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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.

The opioid buprenorphine alters breathing and the cytokine leptin stimulates breathing. Obesity increases the risk for respiratory disorders and can lead to leptin resistance. This study tested the hypothesis that buprenorphine causes dose-dependent changes in breathing that vary as a function of obesity, leptin status, and sex. Breathing measures were acquired from four congenic mouse lines: female and male wild type C57BL/6J (B6) mice, obese db/db and ob/ob mice with leptin dysfunction, and male B6 mice with diet-induced obesity. Mice were injected intraperitoneally with saline (control) and five doses of buprenorphine (0.1, 0.3, 1.0, 3.0, 10 mg/kg). Buprenorphine caused dose-dependent decreases in respiratory frequency while increasing tidal volume, minute ventilation, and respiratory duty cycle. The effects of buprenorphine varied significantly with leptin status and sex. Buprenorphine decreased minute ventilation variability in all mice. The present findings highlight leptin status as an important modulator of respiration and encourage future studies aiming to elucidate the mechanisms through which leptin status alters breathing., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The preBötzinger complex (preBötC) is a medullary area essential for normal breathing and widely recognized as necessary and sufficient to generate the inspiratory phase of respiration. It has been studied mainly in rodents. Here we report the main results of our studies revealing the characteristics of the rabbit preBötC identified by means of neuronal recordings, D,L-homocysteic acid microinjections and histological controls. A crucial role in the respiratory rhythmogenesis within this neural substrate is played by excitatory amino acids, but also GABA and glycine display important contributions. Increases in respiratory frequency are induced by microinjections of neurokinins, somatostatin as well by serotonin (5-HT) through an action on 5-HT 1A and 5-HT 3 receptors or the disinhibition of a GABAergic circuit. Respiratory depression is observed in response to microinjections of the μ-opioid receptor agonist DAMGO. Our results show similarities and differences with the rodent preBötC and emphasize the importance of comparative studies on the mechanisms underlying respiratory rhythmogenesis in different animal species., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Effects of acetylcholine (ACh) on respiratory activity have been an intriguing theme especially in relation to central chemoreception and the control of hypoglossal nerve activity. We studied the effects of ACh on hypoglossal and phrenic (C4) nerve activities and inspiratory and pre-inspiratory neurons in the rostral ventrolateral medulla in brainstem-spinal cord preparations from newborn rats. ACh application increased respiratory rhythm, decreased inspiratory hypoglossal and C4 nerve burst amplitude, and enhanced pre-inspiratory hypoglossal activity. ACh induced membrane depolarization of pre-inspiratory neurons that might be involved in facilitation of respiratory rhythm by ACh. Effects of ACh on hypoglossal and C4 nerve activity were partially reversed by a nicotinic receptor blocker, mecamylamine. Further application of a muscarinic receptor antagonist, oxybutynin, resulted in slight increase of hypoglossal (but not C4) burst amplitude. Thus, ACh induced different effects on hypoglossal and C4 nerve activity in the brainstem-spinal cord preparation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Neonatal foals may require prolonged sedation to permit ventilatory support in the first few days of life. The objective of this study was to evaluate and compare the cardiopulmonary effects and clinical recovery characteristics of 2 sedative/analgesia protocols in healthy foals receiving assisted ventilation. Foals were randomized to receive dexmedetomidine, butorphanol, and propofol (DBP) or midazolam, butorphanol, and propofol (MBP) during a 24-hour period. Infusion rates of dexmedetomidine, midazolam, and propofol were adjusted and propofol boluses administered according to set protocols to maintain optimal sedation and muscle relaxation. Ventilatory support variables were adjusted to preset targets. Physiologic variables were recorded, cardiac output (CO) measured (thermodilution), and arterial and mixed venous blood collected for gas analysis at intervals up to 24 hours. Foals in group DBP received dexmedetomidine [2.4 ± 0.5 μg/kg body weight (BW) per hour], butorphanol (13 μg/kg BW per hour), and propofol (6.97 ± 0.86 mg/kg BW per hour), whereas foals in group MBP received midazolam (0.14 ± 0.04 mg/kg BW per hour), butorphanol (13 μg/kg BW per hour), and propofol (5.98 ± 1.33 mg/kg BW per hour). Foals in the DBP group received significantly more propofol boluses (9.0 ± 3.0) than those in the MBP group (4.0 ± 2.0). Although physiologic variables remained within acceptable limits, heart rate (HR), mean arterial pressure (MAP), and cardiac index (CI) were lower in foals in the DBP group than in the MBP group. Times to sternal recumbency, standing, and nursing were significantly shorter in the DBP than MBP group. We found that MBP and DBP protocols are suitable to assist ventilatory support in neonatal foals, although MBP results in a prolonged recovery compared to DBP., (Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.)

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 1β (IL-1β), 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-1β, 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.

Aerial translocation of captured black rhinoceroses (Diceros bicornis) has been accomplished by suspending them by their feet. We expected this posture would compromise respiratory gas exchange more than would lateral recumbency. Because white rhinoceroses (Ceratotherium simum) immobilized with etorphine alone are hypermetabolic, with a high rate of carbon dioxide production (VCO2), we expected immobilized black rhinoceroses would also have a high VCO2. Twelve (nine male, three female; median age 8 yr old [range: 4-25]; median weight 1,137 kg [range: 804-1,234] body weight) wild black rhinoceroses were immobilized by aerial darting with etorphine and azaperone. The animals were in lateral recumbency or suspended by their feet from a crane for approximately 10 min before data were collected. Each rhinoceros received both treatments sequentially, in random order. Six were in lateral recumbency first and six were suspended first. All animals were substantially hypoxemic and hypercapnic in both postures. When suspended by the feet, mean arterial oxygen pressure (PaO2) was 42 mm Hg, 4 mm Hg greater than in lateral recumbency (P=0.030), and arterial carbon dioxide pressure (PaCO2) was 52 mm Hg, 3 mm Hg less than in lateral recumbency (P=0.016). Tidal volume and minute ventilation were similar between postures. The mean VCO2 was 2 mL/kg/min in both postures and was similar to, or marginally greater than, VCO2 predicted allometrically. Suspension by the feet for 10 min did not impair pulmonary function more than did lateral recumbency and apparently augmented gas exchange to a small degree relative to lateral recumbency. The biological importance in these animals of numerically small increments in PaO2 and decrements in PaCO2 with suspension by the feet is unknown. Black rhinoceroses immobilized with etorphine and azaperone were not as hypermetabolic as were white rhinoceroses immobilized with etorphine., (© Wildlife Disease Association 2021.)

