Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis: The ISABELA 1 and 2 Randomized Clinical Trials.

Importance: There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF). Objective: To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF. Design, Setting, and Participants: The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2. Interventions: Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks. Main Outcomes and Measures: The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George's Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life). Results: At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was -124.6 mL (95% CI, -178.0 to -71.2 mL) with 600 mg of ziritaxestat vs -147.3 mL (95% CI, -199.8 to -94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, -52.3 to 97.6 mL]), and -173.9 mL (95% CI, -225.7 to -122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, -26.7 mL [95% CI, -100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was -173.8 mL (95% CI, -209.2 to -138.4 mL) with 600 mg of ziritaxestat vs -176.6 mL (95% CI, -211.4 to -141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, -46.9 to 52.4 mL]) and -174.9 mL (95% CI, -209.5 to -140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, -47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo. Conclusions and Relevance: Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. Trial Registration: ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444.

Adenosine A2a receptors modulate TrkB receptor-dependent respiratory plasticity in neonatal rats.

Neuroplasticity is a fundamental property of the respiratory control system, enabling critical adaptations in breathing to meet the challenges, but little is known whether neonates express neuroplasticity similar to adults. We tested the hypothesis that, similar to adults, tyrosine receptor kinase B (TrkB) or adenosine A2a receptor activation in neonates are independently sufficient to elicit respiratory motor facilitation, and that co-induction of TrkB and A2a receptor-dependent plasticity undermines respiratory motor facilitation. TrkB receptor activation with 7,8-dihydroxyflavone (DHF) in neonatal brainstem-spinal cord preparations induced a long-lasting increase in respiratory motor output in 55 % of preparations, whereas adenosine A2a receptor activation with CGS21680 only sporadically induced respiratory motor plasticity. CGS21680 and DHF co-application prevented DHF-dependent respiratory motor facilitation, whereas co-application of MSX-3 (adenosine A2a receptor antagonist) and DHF more rapidly induced respiratory motor plasticity. Collectively, these data suggest that mechanisms underlying respiratory neuroplasticity may be only partially operational in early neonatal life, and that adenosine A2a receptor activation undermines TrkB-induced respiratory plasticity.

Effect of tiger milk mushroom (Lignosus rhinocerus) supplementation on respiratory health, immunity and antioxidant status: an open-label prospective study.

Tiger milk mushroom (TMM; Lignosus rhinocerus) have been used for a long time by indigenous communities in South East Asia regions as traditional medicine for different ailments, including respiratory disorders. The beneficial effects of TMM have been proven through in vivo and in vitro models, but these effects have yet to be validated in a clinical study. In this study, the beneficial effects of TMM supplementation were investigated in 50 voluntary participants. Participants were required to take 300 mg of TMM twice daily for three months. Level of interleukin 1ß (IL-1ß), interleukin 8 (IL-8), immunoglobulin A (IgA), total antioxidant capacity, malondialdehyde (MDA), 3-nitrotyrosine (3-NT), 8-hydroxydeoxyguanosine (8-OHdG), pulmonary function and respiratory symptoms were assessed during baseline and monthly follow-up visits. Results demonstrated that supplementation of TMM significantly (p < 0.05) suppressed the level of IL-1ß, IL-8, MDA, as well as respiratory symptoms. In additional to that, TMM also significantly (p < 0.05) induced the level of IgA, total antioxidant capacity, as well as pulmonary function. Analyses of data indicated that gender and BMI were factors influencing the outcomes of antioxidant status. Collectively, our findings suggested that TMM supplementation effectively improves respiratory health, immunity and antioxidant status.

Platinum accumulation in the brain and alteration in the central regulation of cardiovascular and respiratory functions in oxaliplatin-treated rats.

Oxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. Neurotoxicity is one of its major adverse effects that often demands dose limitation. However, the effects of chronic oxaliplatin on the toxicity of the autonomic nervous system regulating cardiorespiratory function and adaptive reflexes are unknown. Male Sprague Dawley rats were treated with intraperitoneal oxaliplatin (3 mg kg-1 per dose) 3 times a week for 14 days. The effects of chronic oxaliplatin treatment on baseline mean arterial pressure (MAP); heart rate (HR); splanchnic sympathetic nerve activity (sSNA); phrenic nerve activity (PNA) and its amplitude (PNamp) and frequency (PNf); and sympathetic reflexes were investigated in anaesthetised, vagotomised and artificially ventilated rats. The same parameters were evaluated after acute oxaliplatin injection, and in the chronic treatment group following a single dose of oxaliplatin. The amount of platinum in the brain was determined with atomic absorption spectrophotometry. Chronic oxaliplatin treatment significantly increased MAP, sSNA and PNf and decreased HR and PNamp, while acute oxaliplatin had no effects. Platinum was accumulated in the brain after chronic oxaliplatin treatment. In the chronic oxaliplatin treatment group, further administration of a single dose of oxaliplatin increased MAP and sSNA. The baroreceptor sensitivity and somatosympathetic reflex were attenuated at rest while the sympathoexcitatory response to hypercapnia was increased in the chronic treatment group. This is the first study to reveal oxaliplatin-induced alterations in the central regulation of cardiovascular and respiratory functions as well as reflexes that may lead to hypertension and breathing disorders which may be mediated via accumulated platinum in the brain.

Impaired cardiorespiratory responses to hypercapnia in neonatal mice lacking PAC1 but not VPAC2 receptors.

The evidence is mounting for a role for abnormal signaling of the stress peptide pituitary adenylate cyclase activating polypeptide (PACAP) and its canonical receptor PAC1 in the pathogenesis of sudden infant death syndrome. In this study, we investigated whether the PACAP receptors PAC1 or VPAC2 are involved in the neonatal cardiorespiratory response to hypercapnic stress. We used head-out plethysmography and surface ECG electrodes to assess cardiorespiratory responses to an 8% hypercapnic challenge in unanesthetized and spontaneously breathing 4-day-old PAC1 or VPAC2 knockout (KO) and wild-type mouse pups. We demonstrate that compared with WTs, breathing frequency (RR) and minute ventilation ([Formula: see text]) in PAC1 KO pups were significantly blunted in response to hypercapnia. Although heart rate was unaltered in PAC1 KO pups during hypercapnia, heart rate recovery posthypercapnia was impaired. In contrast, cardiorespiratory impairments in VPAC2 KO pups were limited to only an overall higher tidal volume (VT), independent of treatment. These findings suggest that PACAP signaling through the PAC1 receptor plays a more important role than signaling through the VPAC2 receptor in neonatal respiratory responses to hypercapnia. Thus deficits in PACAP signaling primarily via PAC1 may contribute to the inability of infants to mount an appropriate protective response to homeostatic stressors in childhood disorders such as SIDS.

[The effect of air pollution in diffuse interstitial lung disease]. / Rôle de la pollution au cours des pneumopathies interstitielles diffuses.

Few studies have examined the effects of air pollution in diffuse interstitial lung disease and they have focused on small numbers of patients. Most data are available in idiopathic pulmonary fibrosis and studies suggest that the level of exposure to pollutants may influence the development of acute exacerbations (ozone and NO2), their incidence (NO2), decline in respiratory function (PM10) and death (PM10 and PM2.5). Several studies show an increase in the incidence of rheumatoid arthritis in people living near busy roads. In systemic scleroderma, hypersensitivity pneumonitis and sarcoidosis although negative effects of pollution have been reported the data are insufficient to be conclusive. Nevertheless, the observed effects of air pollution are consistent with those described for other chronic respiratory diseases. Exposure to pollution induces oxidative stress, chronic inflammation and shortening of telomeres, which are all mechanisms described in fibrogenesis. New epidemiological studies are needed with individual measurements of exposure to outdoor and indoor pollution, as well as fundamental studies to clarify the effect of pollution on fibrogenesis.

