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An open‐label, randomized, crossover study in healthy volunteers compared the reversal of remifentanil‐induced respiratory depression by intranasal (IN) naloxone hydrochloride (4 mg) to IN nalmefene (2.7 mg) (NCT 04828005). Subjects were administered a hypercapnic gas mixture which produces an elevation in minute ventilation (MV), a result of the ventilatory response to hypercapnia. Subjects breathed a hypercapnic gas mixture through a tight‐fitting mask for an initial period of 46 min prior to a series of mask "holidays" introduced to reduce subject discomfort and encourage study completion. Ten minutes after initiating the hypercapnic gas mixture, a remifentanil bolus was administered, and an infusion continued for the study duration. Subjects were administered either naloxone or nalmefene 15 min after initiating the remifentanil infusion and MV monitored for 21 min followed by a mask holiday. Both nalmefene and naloxone produced a time‐dependent reversal of remifentanil‐induced reductions in MV measured 2.5–20 min post administration. At the primary endpoint (5 min post administration), nalmefene increases in MV (5.75 L/min) were nearly twice that produced by naloxone (3.01 L/min) (P <.0009); the point estimate favors nalmefene, demonstrating non‐inferiority and superiority. In this model of opioid‐induced respiratory depression, nalmefene has a more rapid onset of action than naloxone, which required 20 min to achieve a comparable reversal of respiratory depression. Both nalmefene and naloxone were well tolerated by healthy volunteers. This rapid onset of action may prove particularly valuable in an era when over 90% of fatalities are linked to synthetic opioid overdose. [ABSTRACT FROM AUTHOR]

The review discusses the potential relationship between hypoxia resistance and longevity, the influence of carbon dioxide on the mechanisms of aging of the mammalian organism, and intermittent hypercapnic–hypoxic effects on the signaling pathways of aging mechanisms. In the article, we focused on the potential mechanisms of the gero-protective efficacy of carbon dioxide when combined with hypoxia. The review summarizes the possible influence of intermittent hypoxia and hypercapnia on aging processes in the nervous system. We considered the perspective variants of the application of hypercapnic–hypoxic influences for achieving active longevity and the prospects for the possibilities of developing hypercapnic–hypoxic training methods. [ABSTRACT FROM AUTHOR]

Background Aims Methods Results Conclusions Identification of hypoxaemia and hypercapnia is essential for the diagnosis and treatment of acute respiratory failure. While arterial blood gas (ABG) analysis is standard for PO2 and PCO2 measurement, venous blood gas (VBG) analysis is increasingly used as an alternative. Previous systematic reviews established that VBG reporting of PO2 and PCO2 is less accurate, but the impacts on clinical management and patient outcomes are unknown.This study aimed to systematically review available evidence of the clinical impacts of using ABGs or VBGs and examine the arteriovenous difference in blood gas parameters.A comprehensive search of the MEDLINE, Embase and Cochrane Library databases since inception was conducted. Included studies were prospective or cross‐sectional studies comparing peripheral ABG to peripheral VBG in adult non‐critical care inpatients presenting with respiratory symptoms.Of 15 119 articles screened, 15 were included. No studies were found that examined clinical impacts resulting from using VBG compared to ABG. Included studies focused on the agreement between ABG and VBG measurements of pH, PO2, PCO2 and HCO3−. Due to the heterogeneity of the included studies, qualitative evidence synthesis was performed. While the arteriovenous difference in pH and HCO3− was generally predictable, the difference in PO2 and PCO2 was more significant and less predictable.Our study reinforces the notion that VBG is not comparable to ABG for physiological measurements. However, a key revelation from our research is the significant lack of data regarding the clinical implications of using VBG instead of ABG, a common scenario in clinical practice. This highlights a critical knowledge gap. [ABSTRACT FROM AUTHOR]

Background: Overlap syndrome (OS), the coexistence of chronic obstructive pulmonary disease and obstructive sleep apnea, is frequently characterized by the presence of daytime hypercapnia (pCO2 ≥ 45 mmHg). The aim of this study was to investigate potential differences in anthropometric, sleep and respiratory characteristics between hypercapnic and normocapnic patients with OS. Methods: Consecutive patients who underwent polysomnography, pulmonary function testing and arterial blood gases and had been diagnosed with OS were enrolled in the study. Results: According to pCO2 levels in wakefulness, the patients were divided into group A, consisting of OS patients without hypercapnia (n = 108) or group B, consisting of OS patients with hypercapnia (n = 55). The majority of included patients in both groups were males (n = 92 in group A vs. n = 50 in group B). Group B had increased BMI (p = 0.001), neck (p = 0.017) and waist circumference (p = 0.013), higher scores in Epworth sleepiness scale (ESS) (p = 0.008), increased sleep efficiency (p = 0.033), oxygen desaturation index (p = 0.004) and time with oxyhemoglobin saturation <90% (p = 0.006) than group A. Also, Group B had decreased average and minimum oxyhemoglobin saturation during sleep (p < 0.001). Hypercapnic patients had lower FEV1% (p = 0.003), FVC% (p = 0.004), pO2 and pCO2 (p < 0.001 for both) values compared with normocapnic patients. In binary regression analysis, which assessed various predictors on the likelihood of having hypercapnia, it was found that BMI (OR: 1.313, 95% CI: 1.048–1.646, p = 0.018) and FVC (OR: 0.913, 95% CI: 0.845–0.986, p = 0.020) were the major determinants of hypercapnia in OS patients. Conclusions: Hypercapnic OS patients were more obese and sleepy and presented worse respiratory function in wakefulness and sleep hypoxia characteristics compared with normocapnic OS patients. [ABSTRACT FROM AUTHOR]

We aimed to determine the relative contribution of hypercapnia and hypoxia to the bradycardic response to apneas. We hypothesized that apneas with hypercapnia would cause greater bradycardia than normoxia, similar to the response seen with hypoxia, and that apneas with hypercapnic hypoxia would induce greater bradycardia than hypoxia or hypercapnia alone. Twenty‐six healthy participants (12 females; 23 ± 2 years; BMI 24 ± 3 kg/m2) underwent three gas challenges: hypercapnia (+5 torr end tidal partial pressure of CO2 [PETCO2]), hypoxia (50 torr end tidal partial pressure of O2 [PETO2]), and hypercapnic hypoxia (combined hypercapnia and hypoxia), with each condition interspersed with normocapnic normoxia. Heart rate and rhythm, blood pressure, PETCO2, PETO2, and oxygen saturation were measured continuously. Hypercapnic hypoxic apneas induced larger bradycardia (−19 ± 16 bpm) than normocapnic normoxic apneas (−11 ± 15 bpm; p = 0.002), but had a comparable response to hypoxic (−19 ± 15 bpm; p = 0.999) and hypercapnic apneas (−14 ± 14 bpm; p = 0.059). Hypercapnic apneas were not different from normocapnic normoxic apneas (p = 0.134). After removal of the normocapnic normoxic heart rate response, the change in heart rate during hypercapnic hypoxia (−11 ± 16 bpm) was similar to the summed change during hypercapnia+hypoxia (−9 ± 10 bpm; p = 0.485). Only hypoxia contributed to this bradycardic response. Under apneic conditions, the cardiac response is driven by hypoxia. [ABSTRACT FROM AUTHOR]

