergency situation and assessment of minute ventilation would allow clinicians to evaluate changes in pulmonary mechanics allowing short-term modifications, potential reductions in key outcome measures such as hypocarbia and possible reduction in medium to long-term adverse respiratory outcomes. Further studies of the potential benefits of enhanced monitoring are required in this high-risk area.

Time course of pulmonary burden in mice exposed to residual oil fly ash.

Residual oil fly ash (ROFA) is a common pollutant in areas where oil is burned. This particulate matter (PM) with a broad distribution of particle diameters can be inhaled by human beings and putatively damage their respiratory system. Although some studies deal with cultured cells, animals, and even epidemiological issues, so far a comprehensive analysis of respiratory outcomes as a function of the time elapsed after exposure to a low dose of ROFA is wanted. Thus, we aimed to investigate the time course of mechanical, histological, and inflammatory lung changes, as well as neutrophils in the blood, in mice exposed to ROFA until 5 days after exposure. BALB/c mice (25 ± 5 g) were randomly divided into 7 groups and intranasally instilled with either 10 μL of sterile saline solution (0.9% NaCl, CTRL) or ROFA (0.2 μg in 10 μL of saline solution). Pulmonary mechanics, histology (normal and collapsed alveoli, mononuclear and polymorphonuclear cells, and ultrastructure), neutrophils (in blood and bronchoalveolar lavage fluid) were determined at 6 h in CTRL and at 6, 24, 48, 72, 96, and 120 h after ROFA exposure. ROFA contained metal elements, especially iron, polycyclic aromatic hydrocarbons (PAHs), and organochlorines. Lung resistive pressure augmented early (6 h) in the course of lung injury and other mechanical, histological and inflammatory parameters increased at 24 h, returning to control values at 120 h. Blood neutrophilia was present only at 24 and 48 h after exposure. Swelling of endothelial cells with adherent neutrophils was detected after ROFA instillation. No neutrophils were present in the lavage fluid. In conclusion, the exposure to ROFA, even in low doses, induced early changes in pulmonary mechanics, lung histology and accumulation of neutrophils in blood of mice that lasted for 4 days and disappeared spontaneously.

Chapter 9 - The effects of head-up and head-down tilt on central respiratory chemoreflex loop gain tested by hyperoxic rebreathing

Central respiratory chemosensitivity is mediated via chemoreceptor neurons located throughout brain stem tissue. These receptors detect proximal CO2/[H(+)] (i.e., controller gain) and modulate breathing in a classic negative feedback loop. Loop gain (responsiveness) is the theoretical product of controller (chemoreceptors), mixing/feedback (cardiovascular and cerebrovascular systems), and plant (pulmonary system) gains. The level of chemoreceptor stimulation is determined by interactions between mixing and plant gains. The extent to which steady-state changes in body position may affect central chemoreflex loop gain in response to CO2 is unclear. Because of the potential effects of tilt on pulmonary mechanics, we hypothesized that plant gain would be altered by head-up and head-down tilt (HUT, HDT) during hyperoxic rebreathing, which theoretically isolates plant gain by eliminating systemic arterial-tissue gradients. Sixteen subjects (eight females) underwent hyperoxic rebreathing tests on a tilt table to quantify central chemoreflex loop gain in five steady-state positions: 90° HUT, 45° HUT, supine, 45° HDT, and 90° HDT. Respiratory responses (tidal volume, VT; frequency, fR; minute ventilation, VE) were quantified during steady-state and increases in CO2 during rebreathing by linear regression above the ventilatory recruitment threshold (VRT). Using one-factor analysis of variance, we found that there were no differences in the respiratory responses between the five positions (VRT, P=0.711; VT, P=0.290; fR, P=0.748; VE, P=0.325). Our findings suggest that during steady-state orthostatic stress, the ability of subjects to mount a normal ventilatory response to increased CO2 was unaffected, despite any potential changes in pulmonary mechanics associated with positional challenges.

Heme Oxygenase Inhibition Enhances Neutrophil Migration Into the Bronchoalveolar Spaces and Improves the Outcome of Murine Pneumonia-Induced Sepsis

A reduction of the neutrophil migration into the site of infection during cecal ligation and puncture-induced sepsis increases host mortality. Inhibition of heme oxygenase (HO) prevents this neutrophil paralysis and improves host survival in the cecal ligation and puncture model. Taking into account that almost 50% of all sepsis cases are a consequence of pneumonia, we designed the present study to determine the role of HO in an experimental model of pneumonia-induced sepsis. The objective of this study was to evaluate whether the inhibition of HO improves the outcome and pathophysiologic changes of sepsis induced by an intratracheal instillation of Klebsiella pneumoniae. The pretreatment of mice subjected to pneumonia-induced sepsis with ZnDPBG (zinc deuteroporphyrin 2,4-bis glycol), a nonspecific HO inhibitor, increased the number of neutrophils in the bronchoalveolar spaces, reduced the bacterial load at the site of infection, and prevented the upregulation of CD11b and the downregulation of CXCR2 on blood neutrophils. Moreover, the pretreatment with ZnDPBG decreased alveolar collapse, attenuating the deleterious changes in pulmonary mechanics and gas exchanges and, as a consequence, improved the survival rate of mice from 0% to ∼20%. These results show that heme oxygenase is involved in the pathophysiology of pneumonia-induced sepsis and suggest that HO inhibitors could be helpful for the management of this disease.