Lower respiratory tract delivery, airway clearance, and preclinical efficacy of inhaled GM-CSF in a postinfluenza pneumococcal pneumonia model.

Inhaled granulocyte/macrophage colony-stimulating factor (GM-CSF) shows promise as a therapeutic to treat viral and bacterial pneumonia, but no mouse model of inhaled GM-CSF has been described. We sought to 1) develop a mouse model of aerosolized recombinant mouse GM-CSF administration and 2) investigate the protection conferred by inhaled GM-CSF during influenza A virus (IAV) infection against secondary bacterial infection with pneumococcus. To assess lower respiratory tract delivery of aerosolized therapeutics, mice were exposed to aerosolized fluorescein (FITC)-labeled dextran noninvasively via an aerosolization tower or invasively using a rodent ventilator. The efficiency of delivery to the lower respiratory tracts of mice was 0.01% noninvasively compared with 0.3% invasively. The airway pharmacokinetics of inhaled GM-CSF fit a two-compartment model with a terminal phase half-life of 1.3 h. To test if lower respiratory tract levels were sufficient for biological effect, mice were infected intranasally with IAV, treated with aerosolized recombinant mouse GM-CSF, and then secondarily infected with Streptococcus pneumoniae. Inhaled GM-CSF conferred a significant survival benefit to mice against secondary challenge with S. pneumoniae (P < 0.05). Inhaled GM-CSF did not reduce airway or lung parenchymal bacterial growth but significantly reduced the incidence of S. pneumoniae bacteremia (P < 0.01). However, GM-CSF overexpression during influenza virus infection did not affect lung epithelial permeability to FITC-dextran ingress into the bloodstream. Therefore, the mechanism of protection conferred by inhaled GM-CSF appears to be locally mediated improved lung antibacterial resistance to systemic bacteremia during IAV infection.

Effects of propofol, desflurane, and sevoflurane on respiratory functions following endoscopic endonasal transsphenoidal pituitary surgery: a prospective randomized study.

BACKGROUND: General anesthesia with intravenous or inhalation anesthetics reduces respiratory functions. We investigated the effects of propofol, desflurane, and sevoflurane on postoperative respiratory function tests. METHODS: This single-center randomized controlled study was performed in a university hospital from October 2015 to February 2017. Ninety patients scheduled for endoscopic endonasal transsphenoidal pituitary surgery were randomly categorized into either of these three groups: propofol (n = 30, the Group TIVA), desflurane (n = 30, the Group D) or sevoflurane (n = 30, the Group S). We analyzed the patients before, after, and 24 h following surgery, to identify the following parameters: forced expiratory volume in 1 second (FEV1) %, forced vital capacity (FVC) %, FEV1/FVC, and arterial blood gases (ABG). Furthermore, we also recorded the intraoperative dynamic lung compliance and airway resistance values. RESULTS: We did not find any significant differences in FEV1 values (primary outcome) among the groups (P = 0.336). There was a remarkable reduction in the FEV1 and FVC values in all groups postoperatively relative to the baseline (P < 0.001). The FVC, FEV1/FVC, ABG analysis, compliance, and airway resistance were similar among the groups. Intraoperative dynamic compliance values were lower at the 1st and 2nd hours than those immediately after intubation (P < 0.001). CONCLUSIONS: We demonstrated that propofol, desflurane, and sevoflurane reduced FEV1 and FVC values postoperatively, without any significant differences among the drugs.

Effect of preoperative inhaled budesonide on pulmonary injury after cardiopulmonary bypass: A randomized pilot study.