Background: A critical parameter of extracorporeal CO2 removal (ECCO2R) applications is the CO2 removal rate (VCO2). Low‐flow venovenous extracorporeal support with large‐size membrane lung remains undefined. This study aimed to evaluate the VCO2 of a low‐flow ECCO2R with large‐size membrane lung using a renal replacement therapy platform in an experimental animal model. Methods: Twelve healthy pigs were placed under mechanical ventilation and connected to an ECCO2R‐CRRT system (surface area = 1.8 m2; OMNIset®, BBraun, Germany). Respiratory settings were reduced to induce two degrees of hypercapnia. VCO2 was recorded under different combinations of PaCO2 (50–69 or 70–89 mm Hg), extracorporeal blood flow (ECBF; 200 or 350 mL/min), and gas flow (4, 6, or 10 L/min). Results: VCO2 increased with ECBF at all three gas flow rates. In severe hypercapnia, the increase in sweep gas flow from 4 to 10 L/min increased VCO2 from 86.38 ± 7.08 to 96.50 ± 8.71 mL/min at an ECBF of 350 mL/min, whereas at ECBF of 200 mL/min, any increase was less effective. But in mild hypercapnia, the increase in sweep gas flow result in significantly increased VCO2 at two ECBF. VCO2 increased with PaCO2 from 50–69 to 70–89 mm Hg at an ECBF of 350 mL/min, but not at ECBF of 200 mL/min. Post‐membrane lung PCO2 levels were similar for different levels of premembrane lung PCO2 (p = 0.08), highlighting the gas exchange diffusion efficacy of the membrane lung in gas exchange diffusion. In severe hypercapnia, the reduction of PaCO2 elevated from 11.5% to 19.6% with ECBF increase only at a high gas flow of 10 L/min (p < 0.05) and increase of gas flow significantly reduced PaCO2 only at a high ECBF of 350 mL/min (p < 0.05). Conclusions: Low‐flow venovenous extracorporeal ECCO2R‐CRRT with large‐size membrane lung is more efficient with the increase of ECBF, sweep gas flow rate, and the degree of hypercapnia. The influence of sweep gas flow on VCO2 depends on the ECBF and degree of hypercapnia. Higher ECBF and gas flow should be chosen to reverse severe hypercapnia. [ABSTRACT FROM AUTHOR]

In Parkinson's disease (PD), along with typical motor dysfunction, abnormal breathing is present; the cause of which is not well understood. The study aimed to analyze the effects of stimulation of the serotonergic system with 5-HT1A and 5-HT2A agonists in a model of PD induced by injection of 6-hydroxydopamine (6-OHDA). To model PD, bilateral injection of 6-OHDA into both striata was performed in male Wistar rats. Respiratory disturbances in response to 7% hypercapnia (CO2 in O2) in the plethysmographic chamber before and after stimulation of the serotonergic system and the incidence of apnea were studied in awake rats 5 weeks after 6-OHDA or vehicle injection. Administration of 6-OHDA reduced the concentration of serotonin (5-HT), dopamine (DA) and norepinephrine (NA) in the striatum and the level of 5-HT in the brainstem of treated rats, which have been associated with decreased basal ventilation, impaired respiratory response to 7% CO2 and increased incidence of apnea compared to Sham-operated rats. Intraperitoneal (i.p.) injection of the 5-HT1AR agonist 8-OH-DPAT and 5-HT2AR agonist NBOH-2C-CN increased breathing during normocapnia and hypercapnia in both groups of rats. However, it restored reactivity to hypercapnia in 6-OHDA group to the level present in Sham rats. Another 5-HT2AR agonist TCB-2 was only effective in increasing normocapnic ventilation in 6-OHDA rats. Both the serotonergic agonists 8-OH-DPAT and NBOH-2C-CN had stronger stimulatory effects on respiration in PD rats, compensating for deficits in basal ventilation and hypercapnic respiration. We conclude that serotonergic stimulation may have a positive effect on respiratory impairments that occur in PD. [ABSTRACT FROM AUTHOR]

Extracorporeal Cardiopulmonary Resuscitation (ECPR) has potential benefits compared to conventional Cardiopulmonary Resuscitation (CCPR) in children. Although no randomised trials for paediatric ECPR have been conducted, there is extensive literature on survival, neurological outcome and risk factors for survival. Based on current literature and guidelines, we suggest recommendations for deployment of paediatric ECPR emphasising the requirement for protocols, training, and timely intervention to enhance patient outcomes. Factors related to outcomes of paediatric ECPR include initial underlying rhythm, CCPR duration, quality of CCPR, medications during CCPR, cannulation site, acidosis and renal dysfunction. Based on current evidence and experience, we provide an approach to patient selection, ECMO initiation and management in ECPR regarding blood and sweep flow settings, unloading of the left ventricle, diagnostics whilst on ECMO, temperature targets, neuromonitoring as well as suggested weaning and decannulation strategies. [ABSTRACT FROM AUTHOR]

Background: Cerebral hypoxia is a frequent cause of secondary brain damage in patients with acute brain injury. Although hypercapnia can increase intracranial pressure, it may have beneficial effects on tissue oxygenation. We aimed to assess the effects of hypercapnia on brain tissue oxygenation (PbtO2). Methods: This single-center retrospective study (November 2014 to June 2022) included all patients admitted to the intensive care unit after acute brain injury who required multimodal monitoring, including PbtO2 monitoring, and who underwent induced moderate hypoventilation and hypercapnia according to the decision of the treating physician. Patients with imminent brain death were excluded. Responders to hypercapnia were defined as those with an increase of at least 20% in PbtO2 values when compared to their baseline levels. Results: On a total of 163 eligible patients, we identified 23 (14%) patients who underwent moderate hypoventilation (arterial partial pressure of carbon dioxide [PaCO2] from 44 [42–45] to 50 [49–53] mm Hg; p < 0.001) during the study period at a median of 6 (4–10) days following intensive care unit admission; six patients had traumatic brain injury, and 17 had subarachnoid hemorrhage. A significant overall increase in median PbtO2 values from baseline (21 [19–26] to 24 [22–26] mm Hg; p = 0.02) was observed. Eight (35%) patients were considered as responders, with a median increase of 7 (from 4 to 11) mm Hg of PbtO2, whereas nonresponders showed no changes (from − 1 to 2 mm Hg of PbtO2). Because of the small sample size, no variable independently associated with PbtO2 response was identified. No correlation between changes in PaCO2 and in PbtO2 was observed. Conclusions: In this study, a heterogeneous response of PbtO2 to induced hypercapnia was observed but without any deleterious elevations of intracranial pressure. [ABSTRACT FROM AUTHOR]