The assessment of ventilatory efficiency is critical to understanding the matching of ventilation (VE) and perfusion in the lungs during exercise. This study aimed to establish a causal physiological relationship between ventilatory efficiency and resistance exercise performance after beetroot juice (BJ) intake. Eleven well-trained males performed a resistance exercise test after drinking 140 mL of BJ (~12.8 mmol NO 3 - ) or a placebo (PL). Ventilatory efficiency was assessed by the VE•VCO 2 -1 slope, the oxygen uptake efficiency slope and the partial pressure of end-tidal carbon dioxide (PetCO 2 ). The two experimental conditions were controlled using a randomized, double-blind crossover design. The resistance exercise test involved repeating the same routine twice, which consisted of wall ball shots plus a full squat (FS) with a 3 min rest or without a rest between the two exercises. A higher weight lifted was detected in the FS exercise after BJ intake compared with the PL during the first routine ( p = 0.004). BJ improved the VE•VCO 2 -1 slope and the PetCO 2 during the FS exercise in the first routine and at rest ( p < 0.05). BJ intake improved the VE•VCO 2 -1 slope and the PetCO 2 coinciding with the resistance exercise performance. The ergogenic effect of BJ could be induced under aerobic conditions at rest.

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 (V T ), 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.

Ketamine-free, midazolam-based protocols have successfully immobilized cervids in the past but their impact on physiological function has not yet been thoroughly investigated. Six deer received IM dexmedetomidine (30.96 ± 3.06 µg/kg) and midazolam (0.31 ± 0.03 mg/kg). Heart rates (HR), respiratory rates ( f ), rectal temperature, mean arterial blood pressure (MAP), and oxygen saturation (SpO 2 ) were recorded 25 min after drug delivery (T25) and every 5 min until T55. An arterial blood sample was collected at T40. Mean HR and temperature significantly decreased throughout sedation, but were maintained above critical values (> 60 beats/ min and 37°C, respectively). Although not statistically different, f clinically decreased during sedation. MAP remained within acceptable ranges (60-80 mmHg) and SpO 2 above 95%. Mean PaO 2 was normal (>80 mmHg), but a mild hypoxemia was observed on two occasions. Recovery was smooth yet prolonged, as the first head movement, attempt to stand, sternal recumbency, and standing position were recorded within 9.36 ± 3.47, 10.32 ± 1.37, 13.13 ± 2.70, and 15.34 ± 2.57 min after IM atipamezole, respectively. This protocol was effective for short-term procedures in captive brown brocket deer, and appeared to be safe on the basis of arterial blood gases and cardiorespiratory variables.

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.

The effects of high external ammonia (HEA) exposure on breathing and the potential involvement of ammonia transporting Rh proteins in ammonia sensing were assessed in larval and adult zebrafish. Acute exposure of adults to either 250 or 500 μM (NH 4 ) 2 SO 4 caused increases in ventilation amplitude (A VENT ) without affecting frequency (f VENT ), resembling the ventilatory response to hypercapnia rather than hypoxia, during which f VENT was increased exclusively. The hyperventilatory response to HEA was prevented by hyperoxia, indicating that control of breathing through ammonia sensing is likely secondary to O 2 chemoreception. Neuroepithelial cells (NECs) isolated from gill filaments exhibited a significant increase of intracellular [Ca 2+ ] in response to 1 mM NH 4 Cl but this response was small (roughly 30%) compared to the response to hypercapnia (37.5 mmHg; ~800% increase). Immunohistochemistry (IHC) failed to reveal the presence of Rh proteins (Rhcgb, Rhbg or Rhag) in gill filament NECs. Knockout of rhcgb did not affect the ventilatory response of adults to HEA. Larvae at 4 days post fertilization (dpf) responded to HEA with increases in f VENT (A VENT was not measured). The hyperventilatory response of larvae to HEA was attenuated (60% reduction) after treatment from 0 to 4 dpf with the sympathetic neurotoxin 6-hydroxydopamine. In larvae, Rhcgb, Rhbg and Rhag were undetectable by IHC in cutaneous NECs yet the f VENT to HEA following Rhbg knockdown was slightly (22%) attenuated. Thus, the hyperventilatory response to external ammonia in adult zebrafish, while apparently initiated by activation of NECs, does not require Rhcgb, nor is the entry of ammonia into NECs reliant on other Rh proteins. The lack of colocalization of Rh proteins with NECs suggests that the entry of ammonia into NECs in larvae, also is not facilitated by this family of ammonia channels., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Climate change models predict that atmospheric carbon dioxide [ CO 2 ] levels will be between 700 and 900 ppm within the next 80 y. Despite this, the direct physiological effects of exposure to slightly elevated atmospheric CO 2 (as compared with ∼ 410  ppm experienced today), especially when exposures extend from preconception to adulthood, have not been thoroughly studied., Objectives: In this study we aimed to assess the respiratory structure and function effects of long-term exposure to 890  ppm CO 2 from preconception to adulthood using a mouse model., Methods: We exposed mice to CO 2 ( ∼ 890  ppm ) from prepregnancy, through the in utero and early life periods, until 3 months of age, at which point we assessed respiratory function using the forced oscillation technique, and lung structure., Results: CO 2 exposure resulted in a range of respiratory impairments, particularly in female mice, including higher tissue elastance, longer chord length, and lower lung compliance. Importantly, we also assessed the lung function of the dams that gave birth to our experimental subjects. Even though these mice had been exposed to the same level of increased CO 2 for a similar amount of time ( ∼ 8 wk ), we measured no impairments in lung function. This suggests that the early life period, when lungs are undergoing rapid growth and development, is particularly sensitive to CO 2 ., Discussion: To the best of our knowledge, this study, for the first time, shows that long-term exposure to environmentally relevant levels of CO 2 can impact respiratory function in the mouse. https://doi.org/10.1289/EHP7305.

