Baseline Ventilation Research Articles

Energy-efficient ventilation strategies at hospital front desks for minimizing infectious particle dispersion: Considering patient postures and airflow optimization

This research presents a novel examination of infectious particle dispersion at hospital front desks, analysing the impact of different patient postures on particle dynamics. It evaluates the efficacy of various ventilation strategies in mitigating particle spread within this high-risk area. Specifically, this study innovatively assesses particle dispersion associated with three common patient postures: upright standing, sitting in a wheelchair, and lying on a mobile bed. Results showed the baseline ventilation that considers the upright standing patient has the highest particles (34) adhered on the nurse. Particle adherence decreases with the sitting (29 particles) and lying postures (20 particles), underscoring the significant influence of human posture on particle distribution. The key contribution of this study is the identification of an optimized ventilation strategy which installs low-level wall-mounted air supply diffusers and ceiling-mounted exhaust grilles, as demonstrated in Case 3. This strategy effectively reduces particle deposition on the nurses and visitors by 52.9 % and 40 %, respectively. These findings advocate for practical infection control measures, like barriers between nurses and patients, to better protect healthcare workers. The study also suggests that future research should account for more crowded environments and occupant movement to better reflect real-world conditions at hospital front desks.

Efficacy of avalglucosidase alfa on forced vital capacity percent predicted in treatment-naïve patients with late-onset Pompe disease: A pooled analysis of clinical trials

BackgroundThe efficacy of avalglucosidase alfa (AVA) versus alglucosidase alfa (ALG) on forced vital capacity percent predicted (FVCpp) in patients with late-onset Pompe disease (LOPD) has been assessed in the Phase 3 COMET trial (NCT02782741). Due to the rarity of LOPD and thus small sample size in COMET, additional data were analyzed to gain further insights into the efficacy of AVA versus ALG. MethodsData from treatment-naive patients with LOPD were pooled from COMET and Phase 1/2 NEO1/NEO-EXT (NCT01898364/NCT02032524) trials for patients treated with AVA, and Phase 3 LOTS trial (NCT00158600) for patients treated with ALG. Regression analyses using mixed models with repeated measures consistent with those pre-specified in COMET were performed post-hoc. Analyses were adjusted for trials and differences in baseline characteristics. Four models were developed: Model 1 considered all trials; Model 2 included Phase 3 trials; Model 3 included Phase 3 trials and was adjusted for baseline ventilation use; Model 4 included COMET and NEO1/NEO-EXT (i.e., AVA trials only). ResultsOverall, 100 randomized patients from COMET (AVA, n = 51, ALG, n = 49), 60 from LOTS (ALG arm only), and three patients from NEO1/NEO-EXT (who received open-label AVA only) were considered for analysis. Mean age at enrollment was similar across trials (45.3–50.3 years); however, patients from LOTS had a longer mean duration of disease versus COMET and NEO1/NEO-EXT trials (9.0 years and 0.5–2.2 years, respectively) and younger mean age at diagnosis (36.2 years and 44.7–48.6 years, respectively). Least squares mean (95% confidence interval) improvement from baseline in FVCpp at Week 49–52 for AVA versus ALG was 2.43 (−0.13; 4.99) for COMET (n = 98); 2.31 (0.06; 4.57) for Model 1 (n = 160); 2.43 (0.21; 4.65) for Model 2 (n = 157); 2.80 (0.54; 5.05) for Model 3 (n = 154); and 2.27 (−0.30; 4.45) for Model 4 (n = 101). ConclusionsModels 1 to 3, which had an increased sample size versus COMET, demonstrated a nominally significant effect on FVCpp favoring AVA versus ALG after 1 year of treatment, consistent with results from COMET.

Chronic Hyperoxia Augments the Hypercapnic Ventilatory Response in Adult Rats

Rats exposed to 4 – 14 days of 60% O2 as adults exhibit a modest enhancement of their hypoxic ventilatory response (HVR) (Danielson & Bavis, Physiology 38(S1): 5730119, 2023). To determine whether this plasticity is unique to the HVR or a general increase in excitability of the respiratory control system, we tested the hypothesis that chronic hyperoxia would also enhance the hypercapnic ventilatory response (HCVR). The ventilatory response to 7% CO2 was measured by whole-body plethysmography in adult, Sprague-Dawley rats immediately after 4 and 14 days of exposure to 60% O2 or an equivalent time period in room air. Baseline ventilation and the HCVR were unchanged after 4 days of hyperoxia. The HCVR was increased after 14 days (Treatment × FICO2, P=0.004), with hypercapnic ventilation being approximately 15% greater than in control rats. However, this effect was no longer significant after accounting for variation in metabolic rate, and the HCVR was fully recovered when rats were restudied four weeks after they were returned to room air. In a follow-up experiment, pulse oximetry was performed in isoflurane-anesthetized rats breathing room air or 12% O2. Exposure to 4 – 14 days of 60% O2 did not impair gas exchange, so augmented ventilatory responses likely reflect changes in the neural control of breathing and/or metabolism rather than differences in the levels of hypoxemia and hypercapnia experienced by rats during the tests. In conclusion, chronic hyperoxia elicits plasticity in both the HVR and HCVR of adult rats, but these responses recover in less than one month after rats are returned to room air. Supported by NIH grant P20 GM-103423 (Maine INBRE). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effect of demand-controlled ventilation strategies on indoor air pollutants in a classroom: A Norwegian case study