The review introduces the stages of formation and experimental confirmation of the hypothesis regarding the mutual potentiation of neuroprotective effects of hypoxia and hypercapnia during their combined influence (hypercapnic hypoxia). The main focus is on the mechanisms and signaling pathways involved in the formation of ischemic tolerance in the brain during intermittent hypercapnic hypoxia. Importantly, the combined effect of hypoxia and hypercapnia exerts a more pronounced neuroprotective effect compared to their separate application. Some signaling systems are associated with the predominance of the hypoxic stimulus (HIF-1α, A1 receptors), while others (NF-κB, antioxidant activity, inhibition of apoptosis, maintenance of selective blood–brain barrier permeability) are mainly modulated by hypercapnia. Most of the molecular and cellular mechanisms involved in the formation of brain tolerance to ischemia are due to the contribution of both excess carbon dioxide and oxygen deficiency (ATP-dependent potassium channels, chaperones, endoplasmic reticulum stress, mitochondrial metabolism reprogramming). Overall, experimental studies indicate the dominance of hypercapnia in the neuroprotective effect of its combined action with hypoxia. Recent clinical studies have demonstrated the effectiveness of hypercapnic–hypoxic training in the treatment of childhood cerebral palsy and diabetic polyneuropathy in children. Combining hypercapnic hypoxia with pharmacological modulators of neuro/cardio/cytoprotection signaling pathways is likely to be promising for translating experimental research into clinical medicine. [ABSTRACT FROM AUTHOR]

Introduction: Advanced chronic obstructive pulmonary disease (COPD) is associated with chronic hypercapnic failure. The present work aimed to comprehensively investigate inspiratory muscle function as a potential key determinant of hypercapnic respiratory failure in patients with COPD. Methods: Prospective patient recruitment encompassed 61 stable subjects with COPD across different stages of respiratory failure, ranging from normocapnia to isolated nighttime hypercapnia and daytime hypercapnia. Arterialized blood gas analyses and overnight transcutaneous capnometry were used for patient stratification. Assessment of respiratory muscle function encompassed body plethysmography, maximum inspiratory pressure (MIP), diaphragm ultrasound, and transdiaphragmatic pressure recordings following cervical magnetic stimulation of the phrenic nerves (twPdi) and a maximum sniff manoeuvre (Sniff Pdi). Results: Twenty patients showed no hypercapnia, 10 had isolated nocturnal hypercapnia, and 31 had daytime hypercapnia. Body plethysmography clearly distinguished patients with and without hypercapnia but did not discriminate patients with isolated nocturnal hypercapnia from those with daytime hypercapnia. In contrast to ultrasound parameters and transdiaphragmatic pressures, only MIP reflected the extent of hypercapnia across all three stages. MIP values below −48 cmH2O predicted nocturnal hypercapnia (area under the curve = 0.733, p = 0.052). Conclusion: In COPD, inspiratory muscle dysfunction contributes to progressive hypercapnic failure. In contrast to invasive tests of diaphragm strength only MIP fully reflects the pathophysiological continuum of hypercapnic failure and predicts isolated nocturnal hypercapnia. [ABSTRACT FROM AUTHOR]

Background: Although dysarthria and respiratory failure are widely described in literature as part of the natural history of Amyotrophic lateral sclerosis (ALS), the specific interaction between them has been little explored. Aim: To investigate the relationship between chronic respiratory failure and the speech of ALS patients. Materials and methods: In this cross-sectional retrospective study we reviewed the medical records of all patients diagnosed with ALS that were accompanied by a tertiary referral center. In order to determine the presence and degree of speech impairment, the Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R) speech sub-scale was used. Respiratory function was assessed through spirometry and through venous blood gasometry obtained from a morning peripheral venous sample. To determine whether differences among groups classified by speech function were significant, maximum and mean spirometry values of participants were compared using multivariate analysis of variance (MANOVA) with Tukey's post hoc test. Results: Seventy-five cases were selected, of which 73.3% presented speech impairment and 70.7% respiratory impairment. Respiratory and speech functions were moderately correlated (seated FVC r = 0.64; supine FVC r = 0.60; seated FEV1 r = 0.59 and supine FEV1 r = 0.54, p <.001). Multivariable logistic regression revealed that the following variables were significantly associated with the presence of speech impairment after adjusting for other risk factors: seated FVC (odds ratio [OR] = 0.862) and seated FEV1 (OR = 1.106). The final model was 81.1% predictive of speech impairment. The presence of daytime hypercapnia was not correlated to increasing speech impairment. Conclusion: The restrictive pattern developed by ALS patients negatively influences speech function. Speech is a complex and multifactorial process, and lung volume presents a pivotal role in its function. Thus, we were able to find that lung volumes presented a significant correlation to speech function, especially in those with bulbar onset and respiratory impairment. Neurobiological and physiological aspects of this relationship should be explored in further studies with the ALS population. [ABSTRACT FROM AUTHOR]

Episodic increases in cerebral blood flow (CBF) are thought to contribute to improved cerebrovascular function and health. Head-out water immersion (HOWI) may be a useful modality to increase CBF secondary to the hydrostatic pressure placed on the body. However, it is unclear whether water temperatures common to the general public elicit similar cerebrovascular responses. We tested the hypothesis that mean middle cerebral artery blood velocity (MCAvmean) and cerebrovascular reactivity to CO2 (CVRCO2) would be higher during an acute bout of thermoneutral (TN; 35°C) vs. cool (COOL; 25°C) HOWI. Ten healthy participants (age: 23±3 y; 4 women) completed two randomized HOWI visits. Right MCAvmean, end-tidal CO2 (PETCO2) mean arterial pressure (MAP), and MCA conductance (MCAvmean/MAP) were continuously recorded. CVRCO2 was assessed using a stepped hypercapnia protocol before (PRE), at 30 minutes of HOWI (HOWI), immediately after HOWI (POST-1), and 45 minutes after HOWI (POST-2). Absolute values are reported as mean ± SD. MCAvmean, PETCO2, MAP, and CVRCO2 were not different between conditions at any timepoint (all P≥0.17). In COOL, MCAvmean increased from PRE (61±9 cm/s) during HOWI (68±11 cm/s), at POST-1 (69±11 cm/s), and POST-2 (72±8 cm/s) (all P<0.01), and in TN from PRE to POST-1 (66±13 vs. 71±14 cm/s; P = 0.05). PETCO2 did not change over time in either condition. In COOL, MAP increased from PRE (85±5 mmHg) during HOWI (101±4 mmHg), at POST-1 (97±7 mmHg), and POST-2 (96±9 mmHg), and in TN from PRE (88±5 mmHg) at HOWI (98±7 mmHg) and POST-1 (99±8 mmHg) (all P<0.01). In COOL, CVRCO2 increased from PRE to HOWI (1.66±0.55 vs. 1.92±0.52 cm/s/mmHg; P = 0.04). MCA conductance was not different between or within conditions. These data indicate that 30 minutes of cool HOWI augments MCAvmean and that the increase in MCAvmean persists beyond cool HOWI. However, cool HOWI does not alter CVRCO2 in healthy young adults. [ABSTRACT FROM AUTHOR]