All inhalation anesthetics used clinically including isoflurane can suppress breathing; since this unwanted side effect can persist during the postoperative period and complicate patient recovery, there is a need to better understand how isoflurane affects cellular and molecular elements of respiratory control. Considering that astrocytes in a brainstem region known as the retrotrapezoid nucleus (RTN) contribute to the regulation of breathing in response to changes in CO 2 /H + (i.e., function as respiratory chemoreceptors), and astrocytes in other brain regions are highly sensitive to isoflurane, we wanted to determine whether and how RTN astrocytes respond to isoflurane. We found that RTN astrocytes in slices from neonatal rat pups (7-12 days postnatal) respond to clinically relevant levels of isoflurane by inhibition of a CO 2 /H + -sensitive Kir4.1/5.1-like conductance [50% effective concentration (EC 50 ) = 0.8 mM or ~1.7%]. We went on to confirm that similar levels of isoflurane (EC 50  = 0.53 mM or 1.1%) inhibit recombinant Kir4.1/5.1 channels but not homomeric Kir4.1 channels expressed in HEK293 cells. We also found that exposure to CO 2 /H + occluded subsequent effects of isoflurane on both native and recombinant Kir4.1/5.1 currents. These results identify Kir4.1/5.1 channels in astrocytes as novel targets of isoflurane. These results suggest astrocyte Kir4.1/5.1 channels contribute to certain aspects of general anesthesia including altered respiratory control. NEW & NOTEWORTHY An unwanted side effect of isoflurane anesthesia is suppression of breathing. Despite this clinical significance, effects of isoflurane on cellular and molecular elements of respiratory control are not well understood. Here, we show that isoflurane inhibits heteromeric Kir4.1/5.1 channels in a mammalian expression system and a Kir4.1/5.1-like conductance in astrocytes in a brainstem respiratory center. These results identify astrocyte Kir4.1/5.1 channels as novel targets of isoflurane and potential substrates for altered respiratory control during isoflurane anesthesia.

Objective: To investigate the effects of sedative doses of intravenous (IV) medetomidine (MED) or dexmedetomidine (DEX) on selected respiratory variables in dogs., Study Design: Randomized, blinded, crossover study., Animals: A total of eight healthy adult research Beagles., Methods: Dogs breathing room air had an electrical impedance tomography belt placed around the chest and were maintained in right lateral recumbency. Respiratory rate (f R ) in movements minute -1 (mpm) and changes in thoracic impedance (ΔZ) in arbitrary units (AU) were recorded for 120 seconds before (T0) and exactly 10 minutes (T10) after the administration of IV DEX (10 μg kg -1 ) or MED (20 μg kg -1 ), with a minimum washout period of 10 days between treatments. Minute ΔZ (ΔZ˙) was calculated by multiplying median ΔZ with f R . Data are presented as median (interquartile range). Significance for an overall effect of drugs (DEX versus MED) or treatment (T0 versus T10) was quantified with a two-way analysis of variance for repeated measures, followed by, when appropriate, Wilcoxon's signed rank test for each factor., Results: Overall, f R decreased from 26 (22-29) mpm at T0 to 13 (10-21) mpm at T10 (p = 0.003) and ΔZ increased from 1.133 (0.856-1.599) AU at T0 to 1.650 (1.273-2.813) AU at T10 (p = 0.007), but ΔZ˙ did not change [30.375 (23.411-32.445) AU minute -1 at T0 and 30.581 (22.487-35.091) AU minute -1 at T10]. There was no difference between DEX and MED. Most dogs developed a peculiar breathing pattern characterized by clusters of breaths followed by short periods of apnoea., Conclusions and Clinical Relevance: Both drugs caused a change in breathing pattern, reduction in f R and increase in ΔZ but did not affect ΔZ˙. It is likely that (dex)medetomidine resulted in reduction in f R and increase in tidal volume without impacting minute volume., (Copyright © 2020 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Among prematurity complications, the most important disorder is structural immaturity and inadequate production of pulmonary surfactant. Betamethasone is the drug of choice to artificially improve pulmonary capacity, thus we aimed to verify the effect of prenatal maternal treatment on lung development of premature puppies. Pregnant bitches were allocated in Term Group (n = 7), Preterm-Treated Group (interrupted pregnancies with maternal administration of betamethasone; n = 7), Preterm-Control Group (untreated interrupted pregnancies; n = 7), Extremely-Preterm Group (interrupted pregnancies at 55d; n = 6). Puppies were subjected to chest radiographic at birth, morphometric description of pulmonary structures and immunohistochemical analysis of surfactant protein B, proliferating cell nuclear antigen and cytokeratin were performed. In Preterm-Treated Group it was possible to more clearly identify cardiac silhouette and lung parenchyma by X-Ray. Saccular formation was higher in Preterm Groups, while Term Group had higher subsaccular development. Lung septation was higher in Treated and Term Groups. Term Group had higher number of cells marked for SP-B, whereas higher proliferation was observed in Extreme-Preterm and Preterm-Control Groups. Preterm Treated and Term Groups had higher tissue differentiation. In conclusion, antenatal maternal corticotherapy in dogs acted by increasing lung morphology and development of areas of gas exchange, regulate metabolism of pulmonary fluids rather than stimulate surfactant production., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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 NO 2 ), their incidence (NO 2 ), decline in respiratory function (PM 10 ) and death (PM 10 and PM 2.5 ). 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., (Copyright © 2020. Published by Elsevier Masson SAS.)

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.

