Increase In Minute Ventilation Research Articles

003 Treatment of Sleep Disordered Breathing with Leptin Loaded Exosomes

Abstract Introduction Obstructive sleep apnea (OSA) is characterized by recurrent periods of upper airway obstruction. The prevalence of OSA exceeds 50% in obese individuals and in 10–20% of obese patients OSA coexists with obesity hypoventilation syndrome (OHS) defined as daytime hypercapnia and hypoventilation during sleep attributed to the depressed control of breathing. There is no effective pharmacotherapy for OSA and OHS. Leptin is a potent respiratory stimulant and a potential therapeutic candidate. However, diet-induced obesity (DIO) results in reduced permeability of the blood-brain barrier (BBB) for leptin. Previous studies have shown that the BBB can be penetrated by exosomes, natural nanoparticles that can be used as drug delivery vehicles. In this study, we aimed to determine if exosomes overcome the BBB and treat OSA and OHS in DIO mice. Methods o examine the ability of exosomes to cross the BBB, male, lean (n=5) and DIO (n=5) C57BL/6J mice were injected with fluorescent exosomes or saline into the lateral tail vein. After 4h fluorescent exosomes biodistribution was evaluated by an in vitro imaging system (IVIS). Saline injected mice images were used for background adjustment. A separate subgroup of male, DIO (n=10) and lean (n=10) mice were headmounted with EEG and nuchal EMG leads. Sleep studies were performed in a plethysmography chamber and mice received saline, empty exosomes, free leptin, or leptin-loaded exosomes in a crossover manner. Results Exosomes were successfully delivered to the brain and the transport across the BBB was more efficient in DIO mice with 2-times greater relative fluorescence units measured in DIO when compared to lean mice (p<0.005). In DIO mice, exosomal leptin induced dramatic 1.7-2.2-fold increases in minute ventilation and 1.5-2.0-fold increases in maximal inspiratory flow during both flow-limited (upper airway/sleep apnea) and non-flow limited breathing (control of breathing) (p<0.05). In contrast, free leptin had no effect. Lean mice did not present significant sleep disordered breathing and no differences were observed between groups. Conclusion We demonstrated that exosomes overcome the BBB and that leptin-loaded exosomes treat OSA and OHS in DIO mice. Support (if any) R01HL 128970, R01HL 138932, R61 HL156240, U18 DA052301, FAPESP 2018/08758-3

Ampakines enhance phrenic nerve output in a ZFN rat model of Pompe Disease

Pompe disease (PD) is caused by mutations in the gene encoding acid-α-glucosidase (GAA), an enzyme that degrades lysosomal glycogen. The resultant glycogen accumulation is associated with neurodegeneration, cardiac deficits, and impaired phrenic motoneuron and diaphragm activation. Cardiorespiratory failure is the leading cause of death in early-onset PD patients. We previously reported that a drug which acts as a positive allosteric modulator of AMPA receptors, ampakine CX717, could stimulate phrenic motor output and increase minute ventilation in a mouse model of Pompe disease (Gaa-/-). We recently created a new rat model of PD that better recapitulates the clinical phenotype of early onset PD, called the Zinc Finger Nuclease (ZFN) KO model. Phrenic nerve recordings were performed on urethane anesthetized ZFN KO rats of both sexes, and age-matched wild type (WT) controls during a baseline normoxic period, followed by a brief exposure to hypoxia (PaO2 ~ 30mmHg) and a maximal respiratory challenge with combined hypoxia-hypercapnia. Recordings were done before and after treatment with ampakine CX717 (15mg/kg) or its vehicle control (2-Hydroxypropyl)-β-cyclodextrin. Our goal was to build upon the prior data from the Gaa-/-mouse, by using the ZFN KO model to test the hypothesis that in addition to stimulating basal or “eupneic” phrenic output, ampakine CX717 could also increase the ability to respond to acute respiratory challenge. We also aimed to determine if the extent of phrenic motor deficits were different between male and female ZFN KO rats. The data confirm that both male and female ZFN KO rats exhibit cardiac irregularities and phrenic motor deficits when compared to WT controls. However, a sex difference was apparent as male ZFN KO rats exhibit greater phrenic motor deficits and blunted responses to gas challenges compared to female ZFN KO rats. Ampakine treatment enhanced phrenic output and improved the ability to respond to respiratory challenge in both sexes of the ZNF rat model of PD. We conclude that 1) sex differences are present in the phrenic motor phenotype of ZFN KO rats, 2) the ability of low dose CX717to stimulate phrenic motor output in PD is reproducible across two species, and 3) low dose CX717 can enhance the ability to respond to respiratory challenge in PD rats These data suggest that ampakines may serve as a viable adjunctive therapy for respiratory insufficiency in PD patients.