The choice of the minimum ventilation rate (Vmin) in a demand-controlled ventilation strategy can influence energy demand but also introduce outdoor air pollutants. The latter may have direct health effects, as well as affect indoor chemical reactions. In this paper, we evaluate the effect of ventilation rates and operation hours on the level of CO2, nitrogen dioxide (NO2), and ozone (O3) in a classroom during normal use. We compared the baseline ventilation scenario (S0) with a Vmin of 430 m3/h with S1; Vmin of 150 m3/h for normal ventilation operation time (6:30-17:00) and continuous ventilation for 24h (S2). We found that S1 with reduced Vmin would lower the ozone concentration by 35% during the hours before occupancy compared to S0. Moreover, continuous ventilation during night time with a low Vmin resulted in almost as high O3 concentrations as the baseline ventilation scenario. As O3 reacts easily with certain VOCs to produce secondary organic aerosols, the level of Vmin and the ventilation duration would impact the indoor air quality upon entering the classroom.

Fourteen-day E-Cigarette Exposure Disrupts Ventilation Patterns and Serum IL-1B Levels in Adolescent Rats

E-cigarettes are devices used to deliver vaporized liquids often containing nicotine and other chemicals. The purpose of this study was to investigate the effects of 14 days of e-cigarette vapor exposure in adolescent rats on lung function and inflammatory cytokine expression. Seventeen male long-evans rats were assigned to vape or air groups. The animals were exposed to either air or 5% nicotine vapor using a whole-body exposure chamber, once a day for ten minutes for fourteen consecutive days. Ventilation recordings were completed on day 0 (before exposure) and day 15 (after exposure) using unrestrained whole-body plethysmography. Both lung tissue and blood was collected for molecular assays. Baseline and post-exposure ventilation data were compared between air and vape groups across three different parameters: frequency, tidal volume, and minute ventilation. These parameters were compared resulting in three distinct 2x2 (time x treatment) Mixed Model ANOVAs. Between baseline and post-treatment measurements there was a significant decrease in values in minute ventilation (p=0.0312) and tidal volume (p=0.0031). Between treatment groups there was a significant difference in minute ventilation (p=0.0128) and frequency (p=0042). There were also significant alterations to the presence of IL-1B in the serum (p=0.0003), but not lung tissue (p=0.6525). In conclusion, following two weeks of e-cigarette vapor exposure, ventilation patterns were altered in the vapor exposed animals which decreased in tidal volume and minute ventilation suggesting possible impairment of lung function and e-cigarette exposure modified the expression of pro-inflammatory cytokine, IL-1B.

Neoadjuvant immune checkpoint inhibitor therapy and chemotherapy improve pulmonary ventilation and diffusion function in patients with lung cancer.

To investigate changes of pulmonary ventilation function and diffusion function in lung cancer patients after neoadjuvant immune checkpoint inhibitors (ICIs) therapy combined with chemotherapy treatment. Patients with newly diagnosed lung cancer (Ⅱa-Ⅲb) admitted to Zhejiang Cancer Hospital from October 2021 to July 2022, who received ICIs combined with chemotherapy for more than two courses were enrolled. Patients underwent pulmonary ventilation function and diffusion function assessments before and after treatment. The demographic information, sizes and locations of cancer lesions, doses and duration of ICIs used, pulmonary function results before and after treatment, and the tumor regression were documented. The changes of pulmonary function parameters before and after the treatment were analyzed with paired t test and Wilcoxon rank-sum test. The factors influencing the pulmonary function changes were analyzed by multiple linear Lasso regression and ridge regression. Among the 52 patients, 50 cases were males (96.15%) and 43 cases were squamous carcinoma (82.69%). The medium age of the patients was 67 years. After neoadjuvant therapy, 36 patients (69.23%) showed remission of tumor lesions. After treatment, the parameters of pulmonary ventilation inspiratory vital capacity (IVC) and the area under the expiratory flow-volume curve (AREAex), and the parameter of pulmonary diffusion total lung capacity increased compared with the baseline (all P<0.05). Forced vital capacity (FVC) and forced expiratory volume in first second (FEV1) also showed an increasing trend. Multivariate linear Lasso regression and ridge regression showed that baseline IVC had a significant negative effect on IVC improvement (Beta=－0.435, t=－2.968, P<0.01), baseline TLC had a significant negative effect on the improvement of TLC (Beta=－0.266, t=－2.474, P<0.05), and the remission of obstructive pneumonia favored the improvement of TLC (Beta=0.308, t=2.443, P<0.05). After ICIs neoadjuvant treatment combined with chemotherapy, the lung ventilation and diffusion function can be improved in lung cancer patients, particularly for those with reduced baseline ventilation and diffusion function.