Augmented Pulmonary Responses to Acute Ozone Exposure in Obese Mice: Roles of TNFR2 and IL-13

Background: Acute ozone (O3) exposure results in greater inflammation and airway hyperresponsiveness (AHR) in obese versus lean mice.Objectives: We examined the hypothesis that these augmented responses to O3 are the result of greater signaling through tumor necrosis factor receptor 2 (TNFR2) and/or interleukin (IL)-13.Methods: We exposed lean wild-type (WT) and TNFR2-deficient (TNFR2–/–) mice, and obese Cpefat and TNFR2-deficient Cpefat mice (Cpefat/TNFR2–/–), to O3 (2 ppm for 3 hr) either with or without treatment with anti–IL-13 or left them unexposed.Results: O3-induced increases in baseline pulmonary mechanics, airway responsiveness, and cellular inflammation were greater in Cpefat than in WT mice. In lean mice, TNFR2 deficiency ablated O3-induced AHR without affecting pulmonary inflammation; whereas in obese mice, TNFR2 deficiency augmented O3-induced AHR but reduced inflammatory cell recruitment. O3 increased pulmonary expression of IL-13 in Cpefat but not WT mice. Flow cytometry analysis of lung cells indicated greater IL-13–expressing CD4+ cells in Cpefat versus WT mice after O3 exposure. In Cpefat mice, anti–IL-13 treatment attenuated O3-induced increases in pulmonary mechanics and inflammatory cell recruitment, but did not affect AHR. These effects of anti–IL-13 treatment were not observed in Cpefat/TNFR2–/– mice. There was no effect of anti–IL-13 treatment in WT mice.Conclusions: Pulmonary responses to O3 are not just greater, but qualitatively different, in obese versus lean mice. In particular, in obese mice, O3 induces IL-13 and IL-13 synergizes with TNF via TNFR2 to exacerbate O3-induced changes in pulmonary mechanics and inflammatory cell recruitment but not AHR.

Predicting Nocturnal Hypoventilation in Hypercapnic Chronic Obstructive Pulmonary Disease Patients Undergoing Long-Term Oxygen Therapy

Background: Chronic obstructive pulmonary disease (COPD) patients are very sensitive to changes in pulmonary mechanics and central ventilation control during sleep and may develop significant gas exchange alterations with increased hypoxemia and hypercapnia. Oxygen therapy improves nocturnal desaturation but can worsen hypoventilation. Objectives: To analyze the prevalence of nocturnal hypoventilation (NHV) in hypercapnic COPD patients and to determine predictive factors for this phenomenon. Methods: This was a prospective multicenter study which enrolled 80 clinically stable COPD patients with hypercapnic respiratory failure who fulfilled the conventional criteria for long-term oxygen therapy (LTOT). All patients had undergone pulmonary function testing, blood gas analysis, and respiratory polygraphy. Arterial blood gas samples were obtained while patients were awake and during sleep. NHV was considered when an increase in PaCO₂ >10 mm Hg was observed in any nocturnal arterial blood gas sample as compared to the awake levels. Results: Seventeen patients (21%) developed NHV. NHV was associated with the values of BMI, hemoglobin, hematocrits, DLCO, and PaO₂ reached after oxygen administration. In the logistic regression analysis BMI (OR 1.26, 95% CI 1.068–1.481; p = 0.006) and the diurnal increase of PaO₂ after O₂ (OR 0.89, 95% CI 0.807–0.972; p = 0.010) were the variables that best discriminated with a sensitivity of 82% and a specificity of 78%. Conclusions: NHV is a relatively common finding in stable hypercapnic COPD patients undergoing LTOT and it is related to a higher BMI and lower PaO₂ after oxygen administration.

Inhibition of PI3K by PX-866 Prevents Transforming Growth Factor-α–Induced Pulmonary Fibrosis

Transforming growth factor-alpha (TGFalpha) is a ligand for the epidermal growth factor receptor (EGFR). EGFR activation is associated with fibroproliferative processes in human lung disease and animal models of pulmonary fibrosis. EGFR signaling activates several intracellular signaling pathways including phosphatidylinositol 3'-kinase (PI3K). We previously showed that induction of lung-specific TGFalpha expression in transgenic mice caused progressive pulmonary fibrosis over a 4-week period. The increase in levels of phosphorylated Akt, detected after 1 day of doxycycline-induced TGFalpha expression, was blocked by treatment with the PI3K inhibitor, PX-866. Daily administration of PX-866 during TGFalpha induction prevented increases in lung collagen and airway resistance as well as decreases in lung compliance. Treatment of mice with oral PX-866 4 weeks after the induction of TGFalpha prevented additional weight loss and further increases in total collagen, and attenuated changes in pulmonary mechanics. These data show that PI3K is activated in TGFalpha/EGFR-mediated pulmonary fibrosis and support further studies to determine the role of PI3K activation in human lung fibrotic disease, which could be amenable to targeted therapy.