Pulmonary drug delivery has gained great interest as an important subject of research over the past decades given the lung diseases which are affecting millions of people suffer from these diseases. Drug delivery into the respiratory system is influenced by many anatomical and physiological factors such as lung morphometry, breathing patterns, fluid dynamics, particle properties, etc. The respiratory airway structure is one of these parameters which greatly influences the deposition pattern of inhaled drug particles. There have been a wide variety of major morphometric studies, conducted using cadavers to increase an understanding of the respiratory airway anatomy and provide important information for developing realistic airway models. Casting as one of the first methods, was utilized for morphometric studies providing a hollow model for in vitro investigations. The above-mentioned morphometric data were utilized to describe the first idealized airway model as a simple symmetric description of the branching airways, later followed by more realistic asymmetric models. However, even these asymmetric airway models were not good enough to reflect the anatomical complexities of the human respiratory airway and contained several major limitations which made them inefficient. Further attempts alongside with the progress of technology led to introduction of the stochastic and image-based models which provided more realistic and efficient tools for numerical and experimental investigations. The main objective of this study is to provide a comprehensive review about the development of different perspectives of the respiratory airway modeling over the past decades. The following sections will present useful information about anatomy of the human respiratory tract, and different viewpoints of the respiratory airway modeling, including their historical routes, strengths, and deficiencies., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Apnea remains one of the most concerning and prevalent respiratory disorders spanning all ages from infants (particularly those born preterm) to adults. Although the pathophysiological consequences of apnea are fairly well described, the neural mechanisms underlying the etiology of the different types of apnea (central, obstructive, and mixed) still remain incompletely understood. From a developmental perspective, however, research into the respiratory neural control system of immature animals has shed light on both central and peripheral neural pathways underlying apnea of prematurity (AOP), a highly prevalent respiratory disorder of preterm infants. Animal studies have also been fundamental in furthering our understanding of how clinical interventions (e.g. pharmacological and mechanical) exert their beneficial effects in the clinical treatment of apnea. Although current clinical interventions such as supplemental O 2 and positive pressure respiratory support are critically important for the infant in respiratory distress, they are not fully effective and can also come with unfortunate, unintended (and long-term) side-effects. In this review, we have chosen AOP as one of the most common clinical scenarios involving apnea to highlight the mechanistic basis behind how some of the interventions could be both beneficial and also deleterious to the respiratory neural control system. We have included a section on infants with critical congenital heart diseases (CCHD), in whom apnea can be a clinical concern due to treatment with prostaglandin, and who may benefit from some of the treatments used for AOP., (Published by Elsevier B.V.)

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.

Proinflammatory cytokines like interleukin-1β (IL-1β) affect the control of breathing. Our aim is to determine the effect of the anti-inflammatory cytokine IL-10 οn the control of breathing. IL-10 knockout mice (IL-10 -/- , n = 10) and wild-type mice (IL-10 +/+ , n = 10) were exposed to the following test gases: hyperoxic hypercapnia 7% CO 2 -93% O 2 , normoxic hypercapnia 7% CO 2 -21% O 2 , hypoxic hypercapnia 7% CO 2 -10% O 2 , and hypoxic normocapnia 3% CO 2 -10% O 2 . The ventilatory function was assessed using whole body plethysmography. Recombinant mouse IL-10 (rIL-10; 10 μg/kg) was administered intraperitoneally to wild-type mice ( n = 10) 30 min before the onset of gas challenge. IL-10 was administered in neonatal medullary slices (10-30 ng/ml, n = 8). We found that IL-10 -/- mice exhibited consistently increased frequency and reduced tidal volume compared with IL-10 +/+ mice during room air breathing and in all test gases (by 23.62 to 33.2%, P < 0.05 and -36.23 to -41.69%, P < 0.05, respectively). In all inspired gases, the minute ventilation of IL-10 -/- mice was lower than IL-10 +/+ (by -15.67 to -22.74%, P < 0.05). The rapid shallow breathing index was higher in IL-10 -/- mice compared with IL-10 +/+ mice in all inspired gases (by 50.25 to 57.5%, P < 0.05). The intraperitoneal injection of rIL-10 caused reduction of the respiratory rate and augmentation of the tidal volume in room air and also in all inspired gases (by -12.22 to -29.53 and 32.18 to 45.11%, P < 0.05, respectively). IL-10 administration in neonatal rat ( n = 8) in vitro rhythmically active medullary slice preparations did not affect either rhythmicity or peak amplitude of hypoglossal nerve discharge. In conclusion, IL-10 may induce a slower and deeper pattern of breathing.