Multi-Zonal Analysis of Indoor Air Quality in a Higher Educational Building in the UK

This study focuses on the indoor air quality (IAQ) in a higher educational building, the London College in the UK. In this regard, indoor CO2 levels, as well as three contaminants with detrimental effects on human health: NO2, PM2.5, and SARS-CoV-2, are investigated. Various IAQ enhancement strategies are analyzed, including increased ventilation, background ventilation, improved airflow through opened doors, and the use of HEPA air cleaners. Results revealed that background ventilation and open doors during occupied periods reduced CO2 concentrations to around 1000 ppm. However, the effectiveness of background ventilation was influenced by outdoor conditions, such as wind speed and direction. The most effective method for reducing PM2.5 levels was installing an air cleaner alongside a commercial kitchen hood, resulting in a 15% greater reduction compared to background ventilation. To control the SARS-CoV-2 level, combining background ventilation or opening the doors with a 16,000 m3/h ventilation rate or using an air cleaner with baseline ventilation resulted in a basic reproductive number below 1. Overall, the research highlights the importance of background ventilation and open doors in enclosed spaces without operable windows for natural airflow. Additionally, the effectiveness of air purifiers in reducing particle and biological contaminant concentrations is demonstrated, providing valuable insights for improving IAQ in educational buildings.

Effects of apparatus dead space on volumetric capnograms in neonates with healthy lungs: a simulation study.

Volumetric capnography in healthy ventilated neonates showed deformed waveforms, which are supposedly due to technological limitations of flow and carbon dioxide sensors. This bench study analyzed the role of apparatus dead space on the shape of capnograms in simulated neonates with healthy lungs. We simulated mechanical breaths in neonates of 2, 2.5, and 3 kg of body weight using a neonatal volumetric capnography simulator. The simulator was fed by a fixed amount of carbon dioxide of 6 mL/kg/min. Such simulator was ventilated in a volume control mode using fixed ventilatory settings with a tidal volume of 8 mL/kg and respiratory rates of 40, 35, and 30 breaths per minute for the 2, 2.5 and 3 kg neonates, respectively. We tested the above baseline ventilation with and without an additional apparatus dead space of 4 mL. Simulations showed that adding the apparatus dead space to baseline ventilation increased the amount of re-inhaled carbon dioxide in all neonates: 0.16 ± 0.01 to 0.32 ± 0.03 mL (2 kg), 0.14 ± 0.02 to 0.39 ± 0.05 mL (2.5 kg), and 0.13 ± 0.01 to 0.36 ± 0.05 mL (3 kg); (p < .001). Apparatus dead space was computed as part of the airway dead space, and therefore, the ratio of airway dead space to tidal volume increased from 0.51 ± 0.04 to 0.68 ± 0.06, from 0.43 ± 0.04 to 0.62 ± 0.01 and from 0.38 ± 0.01 to 0.60 ± 0.02 in the 2, 2.5 and 3 kg simulated neonates, respectively (p < .001). Compared to baseline ventilation, adding apparatus dead space decreased the ratio of the volume of phase III to VT size from 31% to 11% (2 kg), from 40% to 16% (2.5 kg) and from 50% to 18% (3 kg); (p < .001). The addition of a small apparatus dead space artificially deformed the volumetric capnograms in simulated neonates with healthy lungs.

The effect of diet-induced obesity on sleep and breathing in female mice.

Obesity and male sex are main risk factors for sleep-disordered breathing (SDB). We have shown that male diet-induced obesity (DIO) mice develop hypoventilation, sleep apnea, and sleep fragmentation. The effects of DIO on breathing and sleep architecture in females have not been investigated. We hypothesized that female mice are less susceptible to the detrimental effects of DIO on sleep and SDB compared to males. Female DIO-C57BL/6J and lean C57BL/6J mice underwent 24-hour metabolic studies and were exposed to 8% CO2 to measure the hypercapnic ventilatory response (HCVR), and sleep studies. Ventilatory response to arousals was calculated as ratio of the average and peak minute ventilation (VE) during each arousal relative to the baseline VE. Breathing stability was measured with Poincaré plots of VE. Female obesity was associated with decreased metabolism, indicated by reduced oxygen consumption (VO2) and CO2 production (VCO2). VE in 8% CO2 and HCVR were significantly attenuated during wakefulness. NREM sleep duration was reduced in DIO mice, but REM sleep was preserved. Ventilation during NREM and REM sleep was augmented compared to lean mice. Arousal frequency was similar between groups. Obesity increased the frequency of spontaneous arousals, whereas the apnea index was 4-fold reduced in DIO compared to lean mice. Obesity decreased pre- and post-apnea arousals. Obese mice had more stable breathing with reduced ventilatory response to arousals, compared to lean females. We conclude that obese female mice are protected against SDB, which appears to be related to an attenuated CO2 responsiveness, compared to the lean state.