BACKGROUND: Cardiopulmonary bypass can result in lung injury. This prospective, double-blinded, randomized trial aimed to evaluate the protective effect of inhaled budesonide on lung injury after cardiopulmonary bypass. METHODS: Sixty patients, aged 25 to 65 years, requiring cardiopulmonary bypass were randomized to groups treated with saline or budesonide inhalation preoperatively. The respiratory mechanics were recorded. Bronchoalveolar lavage fluid was collected before cardiopulmonary bypass and after sternal closure. Serum and bronchoalveolar lavage fluid levels of proinflammatory and anti-inflammatory factors were analyzed. The primary end point was the lowest ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen after cardiopulmonary bypass. The durations of ventilation and postoperative recovery time were noted. RESULTS: Budesonide significantly improved respiratory mechanics after cardiopulmonary bypass. Budesonide improved the partial pressure of arterial oxygen to the fraction of inspired oxygen ratio from 8 to 48 hours after the operation. Budesonide shortened the durations of mechanical ventilation and postoperative recovery time. Budesonide decreased the levels of proinflammatory factors while increasing the levels of anti-inflammatory factors in bronchoalveolar lavage fluid and serum (all P < .05). The macrophage and neutrophil counts, and protein and elastase concentrations were decreased by budesonide treatment. CONCLUSIONS: Budesonide treatment shortened the durations of mechanical ventilation, inhibited local and systemic inflammation, and improved respiratory function after cardiopulmonary bypass.

The effects of oil induced respiratory impairment on two indices of hypoxia tolerance in Atlantic croaker (Micropogonias undulatus).

The Gulf of Mexico was home to the Deepwater Horizon oil spill, and is also known to exhibit seasonal declines in oxygen availability. Oil exposure in fish is known to impact oxygen uptake through cardiac impairment, which raises questions about the additive effects of these two stressors. Here we explore this question on the Atlantic croaker using two measures of hypoxia tolerance: critical oxygen threshold (Pcrit), and time to loss of equilibrium (LOE). We first demonstrated that 24 h exposure to 10.1 and 23.2 µg l-1 ΣPAH50 significantly impaired oxygen uptake. There was no effect of exposure on Pcrit or LOE. Exposure did result in significantly different repeatability between pre- and post-exposure Pcrit, suggesting that hypoxia tolerant individual may see greater impacts following exposure. These results suggest oil exposure does not have wide scale detrimental outcomes for hypoxia tolerance in fish, yet there may be fine scale impairments of ecological significance.

Risk factors for impaired pulmonary function and cardiorespiratory fitness in very long-term adult survivors of childhood acute lymphoblastic leukemia after treatment with chemotherapy only.

BACKGROUND: Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk of late treatment-related side-effects. Data regarding prevalence and risk factors for impairments in pulmonary function and cardiorespiratory fitness are limited, and reported findings are inconsistent and inconclusive. MATERIAL AND METHODS: In a cross-sectional study, 116 ALL survivors (median 5 years at diagnosis, 29 years at follow-up, 53% females) were examined, median 23 years after treatment with chemotherapy only. Individual cumulative doses of cytostatic agents were calculated. Methods included blood tests, echocardiography, pulmonary function tests and cardiorespiratory exercise test. RESULTS: Females had lower % predicted gas diffusing capacity (DLCO) than males (mean [SD] 84 [13] versus 97 [14], p < .001). Impairment in DLCO was found in 34% females versus 7% males, p < .001. In a multiple linear regression model, female gender, body mass index (BMI) and smoking were risk factors for reduced % predicted DLCO, with a borderline significant effect of left ventricular ejection fraction (LVEF). Impaired cardiorespiratory fitness was found in 42% of the survivors, with a borderline increased risk in females, p = .06. Smoking and BMI were risk factors for reduced % predicted VO2peak. Subjects exposed to anthracyclines had lower LVEF% and % predicted VO2peak than those not exposed, (mean [SD] 56.2 [4.3] versus 59.2 [5.2], p = .01 and 86.9 [18.4] versus 92.8 [18.4], p = .03, respectively). CONCLUSIONS: Impairments in pulmonary function and cardiorespiratory fitness are common in very long-term survivors of childhood ALL. Risk factors are female gender, BMI and smoking. In order to preserve pulmonary function and cardiorespiratory fitness, we suggest increased attention and targeted advice on modifiable lifestyle factors such as smoking, inactivity and overweight.