Roles of HIF‐1 on ventilatory, metabolic and mitochondrial cox responses to hypoxia in rats

The lack of oxygen at high altitudes presents constraints for mammals. One of the mechanisms involved in the response to hypoxia is the stabilization of HIF-1 (Hypoxia Inducible Factor 1) which contributes to ventilatory and metabolic responses, reduces mitochondrial respiration and stimulates anaerobic glycolysis. Upon acute hypoxia exposure, the expression of HIF-1 reaches peak levels after a few hours of hypoxic exposure. In rats, however, the expression of HIF-1 in hypoxia appears to be limited, as are the ventilatory and metabolic responses in comparison to other species better adapted to altitude. The purpose of this study is to better understand the interactions between hypoxia and HIF-1 and to determine if there are other mechanisms possibly related to hypoxic responses. To this end, we measured ventilation and metabolic rate under resting conditions (whole body plethysmography) and mitochondrial respiration of the cerebral cortex and liver (oxygraphy) in adult male SD rats exposed in normoxia (21% O2 - 6h), in hypoxia (10% O2 - 6h), in normoxia after injection of a HIF-1 stabilizer (deferoxamine; 100mg/kg), and in hypoxia after injection of a HIF-1 inhibitor (2-methoxyestradiol; 5mg/kg). Hypoxia reduces metabolism, increases minute ventilation and respiratory rate by 171 and 59% respectively and increases cytochrome c oxidase (COX) activity by an average of 72% in the cortex. Stabilization of HIF-1 in normoxia doesn't result in any of these responses. However, inhibition of HIF-1 in hypoxia decreases ventilatory responses by 30% for minute ventilation and 23% for respiratory rate and completely blocks the increase in COX activity. HIF-1 would therefore be totally responsible for the IV complex responses observed in hypoxia, but would only be partially involved in the ventilatory response. There thus appears to be an interaction between HIF-1 and other factors induced in hypoxia to establish ventilatory responses.

Prone Position in Mechanically Ventilated COVID-19 Patients: A Multicenter Study.

Background: The prone position (PP) is increasingly used in mechanically ventilated coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS) patients. However, studies investigating the influence of the PP are currently lacking in these patients. This is the first study to investigate the influence of the PP on the oxygenation and decarboxylation in COVID-19 patients. Methods: A prospective bicentric study design was used, and in mechanically ventilated COVID-19 patients, PP was indicated from a partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FIO2) ratio of <200. Patients were left prone for 16 h each. Pressure levels, FIO2, were adjusted to ensure a PaO2 greater than 60 mmHg. Blood gas analyses were performed before (baseline 0.5 h), during (1/2/5.5/9.5/13 h), and after being in the PP (1 h), the circulatory/ventilation parameters were continuously monitored, and lung compliance (LC) was roughly calculated. Responders were defined compared to the baseline value (PaO2/FIO2 ratio increase of ≥15%; partial pressure of carbon dioxide (PaCO2) decrease of ≥2%). Results: 13 patients were included and 36 PP sessions were conducted. Overall, PaO2/FIO2 increased significantly in the PP (p < 0.001). Most PaO2/FIO2 responders (29/36 PP sessions, 77%) were identified 9.5 h after turning prone (14% slow responders), while most PaCO2 responders (15/36 PP sessions, 42%) were identified 13 h after turning prone. A subgroup of patients (interval intubation to PP ≥3 days) showed less PaO2/FIO2 responders (16% vs. 77%). An increase in PaCO2 and minute ventilation in the PP showed a significant negative correlation (p < 0.001). LC (median before the PP = 38 mL/cm H2O; two patients with LC >80 mL/cm H2O) showed a significant positive correlation with the 28 day survival of patients (p = 0.01). Conclusion: The PP significantly improves oxygenation in COVID-19 ARDS patients. The data suggest that they also benefit most from an early PP. A decrease in minute ventilation may result in fewer PaCO2 responders. LC may be a predictive outcome parameter in COVID-19 patients. Trial registration: Retrospectively registered.

Ventilatory constraint is more severe in walking than cycling in patients with COPD.