0255 Female Mice Are Less Susceptible to the Effects of Diet-Induced Obesity on Sleep and Sleep-Disordered Breathing

Abstract Introduction Diet-induced obesity (DIO) in male mice is a well-established model of sleep-disordered breathing (SDB). Male DIO mice manifest hypoventilation, increased apnea severity, and sleep fragmentation. The effects of DIO on breathing during sleep and sleep architecture in females have been insufficiently investigated. We hypothesized that female mice are less susceptible to the detrimental effects of DIO on sleep and SDB compared to males. Methods Full-polysomnographies were performed in 15 lean female C57BL/6J and 14 female DIO-C57BL/6J mice using a whole-body plethysmography chamber. Ventilatory response to an arousal was calculated as ratio of the average minute ventilation (VE) during each arousal (2.5s) relative to the baseline VE. Breathing stability was measured using Poincaré plots of VE. Mice were exposed to 8% CO2 to measure the hypercapnic ventilatory response (HCVR). Mice underwent 24-h metabolic studies. Results Obesity was associated with hypometabolism, indicated by reduced oxygen consumption (VO2) and CO2 production in DIO mice. VE in 8% CO2 and HCVR were significantly suppressed suggesting a decreased CO2 sensitivity in obese animals. NREM sleep duration was reduced, but REM sleep was preserved. Arousal frequency and VE during NREM and REM sleep were similar between groups. However, apnea severity was 4-fold augmented in lean females compared to DIO mice (14.7±3.9 vs 74.2±11.9 events/h; P&amp;lt; 0.001). In lean mice, the increased frequency of apneas was mainly attributed to sleep fragmentation since the events were predominantly post-arousals. Breathing stability during sleep was significantly increased in lean mice. Ventilatory response to an arousal was 30% increased in lean females compared to DIO group. Conclusion Our results suggest potential sex differences in the effects of DIO on breathing during sleep and sleep architecture. DIO in females appears to be less detrimental regarding SDB severity. The mechanisms underlying the augmented SDB severity in lean females are unknown, but an exacerbated CO2 responsiveness during sleep related to sleep fragmentation could play an important role. Support (if any) American Heart Association Postdoctoral Fellowship Award 828142, NHLBI grant NIH R01s HL128970, HL133100, and HL13892, American Academy of Sleep Medicine Foundation 238-BS-20, and American Thoracic Society Unrestricted Award.

Seizures Cause Prolonged Impairment of Ventilation, CO2 Chemoreception and Thermoregulation.

Sudden unexpected death in epilepsy (SUDEP) has been linked to respiratory dysfunction, but the mechanisms underlying this association remain unclear. Here we found that both focal and generalized convulsive seizures (GCSs) in epilepsy patients caused a prolonged decrease in the hypercapnic ventilatory response (HCVR; a measure of respiratory CO2 chemoreception). We then studied Scn1a R1407X/+ (Dravet syndrome; DS) and Scn8a N1768D/+ (D/+) mice of both sexes, two models of SUDEP, and found that convulsive seizures caused a postictal decrease in ventilation and severely depressed the HCVR in a subset of animals. Those mice with severe postictal depression of the HCVR also exhibited transient postictal hypothermia. A combination of blunted HCVR and abnormal thermoregulation is known to occur with dysfunction of the serotonin (5-hydroxytryptamine; 5-HT) system in mice. Depleting 5-HT with para-chlorophenylalanine (PCPA) mimicked seizure-induced hypoventilation, partially occluded the postictal decrease in the HCVR, exacerbated hypothermia, and increased postictal mortality in DS mice. Conversely, pretreatment with the 5-HT agonist fenfluramine reduced postictal inhibition of the HCVR and hypothermia. These results are consistent with the previous observation that seizures cause transient impairment of serotonergic neuron function, which would be expected to inhibit the many aspects of respiratory control dependent on 5-HT, including baseline ventilation and the HCVR. These results provide a scientific rationale to investigate the interictal and/or postictal HCVR as noninvasive biomarkers for those at high risk of seizure-induced death, and to prevent SUDEP by enhancing postictal 5-HT tone.SIGNIFICANCE STATEMENT There is increasing evidence that seizure-induced respiratory dysfunction contributes to the pathophysiology of sudden unexpected death in epilepsy (SUDEP). However, the cellular basis of this dysfunction has not been defined. Here, we show that seizures impair CO2 chemoreception in some epilepsy patients. In two mouse models of SUDEP we found that generalized convulsive seizures impaired CO2 chemoreception, and induced hypothermia, two effects reported with serotonergic neuron dysfunction. The defects in chemoreception and thermoregulation were exacerbated by chemical depletion of serotonin and reduced with fenfluramine, suggesting that seizure-induced respiratory dysfunction may be due to impairment of serotonin neuron function. These findings suggest that impaired chemoreception because of transient inhibition of serotonergic neurons may contribute to the pathophysiology of SUDEP.