Concerns are repeatedly raised about possible adverse respiratory effects of wearing filtering face pieces (FFP) during physical activity. This study compared the impact of FFP type 2 (NF95) on pulmonary function, blood gas values, metabolism and discomfort during light, moderate and vigorous physical activity. Healthy adults (n = 13; 6 females, 7 males; mean 31.3, SD 5.5 years) participated in this randomized two-armed (Ergometer cycling with a FFP type 2 vs. no mask) crossover trial. Baseline cardiopulmonary exercise testing and two interventions (masked and unmasked ergometer cycling 40%, 50% and 70% VO2max, 10 min each) were separated by 48 h washout periods. Spiroergometric data (End tidal carbon dioxide partial pressure PetCO2; breathing frequency; inspiration time), blood gas analysis outcomes (capillary carbon dioxide partial pressure, pCO2) and subjective response (Breathing effort and perceived exertion) were contrasted between conditions using ANOVAs. All participants completed the crossover trial, seven started with the FFP2 condition (No adverse events or side effects). FFP2 decreased breathing frequency, prolonged inspiration time, increased perceived breathing effort and PetCO2 (p <.05). Blood pCO2 in millimetres mercury increased during exercise with 50%VO2max (mean 36.67, SD 3.19 vs. mean 38.46, SD 2.57; p <.05) and 70%VO2max (35.04, 2.84 vs. 38.17, 3.43; p <.05) but not during exercise with 40%VO2max (36.55, 2.73 vs. 38.70). Perceived exertion was not affected (p > 0.05) by mask wearing. Conclusion: Mask-induced breathing resistance decreased respiratory performance and limited pulmonary gas exchange. While FFP2 affected subjective breathing effort per se, invasive diagnostics showed that statistically significant metabolic effects are induced from moderate intensity upwards. Trial registration: DRKS-ID: DRKS00030181, Date of registration: 05/09/2022 (German Register for Clinical Trials). [ABSTRACT FROM AUTHOR]

Non-invasive positive pressure ventilation (NIPPV) is increasingly used as a treatment method for patients with respiratory failure. The first recommendations for the use of NIPPV in Slovakia were developed by the Slovak Society of Pulmonology and Phthisiology in 2007 and were partially revised in 2015. New scientific evidence prompted the present update, which is based on widely accepted international guidelines and was adapted to address local needs. Important features of the present update include a classification of acute indications for NIPPV into three categories based on the level of supporting evidence, namely 1. definite indications for in-hospital use of NIPPV; 2. possible indications for in-hospital use of NIPPV; and 3. disorders and states in which in-hospital use of NIPPV is not recommended. The current update also reflects the importance of comorbid sleep-related breathing disorders and other chronic respiratory conditions, as well as the use and limitations of continuous positive airway pressure therapy. Since oxygen therapy is often administered along with NIPPV, guidance on the safe use of oxygen in NIPPV-treated patients has also been included. Also, the present update extends the range of its users, addressing the needs of specialists in pediatric respiratory medicine as a novelty. [ABSTRACT FROM AUTHOR]

Hypercapnia occurs when the partial pressure of carbon dioxide (CO2) in the blood exceeds 45 mmHg. Hypercapnia is associated with several lung pathologies and is transcriptionally linked to suppression of immune and inflammatory signalling through poorly understood mechanisms. Here we propose Orphan Nuclear Receptor Family 4A (NR4A) family members NR4A2 and NR4A3 as potential transcriptional regulators of the cellular response to hypercapnia in monocytes. Using a THP-1 monocyte model, we investigated the sensitivity of NR4A family members to CO2 and the impact of depleting NR4A2 and NR4A3 on the monocyte response to buffered hypercapnia (10% CO2) using RNA-sequencing. We observed that NR4A2 and NR4A3 are CO2-sensitive transcription factors and that depletion of NR4A2 and NR4A3 led to reduced CO2-sensitivity of mitochondrial and heat shock protein (Hsp)-related genes, respectively. Several CO2-sensitive genes were, however, refractory to depletion of NR4A2 and NR4A3, indicating that NR4As regulate certain elements of the cellular response to buffered hypercapnia but that other transcription factors also contribute. Bioinformatic analysis of conserved CO2-sensitive genes implicated several novel putative CO2-sensitive transcription factors, of which the ETS Proto-Oncogene 1 Transcription Factor (ETS-1) was validated to show increased nuclear expression in buffered hypercapnia. These data give significant insights into the understanding of immune responses in patients experiencing hypercapnia. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of therapeutic hypercapnia on the expression and function of gamma delta T (γδ T) cells during ischemia‐reperfusion injury (IRI) after lung transplantation. Methods: We randomly divided male Wistar rats into three groups (n = 6 in each group), the control group (group N), the IRI group (group I), and the therapeutic hypercapnia group (group H). We then assessed pulmonary edema, neutrophil infiltration, wet‐to‐dry (W/D) weight ratio, and microscopic histopathology and separately measured the levels of γδT cell surface antigen (TCR) and Interleukin‐17 (IL‐17) using flow cytometry and enzyme‐linked immunosorbent assays (ELISAs). Results: The infiltration of neutrophils and the expression of TCR and IL‐17 were significantly increased in the I group compared to the control, and the biopsy edema in group I was more severe. Arterial partial pressure of oxygen (PaO2) was decreased after reperfusion in group I compared with the control group. W/D weight ratio, neutrophil infiltration, and the expression of TCR and IL‐17 decreased drastically in the H group compared to the I group. Conclusion: Our findings suggest that γδ T lymphocytes were directly involved in lung injury. In addition, therapeutic hypercapnia effectively reduced the expression of γδ T cells and IL‐17, and this has the potential to become a treatment strategy for IRI and an intervention to improve lung function. [ABSTRACT FROM AUTHOR]