Due to its effectivity in assessing functional capacity and adding prognostic information to the staging of chronic obstructive pulmonary disease (COPD) patients, the 6-min walk test (6MWT) is extensively used in clinical evaluation. Currently, there is little information about the physiological response this test elicits in patients, especially when compared to cardiopulmonary exercise test (CPET). The aim of the study was to compare ventilatory and metabolic responses between these tests commonly used for the assessment of clinical outcome. A group of 20 patients with moderate to very severe COPD were tested for their pulmonary function (flow-volume curve, static lung volumes), occlusion mouth pressures and breath-by-breath measurement of flow, volumes, and oxygen (O2) and carbon dioxide (CO2) concentration during the 6MWT and CPET. All parameters measured during both exercise tests were assessed over the throughout of the tests and compared between each other at specified time points. Serially measured inspiratory vital capacity (IVC) decreased more rapidly and extensively during the walk-test (p ​< ​0,0001). This was accompanied by a limited increase in tidal volume (VT) and minute ventilation (VE), which were significantly lower in the course of the 6MWT (p ​= ​0,0003 and p ​= ​0,0097, respectively). We also noticed a significant decrease in hemoglobin oxygen saturation (SpO2) during the 6MWT which was correlated to percent decrease in IVC (p ​= ​0,0206). Over the course of the 6MWT, oxygen consumption (VO2) and VT reached plateau within 2 ​min, while carbon dioxide production (VCO2) and VE within 3 ​min. During CPET, VO2, VCO2 and VE rose continuously, while VT reached plateau within 4 ​min. The 6MWT seems to be a rather endurance-based test associated with more pronounced dynamic lung hyperinflation and mechanical constraint of ventilation in comparison to cycling.

Maximizing Participant and Staff Safety During Assessment of Physical Function in the COVID-19 Era.

Physical performance measures, including cardiopulmonary exercise testing (CPXT), are widely used in geriatric practice and aging research. Theoretically, research participants and study personnel could get infected in the closed environment of the exercise laboratory by contact with respiratory droplets from an infected person, by breathing virus-laden aerosols, or by touching fomites. Older adults are at increased risk of developing more severe disease and of dying from SARS-CoV-2 infection. This special article offers guidance-informed by a synthesis of scientific data and recommendations of the CDC and WHO-on procedures that can be implemented in exercise laboratories to minimize risk of SARS-CoV-2 and other respiratory infections. Most tests of physical function (e.g., gait speed, Short Physical Performance Battery) are not aerosol-generating and are associated with only a small increase in minute ventilation; in contrast, CPXT markedly increases minute ventilation and is potentially aerosol-generating. Researchers should evaluate the benefit-to-risk ratio of information gained from the laboratory assessment versus the risk of SARS-CoV2 infection. Risk mitigation strategies described here fall into four categories: personal hygiene and the use of personal protective equipment; standardized screening; reconfiguration of laboratory space; and optimization of laboratory ventilation. The proposed safety measures are not intended to replace institutional policy, state, or federal guidelines; they may not apply to all settings and are expected to evolve as more definitive information becomes available. These practical measures to maximize protection against SARS-CoV2 infection can help maximize participant and staff safety, reduce anxiety, and facilitate protocol adherence, and study integrity.

Air pollution concentration and period of the day modulates inhalation of PM2.5 during moderate- and high-intensity interval exercise

The increase in minute ventilation during exercise led to higher inhalation of air pollution and, consequently, to exacerbation of health issues. Therefore, the intensity of exercise and the air pollution concentration of the environment could be determinant variables to poor outcomes. This study aimed to investigate the inhaled dose of particulate matter 2.5 (PM2.5) during a moderate- and high-intensity interval exercise session performed in the morning and evening at different locations of Porto Alegre City. Eighteen individuals performed a cardiopulmonary exercise test, a moderate-intensity interval exercise (MIIE), and a high-intensity interval exercise (HIIE). Heart rate was monitored to estimate minute ventilation and total ventilation of the session. The concentration of PM2.5 was measured during the morning (6–8a.m.) and evening (6–8p.m.) by fixed-site monitors placed at five points of Porto Alegre City. The PM2.5 inhalation during MIIE and HIIE performed in the morning and evening in the monitoring points was estimated. HIIE showed higher minute ventilation (VE) (p = 0.0048) and total ventilation did not differ between groups (p = 0.4648). PM2.5 concentrations were higher during the mornings (p < 0.001). Monitored point 1 had higher levels of PM2.5 in the morning and evening (p < 0.001). The inhalation of PM2.5 in the morning showed no difference in MIIE (p = 0.8172) and HIIE (p = 0.7306) groups among the points. In the evening, the inhalation of PM2.5 was higher in point 1 in MIIE and HIIE group (p < 0.001). MIIE and HIIE had higher inhalation of PM2.5 in the morning than in the evening (p < 0.001). Total ventilation of exercise is a crucial factor that contributes to the inhalation dose of air pollution.

Ventilatory inefficiency during graded exercise in COPD: A pragmatic approach.