L-DOPA Improves Ventilation but Not the Ventilatory Response to Hypercapnia in a Reserpine Model of Parkinson's Disease.

Parkinson's disease (PD) is a neurological disorder characterized by progressive degeneration of the substantia nigra that affects mainly movement control. However, pathological changes associated with the development of PD may also alter respiration and can lead to chronic episodes of hypoxia and hypercapnia. The mechanism behind impaired ventilation in PD is unclear. Therefore, in this study, we explore the hypercapnic ventilatory response in a reproducible reserpine-induced (RES) model of PD and parkinsonism. We also investigated how dopamine supplementation with L-DOPA, a classic drug used to treat PD, would affect the breathing and respiratory response to hypercapnia. Reserpine treatment resulted in decreased normocapnic ventilation and behavioral changes manifested as low physical activity and exploratory behavior. The respiratory rate and the minute ventilation response to hypercapnia were significantly higher in sham rats compared to the RES group, while the tidal volume response was lower. All of this appears to be due to reduced baseline ventilation values produced by reserpine. L-DOPA reversed reduced ventilation, indicating a stimulatory effect of DA on breathing, and showed the potency of DA supplementation in restoring normal respiratory activity.

Breathing irregularities in spontaneously hypertensive neonate rats

An excessive sympathetic drive is commonly observed in hypertensive patients and critically contributes to increasing arterial pressure levels. The quality of postnatal life can impact sympathetic control in adulthood. Spontaneously hypertensive (SH) rats, an experimental model of neurogenic hypertension, exhibit breathing irregularities in adult life. In this study, we investigated whether SH rats display breathing abnormalities after birth, which could be a risk factor for developing sympathetic overactivity. Using head-out plethysmography, we found that the neonate (P0-2, male and female) SH rats (n=9) exhibited lower minute ventilation than age-matched normotensive rats (NT, n=14; 816±177 vs 1261±189 ml/min/kg, P&lt;0.05) under resting conditions, mainly due to reductions in respiratory frequency (93±15 vs 132±13 cpm, P&lt;0.05). The reduced baseline ventilation in the SH group was accompanied by a greater prevalence of periods of apneas and respiratory irregularities (P&lt;0.05). Under hypoxia conditions (10% O2, 10 min), SH and NT rats (n=9/each) mounted similar transient increases in minute ventilation during the initial period of exposure due to increments in tidal volume. In contrast, the respiratory frequency in the SH rats decreased progressively below baseline levels during hypoxia exposure (42% reduction, P&lt;0.05), while it remained similar to pre-hypoxia values in the control group. In rhythmic in vitro preparations from neonate SH rats (n=2), we identified ectopic bursts in the hypoglossal activity and prolonged inspiratory-related bursts in the preBötzinger complex compared to preparations from NT rats (n=2). Our findings indicate that breathing irregularities in SH rats are present from birth and could be linked to dysfunctions in the inspiratory rhythm-generating network. Financial support: FAPESP, CNPq. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Neurological and respiratory effects of lung protective ventilation in acute brain injury patients without lung injury: brain vent, a single centre randomized interventional study