Objective: To observe the effects of prolonged exposure to high concentrations of PM 2.5 on the trachea and lungs of mice and to determine whether the damages to the trachea and lung are induced by necroptosis., Methods: Six- to eight-week-old female Balb/C mice of PM group were restrained in an animal restraining device using a nose-only "PM 2.5 online enrichment system" for 8 weeks, in Shijiazhuang, Hebei, China. Anti -Fas group was exposed to PM 2.5 inhalation and anti-Fas treatment via intranasal instillation. The mice in the control group inhaled filtered clean air. PM 2.5 sample was collected and analyzed. Airway Hyperresponsiveness (AHR) was tested. Lung tissue and bronchoalveolar lavage fluid (BALF) were analyzed for Hematoxylin and eosin (HE) staining, electron microscopy, cellular inflammation, cytokines, Tunel, Fas, RIPK3 and MLKL expression., Results: Compared to the other two groups, PM group displayed significantly increased AHR, neutrophils in BALF, significant bronchitis and alveolar epithelial hyperplasia and inflammation and necroptosis which were indicated by increased TUNEL, Fas, RIPK3 and MLKL measure., Conclusion: Our findings suggest that PM 2.5 can enhance AHR and these changes are induced by necroptosis-related inflammation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Severe periictal respiratory depression is thought to be linked to risk of sudden unexpected death in epilepsy (SUDEP) but its determinants are largely unknown. Interindividual differences in the interictal ventilatory response to CO 2 (hypercapnic ventilatory response [HCVR] or central respiratory CO 2 chemosensitivity) may identify patients who are at increased risk for severe periictal hypoventilation. HCVR has not been studied previously in patients with epilepsy; therefore we evaluated a method to measure it at bedside in an epilepsy monitoring unit (EMU) and examined its relationship to postictal hypercapnia following generalized convulsive seizures (GCSs)., Methods: Interictal HCVR was measured by a respiratory gas analyzer using a modified rebreathing technique. Minute ventilation (V E ), tidal volume, respiratory rate, end tidal (ET) CO 2 and O 2 were recorded continuously. Dyspnea during the test was assessed using a validated scale. The HCVR slope (ΔV E /ΔETCO 2 ) for each subject was determined by linear regression. During the video-electroencephalography (EEG) study, subjects underwent continuous respiratory monitoring, including measurement of chest and abdominal movement, oronasal airflow, transcutaneous (tc) CO 2 , and capillary oxygen saturation (SPO 2 )., Results: Sixty-eight subjects completed HCVR testing in 151 ± (standard deviation) 58 seconds, without any serious adverse events. HCVR slope ranged from -0.94 to 5.39 (median 1.71) L/min/mm Hg. HCVR slope correlated with the degree of unpleasantness and intensity of dyspnea and was inversely related to baseline ETCO 2 . Both the duration and magnitude of postictal tcCO 2 rise following GCSs were inversely correlated with HCVR slope., Significance: Measurement of the HCVR is well tolerated and can be performed rapidly and safely at the bedside in the EMU. A subset of individuals has a very low sensitivity to CO 2 , and this group is more likely to have a prolonged increase in postictal CO 2 after GCS. Low interictal HCVR may increase the risk of severe respiratory depression and SUDEP after GCS and warrants further study., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Medetomidine is an α-2 adrenoceptor agonist commonly combined with ketamine for immobilization of nondomestic mammals. However, it may cause some remarkable adverse effects such as bradycardia, hypertension, and hypoxemia. Vatinoxan (previously called MK-467 and L-659,066) is an α-2 adrenoceptor antagonist that affects mostly the peripheral receptors due to its minimal ability to cross the blood-brain barrier. Therefore it alleviates the peripheral cardiovascular and pulmonary effects of medetomidine while sedation is maintained. In this study, the hypothesis was that vatinoxan would dose-dependently alleviate medetomidineinduced bradycardia, hypertension, and hypoxemia when administered intravenously (IV) after medetomidine and ketamine were administered intramuscularly (IM) to markhors ( Capra falconeri heptneri ), without impairing the immobilization. Various doses of vatinoxan were studied. In this prospective, randomized, assessor-blinded, clinical crossover study, eight markhors were immobilized two times (16 paired immobilizations altogether) with medetomidine (80 µg/kg) and ketamine (1.5 mg/kg), according to the estimated weight, IM in the same dart. Approximately 19 min later, vatinoxan (117-297 µg/kg) or saline placebo was injected IV. Atipamezole was used as a reversal agent. Pulse and respiratory rates, indirect blood pressures, arterial oxygen saturation, and body temperature were measured and blood samples collected. In general, vatinoxan alleviated the hypertension induced by medetomidine without affecting the quality of immobilization. The dose of vatinoxan correlated significantly with the reduction in arterial blood pressure. Vatinoxan showed potential to enhance cardiovascular function in captive nondomestic small ruminants immobilized with medetomidine-ketamine., (© 2019 by American Association of Zoo Veterinarians.)

Objective: Hypothermia, the gold standard after a hypoxic-ischemic insult, is not beneficial in all treated newborns. Cannabidiol is neuroprotective in animal models of newborn hypoxic-ischemic encephalopathy. This study compared the relative efficacies of cannabidiol and hypothermia in newborn hypoxic-ischemic piglets and assessed whether addition of cannabidiol augments hypothermic neuroprotection., Methods: One day-old HI (carotid clamp and FiO 2 10% for 20 min) piglets were randomized to vehicle or cannabidiol 1 mg/kg i.v. u.i.d. for three doses after being submitted to normothermia or 48 h-long hypothermia with a subsequent rewarming period of 6 h. Non-manipulated piglets (naïve) served as controls. Hemodynamic or respiratory parameters as well as brain activity (aEEG amplitude) were monitored throughout the experiment. Following termination, brains were obtained for histological (TUNEL staining, apoptosis; immunohistochemistry for Iba-1, microglia), biochemical (protein carbonylation, oxidative stress; and TNFα concentration, neuroinflammation) or proton magnetic resonance spectroscopy (Lac/NAA: metabolic derangement; Glu/NAA: excitotoxicity)., Results: HI led to sustained depressed brain activity and increased microglial activation, which was significantly improved by cannabidiol alone or with hypothermia but not by hypothermia alone. Hypoxic-ischemic-induced increases in Lac/NAA, Glu/NAA, TNFα or apoptosis were not reversed by either hypothermia or cannabidiol alone, but combination of the therapies did. No treatment modified the effects of HI on oxidative stress or astroglial activation. Cannabidiol treatment was well tolerated., Conclusions: cannabidiol administration after hypoxia-ischemia in piglets offers some neuroprotective effects but the combination of cannabidiol and hypothermia shows some additive effect leading to more complete neuroprotection than cannabidiol or hypothermia alone., (Copyright © 2018. Published by Elsevier Ltd.)

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., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

To investigate the effects of etomidate, emulsified isoflurane, and their combination with dexmedetomidine on physiological parameters, electrocardiogram (ECG) results, and the quality of induction and recovery during isoflurane maintenance anaesthesia. 5 mixed-breed dogs received each of four treatments: etomidate (E group); emulsified isoflurane (EI group); both dexmedetomidine and etomidate (DE group); or both dexmedetomidine and emulsified isoflurane (DEI group). All drugs were IV injection administered for induction, followed by 1.5 MAC (minimal alveolar concentration) of isoflurane to maintain anaesthesia. Rectal temperature (RT), respiratory rate (RR), heart rate (HR), mean arterial pressure (MAP), and ECG were measured at baseline, 0, 5, 10, 20, 40, and 60 minutes after intubation. The quality of induction and recovery was evaluated for all dogs. All the anaesthetic procedures provided good conditions for induction of anaesthesia. The quality of induction and recovery in the E group was worse than other groups. The decrease of RR in the E and DE groups was stronger than that in the EI and DEI groups. The dogs in the E group had the most significant prolongation of the Q-T interval and changes in the S-T segment. Deviation and extension of the S-T segment were noted in the El group. The dogs in the DE and DEI groups had fewer changes in the ECG results than those in the E and EI groups. The addition of dexmedetomidine caused less effect on cardiopulmonary parameters and the ECG results than either etomidate or emulsified isoflurane alone. Thus, etomidate or emulsified isoflurane in combination with dexmedetomidine may be useful clinically for the induction of anaesthesia., Competing Interests: The authors have declared that no competing interests exist.

