Nintedanib plus Sildenafil in Patients with Idiopathic Pulmonary Fibrosis.

BACKGROUND: Nintedanib is an approved treatment for idiopathic pulmonary fibrosis (IPF). A subgroup analysis of a previously published trial suggested that sildenafil may provide benefits regarding oxygenation, gas exchange as measured by the diffusion capacity of the lungs for carbon monoxide (DlCO), symptoms, and quality of life in patients with IPF and severely decreased DlCO. That idea was tested in this trial. METHODS: We randomly assigned, in a 1:1 ratio, patients with IPF and a DlCO of 35% or less of the predicted value to receive nintedanib at a dose of 150 mg twice daily plus sildenafil at a dose of 20 mg three times daily (nintedanib-plus-sildenafil group) or nintedanib at a dose of 150 mg twice daily plus placebo three times daily (nintedanib group) for 24 weeks. The primary end point was the change from baseline in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 12 (the total score ranges from 0 to 100, with higher scores indicating worse health-related quality of life). Secondary end points included measures of dyspnea and safety. RESULTS: A total of 274 patients underwent randomization. There was no significant difference in the adjusted mean change from baseline in the SGRQ total score at week 12 between the nintedanib-plus-sildenafil group and the nintedanib group (-1.28 points and -0.77 points, respectively; P=0.72). A benefit from sildenafil treatment was not observed with regard to dyspnea as measured with the use of the University of California, San Diego, Shortness of Breath Questionnaire. No new safety signals were observed, as compared with previous trials. CONCLUSIONS: In patients with IPF and a DlCO of 35% or less of the predicted value, nintedanib plus sildenafil did not provide a significant benefit as compared with nintedanib alone. No new safety signals were identified with either treatment regimen in this population of patients. (Funded by Boehringer Ingelheim; INSTAGE ClinicalTrials.gov number, NCT02802345 .).

Almitrine Infusion in Severe Acute Respiratory Syndrome Coronavirus 2-Induced Acute Respiratory Distress Syndrome: A Single-Center Observational Study.

OBJECTIVES: Treating acute respiratory failure in patients with coronavirus disease 2019 is challenging due to the lack of knowledge of the underlying pathophysiology. Hypoxemia may be explained in part by the loss of hypoxic pulmonary vasoconstriction. The present study assessed the effect of almitrine, a selective pulmonary vasoconstrictor, on arterial oxygenation in severe acute respiratory syndrome coronavirus 2-induced acute respiratory distress syndrome. DESIGN: Single-center retrospective observational study. SETTING: ICU of Lille Teaching Hospital, France, from February 27, 2020, to April 14, 2020. PATIENTS: Patients with coronavirus disease 2019 pneumonia confirmed by positive reverse transcriptase-polymerase chain reaction for severe acute respiratory syndrome-coronavirus 2 and acute respiratory distress syndrome according to Berlin definition. Data focused on clinicobiological features, ventilator settings, therapeutics, outcomes, and almitrine-related adverse events. INTERVENTIONS: Almitrine was considered in patients with severe hypoxemia (Pao2/Fio2 ratio < 150 mm Hg) in addition to the recommended therapies, at an hourly IV delivery of 10 µg/kg/min. Comparative blood gases were done before starting almitrine trial and immediately after the end of the infusion. A positive response to almitrine was defined by an increase of Pao2/Fio2 ratio greater than or equal to 20% at the end of the infusion. MEASUREMENTS AND MAIN RESULTS: A total of 169 patients were enrolled. Thirty-two patients with acute respiratory distress syndrome received an almitrine infusion trial. In most cases, almitrine was infused in combination with inhaled nitric oxide (75%). Twenty-one patients (66%) were responders. The median Pao2/Fio2 ratio improvement was 39% (9-93%) and differs significantly between the responders and nonresponders (67% [39-131%] vs 6% [9-16%], respectively; p < 0.0001). The 28-day mortality rates were 47.6% and 63.6% (p = 0.39) for the responders and nonresponders, respectively. Hemodynamic parameters remained similar before and after the trial, not suggesting acute cor pulmonale. CONCLUSIONS: Almitrine infusion improved oxygenation in severe acute respiratory syndrome coronavirus 2-induced acute respiratory distress syndrome without adverse effects. In a multistep clinical approach to manage severe hypoxemia in this population, almitrine could be an interesting therapeutic option to counteract the loss of hypoxic pulmonary vasoconstriction and redistribute blood flow away from shunting zones.

Inhaled nitric oxide reduces the intrapulmonary shunt to ameliorate severe hypoxemia after acute type A aortic dissection surgery.