To investigate the effect of hypoxaemia, hypotension and hypercapnia, among others, on quality of recovery from general anaesthesia in horses. Retrospective, single-centre study. A sample of 1226 horses that underwent general anaesthesia between June 2017 and June 2021. Horses and ponies weighing > 200 kg, aged > 6 months, anaesthetized using a xylazine- or medetomidine-isoflurane balanced anaesthesia protocol and presenting a complete anaesthetic record were included. Data were extracted from the clinic record system and from the original anaesthesia records. Recoveries were divided into 'good' and 'bad' based on the available recovery scores. Influence of hypoxaemia [PaO 2 < 60 mmHg (7.99 kPa)], hypotension (mean arterial pressure < 70 mmHg for at least 15 minutes) and hypercapnia [PaCO 2 > 60 mmHg (7.99 kPa)], anaesthesia protocol, body weight, age, breed, sex, American Society of Anesthesiologists status, type of procedure, emergency or nonemergency, duration of anaesthesia, positioning, times spent in lateral and sternal recumbency during recovery, time until standing and nonassisted or assisted recovery on the assigned recovery score (good/bad) were investigated using generalized linear regression analysis (p < 0.05). Hypoxaemia and prolonged duration of anaesthesia were significantly associated with a bad recovery score. No other factors had a significant influence on recovery quality. Hypoxaemia and prolonged anaesthesia duration have a negative effect on quality of anaesthetic recovery in horses. Clinically, this highlights the importance of keeping anaesthetic time as short as possible and to monitor oxygenation and treat hypoxaemia as soon as possible. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to compare cerebrovascular reactivity between patients with migraine and controls using state‐of‐the‐art magnetic resonance imaging (MRI) techniques. Background: Migraine is associated with an increased risk of cerebrovascular disease, but the underlying mechanisms are still not fully understood. Impaired cerebrovascular reactivity has been proposed as a link. Previous studies have evaluated cerebrovascular reactivity with different methodologies and results are conflicting. Methods: In this single‐center, observational, case–control study, we included 31 interictal patients with migraine without aura (aged 19–66 years, 17 females) and 31 controls (aged 22–64 years, 18 females) with no history of vascular disease. Global and regional cerebrovascular reactivities were assessed with a dual‐echo arterial spin labeling (ASL) 3.0 T MRI scan of the brain which measured the change in cerebral blood flow (CBF) and BOLD (blood oxygen level dependent) signal to inhalation of 5% carbon dioxide. Results: When comparing patients with migraine to controls, cerebrovascular reactivity values were similar between the groups, including mean gray matter CBF‐based cerebrovascular reactivity (3.2 ± 0.9 vs 3.4 ± 1% ΔCBF/mmHg CO2; p = 0.527), mean gray matter BOLD‐based cerebrovascular reactivity (0.18 ± 0.04 vs 0.18 ± 0.04% ΔBOLD/mmHg CO2; p = 0.587), and mean white matter BOLD‐based cerebrovascular reactivity (0.08 ± 0.03 vs 0.08 ± 0.02% ΔBOLD/mmHg CO2; p = 0.621).There was no association of cerebrovascular reactivity with monthly migraine days or migraine disease duration (all analyses p > 0.05). Conclusion: Cerebrovascular reactivity to carbon dioxide seems to be preserved in patients with migraine without aura. Plain Language Summary: Patients with migraine have a higher risk of vascular diseases, possibly due to a decreased function of the blood vessels, but past studies have not consistently shown this. We compared the function of blood vessels in the brains of patients with migraine and those without migraine by looking how brain blood flow changed in response to breathing in carbon dioxide. We found no differences in the ways in which blood vessels responded to inhaled carbon dioxide between the groups, which suggests that this aspect of blood vessel function does not differ between patients with and without migraine. [Correction added on 20th March 2024, after first online publication: The "Plain Language Summary" section has been added]. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative brain disease that is the most common cause of dementia among the elderly. In addition to dementia, which is the loss of cognitive function, including thinking, remembering, and reasoning, and behavioral abilities, AD patients also experience respiratory disturbances. The most common respiratory problems observed in AD patients are pneumonia, shortness of breath, respiratory muscle weakness, and obstructive sleep apnea (OSA). The latter is considered an outcome of Alzheimer's disease and is suggested to be a causative factor. While this narrative review addresses the bidirectional relationship between obstructive sleep apnea and Alzheimer's disease and reports on existing studies describing the most common respiratory disorders found in patients with Alzheimer's disease, its main purpose is to review all currently available studies using animal models of Alzheimer's disease to study respiratory impairments. These studies on animal models of AD are few in number but are crucial for establishing mechanisms, causation, implementing potential therapies for respiratory disorders, and ultimately applying these findings to clinical practice. This review summarizes what is already known in the context of research on respiratory disorders in animal models, while pointing out directions for future research. [ABSTRACT FROM AUTHOR]

After a fortuitous observation of two cases of chemosensitivity recovery in women with congenital central hypoventilation syndrome (CCHS) who took desogestrel, we aimed to evaluate the ventilatory response to hypercapnia of five CCHS patients with or without treatment consisting of desogestrel (DESO) or levonorgestrel (LEVO). Only two patients became responsive to hypercapnia under treatment, according to their basal vagal heart rate variability. These results suggest that heart rate variability may be promising tool to discriminate patients susceptible to become responsive to hypercapnia under DESO-LEVO treatment. Clinical Trials Identifier NCT01243697 [ABSTRACT FROM AUTHOR]