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.

Ensuring adequate ventilation and oxygenation and delivering inhaled anesthetic agent to the patient remain core responsibilities of the anesthesia provider during general anesthesia. Because of the emphasis placed on physiology, pharmacology, clinical sciences, and administrative duties, the stellar anesthesia workstation technology may be underutilized by the anesthesia community. Target-controlled O2 and agent delivery and automated end-expired CO2 control have entered the clinical arena, with only cost, luddism, and administrative hurdles preventing their more widespread use. This narrative review will explain technological aspects of existing and recently introduced anesthesia workstations. Concepts rather than particular anesthesia machines will be addressed, but examples will mostly pertain to the more recently introduced workstations. The anesthesia workstation consists of a ventilator, a carrier gas and agent delivery system, a scavenging system, and monitors. Mainly, the circle breathing circuit configuration, ventilator, and carrier gas and agent delivery technology are discussed. Occasionally, technical details are provided to give the reader a taste of the modern technology.

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 (P crit ), and time to loss of equilibrium (LOE). We first demonstrated that 24 h exposure to 10.1 and 23.2 μg l -1 ΣPAH 50 significantly impaired oxygen uptake. There was no effect of exposure on P crit or LOE. Exposure did result in significantly different repeatability between pre- and post-exposure P crit , 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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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 VO 2 peak. Subjects exposed to anthracyclines had lower LVEF% and % predicted VO 2 peak 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.

Asthma represents an episodic and fluctuating behavior characterized with decreased complexity of respiratory dynamics. Several evidence indicate that asthma severity or control is associated with alteration in variability of lung function. The pathophysiological basis of alteration in complexity of breathing pattern in asthma has remained poorly understood. Regarding the point that Rho-kinase is involved in pathophysiology of asthma, in present study we investigated the effect of Rho-kinase inhibition on complexity of respiratory dynamics in a guinea pig model of asthma. Male Dunkin Hartley guinea pigs were exposed to 12 series of inhalations with ovalbumin or saline. Animals were treated by the Rho-kinase inhibitor Y-27632 (1mM aerosols) prior to each allergen challenge. We recorded respiration of conscious animals using whole-body plethysmography. Exposure to ovalbumin induced lung inflammation, airway hyperresponsiveness and remodeling including goblet cell hyperplasia, increase in the thickness of airways smooth muscles and subepithelial collagen deposition. Complexity analysis of respiratory dynamics revealed a dramatic decrease in irregularity of respiratory rhythm representing less complexity in asthmatic guinea pigs. Inhibition of Rho-kinase reduced the airway remodeling and hyperreponsiveness, but had no significant effect on lung inflammation and complexity of respiratory dynamics in asthmatic animals. It seems that airway hyperresponsiveness and remodeling do not significantly affect the complexity of respiratory dynamics. Our results suggest that inflammation might be the probable cause of shift in the respiratory dynamics away from the normal fluctuation in asthma.

AWL3106 composed of opioid (dermorphin) and tachykinin (substance P 7-11 ) pharmacophores is a new compound with high analgesic potency and markedly reduced ability to induce tolerance and dependence. The present study aimed to determine the respiratory and cardiovascular responses evoked by this peptide in urethane-chloralose anaesthetized, spontaneously breathing rats in the presence or absence of vagal connection. Intravenous injection of AWL3106 at a dose of 0.3μmol/kg in intact rats resulted in apnoea lasting 5.1 ± 0.7s. Breathing that followed was of diminished frequency (F) and augmented tidal volume (V T ) with no significant impact on minute ventilation. AWL3106-challenge induced biphasic fall in arterial blood pressure with no effect on heart rate. Midcervical and supranodosal sectioning the vagal nerves prevented the occurrence of the apnoea and abrogated the post-AWL3106 reduction in F but failed to eliminate the increase in V T . Hypotensive response appeared to be less profound following supranodose vagotomy. NaloxoneHCl abolished solely the occurrence of apnoea. However additional blockade of tachykinin NK 1 receptors with SR140333 was required to abolish V T increase, deceleration of breathing and to markedly suppress AWL3106-induced hypotension. The present study shows that extravagally controlled stimulation of V T maintains fairly regular ventilation by levelling the bradypnoeic effects. Although the peptide showed no cardiac effects, hypotension occurring beyond the vagal loop may limit future therapeutic benefits of this chimeric compound., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Myocardial ischemia affects mitochondrial functions, leading to ionic imbalance and susceptibility to ventricular fibrillation. Trimetazidine, a metabolic agent, is clinically used in anti-anginal therapy., Methods: In this study, the rats were orally treated by gavage with trimetazidine 10 mg/kg/d for 7 days, and the effects of trimetazidine on mitochondrial respiratory function, biosynthesis, and fission/fusion in rats with acute myocardial ischemia were evaluated., Results: It has been suggested that acute myocardial ischemia leads to a damage to mitochondrial functions. However, compared with ischemia group without trimetazidine administration, a significant reduction in the infarct size was observed in trimetazidine-treated ischemia group (31.24±3.02% vs. 52.87±4.89%). Trimetazidine preserved the mitochondrial structure and improved respiratory control ratio and complex I activity. Furthermore, trimetazidine improved mitochondrial biosynthesis and fission/fusion, as demonstrated by the promotion of peroxisome proliferator-activated receptor gamma (PPARγ) co-activator 1α (PGC-1α), mitofusins 1 (Mfn1), dynamin-related protein 1 (Drp1), and optic atrophy 1 (Opa1) expressions in rats with acute myocardial ischemia., Conclusion: Taken together, it was suggested that in this rat model of myocardial ischemia, trimetazidine demonstrated cardioprotective effects attributing to the preservation of mitochondrial respiratory function, biosynthesis, and fission/fusion and, thus, could be considered as an agent for cardioprotection.