Biological changes in C57BL/6 mice following 3 weeks of inhalation exposure to cigarette smoke or e-vapor aerosols.

We compared early biological changes in mice after inhalation exposures to cigarette smoke or e-vapor aerosols (MarkTen® cartridge with Carrier, Test-1, or Test-2 formulations; 4% nicotine). Female C57BL/6 mice were exposed to 3R4F cigarette smoke or e-vapor aerosols by nose-only inhalation for up to 4 hours/day, 5 days/week, for 3 weeks. The 3R4F and e-vapor exposures were set to match the target nose port aerosol nicotine concentration (∼41 µg/L). Only the 3R4F group showed postexposure clinical signs such as tremors and lethargy. At necropsy, the 3R4F group had significant increases in lung weight and changes in bronchoalveolar lavage parameters, as well as microscopic findings in the respiratory tract. The e-vapor groups had minimal microscopic changes, including squamous metaplasia in laryngeal epiglottis, and histiocytic infiltrates in the lung (Test-2 group only). The 3R4F group had a higher incidence and severity of microscopic findings compared to any e-vapor group. Transcriptomic analysis also showed that the 3R4F group had the highest number of differentially expressed genes compared to Sham Control. Among e-vapor groups, Test-2 group had more differentially expressed genes but the magnitude of gene expression-based network perturbations in all e-vapor groups was ∼94% less than the 3R4F group. On proteome analysis in the lung, differentially regulated proteins were detected in the 3R4F group only. In conclusion, 3-weeks of 3R4F exposure induced molecular and microscopic changes associated with smoking-related diseases in the respiratory tract, while e-vapor exposures showed substantially reduced biological activities.

Postoperative respiratory effects of intravenous fentanyl compared to intravenous methadone in dogs following spinal surgery.

OBJECTIVE: To evaluate the 24-hour postoperative respiratory effects of either intravenous fentanyl administered as a constant rate infusion or boluses of methadone, in dogs following spinal surgery, assessed by serial arterial blood gas analyses. STUDY DESIGN: Prospective, randomized clinical study. ANIMALS: Thirty-two healthy dogs (American Society of Anesthesiologists I/II) anaesthetized for elective caudal thoracic and/or lumbar decompression spinal surgery. METHODS: Dogs were assigned randomly to be administered a fentanyl constant rate infusion (5 µg kg-1 hour-1; group F, n = 14) or methadone boluses (0.2 mg kg-1, every 4 hours; group M, n = 15) postoperatively for 24 hours. Each dog's anaesthesia protocol was customized. Arterial blood samples were collected from an arterial cannula, placed under anaesthesia, at 4, 8, 12 and 24 hours postextubation, while breathing room air. Cardiorespiratory variables, Glasgow composite pain scale (GCPS) and sedation (SED) scores were also recorded at these time points. Independent t tests, repeated measures anova and Mann-Whitney U tests were used. Significance was defined as p < 0.05. RESULTS: There were no significant differences found between groups in any of the overall mean values or at any time point for values of partial pressure of oxygen [13.9 ± 2.1 kPa (103.9 ± 16.1 mmHg) and 12.6 ± 2.0 kPa (94.7 ± 15.2 mmHg)], partial pressure of carbon dioxide [4.8 ± 0.6 kPa (36 ± 4.2 mmHg) and 4.9 ± 0.6 kPa (36.5 ± 4.5 mmHg)], pH (7.38 ± 0.03 and 7.40 ± 0.03), bicarbonate (21.5 ± 2.3 mm and 21.9 ± 6.6 mm) and base excess (-3.4 ± 2.6 mm and -2 ± 3 mm) for groups F and M, respectively. Cardiorespiratory variables, GCPS and SED scores were also similar between groups. CONCLUSIONS AND CLINICAL RELEVANCE: At the doses studied, neither fentanyl nor methadone caused respiratory depression postoperatively in dogs following caudal thoracic and/or lumbar spinal surgery.