BACKGROUND: To assess the relationship between the intrapulmonary shunt and PaO2/FiO2 in severe hypoxemic patients after acute type A aortic dissection (ATAAD) surgery and to evaluate the effect of inhaled nitric oxide (iNO) on intrapulmonary shunt. METHODS: Postoperative ATAAD patients with PaO2/FiO2 ≤ 150 mmHg were enrolled. Intrapulmonary shunt was calculated from oxygen content of different sites (artery [CaO2], mixed venous [CvO2], and alveolar capillary [CcO2]) using the Fick equation, where intrapulmonary shunt = (CcO2-CaO2)/(CcO2-CvO2). Related variables were measured at baseline (positive end expiratory pressure [PEEP] 5 cm H2O), 30 min after increasing PEEP (PEEP 10 cm H2O), 30 min after 5 ppm iNO therapy (PEEP 10 cm H2O + iNO), and 30 min after decreasing PEEP (PEEP 5 cm H2O + iNO). RESULTS: A total of 20 patients were enrolled between April 2019 and December 2019. Intrapulmonary shunt and PaO2/FiO2 were correlated in severe hypoxemic, postoperative ATAAD patients (adjusted R2 = 0.467, p < 0.001). A mixed model for repeated measures revealed that iNO, rather than increasing PEEP, significantly decreased the intrapulmonary shunt (by 15% at a PEEP of 5 cm H2O and 16% at a PEEP of 10 cm H2O, p < 0.001 each) and increased PaO2/FiO2 (by 63% at a PEEP of 5 cm H2O and 65% at a PEEP of 10 cm H2O, p < 0.001 each). After iNO therapy, the decrement of intrapulmonary shunt and the increment of PaO2/FiO2 were also correlated (adjusted R2 = 0.375, p < 0.001). CONCLUSIONS: This study showed that intrapulmonary shunt and PaO2/FiO2 were correlated in severe hypoxemic, postoperative ATAAD patients. Furthermore, iNO, rather than increasing PEEP, significantly decreased the intrapulmonary shunt to improve severe hypoxemic conditions.

Novel coronavirus SARS-CoV-2 (Covid-19) dynamics inside the human body.

A knowledge-based cybernetic framework model representing the dynamics of SARS-CoV-2 inside the human body has been studied analytically and in silico to explore the pathophysiologic regulations. The following modeling methodology was developed as a platform to introduce a predictive tool supporting a therapeutic approach to Covid-19 disease. A time-dependent nonlinear system of ordinary differential equations model was constructed involving type-I cells, type-II cells, SARS-CoV-2 virus, inflammatory mediators, interleukins along with host pulmonary gas exchange rate, thermostat control, and mean pressure difference. This formalism introduced about 17 unknown parameters. Estimating these unknown parameters requires a mathematical association with the in vivo sparse data and the dynamic sensitivities of the model. The cybernetic model can simulate a dynamic response to the reduced pulmonary alveolar gas exchange rate, thermostat control, and mean pressure difference under a very critical condition based on equilibrium (steady state) values of the inflammatory mediators and system parameters. In silico analysis of the current cybernetical approach with system dynamical modeling can provide an intellectual framework to help experimentalists identify more active therapeutic approaches.

The effect of dopamine on pulmonary diffusing capacity and capillary blood volume responses to exercise in young healthy humans.

NEW FINDINGS: What is the Central question? Does dopamine, a pulmonary vascular vasodilator, contribute to the regulation of pulmonary diffusing capacity and capillary blood volume responses to exercise and exercise tolerance? What are the main findings and their importance? Dopamine appears not to be important for regulating pulmonary diffusing capacity or pulmonary capillary blood volume during exercise in healthy participants. Dopamine blockade trials demonstrated that endogenous dopamine is important for maintaining exercise tolerance; however, exogenous dopamine does not improve exercise tolerance. ABSTRACT: Pulmonary capillary blood volume (Vc ) and diffusing membrane capacity (Dm ) expansion are important contributors to the increased pulmonary diffusing capacity (DLCO ) observed during upright exercise. Dopamine is a pulmonary vascular vasodilator, and recent studies suggest that it may play a role in Vc regulation through changes in pulmonary vascular tone. The purpose of this study was to examine the effect of exogenous dopamine and dopamine receptor-2 (D2 -receptor) blockade on DLCO , Vc and Dm at baseline and during cycle exercise, as well as time-to-exhaustion at 85% of V̇O2peak . We hypothesized that dopamine would increase DLCO , Vc , Dm and time-to-exhaustion, while D2 -receptor blockade would have the opposite effect. We recruited 14 young, healthy, recreationally active subjects ( V̇O2peak 45.8 ± 6.6 ml kg-1  min-1 ). DLCO , Vc and Dm were determined at baseline and during exercise at 60% and 85% of V̇O2peak under the following randomly assigned and double blinded conditions: (1) intravenous saline and placebo pill, (2) intravenous dopamine (2 µg kg-1  min-1 ) and placebo pill, and (3) intravenous saline and D2 -receptor antagonist (20 mg oral metoclopramide). Exogenous dopamine and dopamine blockade had no effect on DLCO , Vc and Dm responses at baseline or during exercise. Dopamine blockade reduced time-to-exhaustion by 47% (P = 0.04), but intravenous dopamine did not improve time-to-exhaustion. While dopamine modulation did not affect DLCO , Vc or Dm , the reduction in time-to-exhaustion with D2 -receptor blockade suggests that endogenous dopamine is important for exercise tolerance.