Background: Current obstructive sleep apnea treatment relies on manual PAP titration, but it has limitations. Complex interactions during titration and variations in SpO2 data accuracy pose challenges. Patients with co-occurring chronic hypercapnia may require precise oxygen titration. To address these issues, we propose a Clinical Decision Support System using Markov decision processes. Methods: This study, compliant with data protection laws, focused on adults with OSA-induced hypoxemia utilizing supplemental oxygen and CPAP/BiPAP therapy. PAP titration, conducted over one night, involved vigilant monitoring of vital signs and physiological parameters. Adjustments to CPAP pressure, potential BiLevel transitions, and supplemental oxygen were precisely guided by patient metrics. Markov decision processes outlined three treatment actions for disorder management, incorporating expert medical insights. Results: In our study involving 14 OSA patients (average age: 63 years, 27% females, BMI 41 kg m−2), significant improvements were observed in key health parameters after manual titration. The initial AHI of 61.8 events per hour significantly decreased to an average of 18.0 events per hour after PAP and oxygen titration (p < 0.0001), indicating a substantial reduction in sleep-disordered breathing severity. Concurrently, SpO2 levels increased significantly from an average of 79.7% before titration to 89.1% after titration (p < 0.0003). Pearson correlation coefficients demonstrated aggravation of hypercapnia in 50% of patients (N = 5) with initial pCO2 < 55 mmHg during the increase in CPAP pressure. However, transitioning to BiPAP exhibited a reduction in pCO2 levels, showcasing its efficacy in addressing hypercapnia. Simultaneously, BiPAP therapy correlated with a substantial increase in SpO2, underscoring its positive impact on oxygenation in OSA patients. Markov Decision Process analysis demonstrated realistic patient behavior during stable night conditions, emphasizing minimal apnea and good toleration to high CPAP pressure. Conclusions: The development of a framework for Markov decision processes of PAP and oxygen titration algorithms holds promise for providing algorithms for improving pCO2 and SpO2 values. While challenges remain, including the need for high-quality data, the potential benefits in terms of patient management and care optimization are substantial, and this approach represents an exciting frontier in the realm of telemedicine and respiratory healthcare. [ABSTRACT FROM AUTHOR]

This article, published in Clinical Autonomic Research, explores the relationship between sympathetic vascular transduction and baroreflex sensitivity in patients with severe chronic obstructive pulmonary disease (COPD). The study found that despite the elevated sympathetic tone in COPD patients, neurovascular transduction remained comparable to that of age-matched controls. The researchers hypothesized that this may be due to the compensatory effects of chronic hypercapnia and hypoxia. The findings suggest that the peripheral vasculature in COPD patients has the capacity to respond to sympathetically-mediated vasoconstrictive demands. [Extracted from the article]

Randomized controlled trials have shown a higher risk of postoperative hypoxemia and delayed extubation with opioid‐free anesthesia (OFA), compared with opioid anesthesia. The practice of OFA is not standardized. The objective of this study is to investigate the association between the dexmedetomidine administration protocol used and the occurrence of postoperative respiratory complications. This work is a retrospective, propensity score‐adjusted study (inverse probability of treatment weighting) conducted between January 2019 and September 2021 in a French tertiary care university hospital, including 180 adult patients undergoing major digestive surgery. Comparison of 2 anesthesia protocols: with a continuous intravenous maintenance dose of dexmedetomidine following a bolus (group B+M, n = 105) or with a bolus dose alone (group B, n = 75). The main outcome measure was a composite respiratory end point within 24 hours of surgery. There was no significant difference in the incidence of overall respiratory complications, as assessed by the primary end point. Nevertheless, there were more patients with postoperative hypercapnia in group B+M than in group B (16% vs 2.5%, P =.004). Patients in group B+M were extubated later than patients in group B (group B+M, median 40 minutes, IQR 20‐74 minutes; group B, median 20 minutes, IQR 10‐50 minutes; P =.004). Our study showed negative results for the primary end point. However, data on the increased risk of postoperative hypercapnia in patients receiving a maintenance dose of dexmedetomidine are new. Other prospective randomized studies with greater power are necessary to confirm these data and to make OFA safer, by reducing the prescribed doses of dexmedetomidine. [ABSTRACT FROM AUTHOR]

The cerebral circulation responds differently to increases in mean arterial pressure (MAP), compared to reductions in MAP. We tested the hypothesis that this directional sensitivity is reduced by hypercapnia. Retrospective analysis of 104 healthy subjects (46 male (44%), age range 19–74 years), with five minute recordings of middle cerebral blood velocity (MCAv, transcranial Doppler), non-invasive MAP (Finometer) and end-tidal CO2 (capnography) at rest, during both poikilocapnia and hypercapnia (5% CO2 breathing in air) produced MCAv step responses allowing estimation of the classical Autoregulation Index (ARIORIG), and corresponding values for both positive (ARI+D) and negative (ARI−D) changes in MAP. Hypercapnia led to marked reductions in ARIORIG, ARI+D and ARI−D (p < 0.0001, all cases). Females had a lower value of ARIORIG compared to males (p = 0.030) at poikilocapnia (4.44 ± 1.74 vs 4.74 ± 1.48) and hypercapnia (2.44 ± 1.93 vs 3.33 ± 1.61). The strength of directional sensitivity (ARI+D-ARI−D) was not influenced by hypercapnia (p = 0.46), sex (p = 0.76) or age (p = 0.61). During poikilocapnia, ARI+D decreased with age in females (p = 0.027), but not in males. Directional sensitivity was not affected by hypercapnia, suggesting that its origins are more likely to be inherent to the mechanics of vascular smooth muscle than to myogenic pathways. [ABSTRACT FROM AUTHOR]

African mole-rats live in self-dug burrow systems under hypoxic and hypercapnic conditions. Adaptations to hypoxia include suppression of resting metabolic rate (RMR) and core body temperature (Tb). Because the thyroid hormones (THs) thyroxine (T4) and triiodothyronine (T3) are positive regulators of RMR and Tb, we hypothesized that serum TH concentrations would also be downregulated under hypoxic conditions. To test this hypothesis, we kept Ansell's mole-rats (Fukomys anselli) in terraria filled with soil in which they were allowed to construct underground burrows to achieve chronic intermittent hypoxia and hypercapnia. The animals stayed in these hypoxic and hypercapnic burrows voluntarily, although given the choice to stay aboveground. We collected blood samples before and after treatment to measure serum T4 and T3 concentrations as well as hematological parameters. The free fraction of the transcriptionally-active T3 was significantly decreased after treatment, indicating that cellular TH signaling was downregulated via peripheral mechanisms, consistent with the assumption that aerobic metabolism is downregulated under hypoxic conditions. Furthermore, we found that hematocrit and hemoglobin concentrations were also downregulated after treatment, suggesting that oxygen demand decreases under hypoxia, presumably due to the metabolic shift towards anaerobic metabolism. Taken together, we have identified a potential upstream regulator of physiological adaptations to hypoxia in these highly hypoxia-tolerant animals. [ABSTRACT FROM AUTHOR]