The current approach to measuring ventilatory (in)efficiency (V'E -V'CO2 slope, nadir and intercept) presents critical drawbacks in the evaluation of COPD subjects, owing mainly to mechanical ventilatory constraints. Thus, we aimed to compare the current approach with a new method we have developed for ventilatory efficiency calculation. The new procedure was based on measuring the amount of CO2 cleared by the lungs (V'CO2 , L/min) plotted against a predefined range of increase in minute ventilation (V'E ) (ten-fold increase based on semilog scale) during incremental exercise to symptom-limited maximum tolerance. This value was compared to a hypothetical predicted maximum CO2 output at the predicted maximal voluntary ventilation, defining ventilatory efficiency (ηV'E , %). The results were used to compare 30 subjects with COPD (II-IV Global Initiative for Chronic Obstructive Lung Disease, GOLD) and 10 non-COPD smokers, to establish the best discriminative physiological variable for disease severity through logistic multinomial regression. The new approach was more sensitive to progressive deterioration of airway obstruction, resulting in worse ηV'E as lung function worsens throughout the GOLD panel (ηV'E (%), p<.001), when compared with V'E -V'CO2 slope (p=.715) or V'E -V'CO2 nadir (p=.070), besides showing the best model based on the logistic regression approach. Although requiring more complex calculations compared to the current procedure, the new approach is highly sensitive to true ventilatory/gas-exchange deterioration, even throughout more severe pulmonary lung function in COPD subjects.

Voltage-gated potassium channel proteins and stereoselective S-nitroso-l-cysteine signaling.

S-nitroso-l-cysteine (L-CSNO) behaves as a ligand. Its soluble guanylate cyclase–independent (sGC-independent) effects are stereoselective — that is, not recapitulated by S-nitroso-d-cysteine (D-CSNO) — and are inhibited by chemical congeners. However, candidate L-CSNO receptors have not been identified. Here, we have used 2 complementary affinity chromatography assays — followed by unbiased proteomic analysis — to identify voltage-gated K+ channel (Kv) proteins as binding partners for L-CSNO. Stereoselective L-CSNO–Kv interaction was confirmed structurally and functionally using surface plasmon resonance spectroscopy; hydrogen deuterium exchange; and, in Kv1.1/Kv1.2/Kvβ2-overexpressing cells, patch clamp assays. Remarkably, these sGC-independent L-CSNO effects did not involve S-nitrosylation of Kv proteins. In isolated rat and mouse respiratory control (petrosyl) ganglia, L-CSNO stereoselectively inhibited Kv channel function. Genetic ablation of Kv1.1 prevented this effect. In intact animals, L-CSNO injection at the level of the carotid body dramatically and stereoselectively increased minute ventilation while having no effect on blood pressure; this effect was inhibited by the L-CSNO congener S-methyl-l-cysteine. Kv proteins are physiologically relevant targets of endogenous L-CSNO. This may be a signaling pathway of broad relevance.

Maintaining a high inspired oxygen fraction with the Elisée 350 turbine transport ventilator connected to two portable oxygen concentrators in an austere environment.

Management of critically ill patients requiring mechanical ventilation in austere environments or during disaster response is a logistic challenge. Availability of oxygen cylinders for mechanically ventilated patient may be difficult in such a context. A solution to ventilate patients requiring high fraction of inspired oxygen (FiO2) is to use a ventilator able to be supplied by a low-pressure oxygen source connected with two oxygen concentrators (OCs). We tested the Elisée 350 (ResMedBella Vista, Australia) ventilator paired with two Newlife Intensity 10 (Airsep, Ball Ground, Georgia) OCs and evaluated the delivered FiO2 across a range of minute volumes and combinations of ventilator settings. The ventilators were attached to a test lung, OC flow was adjusted with a Certifier FA ventilator test systems from 2 to 10 L/min and injected into the oxygen inlet port of the Elisée 350. The FiO2 was measured by the analyzer integrated in the ventilator, controlled by the ventilator test system. Several combinations of ventilator settings were evaluated to determine the factors affecting the delivered FiO2. The Elisée 350 ventilator is a turbine ventilator able to deliver high FiO2 when functioning with two OCs. However, modifications of the ventilator settings such as an increase in minute ventilation affect delivered FiO2 even if oxygen flow is constant on the OC. The ability of two OCs to deliver high FiO2 when used with a turbine ventilator makes this method of oxygen delivery a viable alternative to cylinders to ventilate patients requiring an FiO2 of ≥80% in austere place or during disaster response. Feasibility study on test bench, level V.