Respiratory Physiology for the Anesthesiologist.

Respiratory function is fundamental in the practice of anesthesia. Knowledge of basic physiologic principles of respiration assists in the proper implementation of daily actions of induction and maintenance of general anesthesia, delivery of mechanical ventilation, discontinuation of mechanical and pharmacologic support, and return to the preoperative state. The current work provides a review of classic physiology and emphasizes features important to the anesthesiologist. The material is divided in two main sections, gas exchange and respiratory mechanics; each section presents the physiology as the basis of abnormal states. We review the path of oxygen from air to the artery and of carbon dioxide the opposite way, and we have the causes of hypoxemia and of hypercarbia based on these very footpaths. We present the actions of pressure, flow, and volume as the normal determinants of ventilation, and we review the resulting abnormalities in terms of changes of resistance and compliance.

Beetroot Juice Does Not Enhance Supramaximal Intermittent Exercise Performance in Elite Endurance Athletes.

Objective: Nitrate (NO3-)-rich beetroot juice (BR) is recognized as an ergogenic supplement that improves exercise tolerance during submaximal to maximal intensity exercise in recreational and competitive athletes. A recent study has investigated the effectiveness of BR on exercise performance during supramaximal intensity intermittent exercise (SIE) in Olympic-level track cyclists, but studies conducted in elite endurance athletes are scarce. The present study aimed to determine whether BR supplementation enhances the tolerance to SIE in elite endurance athletes.Methods: Eleven elite endurance athletes (age: 21.7 ± 3.7 years, maximal oxygen uptake [Formula: see text] 71.1 ± 5.2 mL·kg-1·min-1) performed an SIE test until exhaustion following either a 3-day BR supplementation (340 mg/d) or a placebo (PL) supplementation (<2.5 mg/d) in a randomized, single blind, placebo-controlled, and crossover study. The exercise test consisted of 15-second cycling exercise bouts at 170% of the maximal aerobic power interspersed with 30-second passive recovery periods. Gas exchange was measured during SIE tests as local muscle O2 delivery and extraction were assessed by near infrared spectroscopy.Results: The number of repetitions completed was not significantly different between BR (13.9 ± 4.0 reps) and PL conditions (14.2 ± 4.5 reps). BR supplementation did not affect oxygen uptake ([Formula: see text]) during SIE tests (BR: 3378.5 ± 681.8 mL·min-1, PL: 3466.1 ± 505.3 mL·min-1). No significant change in the areas under curves was found for local muscle total hemoglobin (BR: 6816.9 ± 1463.1 arbitrary units (a.u.), PL: 6771.5 ± 3004.5 a.u.) and deoxygenated hemoglobin (BR: 6619.7 ± 875.8 a.u., PL: 6332.7 ± 1336.8 a.u.) during time-matched work + recovery periods from SIE tests following BR supplementation.Conclusions: BR supplementation does not enhance the tolerance to SIE in elite endurance athletes and affects neither [Formula: see text] nor local muscle O2 delivery and extraction.

Antenatal sildenafil treatment improves neonatal pulmonary hemodynamics and gas exchange in lambs with diaphragmatic hernia.