IntroductionLung protective ventilation (LPV) comprising low tidal volume (VT) and high positive end-expiratory pressure (PEEP) may compromise cerebral perfusion in acute brain injury (ABI). In patients with ABI, we investigated whether LPV is associated with increased intracranial pressure (ICP) and/or deranged cerebral autoregulation (CA), brain compensatory reserve and oxygenation.MethodsIn a prospective, crossover study, 30 intubated ABI patients with normal ICP and no lung injury were randomly assigned to receive low VT [6 ml/kg/predicted (pbw)]/at either low (5 cmH2O) or high PEEP (12 cmH2O). Between each intervention, baseline ventilation (VT 9 ml/kg/pbw and PEEP 5 cmH2O) were resumed. The safety limit for interruption of the intervention was ICP above 22 mmHg for more than 5 min. Airway and transpulmonary pressures were continuously monitored to assess respiratory mechanics. We recorded ICP by using external ventricular drainage or a parenchymal probe. CA and brain compensatory reserve were derived from ICP waveform analysis.ResultsWe included 27 patients (intracerebral haemorrhage, traumatic brain injury, subarachnoid haemorrhage), of whom 6 reached the safety limit, which required interruption of at least one intervention. For those without intervention interruption, the ICP change from baseline to “low VT/low PEEP” and “low VT/high PEEP” were 2.2 mmHg and 2.3 mmHg, respectively, and considered clinically non-relevant. None of the interventions affected CA or oxygenation significantly. Interrupted events were associated with high baseline ICP (p < 0.001), low brain compensatory reserve (p < 0.01) and mechanical power (p < 0.05).The transpulmonary driving pressure was 5 ± 2 cmH2O in both interventions. Partial arterial pressure of carbon dioxide was kept in the range 34–36 mmHg by adjusting the respiratory rate, hence, changes in carbon dioxide were not associated with the increase in ICP.ConclusionsThe present study found that most patients did not experience any adverse effects of LPV, neither on ICP nor CA. However, in almost a quarter of patients, the ICP rose above the safety limit for interrupting the interventions. Baseline ICP, brain compensatory reserve, and mechanical power can predict a potentially deleterious effect of LPV and can be used to personalize ventilator settings.Trial registrationNCT03278769. Registered September 12, 2017.Graphical

Participation of the angiotensinergic and vasopressinergic mechanisms in the maintenance of cardiorespiratory parameters in sodium depleted rats

Changes in blood volume can be caused by different conditions, such as vomiting, diarrhea, alteration of sodium intake, trauma, or the use of diuretics, which can lead to severe health deterioration. Understanding the mechanisms involved in the maintenance of physiological parameters and the hydroelectrolytic balance of the human body during hypovolemia, can help with preventing and handling these high-risk situations. Hence, this study investigated cardiorespiratory [mean arterial pressure (MAP), heart rate (HR), pulmonary ventilation (VE)] and blood parameters, of sodium depleted rats with furosemide and the roles of the central and peripheral renin-angiotensin and the peripheral vasopressinergic systems in controlling blood pressure in these animals. Different groups under the same conditions received subcutaneous (s.c.) injections of furosemide (diuretic/saliuretic) or vehicle, intracerebroventricular (i.c.v.) or intravenous (i.v.) injections of losartan [angiotensin II (ANG II) AT1 receptor antagonist] or saline, and i.v. injections of Manning compound (AVPX, vasopressin V1 receptor antagonist). Sodium depletion increased the VE (708 ± 71, vs. normovolemic: 478 ± 40 mL/min/kg body wt) and did not modify baseline mean arterial pressure (104 ± 4, vs. normovolemic: 105 ± 4 mmHg) and heart rate (334 ± 20, vs. normovolemic: 379 ± 13 bpm). The i.v. losartan (10 mg/kg of body wt) treatment significantly reduced MAP in all groups and elevated HR, with a greater impact in sodium depleted rats before repletion. On the other hand, the i.c.v. losartan (3.3 μg/kg of body wt) and i.v. AVPX (10 μg/kg of body wt) treatments did not alter the MAP and HR in control, sodium depleted, and sodium repleted rats. These results indicate that sodium depletion affects cardiorespiratory control increasing baseline ventilation and peripheral angiotensinergic mechanisms are relevant for maintaining cardiovascular parameters in sodium depleted rats. Besides, this study suggests vasopressin V1 receptors do not participate in the maintenance of MAP and HR in sodium depleted animals with furosemide.

Low-dose dopamine improves ventilatory efficiency during exercise in heart failure with preserved ejection fraction through inhibition of tonic activity of peripheral chemoreceptors

Abstract Introduction Peripheral chemoreceptors (PChRs) play an important role in adequate oxygenation by 1) maintaining baseline ventilation (tonic activity) and 2) providing hyperventilation in response to acute hypoxia (reflexia). It has been previously shown that in patients with heart failure with reduced ejection fraction hypertonicity and/or hyperreflexia of PChRs contribute to exercise intolerance (ExIn). It is unknown whether similar mechanisms are present in heart failure with preserved ejection fraction (HFpEF) and which component of PChR functionality has a decisive role in this matter. Purpose The aim of this study was to evaluate the role of PChRs in ExIn in patients with HFpEF. Methods All patients underwent assessment of PChRs which included measurements of: 1) tonic activity (TA, decrease in ventilation following pharmacological inhibition of PChRs), 2) reflex response (RR; an increase in ventilation in the response to acute hypoxia). The inhibition of PChRs was achieved with low-dose dopamine infusion (3 μg kg–1 min–1) and the acute hypoxia was produced with brief nitrogen gas administrations. Enrolled patients underwent symptom-limited cardiopulmonary exercise test using cycle ergometer from which peak oxygen consumption (peakVO2) and the slope relating ventilation to carbon dioxide (VE/VCO2 slope) were derived. All measurements (including PChRs' function tests and cardiopulmonary exercise test) were performed twice in a randomized, double-blinded and placebo-controlled manner (dopamine vs normal saline). Results We included 12 stable patients with HFpEF (age: 73±7 years, LVEF: 58±3%). During exercise the inhibition of PChRs with dopamine resulted in the improvement (decrease) in VE/VCO2 slope comparing to placebo (36±3.6 vs 34.3±3.7, p=0.04) but no change regarding peakVO2. There was a correlation between TA and relative magnitude of improvement in VE/VCO2 following PChRs inhibition (R=0.76, p=0.005). We also found a trend for correlation between RR and VE/VCO2 measured during placebo (R=0.56, p=0.059). There was no correlation between TA and RR (p=0.24). Conclusion Both TA and RR of PChRs are involved in ventilatory inefficacy during exercise in HFpEF – but in different ways. While augmented RR is likely an indicator of high VE/VCO2, the elevated TA indicates the magnitude of the improvement in exercise tolerance following PChRs deactivation. Thus, further interventions aimed at the modulation of PChRs should enroll patients based on TA rather than RR. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Science Centre, PRELUDIUM grant