Increased physiological dead space in mechanically ventilated COVID-19 patients recovering from severe acute respiratory distress syndrome: a case report

BackgroundAn ongoing outbreak of coronavirus disease 2019 (COVID-19) is spreading globally. Recently, several articles have mentioned that the early acute respiratory distress syndrome (ARDS) caused by COVID-19 significantly differ from those of ARDS due to other causes. Actually, we newly observed that some mechanically ventilated COVID-19 patients recovering from severe ARDS (more than 14 days after invasive ventilation) often experienced evidently gradual increases in CO2 retention and minute ventilation. However, the underlying mechanics remain unclear.Case presentationTo explain these pathophysiological features and discuss the ventilatory strategy during the late phase of severe ARDS in COVID-19 patients, we first used a metabolic module on a General Electric R860 ventilator (Engstrom Carestation; GE Healthcare, USA) to monitor parameters related to gas metabolism, lung mechanics and physiological dead space in two COVID-19 patients. We found that remarkably decreased ventilatory efficiency (e.g., the ratio of dead space to tidal volume 70–80%, arterial to end-tidal CO2 difference 18–23 mmHg and ventilatory ratio 3–4) and hypermetabolism (oxygen consumption 300–400 ml/min, CO2 elimination 200–300 ml/min) may explain why these patients experienced more severe respiratory distress and CO2 retention in the late phase of ARDS caused by COVID-19.ConclusionDuring the recovery period of ARDS among mechanically-ventilated COVID-19 patients, attention should be paid to the monitoring of physiological dead space and metabolism. Tidal volume (8–9 ml/kg) could be increased appropriately under the limited plateau pressure; however, barotrauma should still be kept in mind.

Peripheral chemoreflex contribution to ventilatory long-term facilitation induced by acute intermittent hypercapnic hypoxia in males and females.

Ventilatory long-term facilitation (vLTF) refers to respiratory neuroplasticity that develops following intermittent hypoxia in both healthy and clinical populations. A sustained hypercapnic background is argued to be required for full vLTF expression in humans. We determined whether acute intermittent hypercapnic hypoxia elicits vLTF during isocapnic-normoxic recovery in healthy males and females. We further assessed whether tonic peripheral chemoreflex drive is necessary and contributes to the expression of vLTF. Following 40min of intermittent hypercapnic hypoxia, minute ventilation was increased throughout 50min of isocapnic-normoxic recovery. Inhibition of peripheral chemoreflex drive with hyperoxia attenuated the magnitude of vLTF. Males and females achieve vLTF through different respiratory recruitment patterns. Ventilatory long-term facilitation (vLTF) refers to respiratory neuroplasticity that manifests as increased minute ventilation ( ) following intermittent hypoxia. In humans, hypercapnia sustained throughout intermittent hypoxia and recovery is considered necessary for vLTF expression. We examined whether acute intermittent hypercapnic hypoxia (IHH) induces vLTF, and if peripheral chemoreflex drive contributes to vLTF throughout isocapnic-normoxic recovery. In 19 individuals (9 females, age: 22±3years; mean±SD), measurements of tidal volume (VT ), breathing frequency (fB ), , and end-tidal gases ( and ), were made at baseline, during IHH and 50min of recovery. Totalling 40min, IHH included 1min intervals of 40s hypercapnic hypoxia (target =50mmHg and =+4mmHg above baseline) and 20s normoxia. During baseline and recovery, dynamic end-tidal forcing maintained resting and and delivered 1min of hyperoxia ( =355±7mmHg) every 5min. The depression in during hyperoxia was considered an index of peripheral chemoreflex drive. Throughout recovery was increased 4.6±3.7lmin-1 from baseline (P<0.01). Hyperoxia depressed at baseline, and augmented depression was evident following IHH (Δ =-0.8±0.9 vs. -1.7±1.3lmin-1 , respectively, P<0.01). The vLTF was similar between sexes (P=0.15), but males had larger increases in VT than females (sex-by-time interaction, P=0.03), and females tended to increase fB (P=0.09). During isocapnic-normoxic recovery following IHH: (1) vLTF is expressed in healthy humans; (2) vLTF expression is attenuated but not abolished with peripheral chemoreflex inhibition by hyperoxia, suggesting a contribution from central nervous pathways in vLTF expression; and (3) males and females develop similar vLTF through different ventilatory recruitment strategies.

Patient-ventilator dyssynchronies: Are they all the same? A clinical classification to guide actions.