OBJECTIVES: Infants with congenital diaphragmatic hernia (CDH) are predisposed to pulmonary hypertension after birth, owing to lung hypoplasia that impairs fetal pulmonary vascular development. Antenatal sildenafil treatment attenuates abnormal pulmonary vascular and alveolar development in rabbit and rodent CDH models, but whether this translates to functional improvements after birth remains unknown. We aimed to evaluate the effect of antenatal sildenafil on neonatal pulmonary hemodynamics and lung function in lambs with diaphragmatic hernia (DH). METHODS: DH was surgically induced at approximately 80 days' gestation in 16 lamb fetuses (term in lambs is approximately 147 days). From 105 days' gestation, ewes received either sildenafil (0.21 mg/kg/h intravenously) or saline infusion until delivery (n = 8 fetuses in each group). At approximately 138 days' gestation, all lambs were instrumented and then delivered via Cesarean section. The lambs were ventilated for 120 min with continuous recording of physiological (pulmonary and carotid artery blood flow and pressure; cerebral oxygenation) and ventilatory parameters, and regular assessment of arterial blood gas tensions. Only lambs that survived until delivery and with a confirmed diaphragmatic defect at postmortem examination were included in the analysis; these comprised six DH-sildenafil lambs and six DH-saline control lambs. RESULTS: Lung-to-body-weight ratio (0.016 ± 0.001 vs 0.013 ± 0.001; P = 0.06) and dynamic lung compliance (0.8 ± 0.2 vs 0.7 ± 0.2 mL/cmH2 O; P = 0.72) were similar in DH-sildenafil lambs and controls. Pulmonary vascular resistance decreased following lung aeration to a greater degree in DH-sildenafil lambs, and was 4-fold lower by 120 min after cord clamping than in controls (0.6 ± 0.1 vs 2.2 ± 0.6 mmHg/(mL/min); P = 0.002). Pulmonary arterial pressure was also lower (46 ± 2 vs 59 ± 2 mmHg; P = 0.048) and pulmonary blood flow higher (25 ± 3 vs 8 ± 2 mL/min/kg; P = 0.02) in DH-sildenafil than in DH-saline lambs at 120 min. Throughout the 120-min ventilation period, the partial pressure of arterial carbon dioxide tended to be lower in DH-sildenafil lambs than in controls (63 ± 8 vs 87 ± 8 mmHg; P = 0.057), and there was no significant difference in partial pressure of arterial oxygen between the two groups. CONCLUSIONS: Sustained maternal antenatal sildenafil infusion reduced pulmonary arterial pressure and increased pulmonary blood flow in DH lambs for the first 120 min after birth. These findings of improved pulmonary vascular function are consistent with improved pulmonary vascular structure seen in two previous animal models. The data support the rationale for a clinical trial investigating the effect of antenatal sildenafil in reducing the risk of neonatal pulmonary hypertension in infants with CDH. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

A shared protocol for porcine surfactant use in pediatric acute respiratory distress syndrome: a feasibility study.

BACKGROUND: Pediatric ARDS still represents a difficult challenge in Pediatric Intensive Care Units (PICU). Among different treatments proposed, exogenous surfactant showed conflicting results. Aim of this multicenter retrospective observational study was to evaluate whether poractant alfa use in pediatric ARDS might improve gas exchange in children less than 2 years old, according to a shared protocol. METHODS: The study was carried out in fourteen Italian PICUs after dissemination of a standardized protocol for surfactant administration within the Italian PICU network. The protocol provides the administration of surfactant (50 mg/kg) divided in two doses: the first dose is used as a bronchoalveolar lavage while the second as supplementation. Blood gas exchange variations before and after surfactant use were recorded. RESULTS: Sixty-nine children, age 0-24 months, affected by Acute Respiratory Distress Syndrome treated with exogenous porcine surfactant were enrolled. Data collection consisted of patient demographics, respiratory variables and arterial blood gas analysis. The most frequent reasons for PICU admission were acute respiratory failure, mainly bronchiolitis and pneumonia, and septic shock. Fifty-four children (78.3%) had severe ARDS (define by oxygen arterial pressure and inspired oxygen fraction ratio (P/F) < 100), 15 (21.7%) had moderate ARDS (100 < P/F < 200). PO2, P/F, Oxygenation Index (OI) and pH showed a significant improvement after surfactant use with respect to baseline (p < 0.001 at each included time-point for each parameter). No significant difference in blood gas variations were observed among four different subgroups of diseases (bronchiolitis, pneumonia, septic shock and others). Overall, 11 children died (15.9%) and among these, 10 (90.9%) had complex chronic conditions. Two children (18.2%) died while being treated with Extracorporeal Membrane Oxygenation (ECMO). Mortality for severe pARDS was 20.4%. CONCLUSION: The use of porcine Surfactant improves oxygenation, P/F ratio, OI and pH in a population of children with moderate or severe pARDS caused by multiple diseases. A shared protocol seems to be a good option to obtain the same criteria of enrollment among different PICUs and define a unique way of use and administration of the drug for future studies.

Effects of crystalloids and colloids on microcirculation, central venous oxygen saturation, and central venous-to-arterial carbon dioxide gap in a rabbit model of hemorrhagic shock.