Inspiratory Effort and Respiratory Mechanics in Patients with Acute Exacerbation of Idiopathic Pulmonary fibrosis: A Preliminary Matched Control Study

BackgroundPatients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) may experience severe acute respiratory failure, even requiring ventilatory assistance. Physiological data on lung mechanics during these events are lacking. MethodsPatients with AE-IPF admitted to Respiratory Intensive Care Unit to receive non-invasive ventilation (NIV) were retrospectively analyzed. Esophageal pressure swing (ΔPes) and respiratory mechanics before and after 2 hours of NIV were collected as primary outcome. The correlation between positive end-expiratory pressure (PEEP) levels and changes of in dynamic compliance (dynCRS) and PaO2/FiO2 ratio was assessed. Further, an exploratory comparison with a historical cohort of ARDS patients matched 1:1 by age, sequential organ failure assessment score, body mass index and PaO2/FiO2 level was performed. ResultsAt baseline, AE-IPF patients presented a high respiratory drive activation with ΔPes = 27 (21–34) cmH2O, respiratory rate (RR) = 34 (30–39) bpm and minute ventilation (VE) = 21 (20–26) L/min. Two hours after NIV application, ΔPes, RR and VE values showed a significant reduction (16 [14–24] cmH2O, p<0.0001, 27 [25–30] bpm, p=0.001, and 18 [17–20] L/min, p=0.003, respectively) while no significant change was found in dynamic transpulmonary pressure, expiratory tidal volume (Vte), dynCRS and dynamic mechanical power. PEEP levels negatively correlated with PaO2/FiO2 ratio and dynCRS (r=–0.67, p=0.03 and r=–0.27, p=0.4, respectively). When compared to AE-IPF, ARDS patients presented lower baseline ΔPes, RR, VE and dynamic mechanical power. Differently from AE-IPF, in ARDS both Vte and dynCRS increased significantly following NIV (p=0.01 and p=0.004 respectively) with PEEP levels directly associated with PaO2/FiO2 ratio and dynCRS (r=0.24, p=0.5 and r=0.65, p=0.04, respectively). ConclusionsIn this study, patients with AE-IPF showed a high inspiratory effort, whose intensity was reduced by NIV application without a significant improvement in respiratory mechanics. In an exploratory analysis, AE-IPF patients showed a different mechanical behavior under spontaneous unassisted and assisted breathing compared with ARDS patients of similar severity.

The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial.

OBJECTIVES:Respiratory failure is a lethal complication of COVID-19 that has remained resistant to drug therapy. Vasoactive intestinal peptide (VIP) is shown in nonclinical studies to upregulate surfactant production, inhibit cytokine synthesis, prevent cytopathy, and block replication of the severe acute respiratory syndrome coronavirus 2 virus in pulmonary cells. The study aims to determine whether Aviptadil (synthetic VIP) can improve survival and recovery in patients with COVID-19 respiratory failure compared with placebo and demonstrate biological effects in such patients.DESIGN:A multicenter, placebo-controlled trial.SETTING:Ten U.S. hospitals: six tertiary-care hospitals and four community hospitals.PATIENTS:A total of 196 patients with COVID-19 respiratory failure.INTERVENTIONS:Participants were randomized 2:1 to receive 3 days of IV Aviptadil or placebo.MEASUREMENTS AND MAIN RESULTS:The primary end point (alive and free from respiratory failure at day 60) did not reach statistical significance (odds ratio [OR], 1.6; 95% CI, 0.86–3.11) for patients treated with Aviptadil when controlling for baseline ventilation status as prespecified in the protocol. There was, however, a statistically significant two-fold odds of improved survival (OR, 2.0; 95% CI, 1.1–3.9) at 60 days (p = 0.035). There was significant improvement in respiratory distress ratio and reduced interleukin 6 cytokine release (p = 0.02) by day 3.Subgroup analysis identified a statistically significant likelihood of achieving primary end point among those treated with high-flow nasal oxygen at baseline (p = 0.039). Subjects on mechanical ventilation also experienced a 10-fold increased odds of survival with drug versus placebo (p = 0.031).CONCLUSIONS:The primary end point did not reach statistical significance, indicating that there was no difference between Aviptadil versus placebo. However, Aviptadil improves the likelihood of survival from respiratory failure at day 60 in critical COVID-19 across all sites of care. Given the absence of drug-related serious adverse events and acceptable safety profile, we believe the benefit versus risk for the use of Aviptadil is favorable for patient treatment.