Current models of respiratory CO2 chemosensitivity are centred around the function of a specific population of neurons residing in the medullary retrotrapezoid nucleus (RTN). However, there is significant evidence suggesting that chemosensitive neurons exist in other brainstem areas, including the rhythm‐generating region of the medulla oblongata – the preBötzinger complex (preBötC). There is also evidence that astrocytes, non‐neuronal brain cells, contribute to central CO2 chemosensitivity. In this study, we reevaluated the relative contributions of the RTN neurons, the preBötC astrocytes, and the carotid body chemoreceptors in mediating the respiratory responses to CO2 in experimental animals (adult laboratory rats). To block astroglial signalling via exocytotic release of transmitters, preBötC astrocytes were targeted to express the tetanus toxin light chain (TeLC). Bilateral expression of TeLC in preBötC astrocytes was associated with ∼20% and ∼30% reduction of the respiratory response to CO2 in conscious and anaesthetized animals, respectively. Carotid body denervation reduced the CO2 respiratory response by ∼25%. Bilateral inhibition of RTN neurons transduced to express Gi‐coupled designer receptors exclusively activated by designer drug (DREADDGi) by application of clozapine‐N‐oxide reduced the CO2 response by ∼20% and ∼40% in conscious and anaesthetized rats, respectively. Combined blockade of astroglial signalling in the preBötC, inhibition of RTN neurons and carotid body denervation reduced the CO2‐induced respiratory response by ∼70%. These data further support the hypothesis that the CO2‐sensitive drive to breathe requires inputs from the peripheral chemoreceptors and several central chemoreceptor sites. At the preBötC level, astrocytes modulate the activity of the respiratory network in response to CO2, either by relaying chemosensory information (i.e. they act as CO2 sensors) or by enhancing the preBötC network excitability to chemosensory inputs. Key points: This study reevaluated the roles played by the carotid bodies, neurons of the retrotrapezoid nucleus (RTN) and astrocytes of the preBötC in mediating the CO2‐sensitive drive to breathe.The data obtained show that disruption of preBötC astroglial signalling, blockade of inputs from the peripheral chemoreceptors or inhibition of RTN neurons similarly reduce the respiratory response to hypercapnia.These data provide further support for the hypothesis that the CO2‐sensitive drive to breathe is mediated by the inputs from the peripheral chemoreceptors and several central chemoreceptor sites. [ABSTRACT FROM AUTHOR]

Hypercapnia is commonly encountered by general and specialist respiratory clinicians. Patients at risk of developing hypercapnic respiratory failure include those with chronic obstructive pulmonary disease (COPD), obesity and neuromuscular disease. Such patients may present to clinicians acutely unwell on the acute medical take or during an inpatient deterioration, or be identified in the stable outpatient setting. In this review, we provide a practical guide to develop clinicians' knowledge, skills and confidence in promptly recognising and managing hypercapnic respiratory failure, and to promote national ventilation quality standards to encourage consistent delivery of high-quality care and optimise outcomes for patients. [ABSTRACT FROM AUTHOR]

Premature birth may result in specific cardiovascular responses to hypoxia and hypercapnia, that might hamper high‐altitude acclimatization. This study investigated the consequences of premature birth on baroreflex sensitivity (BRS) under hypoxic, hypobaric and hypercapnic conditions. Seventeen preterm born males (gestational age, 29 ± 1 weeks), and 17 age‐matched term born adults (40 ± 0 weeks) underwent consecutive 6‐min stages breathing different oxygen and carbon dioxide concentrations at both sea‐level and high‐altitude (3375 m). Continuous blood pressure and ventilatory parameters were recorded in normobaric normoxia (NNx), normobaric normoxic hypercapnia (NNx + CO2), hypobaric hypoxia (HHx), hypobaric normoxia (HNx), hypobaric normoxia hypercapnia (HNx + CO2), and hypobaric hypoxia with end‐tidal CO2 clamped at NNx value (HHx + clamp). BRS was assessed using the sequence method. Across all conditions, BRS was lower in term born compared to preterm (13.0 ± 7.5 vs. 21.2 ± 8.8 ms⋅mmHg−1, main group effect: p < 0.01) participants. BRS was lower in HHx compared to NNx in term born (10.5 ± 4.9 vs. 16.0 ± 6.0 ms⋅mmHg−1, p = 0.05), but not in preterm (27.3 ± 15.7 vs. 17.6 ± 8.3 ms⋅mmHg−1, p = 0.43) participants, leading to a lower BRS in HHx in term born compared to preterm (p < 0.01). In conclusion, this study reports a blunted response of BRS during acute high‐altitude exposure without any influence of changes in inspired CO2 in healthy prematurely born adults. [ABSTRACT FROM AUTHOR]

Background: One of the factors that most affect the quality of life in chronic obstructive pulmonary disease (COPD) is sleep. Our aim in this study is to investigate the etiology of hypercapnia and its relationship with sleep breathing disorders in patients with daytime hypercapnia. Materials and Methods: 38 hypercapnic patients who applied to the sleep laboratory of Atatürk Chest Diseases Hospital and underwent polysomnography (PSG) were included in this study. Pulmonary artery pressure (PAP) measurement was performed in all cases with pulmonary function test (PFT) and echocardiographic examination (ECHO) before PSG. Arterial blood gas (ABG) analysis was performed, and neck circumference (NC) and body mass index (BMI) were recorded. Results: In PSG, apnea-hypopnea index (AHI) was found to be ≥ 5 in 24 of 38 patients (63.16%), and obstructive sleep apnea syndrome (OSAS) was diagnosed. Considering the distribution of cases; COPD + OSAS (overlap syndrome) was determined in 21 patients (55.2%), simple COPD in 10 patients (26.8%), OHS in 3 patients (7.8%), isolated OSAS in 3 patients (7.8%) and primary central alveolar hypoventilation in 1 patient (2.6%). Since there was only 1 patient with primary central alveolar hypoventilation syndrome, it was not included in the analyzes and the remaining 4 groups were compared with each other. No significant difference was detected between the groups in terms of BMI, NC, PFT parameters and PAP. In correlation analysis, it was observed that there was a statistically significant negative correlation between BMI and nighttime SaO2. (r:-0.557, p=0.009). Conclusions: In this study, we detected OSAS in 63.16% of hypercapnic cases. This suggests that current OSAS may be a cause of hypercapnia and OSAS accompanying COPD may cause an increased risk for hypoventilation. Additionally, in our study, BMI was negatively correlated with SaO2, indicating that the risk of OSAS is increased in obese people. In conclusion, we think that people with daytime hypercapnia, especially those who are obese, should be questioned about OSAS and cases with clinical suspicion should be referred to the sleep laboratory. [ABSTRACT FROM AUTHOR]

This article discusses a pilot study that examined the impact of elevated carbon dioxide levels on cerebral autoregulation in patients who had experienced cardiac arrest. The study found that higher levels of carbon dioxide were associated with less efficient cerebral autoregulation. These findings align with previous research suggesting that hypercapnia negatively affects cerebral autoregulation. However, more research is needed to fully understand the underlying mechanism and confirm these results. [Extracted from the article]