Patient ventilatory dyssynchrony (PVD) is a mismatch between the respiratory drive of the patient and ventilatory assistance. It is a complex event seen in almost all ventilated patients and at any ventilator mode, with uncertain significance and prognosis. Due to its different pathophysiological mechanisms, there is still not consensual classification to guide us in selecting the best treatment. In the present review we aimed to summarize some clinical data on PVD, and to propose a clinical classification based on the type of PVD, from potentially innocuous to clearly harmful PVD, which could help clinicians in the decision-making process from adjusting ventilator settings to deeply sedate or paralyze the patient. Clearly, further studies are needed addressing risk factors, physiologic mechanisms and direct consequences of PVD in order to help clinicians to design effective and proven strategies at the bedside.

Ventilatory Responsiveness during Exercise and Performance Impairment in Acute Hypoxia.

An adequate increase in minute ventilation to defend arterial oxyhemoglobin saturation (SpO2) during hypoxic exercise is commonly viewed as an important factor contributing to large inter-individual variations in the degree of exercise performance impairment in hypoxia. Although the hypoxic ventilatory response (HVR) could provide insight into the underpinnings of such impairments, it is typically measured at rest under isocapnic conditions. Thus, we aimed to determine whether 1) HVR at rest and during exercise are similar and 2) exercise HVR is related to the degree of impairment in cycling time trial (TT) performance from normoxia to acute hypoxia (∆TT). Sixteen endurance-trained men (V˙O2peak, 62.5 ± 5.8 mL·kg-1·min-1) performed two poikilocapnic HVR tests: one during seated rest (HVRREST) and another during submaximal cycling (HVREX). On two separate visits, subjects (n = 12) performed a 10-km cycling TT while breathing either room air (FiO2 = 0.21) or hypoxic gas mixture (FiO2 = 0.16) in a randomized order. HVREX was significantly (P < 0.001) greater than HVRREST (1.52 ± 0.47 and 0.22 ± 0.13 L·min-1·%SpO2-1, respectively), and these measures were not correlated (r = -0.16, P = 0.57). ∆TT was not correlated with HVRREST (P = 0.70) or HVREX (P = 0.54), but differences in ventilation and end-tidal CO2 between hypoxic and normoxic TT and the ventilatory equivalent for CO2 during normoxic TT explained ~85% of the variance in performance impairment in acute hypoxia (P < 0.01). We conclude that 1) HVR is not an appropriate measure to predict the exercise ventilatory response or performance impairments in acute hypoxia and 2) an adequate and metabolically matched increase in exercise ventilation, but not the gain in the ventilatory response to hypoxia, is essential for mitigating hypoxia-induced impairments in endurance cycling performance.

Swimming And Respiratory System: Impact Of Exercise On Pro-oxidants Production And Lung Function

The respiratory redox state of swimmers can be affected by the increase of minute ventilation (VE) during exercise and/or by chronic exposure to chlorine used to sanitize the water of swimming pools. However, in indoor-pools, the high-humidity and warm-water temperature are recognized as respiratory protecting factors. The exhaled breath condensate (EBC) is a non-invasive method used to assess the pro-oxidants species (EBC) is a non-invasive method used to assess the pH and pro-oxidants species (nitrite [NO2-], hydrogen peroxide [H2O2]), while spirometry the lung function (FEV1, FEV1/FVC, FEF25-75% ). PURPOSE: To assess the impact of a high-intensity and prolonged-time exercise on the production of [H2O2]EBC, [NO2-]EBC, pHEBC and lung function in swimmers. METHODS: Longitudinal quasi-experimental study. 18 competitive swimmers (8 female) (22±2 years; 53.1±3.5 mL·kg-1·min-1 VO2-máx.) completed 3.500-m of swim in indoor pool treated by chlorine (intensity of 80.2±3.1% of HRmax.) with no exposure to respiratory irritants by 5-days previous to tests. The spirometry test and EBC collection were done at rest, 20-minutes and 24-hours post-exercise and were analyzed using one-way RM-ANOVA test by the GraphPad-Prism software (v.6.0). The p-value<0.05 was considered for differences. RESULTS: The [H2O2]EBC (0.35±0.15 vs 0.28±0.12 vs 0.20±0.10 (umol·L-1 )) and [NO2-]EBC (1.79±0.21 vs 1.37±0.15 vs 1.03±0.16 (umol·L-1 )) decreased significantly at 24-hr post-exercise. The pHEBC (p=0.23 and 0.32) and FEV1, FEV1/FVC, FEF25-75% do not changed significantly between stages. CONCLUSION: A acute high-intensity and prolonged-time swimming session decreased the pro-oxidants production with no changes in lung function in swimmers exposed chronically to exercise and respiratory irritants. More studies are necessary to identify and isolate the plausible factors involucrated in the formation of respiratory pro-oxidants during exercise in athletes chronically exposed to respiratory irritants.