OBJECTIVE: The effects of hydroxyethyl starch (HES) on microcirculation, central venous oxygen saturation (ScvO2), and the central venous-to-arterial carbon dioxide gap (dCO2) are studied in a rabbit model of hemorrhagic shock for elucidating the advantages and drawbacks of resuscitation with HES compared with crystalloids. METHODS: An ear chamber and sublingual mucosa were used to examine blood vessels by intravital microscopy. Hemorrhagic shock was induced by removing nearly half of the blood volume. Twenty-two rabbits received 20 mL of HES by intravenous infusion immediately after bloodletting. Additional HES was then administered intravenously to a total volume of 100 mL. The other 22 rabbits (control) were intravenously given 40 mL of normal saline solution (NSS), followed by additional NSS to a total volume of 200 mL, administered under the same conditions as HES. RESULTS: After the infusion, the vessel density and perfusion rate of the sublingual microcirculation recovered in the HES group. The arteriolar diameter, blood flow velocity, and blood flow rate of the ear microcirculation were maintained in this group, and microcirculatory failure did not develop. In the NSS group, however, all 5 of the aforementioned measured variables were significantly smaller than those in the HES group after the completion of infusion. The recovery of ScvO2 and dCO2 to the respective baseline values was significantly better in the HES group than in the NSS group. CONCLUSION: Intravenous infusion of HES effectively maintains adequate tissue oxygenation and perfusion in hemorrhagic shock.

The Association Between Inhaled Nitric Oxide Treatment and ICU Mortality and 28-Day Ventilator-Free Days in Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVES: To investigate the association between inhaled nitric oxide treatment and ICU mortality and 28-day ventilator-free days in pediatric acute respiratory distress syndrome. DESIGN: Retrospective cohort study. A propensity score for inhaled nitric oxide treatment was developed and used in the analysis. SETTING: Two quaternary care PICUs. PATIENTS: Children with pediatric acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 499 children enrolled in this study with 143 (28.7%) receiving inhaled nitric oxide treatment. Children treated with inhaled nitric oxide were more likely to have a primary diagnosis of pneumonia (72% vs 54.8%; p < 0.001), had a higher initial oxygenation index (median 16.9 [interquartile range, 10.1-27.3] vs 8.5 [interquartile range, 5.8-12.2]; p < 0.001), and had a higher 72-hour maximal Vasoactive-Inotrope Score (median 15 [interquartile range, 6-25] vs 8 [interquartile range, 0-17.8]; p < 0.001) than those not receiving inhaled nitric oxide. Mortality was higher in the inhaled nitric oxide treatment group (25.2% vs 16.3%; p = 0.02), and children in this group had fewer 28-day ventilator-free days (10 d [interquartile range, 0-18 d] vs 17 d (interquartile range 5.5-22 d]; p < 0.0001). We matched 176 children based on propensity score for inhaled nitric oxide treatment. In the matched cohort, inhaled nitric oxide treatment was not associated with mortality (odds ratio, 1.3 [95% CI, 0.56-3.0]) or 28-day ventilator-free days (incidence rate ratio, 0.91 [95% CI, 0.80-1.04]). These results remained consistent in the entire study cohort when the propensity score for inhaled nitric oxide treatment was used for either inverse probability weighting or stratification in regression modeling with the exception that subjects treated with inhaled nitric oxide were more likely to have 0 ventilator-free days (p ≤ 0.02). In secondary analysis stratified by oxygenation response, inhaled nitric oxide treatment was not associated with mortality or 28-day ventilator-free days in children with a positive oxygenation response (all p > 0.2) CONCLUSIONS:: Treatment with inhaled nitric oxide in pediatric acute respiratory distress syndrome is not associated with improvement in either mortality or ventilator-free days and may be associated with harm. Further prospective trials are required to define the role of inhaled nitric oxide treatment in pediatric acute respiratory distress syndrome.

Influence of dietary nitrate supplementation on lung function and exercise gas exchange in COPD patients.