Sustained impairment of respiratory function and swim performance following acute oil exposure in a coastal marine fish.

Acute exposure to crude oil polycyclic aromatic hydrocarbons (PAH) can severely impair cardiorespiratory function and swim performance of larval fish; however, the effects of acute oil exposure on later life stages and the capacity for subsequent recovery is less clear. Red drum (Sciaenops ocellatus) is an economically important apex predator native to the Gulf of Mexico, which was directly exposed to the 2010 Deep Water Horizon (DWH) oil spill. Here we examine impact and recovery of young adult red drum from exposure to concentrations of 0, 4.1, and 12.1µgL-1 ΣPAH50 naturally weathered oil-water accommodated fractions (geometric mean), which are well within the range of concentrations measured during the DWH incident. We focused on aerobic scope (ASc), burst- and critical swimming speeds (Uburst and Ucrit), cost of transport (COT), as well as the capacity to repay oxygen debt following exhaustive exercise (EPOC), which are critical parameters for success of all life stages of fishes. A 24h acute exposure to 4.1µgL-1 ΣPAH caused a significant 9.7 and 12.6% reduction of Uburst and Ucrit respectively, but no change in ASc, COT or EPOC, highlighting a decoupled effect on the respiratory and swimming systems. A higher exposure concentration, 12.1µgL-1 ΣPAH, caused an 8.6 and 8.4% impairment of Uburst and Ucrit, as well as an 18.4% reduction in ASc. These impairments persisted six weeks post-exposure, suggesting that recorded impacts are entrenched. Large predatory fishes are critically dependent on the cardiorespiratory and swimming systems for ecological fitness, and long-term impairment of performance due to acute oil exposure suggests that even acute exposure events may have long lasting impacts on the ecological fitness of affected populations.

Prospective evaluation of respiratory health benefits from reduced exposure to airborne particulate matter.

We aimed to investigate if short-term exposure to reduced particulate matter (PM) air pollution would affect respiratory function in healthy adults. We followed a cohort of 42 healthy participants from a community afflicted with severe PM air pollution to a substantially less polluted area for nine days. We measured daily airborne PM [with an aerodynamic diameter of less than 2.5 µm (PM2.5) and 10 µm (PM10)] and PM2.5 carbon component concentrations. Five repeated respiratory function measurements and fractional exhaled nitric oxide test were made for each participant. Associations between respiratory health and PM exposure were assessed using linear mixed models. Each 10 µg/m3 decrease in same-day PM2.5 was associated with small but consistent increase in the forced expiratory volume in 1 s (FEV1) (9.00 mL) and forced vital capacity (14.35 mL). Our observations indicate that respiratory health benefits can be achieved even after a short-term reduction of exposure to PM. Our results provide strong evidence for more rigorous air pollution controls for the health benefit of populations.

Perioperative respiratory care in obese patients undergoing bariatric surgery: Implications for clinical practice.

Obesity is an increasing problem worldwide. The number of people with obesity doubled since the 1980's to affect an estimated 671 million people worldwide. Obese patients in general have an altered respiratory physiology and can have an impaired lung function, which leads to an increased risk of developing pulmonary complications during anaesthesia and after bariatric surgery (approximately 8%). Therefore the respiratory management of the bariatric surgical patient provides a number of challenges. This review will focus on the perioperative respiratory care in bariatric surgical patients discussing respiratory physiology in the obese and perioperative respiratory care in bariatric surgery. Finally the value of preoperative pulmonary function testing and preoperative OSAS screening will be discussed.

A Patient with Idiopathic Pleuroparenchymal Fibroelastosis Showing a Sustained Pulmonary Function due to Treatment with Pirfenidone.