Respiratory Effects of the Atypical Tricyclic Antidepressant Tianeptine in Human Models of Opioid-induced Respiratory Depression.

Animal data suggest that the antidepressant and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor modulator tianeptine is able to prevent opioid-induced respiratory depression. The hypothesis was that oral or intravenous tianeptine can effectively prevent or counteract opioid-induced respiratory depression in humans. Healthy male and female volunteers participated in two studies that had a randomized, double blind, placebo-controlled, crossover design. First, oral tianeptine (37.5-, 50-, and 100-mg doses with 8 subjects) pretreatment followed by induction of alfentanil-induced respiratory depression (alfentanil target concentration, 100 ng/ml) was tested. Primary endpoint was ventilation at an extrapolated end-tidal carbon dioxide concentration of 55 mmHg (V̇E55). Next, the ability of four subsequent and increasing infusions of intravenous tianeptine (target tianeptine plasma concentrations 400, 1,000, 1,500, and 2,000 ng/ml, each given over 15 min) to counteract remifentanil-induced respiratory depression was determined in 15 volunteers. Ventilation was measured at isohypercpania (baseline ventilation 20 ± 2 l/min). The primary endpoint was minute ventilation during the 60 min of tianeptine versus placebo infusion. Alfentanil reduced V̇E55 to 13.7 (95% CI, 8.6 to 18.8) l/min after placebo pretreatment and to 17.9 (10.2 to 25.7) l/min after 50-mg tianeptine pretreatment (mean difference between treatments 4.2 (-11.5 to 3.0) l/min, P = 0.070). Intravenous tianeptine in the measured concentration range of 500 to 2,000 ng/ml did not stimulate ventilation but instead worsened remifentanil-induced respiratory depression: tianeptine, 9.6 ± 0.8 l/min versus placebo 15.0 ± 0.9 l/min; mean difference, 5.3 l/min; 95% CI, 2.5 to 8.2 l/min; P = 0.001, after 1 h of treatment. Neither oral nor intravenous tianeptine were respiratory stimulants. Intravenous tianeptine over the concentration range of 500 to 2000 ng/ml worsened respiratory depression induced by remifentanil.

Chronic Hypoxia Blunts the Hypoxic Ventilatory Response in Neonatal and Adult Rats

Chronic hypoxia (CH) may affect the control of breathing differently in neonatal versus adult mammals. It is widely accepted that CH blunts the hypoxic ventilatory response (HVR) in neonatal rats but augments hypoxic ventilation in adult rats. However, there is also evidence that longer durations of CH can progressively attenuate the HVR in adult rats too. Therefore, we predicted that short durations of CH (3 days) would blunt the HVR in neonatal rats and augment the HVR in adult rats, but that longer durations of CH (7 days) would blunt the HVR in adult rats. To test these predictions, rats were exposed to 12% O2 (CH) or room air (Control) for 3 days as neonates (from P0 to P3, or from P7 to P10) or as young adults. Baseline ventilation (21% O2) and the acute HVR (12% O2) were measured by plethysmography immediately following the exposure. The adult rats were then returned to the CH and Control chambers for 4 more days before repeating the breathing measurements. Although Sprague‐Dawley rats were used in all experiments, adults from two different commercial suppliers (Charles River Laboratories and Envigo) were used to determine whether genetic background might influence the results. Baseline ventilation was greater in all CH groups regardless of their age, consistent with ventilatory acclimatization. With the exception of CH rats at P10 in which peak hypoxic ventilation (i.e., minute ventilation during the first minute of 12% O2) was also greater than in Controls, hypoxic ventilation was generally similar between CH and Control groups or reduced in the CH group. Accordingly, the change in ventilation from baseline (i.e., HVR) was blunted by CH regardless of the age of the rats, the duration of the CH exposure (adults only), or the substrain of Sprague‐Dawley rat (adults only). The order in which test gases were presented during breathing measurements (i.e., 21% O2 – 12% O2 vs. 12% O2 – 21% O2) did not influence the calculated HVR in adult rats. We conclude that the respiratory plasticity elicited by normobaric CH is similar across ages in Sprague‐Dawley rats.