Effects Of Caffeine On Physiological Responses To Exercise And Time-trial Performance: Influence Of CYP1A2 Genotype.

PURPOSE: The aim of this study was to investigate the influence of CYP1A2 genotype (which influences the rate of caffeine metabolism) on the effects of caffeine on physiological responses to submaximal exercise and cycling time-trial performance. METHODS: Eighty six cyclists were screened for their CYP1A2 genotype before being separated into two groups (AA [wildtype] versus AC or CC variant). Seventeen participants from each group (age: 45 ± 9 yrs; height: 1.81 ± 0.07 m; body mass: 76.4 ± 9.9 kg; V̇O2max: 4.02 ± 0.46 L·min-1) were then matched for self-reported endurance ability before taking part in a randomised, double-blind, placebo controlled study. In Trial 1, participants completed incremental cycling tests to establish the V̇O2-power output relationship and V̇O2max. In trials 2 and 3 participants ingested a capsule containing 5 mg-kg-1 of caffeine or placebo one hour before completing a submaximal incremental cycling test (4-min stages) at 40, 55, 70, and 85% of VO2max, followed by a time trial (~ 30 mins). 95% confidence limits (CL95) were calculated for all estimates. RESULTS: Relative to placebo, caffeine led to a significant reduction in time to complete the time trial (caffeine: 29.21 ± 1.60 mins; placebo: 30.30 ± 1.96 mins); but there was no effect of genotype. During submaximal exercise, caffeine resulted in significant reductions in heart rate (mean difference: 2.4 b·min-1; CL95: 1.1 - 3.8 b·min-1), with effects dissipating as exercise intensity increased. Caffeine also led to submaximal exercise reductions in ratings of perceived exertion (mean difference: 0.5; CL95: 0.2 – 0.8) and significant increases in respiratory exchange ratio (mean difference: 0.013; CL95: 0.002 – 0.025), minute ventilation (mean difference: 3.4 L·min-1; CL95: 0.4 – 6.4 L·min-1), and blood lactate concentration (mean difference: 0.24 mmol·L-1; CL95: 0.11 – 0.37 mmol·L-1). However, the responses were not affected by genotype. CONCLUSION: Caffeine influences physiological responses to submaximal exercise and improves time-trial performance. However, those effects are not influenced by CYP1A2 genotype.

Skin Cooling on Breath-Hold Duration and Predicted Emergency Air Supply Duration During Immersion.

PURPOSE: This study was intended to determine the effect of skin cooling on breath-hold duration and predicted emergency air supply duration during immersion.METHODS: While wearing a helicopter transport suit with a dive mask, 12 subjects (29 ± 10 yr, 78 ± 14 kg, 177 ± 7 cm, 2 women) were studied in 8 and 20°C water. Subjects performed a maximum breath-hold, then breathed for 90 s (through a mouthpiece connected to room air) in five skin-exposure conditions. The first trial was out of water for Control (suit zipped, hood on, mask off). Four submersion conditions included exposure of the: Partial Face (hood and mask on); Face (hood on, mask off); Head (hood and mask off); and Whole Body (suit unzipped, hood and mask off).RESULTS: Decreasing temperature and increasing skin exposure reduced breath-hold time (to as low as 10 ± 4 s), generally increased minute ventilation (up to 40 ± 15 L · min-1), and decreased predicted endurance time (PET) of a 55-L helicopter underwater emergency breathing apparatus. In 8°C water, PET decreased from 2 min 39 s (Partial Face) to 1 min 11 s (Whole Body).CONCLUSION: The most significant factor increasing breath-hold and predicted survival time was zipping up the suit. Face masks and suit hoods increased thermal comfort. Therefore, wearing the suits zipped with hoods on and, if possible, donning the dive mask prior to crashing, may increase survivability. The results have important applications for the education and preparation of helicopter occupants. Thermal protective suits and dive masks should be provided.Madu VC, Carnahan H, Brown R, Ennis K-A, Tymko KS, Hurrie DMG, McDonald GK, Cornish SM, Giesbrecht GG. Skin cooling on breath-hold duration and predicted emergency air supply duration during immersion. Aerosp Med Hum Perform. 2020; 91(7):578-585.

Caffeine prevents prostaglandin E1-induced disturbances in respiratory control in neonatal rats: implications for infants with critical congenital heart disease.