The patient was a 68-year-old man presenting with body weight loss and exertional dyspnea. High-resolution computed tomography of the chest showed dense subpleural consolidation with traction bronchiectasis and volume loss predominantly in bilateral apical lesions and upper lobes. A histopathological analysis of a specimen of the right upper lobe showed histological patterns which were consistent with idiopathic pleuroparenchymal fibroelastotis (IPPFE). Treatment with pirfenidone was introduced with the expectation of its potential benefit. The effect of pirfenidone was satisfactory, and a decline in forced vital capacity was inhibited during treatment. This is the first case report suggesting the efficacy of pirfenidone for patients with IPPFE.

Effects of sevoflurane on cardiopulmonary function in patients undergoing coronary artery bypass.

The objective of the current study was to investigate effects of sevoflurane on cardiopulmonary function in patients undergoing coronary artery bypass grafting (CABG). In this study, 60 cases of patients with coronary heart disease (CHD) were selected and randomly divided into the sevoflurane group (group S) and the control group C (group C) with 30 cases in each group. The two groups received intravenous anesthesia. The patients of group C were only given oxygen mask and physiological saline to keep vein open; while the patients of group S were administered with 1% sevoflurane immediately after the beginning of cardiopulmonary bypass (CPB) until the end of the treatment. The cardiopulmonary functions at 30 min before operation (T0), postoperative 2 h (T1), 6h (T2), 24h (T3) and 48 (T4) were observed. The mean arterial pressure (MAP) of the group S at T1, T2, T3 was lower than that of the group C, as were the heart rate (HR) and left ventricular ejection fraction (LVEF). The creatine kinase isoenzyme (CK-MB) during T1 to T4 in the group S was less than that of the group C, and there were significant differences between the two groups (P less than 0.05). The tidal volume (Vt), vital capacity (Vc) and oxygenation index (PaO2/FiO2) of the two groups during T1 and T2 were decreased, while respiratory frequency (RR) and alveolar-arterial blood oxygen partial pressure (PA-aO2) were increased and they began to decrease during T3 and T4. Vt and Vc of the group S were higher during T1 and T2 periods than those of the group C, while RR was lower than that of the group C; PaO2 / FiO2 during T1 to T4 period of group S was higher than that of group C, while PA-aO2 was significantly lower than that of the control group (P less than 0.05). In conclusion, although LVEF was not improved in the sevoflurane group, sevoflurane may contribute to stabilizing the cardiopulmonary function and preventing from myocardial injury.

Intrauterine endotoxin-induced impairs pulmonary vascular function and right ventricular performance in infant rats and improvement with early vitamin D therapy.

High pulmonary vascular resistance (PVR), proximal pulmonary artery (PA) impedance, and right ventricular (RV) afterload due to remodeling contribute to the pathogenesis and severity of pulmonary hypertension (PH). Intra-amniotic exposure to endotoxin (ETX) causes sustained PH and high mortality in rat pups at birth, which are associated with impaired vascular growth and RV hypertrophy in survivors. Treatment of ETX-exposed pups with antenatal vitamin D (vit D) improves survival and lung growth, but the effects of ETX exposure on RV-PA coupling in the neonatal lung are unknown. We hypothesized that intrauterine ETX impairs RV-PA coupling through sustained abnormalities of PA stiffening and RV performance that are attenuated with vit D therapy. Fetal rats were exposed to intra-amniotic injections of ETX, ETX+vit D, or saline at 20 days gestation (term = 22 days). At postnatal day 14, pups had pressure-volume measurements of the RV and isolated proximal PA, respectively. Lung homogenates were assayed for extracellular matrix (ECM) composition by Western blot. We found that ETX lungs contain decreased α-elastin, lysyl oxidase, collagen I, and collagen III proteins (P < 0.05) compared control and ETX+vit D lungs. ETX-exposed animals have increased RV mechanical stroke work (P < 0.05 vs. control and ETX+vit D) and elastic potential energy (P < 0.05 vs. control and ETX+vit D). Mechanical stiffness and ECM remodeling are increased in the PA (P < 0.05 vs. control and ETX+vit D). We conclude that intrauterine exposure of fetal rats to ETX during late gestation causes persistent impairment of RV-PA coupling throughout infancy that can be prevented with early vit D treatment.