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., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)

Objective: To assess the cardiopulmonary effects caused by reverse Trendelenburg position (RTP) at 5° and 10° in sevoflurane-anesthetized yearling steers., Study Design: Prospective, experimental study., Animals: Eight Holstein steers aged (mean ± standard deviation) 12 ± 2 months and weighing 145 ± 26 kg., Methods: In the first phase of the study, the individual minimum alveolar concentration (MAC) of sevoflurane was determined using electrical stimulation. In the second phase, the effects of RTP were assessed. The animals were anesthetized on three separate events separated by ≥7 days in an incomplete crossover design: control treatment using a table without tilt (RTP0); treatment with the table at 5° RTP (RTP5) and table tilted 10° RTP (RTP10). Subjects were physically restrained in dorsal recumbency on the table, which was already tilted according to each treatment. Anesthesia was induced with sevoflurane at 8% in 5 L minute -1 oxygen via face mask followed by maintenance with sevoflurane at 1.3 MAC and spontaneous breathing. Cardiopulmonary variables were obtained immediately after instrumentation (T 0 ) and then after 30, 60, 120 and 180 minutes (T 30 , T 60 , T 120 and T 180 , respectively)., Results: The mean sevoflurane MAC for the eight steers was 2.12 ± 0.31%. Cardiac output was lower at all time points and the systemic vascular resistance index was higher at T 120 and T 180 in RTP10 compared with RTP0. Oxygen consumption was lower at T 0 and at T 180 in RTP10 compared with RTP0 and at all time points except T 30 compared with RTP5. Oxygen extraction was lower at T 0 in RTP10 compared with RTP0 and RTP5, and at T 60 and T 180 compared with RTP5., Conclusions and Clinical Relevance: RTP 5° and 10° did not improve ventilatory and oxygenation variables in sevoflurane-anesthetized steers when compared with no tilt, however the cardiovascular variables were adversely affected in RTP10., (Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

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 ΣPAH 50 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 (U burst and U crit ), 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 U burst and U crit 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 U burst and U crit , 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., (Copyright © 2017. Published by Elsevier B.V.)

Background: Remifentanil may be used by laboring women for analgesia, despite controversy because of potential apneas. We evaluated candidate variables as early warning alerts for apnea, based on prevalence, positive predictive rate, sensitivity for apnea event detection, and early warning alert time intervals (lead time) for apnea., Methods: We performed a secondary analysis of respiratory physiological data that had been collected during a prospective IRB-approved study of laboring women receiving IV patient-controlled boluses of remifentanil 20 to 60 μg every 1 to 2 minutes. Analyzed data included the respiratory rate (RR), end-tidal CO2 (EtCO2), pulse oximetry (SpO2), heart rate (HR), and the Integrated Pulmonary Index (IPI; Capnostream 20; Medtronic, Boulder, CO) that had been recorded continuously throughout labor. We defined immediate early warning alerts as any drop in a variable value below a prespecified threshold for 15 seconds: RR < 8 breaths per minute (bpm), EtCO2 < 15 mm Hg, and SpO2 < 92%. We defined alerts as "sustained" when the value remained below the threshold for ≥ 10 further seconds. The IPI value (1 to 10; 10 = healthy patient, ≤4 = immediate attention required, 1 = dire condition) was generated from a proprietary algorithm using RR, EtCO2, SpO2, and HR parameters. Apnea was defined as maximal CO2 < 5 mm Hg for at least 30 consecutive seconds., Results: We counted 62 apneas, among 10 of 19 (52.6%) women who received remifentanil (total dose 1725 ± 1392 μg, administered over 160 ± 132 minutes). We counted 331 immediate early warning alerts for the variables; 271 (82%) alerts were sustained for ≥10 seconds. The positive predictive value of alerts for apnea was 35.8% (99% confidence interval [CI]: 27.1-45.6), 28.9% (99% CI: 20.8-38.7), 4.3% (99% CI: 1.9-9.6), and 24.6% (99% CI: 18.3-32.2) for RR, EtCO2, SpO2, and IPI, respectively. The sensitivity for apnea event detection was 100% (99% CI: 90.3-100) for RR (<8 bpm) and IPI (≤4); 75.8% (99% CI: 59.8-86.9) for EtCO2 <15 mm Hg; and 14.5% (99% CI: 6.5-29.4) for SpO2 <92%. We found a statistically significant difference in the timing of RR, EtCO2, SpO2, and IPI alerts for apnea; Friedman's Q = 33.53; P < .0001. The EtCO2 had a median (interquartile range) lead time of -0.2 (-12.2 to 0.7) seconds, and SpO2 had a median (interquartile range) lead time of 40.0 (40.0 to 40.0) seconds., Conclusions: The majority of women receiving IV remifentanil for labor analgesia experienced apneas. Alerts for EtCO2 (<15 mm Hg), RR (<8 bpm), and IPI (≤4) detected most apneas, whereas SpO2 alerts missed the majority of apneas. All variables had a low positive predictive rate, demonstrating the limitations of the respiratory monitors utilized as early warning surveillance for apneas in this setting.