BACKGROUND: During exercise as pulmonary blood flow rises, pulmonary capillary blood volume increases and gas exchange surface area expands through distention and recruitment. We have previously demonstrated that pulmonary capillary recruitment is limited in COPD patients with poorer exercise tolerance. Hypoxia and endothelial dysfunction lead to pulmonary vascular dysregulation possibly in part related to nitric oxide related pathways. PURPOSE: To determine if increasing dietary nitrate might influence lung surface area for gas exchange and subsequently impact exercise performance. METHODS: Subjects had stable, medically treated COPD (n = 25), gave informed consent, filled out the St George Respiratory Questionnaire (SGRQ), had a baseline blood draw for Hgb, performed spirometry, and had exhaled nitric oxide (exNO) measured. Then they performed the intra-breath (IB) technique for lung diffusing capacity for carbon monoxide (DLCO) as well as pulmonary blood flow (Qc). Subsequently they completed a progressive semi-recumbent cycle ergometry test to exhaustion with measures of oxygen saturation (SpO2) and expired gases along with DLCO and Qc measured during the 1st work load only. Subjects were randomized to nitrate supplement group (beetroot juice) or placebo group (black currant juice) for 8 days and returned for repeat of the above protocol. RESULTS: Exhaled nitric oxide levels rose >200% in the nitrate group (p < 0.05) with minimal change in placebo group. The SGRQ suggested a small fall in perceived symptom limitation in the nitrate group, but no measure of resting pulmonary function differed post nitrate supplementation. With exercise, there was no influence of nitrate supplementation on peak VO2 or other measures of respiratory gas exchange. There was a tendency for the exercise DLCO to increase slightly in the nitrate group with a trend towards a rise in the DLCO/Qc relationship (p = 0.08) but not in the placebo group. The only other significant finding was a fall in the exercise blood pressure in the nitrate group, but not placebo group (p < 0.05). CONCLUSION: Despite evidence of a rise in exhaled nitric oxide levels with nitrate supplementation, there was minimal evidence for improvement in exercise performance or pulmonary gas exchange surface area in a stable medically treated COPD population.

Anti-IL-8 antibody potentiates the effect of exogenous surfactant in respiratory failure caused by meconium aspiration.

AIM: Meconium aspiration syndrome (MAS) is life-threatening respiratory failure of newborns which can be treated by exogenous surfactant. In response to meconium, increased levels of chemokine IL-8 (CXCL8) stimulate massive neutrophil infiltration of the lungs. Local accumulation and activation of neutrophils, on-going inflammation, lung edema, and oxidative damage contribute to inactivation of endogenous and therapeutically given surfactants. Therefore, we have hypothesized that addition of monoclonal anti-IL-8 antibody into exogenous surfactant can mitigate the neutrophil-induced local injury and the secondary surfactant inactivation and may finally result in improvement of respiratory functions. METHODS: New Zealand rabbits with intratracheal meconium-induced respiratory failure (meconium 25 mg/ml, 4 ml/kg) were divided into three groups: untreated (M), surfactant-treated (M + S), and treated with combination of surfactant and anti-IL-8 antibody (M + S + anti-IL-8). Surfactant therapy consisted of two lung lavages with diluted porcine surfactant Curosurf (10 ml/kg, 5 mg phospholipids (PL)/ml) followed by undiluted Curosurf (100 mg PL/kg) delivered by means of asymmetric high-frequency jet ventilation (f. 300/min, Ti 20%). In M + S + anti-IL-8 group, anti-IL-8 antibody (100 µg/kg) was added directly to Curosurf dose. Animals were oxygen-ventilated for additional 5 h, respiratory parameters were measured regularly. Subsequently, cell counts in bronchoalveolar lavage fluid (BAL), lung edema formation, oxidative damage, levels of interleukins (IL)-1ß and IL-6 in the lung homogenate were evaluated. RESULTS: Surfactant instillation significantly improved lung function. Addition of anti-IL-8 to surfactant further improved gas exchange and ventilation efficiency and had longer-lasting effect than surfactant-only therapy. Combined treatment showed the trend to reduce neutrophil count in BAL fluid, local oxidative damage, and levels of IL-1ß and IL-6 more effectively than surfactant-alone, however, these differences were not significant. CONCLUSION: Addition of anti-IL-8 antibody to surfactant could potentiate the efficacy of Curosurf on the gas exchange in experimental model of MAS.

The effects of morphine on gas exchange, ventilation pattern and ventilatory responses to hypercapnia and hypoxia in dwarf caiman (Paleosuchus palpebrosus).