Continuous infusion of prostaglandin E1 (PGE1) is used to maintain ductus arteriosus patency in infants with critical congenital heart disease, but it can also cause central apnea suggesting an effect on respiratory neural control. In this study, we investigated whether 1) PGE1 inhibits the various phases of the acute hypoxic ventilatory response (HVR; an index of respiratory control dysfunction) and increases apnea incidence in neonatal rats; and 2) whether these changes would be reversible with caffeine pretreatment. Whole body plethysmography was used to assess the HVR and apnea incidence in neonatal rats 2 h following a single bolus intraperitoneal injection of PGE1 with and without prior caffeine treatment. Untreated rats exhibited a biphasic HVR characterized by an initial increase in minute ventilation followed by a ventilatory decline of the late phase (~5th minute) of the HVR. PGE1 had a dose-dependent effect on the HVR. Contrary to our hypothesis, the lowest dose (1 µg/kg) of PGE1 prevented the ventilatory decline of the late phase of the HVR. However, PGE1 tended to increase postsigh apnea incidence and the coefficient of variability (CV) of breathing frequency, suggesting increased respiratory instability. PGE1 also decreased brainstem microglia mRNA and increased neuronal nitric oxide synthase (nNOS) and platelet-derived growth factor-β (PDGF-β) gene expression. Caffeine pretreatment prevented these effects of PGE1, and the adenosine A2A receptor inhibitor MSX-3 had similar preventative effects. Prostaglandin appears to have deleterious effects on brainstem respiratory control regions, possibly involving a microglial-dependent mechanism. The compensatory effects of caffeine or MSX-3 treatment raises the question of whether prostaglandin may also operate on an adenosine-dependent pathway.

Exposure and Respiratory Tract Deposition Dose of Equivalent Black Carbon in High Altitudes

The traffic microenvironment accounts for a significant fraction of the total daily dose of inhaled air pollutants. The adverse effects of air pollution may be intensified in high altitudes (HA) due to increased minute ventilation (MV), which may result in higher deposition doses compared to that at sea level. Despite this, air quality studies in regions with combined high pollution levels and enhanced inhalation are limited. The main goals of this study are to investigate how the choice of travel mode (walking, microbus, and cable car ride) determines (i) the personal exposure to equivalent black carbon (eBC) and (ii) the corresponding potential respiratory deposited dose (RDD) in HA. For this investigation, we chose La Paz and El Alto in Bolivia as HA representative cities. The highest eBC exposure occurred in microbus commutes (13 μg m−3), while the highest RDD per trip was recorded while walking (6.3 μg) due to increased MV. On the other hand, the lowest eBC exposure and RDD were observed in cable car commute. Compared with similar studies done at sea level, our results revealed that a HA city should reduce exposure by 1.4 to 1.8-fold to achieve similar RDD at sea level, implying that HA cities require doubly aggressive and stringent road emission policies compared to those at sea level.

The physiologic effects of a new generation conducted electrical weapon on human volunteers at rest.

Axon Enterprise, Inc. (Axon) released its newest generation conducted electrical weapon (CEW), the T7, in October 2018. In order to compare the effects of this new CEW to prior generations, we used our previously described methodology to study the physiologic effects of CEWs on human volunteers at rest. This was a prospective, observational study of human subjects consisting of two parts. Part 1 was testing a single cartridge (2-probe) exposure. Subjects received a 10-s exposure from the T7 to the back with a 30cm (12in.) spread between the two probes. Part 2 was testing a simultaneous two-cartridge (4-probe) exposure. Subjects received a 10-s exposure from the T7 to the back with two cartridges with a 10cm (4in.) spread between each probe pair. The probe pairs were arranged cephalad to caudal such that the distance between the top probe of the first cartridge and the bottom probe of the second cartridge was 30cm (12in.). Vital signs were measured immediately before and after the exposure. Continuous spirometry was performed. ECG monitoring was performed immediately before and after the exposure. Venous pH, lactate, potassium, CK, catecholamines, and troponin were measured before and immediately after the exposure, at 1-h post-exposure, and again at 24h. 11 subjects completed part 1 of the study. 9 subjects completed part 2 of the study. No subjects had a dysrhythmia or morphology change in the surface ECG. There were no statistical changes in vital signs pre- and post-exposure. While subjects did not have a statistical change in spirometry parameters pre-exposure to exposure except for a small drop in PETCO2, there was an increase in minute ventilation after the exposure that could have several explanations. A similar pattern was seen with prior generation weapons. No subject had elevated troponin levels. Other blood parameters including venous pH, lactate, potassium, CK, and catecholamines had changes similar to prior generation weapons. Comparison of the data for the single-cartridge exposures against the simultaneous two-cartridge exposures yielded no difference in vital signs, but the minute ventilation was higher for the two-cartridge exposures. The blood data, where there was a difference, was mixed. In our study, the physiologic effects of the Axon T7 are modest, consistent with the electrically-induced motor nerve-driven muscle contraction, and were similar to prior generation weapons.