Background: One possible complication of stellate ganglion block (SGB) is respiratory compromise. No study has yet addressed the comparison of its effect on lung function and clinical features, including Horner's syndrome, changes in temperature, sensory and motor functions, and adverse events of lower versus higher concentrations (LC and HC, respectively) of local anesthetics in an ultrasound-guided SGB., Methods: Fifty patients were randomized into 1 of 2 groups: the LC group (5 mL of 0.5% mepivacaine) and the HC group (5 mL of 1% mepivacaine). One anesthesiologist performed a C6- SGB under ultrasound guidance. Our primary objective was to compare LC and HC of a local anesthetic in terms of its effect on lung function, and the secondary objective was to compare the clinical features between LC and HC of a local anesthetic. Lung function was compared between the 2 groups using the Mann-Whitney U test., Results: The forced vital capacity at 20 minutes post-SGB was not significantly different between the HC and the LC groups (P = .360); the median difference (95% confidence intervals [CI]) was 1 (-1 to 8). Other parameters of lung function were comparable with the forced vital capacity. Patients in the HC group had significantly greater sensory changes than those in the LC group (% decrease compared with the unblocked side); 95.4 ± 2.1 (CI: 91.11-99.73) vs 87.3 ± 3.5 (CI: 80.12-94.49)., Conclusions: Lung function between the LC and HC groups after SGB did not differ significantly. Clinical features between the 2 groups also did not differ clinically, except that patients in the HC group had significantly greater sensory loss in the C6 dermatomes.

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 (PM 2.5 ) and 10 μm (PM 10 )] and PM 2.5 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/m 3 decrease in same-day PM 2.5 was associated with small but consistent increase in the forced expiratory volume in 1 s (FEV 1 ) (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.

Acute respiratory dynamics and histopathology of the lungs and trachea following inhaled exposure to ammonia were investigated. Respiratory dynamic parameters were collected from male Sprague-Dawley rats (300-350 g) during (20 min) and 24 h (10 min) after inhalation exposure for 20 min to 9000, 20,000, and 23,000 ppm of ammonia in a head-only exposure system. Body weight loss, analysis of blood cells, and lungs and trachea histopathology were assessed 1, 3, and 24 h following inhalation exposure to 20,000 ppm of ammonia. Prominent decreases in minute volume (MV) and tidal volume (TV) were observed during and 24 h post-exposure in all ammonia-exposed animals. Inspiratory time (IT) and expiratory time (ET) followed similar patterns and decreased significantly during the exposure and then increased at 24 h post-exposure in all ammonia-exposed animals in comparison to air-exposed controls. Peak inspiratory (PIF) and expiratory flow (PEF) significantly decreased during the exposure to all ammonia doses, while at 24 h post-exposure they remained significantly decreased following exposure to 20,000 and 23,000 ppm. Exposure to 20,000 ppm of ammonia resulted in body weight loss at 1 and 3 h post-exposure; weight loss was significant at 24 h compared to controls. Exposure to 20,000 ppm of ammonia for 20 min resulted in increases in the total blood cell counts of white blood cells, neutrophils, and platelets at 1, 3, and 24 h post-exposure. Histopathologic evaluation of the lungs and trachea tissue of animals exposed to 20,000 ppm of ammonia at 1, 3, and 24 h post-exposure revealed various morphological changes, including alveolar, bronchial, and tracheal edema, epithelial necrosis, and exudate consisting of fibrin, hemorrhage, and inflammatory cells. The various alterations in respiratory dynamics and damage to the respiratory system observed in this study further emphasize ammonia-induced respiratory toxicity and the relevance of efficacious medical countermeasure strategies.

Clarias gariepinus is a facultative air-breathing catfish that exhibits changes in heart rate (ƒ H ) associated with air-breaths (AB). A transient bradycardia prior to the AB is followed by sustained tachycardia during breath-hold. This study evaluated air-breathing and cardiac responses to sustained aerobic exercise in juveniles (total length~20cm), and how exercise influenced variations in f H associated with AB. In particular, it investigated the role of adrenergic and cholinergic control in cardiac responses, and effects of pharmacological abolition of this control on air-breathing responses. Sustained exercise at 15, 30 and 45cms -1 in a swim tunnel caused significant increases in f AB and f H , from approximately 5breathsh -1 and 60heartbeatsmin -1 at the lowest speed, to over 60breathsh -1 and 100beatsmin -1 at the highest, respectively. There was a progressive decline in the degree of variation in f H , around each AB, as f AB increased with exercise intensity. Total autonomic blockade abolished all variation in f H during exercise, and around each AB, but f AB responses were the same as in untreated animals. Cardiac responses were exclusively due to modulation of inhibitory cholinergic tone, which varied from >100% at the lowest speed to <10% at the highest. Cholinergic blockade had no effect on f AB compared to untreated fish. Excitatory β-adrenergic tone was approximately 20% and did not vary with swimming speed, but its blockade increased f AB at all speeds, compared to untreated animals. This reveals complex effects of autonomic control on air-breathing during exercise in C. gariepinus, which deserve further investigation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

To systematically review the quality of evidence comparing the cardiopulmonary effects and quality of anesthesia after induction with alfaxalone vs. other anesthetic agents in dogs and cats. Studies published from 2001 until 20th May 2013 were identified with the terms 'alfaxan' OR 'alfaxalone' OR 'alphaxalone' in electronic databases: Discovery, PubMed, ScienceDirect, and Wiley Interscience. The study design and risk of bias of all included studies were assessed. Twenty-two studies from 408 (22 of 408, 5.39%) satisfied the inclusion criteria. Fourteen studies (14 of 22, 64%) focused on dogs and nine (9 of 22, 40%) on cats. One study had both dogs and cats as subjects. (Hunt et al., 2013) Twelve studies were rated an LOE1, and six of these as ROB1. One, seven, and two studies were rated as LOE2, LOE3, and LOE5, respectively. In dogs, strong evidence shows that induction quality with either alfaxalone-HPCD or propofol is smooth. Moderate evidence supports this finding in cats. In dogs, moderate evidence shows that there is no significant change in heart rate after induction with either alfaxalone-HPCD or propofol. In cats, moderate evidence shows no significant difference in postinduction respiratory rate and heart rate between alfaxalone-HPCD and propofol induction. Strong evidence shows dogs and cats have smooth recoveries after induction using either alfaxalone-HPCD or propofol, before reaching sternal recumbency., (© 2016 John Wiley & Sons Ltd.)