Morphine and other opioids cause respiratory depression in high doses and lower the ventilatory responses to hypoxia and hypercapnia in mammals. Recent studies indicate that turtles respond similarly, but although they are used routinely for post-surgical analgesia, little is known about the physiological effects of opioids in reptiles. We therefore investigated the effects of morphine (10 and 20 mg kg-1) on gas exchange and ventilation in six dwarf caiman (Paleosuchus palpebrosus) using pneumotachography in a crossover design. Intraperitoneal injections of morphine changed the ventilation pattern from a typical intermittent/periodic pattern with a few or several breaths in ventilatory bouts to single breaths and prolonged the apnoea, such that respiratory frequency was depressed, while tidal volume was elevated. Furthermore, the duration of inspiration and especially expiration was prolonged. The resulting decrease in minute ventilation was attended by a lowering of the respiratory exchange ratio (RER) (especially for 20 mg kg-1 dose) indicating CO2 retention with a long time constant for approaching the new steady state. The changes in ventilation pattern and gas exchange reached a new stable level approximately 3 h after the morphine injection and did not significantly affect steady state O2 uptake, i.e. O2 consumption. As expected, the ventilatory response to 5% O2 was lower in morphine-treated caimans, but minute ventilation upon exposure to 2% CO2 did not differ significantly different from control animals.

R-100 improves pulmonary function and systemic fluid balance in sheep with combined smoke-inhalation injury and Pseudomonas aeruginosa sepsis.

BACKGROUND: Septic shock is a major cause of death in intensive care units around the world . The aim of the study was to investigate whether the novel drug R-100 (a superoxide degradation catalyst and nitric oxide donor) improves pulmonary function in a sheep model of septic shock caused by Pseudomonas aeruginosa and smoke inhalation. METHODS: Eleven female sheep were prepared surgically and randomly assigned to a treatment group (n = 5) or a control group (n = 6) after inhalation of cooled cotton smoke and airway instillation of live P. aeruginosa (2.5 × 1011 CFU) by bronchoscope under deep anesthesia and analgesia. The treatment group received an intravenous infusion of a total of 80 mg/kg of R-100 diluted in 500 mL of 5% dextrose. The control group was given 500 mL of 5% dextrose. All animals received intravenous lactated Ringer's solution to maintain a hematocrit level at baseline ± 3%. Blood gas and hemodynamics were measured at baseline and then analyzed every 3 h during the 24-h study period. Results are expressed as mean ± SEM. RESULTS: The treated animals showed significant improvement in their pulmonary gas exchange (PaO2/FiO2 ratio at 24 h: 246 ± 29 vs. 90 ± 40 mmHg control, P < 0.05). Pulmonary arterial pressures were reduced in the treated group (24 h: 26 ± 1 vs. 30 ± 2 cm mmHg control, P < 0.05). The treated animals also had an improved total fluid balance after 24 h (190 ± 45/24 h mL vs. 595 ± 234/24 h mL control, P < 0.05). CONCLUSIONS: Treatment with R-100 improves pulmonary gas exchange and blood oxygenation, and prevents a fluid imbalance in sheep subjected to smoke inhalation and P. aeruginosa.

[Salidroside improves pulmonary fibrosis by down-regulation of cathepsin B and NF-κBp65 in rats].

OBJECTIVE: To investigate the mechanism of salidroside in improvement of pulmonary fibrosis in rats.
 Methods: SD rats were subjected to 6 groups: a blank group, a model group, a pirfenidone group, a high-dose salidroside group, a middle-dose salidroside group, and a low-dose salidroside group. The contents of ALB, ALP, LDH, PC-III and COL4, and the expression levels of cathepsin B (CB) and NF-κBp65 in the 6 groups were analyzed.
 Results: Lung coefficient and oxygen partial pressure in the blank group were lower than those in the model group (P<0.05). Compared with the model group, lung coefficients in the pirfenidone group, the high-dose salidroside group, the middle-dose salidroside group, and the low-dose salidroside group were decreased, while oxygen partial pressures were statistically increased (P<0.05). The contents of ALB, ALP and LDH in the model group were statistically increased (P<0.05) in a dose-dependent manner. Compared with the blank group, the contents of GSH, HYP, PC-III and COL4, and the expression levels of CB and NF-κBp65 in the model group were significantly increased (P<0.05), which were attenuated by alidroside in a dose-dependent manner (P<0.05).
 Conclusion: Salidroside can improve pulmonary fibrosis in rats, and the mechanism may be related to reduce the expression of CB and NF-κBp65.

Effects of dietary phosphate on glucose and lipid metabolism.

Recent epidemiological and animal studies have suggested that excess intake of phosphate (Pi) is a risk factor for the progression of chronic kidney disease and its cardiovascular complications. However, little is known about the impact of dietary high Pi intake on the development of metabolic disorders such as obesity and type 2 diabetes. In this study, we investigated the effects of dietary Pi on glucose and lipid metabolism in healthy rats. Male 8-wk-old Sprague-Dawley rats were divided into three groups and given experimental diets containing varying amounts of Pi, i.e., 0.2 [low Pi(LP)], 0.6 [control Pi(CP)], and 1.2% [high Pi(HP)]. After 4 wk, the HP group showed lower visceral fat accumulation compared with other groups, accompanied by a low respiratory exchange ratio (V̇CO2/V̇O2) without alteration of locomotive activity. The HP group had lower levels of plasma insulin and nonesterified fatty acids. In addition, the HP group also showed suppressed expression of hepatic lipogenic genes, including sterol regulatory element-binding protein-1c, fatty acid synthase, and acetyl-CoA carboxylase, whereas there was no difference in hepatic fat oxidation among the groups. On the other hand, uncoupling protein (UCP) 1 and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression were significantly increased in the brown adipose tissue (BAT) of the HP group. Our data demonstrated that a high-Pi diet can negatively regulate lipid synthesis in the liver and increase mRNA expression related to lipid oxidation and UCP1 in BAT, thereby preventing visceral fat accumulation. Thus, dietary Pi is a novel metabolic regulator.

Nebulized Epinephrine Limits Pulmonary Vascular Hyperpermeability to Water and Protein in Ovine With Burn and Smoke Inhalation Injury.

OBJECTIVES: To test the hypothesis that nebulized epinephrine ameliorates pulmonary dysfunction by dual action-bronchodilation (ß2-adrenergic receptor agonism) and attenuation of airway hyperemia (α1-adrenergic receptor agonism) with minimal systemic effects. DESIGN: Randomized, controlled, prospective, and large animal translational studies. SETTING: University large animal ICU. SUBJECTS: Twelve chronically instrumented sheep. INTERVENTIONS: The animals were exposed to 40% total body surface area third degree skin flame burn and 48 breaths of cooled cotton smoke inhalation under deep anesthesia and analgesia. The animals were then placed on a mechanical ventilator, fluid resuscitated, and monitored for 48 hours in a conscious state. After the injury, sheep were randomized into two groups: 1) epinephrine, nebulized with 4 mg of epinephrine every 4 hours starting 1 hour post injury, n = 6; or 2) saline, nebulized with saline in the same manner, n = 6. MEASUREMENTS AND MAIN RESULTS: Treatment with epinephrine had a significant reduction of the pulmonary transvascular fluid flux to water (p < 0.001) and protein (p < 0.05) when compared with saline treatment from 12 to 48 hours and 36 to 48 hours, respectively. Treatment with epinephrine also reduced the systemic accumulation of body fluids (p < 0.001) with a mean of 1,410 ± 560 mL at 48 hours compared with 3,284 ± 422 mL of the saline group. Hemoglobin levels were comparable between the groups. Changes in respiratory system dynamic compliance, mean airway pressure, PaO2/FiO2 ratio, and oxygenation index were also attenuated with epinephrine treatment. No considerable systemic effects were observed with epinephrine treatment. CONCLUSIONS: Nebulized epinephrine should be considered for use in future clinical studies of patients with burns and smoke inhalation injury.

Noninvasive measurement of renal oxygen extraction fraction under the influence of respiratory challenge.

PURPOSE: To demonstrate the feasibility of using a susceptibility-based magnetic resonance imaging (MRI) technique for measuring renal oxygen extraction fraction (OEF) changes under the influence of carbogen (97% O2 , 3% CO2 ) breathing. MATERIALS AND METHODS: Eight New Zealand White rabbits were included in this study with local animal care committee approval. For OEF measurement, an asymmetric spin echo (ASE) sequence was used to acquire source images and a susceptibility model was utilized for OEF estimation at 3.0T. Within-session and between-day tests were conducted to evaluate the reproducibility of this OEF measurement. OEF changes were measured under respiratory challenge with alternated air and carbogen (97% O2 , 3% CO2 ) breathing. For comparison, blood samples were collected for the measurement of pO2 . RESULTS: The within-session coefficients of variation (CVs) of renal OEF measurements were 6.62% in cortex and 5.92% in medulla, while between-day CVs were 7.52% in cortex and 8.03% in medulla. Under carbogen breathing, renal OEFs decreased significantly from 0.32 ± 0.03 to 0.28 ± 0.02 (P < 0.01) in cortex, and from 0.34 ± 0.04 to 0.31 ± 0.03 (P < 0.01) in medulla. No statistical difference of relative OEF change was seen between cortex and medulla (P = 0.93). In addition, negative correlation between renal OEF and blood pO2 was found (r = 0.68 (P < 0.05) in cortex, and r = 0.64 (P < 0.05) in medulla). CONCLUSION: This study demonstrates the feasibility of using a susceptibility-based OEF measurement method for the evaluation of renal oxygenation changes induced by carbogen breathing. J. Magn. Reson. Imaging 2016;44:230-237.