New Findings: What is the central question of this study?Gonadal hormones modulate cerebrovascular function while insulin‐like growth factor 1 (IGF‐1) facilitates exercise‐mediated cerebral angiogenesis; puberty is a critical period of neurodevelopment alongside elevated gonadal hormone and IGF‐1 activity: but whether exercise training across puberty enhances cerebrovascular function is unkown.What is the main finding and its importance?Cerebral blood flow is elevated in endurance trained adolescent males when compared to untrained counterparts. However, cerebrovascular reactivity to hypercapnia is faster in trained vs. untrained children, but not adolescents. Exercise‐induced improvements in cerebrovascular function are attainable as early as the first decade of life. Global cerebral blood flow (gCBF) and cerebrovascular reactivity to hypercapnia (CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$) are modulated by gonadal hormone activity, while insulin‐like growth factor 1 facilitates exercise‐mediated cerebral angiogenesis in adults. Whether critical periods of heightened hormonal and neural development during puberty represent an opportunity to further enhance gCBF and CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ is currently unknown. Therefore, we used duplex ultrasound to assess gCBF and CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ in n = 128 adolescents characterised as endurance‐exercise trained (males: n = 30, females: n = 36) or untrained (males: n = 29, females: n = 33). Participants were further categorised as pre‐ (males: n = 35, females: n = 33) or post‐ (males: n = 24, females: n = 36) peak height velocity (PHV) to determine pubertal or 'maturity' status. Three‐factor ANOVA was used to identify main and interaction effects of maturity status, biological sex and training status on gCBF and CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$. Data are reported as group means (SD). Pre‐PHV youth demonstrated elevated gCBF and slower CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ mean response times than post‐PHV counterparts (both: P ≤ 0.001). gCBF was only elevated in post‐PHV trained males when compared to untrained counterparts (634 (43) vs. 578 (46) ml min−1; P = 0.007). However, CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ mean response time was faster in pre‐ (72 (20) vs. 95 (29) s; P ≤ 0.001), but not post‐PHV (P = 0.721) trained youth when compared to untrained counterparts. Cardiorespiratory fitness was associated with gCBF in post‐PHV youth (r2 = 0.19; P ≤ 0.001) and CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ mean response time in pre‐PHV youth (r2 = 0.13; P = 0.014). Higher cardiorespiratory fitness during adolescence can elevate gCBF while exercise training during childhood primes the development of cerebrovascular function, highlighting the importance of exercise training during the early stages of life in shaping the cerebrovascular phenotype. [ABSTRACT FROM AUTHOR]

Evaluation of cerebrovascular reactivity (CVR) to hypo- and hypercapnia is a valuable test for the assessment of vasodilatory reserve. While hypercapnia-induced CVR testing is usually performed at normoxia, mild hyperoxia may increase tolerability of hypercapnia by reducing the ventilatory distress. However, the effects of mild hyperoxia on CVR was unknown. We therefore recruited 21 patients with a range of steno-occlusive diseases and 12 healthy participants who underwent a standardized 13-minute step plus ramp CVR test with a carbon dioxide gas challenge at the subject's resting end-tidal partial pressure of oxygen or at mild hyperoxia (P et O2 = 150 mmHg) depending on to which group they were assigned. In 11 patients, the second CVR test was at normoxia to examine test-retest differences. CVR was defined as % Δ Signal/ΔP et CO2. We found that there was no significant difference between CVR test results conducted at normoxia and at mild hyperoxia for participants in Groups 1 and 2 for the step and ramp portion. We also found no difference between test and retest CVR at normoxia for patients with cerebrovascular pathology (Group 3) for step and ramp portion. We concluded normoxic CVR is repeatable, and that mild hyperoxia does not affect CVR. [ABSTRACT FROM AUTHOR]

After an individual experiences a cervical cord injury, the cell body's adaptation to the smaller size of phrenic motoneurons occurs within several weeks. It is not known whether a routine hypercapnic load can alter this adaptation of phrenic motoneurons. We investigated this question by using rats with high cervical cord hemisection. The rats were divided into four groups: control, hypercapnia, sham, and sham hypercapnia. Within 72 h post-hemisection, the hypercapnia groups began a hypercapnic challenge (20 min/day, 4 times/week for 3 weeks) with 7% CO2 under awake conditions. After the 3-week challenge, the phrenic motoneurons in all of the rats were retrogradely labeled with horseradish peroxidase, and the motoneuron sizes in each group were compared. The average diameter, cross-sectional area, and somal surface area of stained phrenic motoneurons as analyzed by software were significantly smaller in only the control group compared to the other groups. The histogram distribution was unimodal, with larger between-group size differences for motoneurons in the horizontal plane than in the transverse plane. Our findings indicate that a routine hypercapnic challenge may increase the input to phrenic motoneurons and alter the propensity for motoneuron adaptations. [ABSTRACT FROM AUTHOR]

Context: High flow nasal canula is usually used for management of acute hypoxemic failure; however, it may have a potential therapeutic benefits in hypercapnia as it can alter tidal volume, end expiratory volume, positive end expiratory pressure, and respiratory rate. Aim: Evaluate safety and efficacy of application HFNC (high flow nasal canula) for patients with mild hypercapnia. Settings and design: A prospective interventional study. Patients and methods: Over six months, thirty eight patients were enrolled, with mild hypercapnia and PH level not less 7.30 and PaCo2 not more 60 mmhg; with applying HFNC, serial checking of arterial blood gases was done. Checkpoints were at 2 h, 12 h, 24 h, and 48 h post application of HFNC. HFNC can be shifted to NIV or invasive MV at any time whenever indicated. Results: Primary pulmonary disorder was chronic obstructive pulmonary disorder in (22 patients) and (16 patients) had interstitial lung disease. For PH in overall, mean values had changed from 7.33 until reached 7.37 at 48 h post HFNC with calculation of P value at each checkpoint from baseline value; significant changes were recorded at 24 h and 48 h post HFNC application. A similar observation was observed for PaCO2. No significant changes were observed at any checkpoint for HCO3. Conclusion: High flow nasal canula is safe in cases with mild hypercapnia with a considerable success rate and a proven high efficacy. Trial registration: Clinicaltrials.gov/NCT05948527, Registered 14 July 2023—Retrospectively registered, https://www.clinicaltrials.gov/NCT05948527. [ABSTRACT FROM AUTHOR]

Isolated exposure to intermittent hypoxia and permissive hypercapnia activates signaling mechanisms that induce ultrastructural changes in mitochondria and endoplasmic reticulum, accompanied by the development of maximal ischemic tolerance in neurons under the combined influence of these factors. However, there are a lack of data on the combined impact of these factors on the ultrastructure of neuronal organelles. The present study aims to comparatively assess the ultrastructural changes in neurons following isolated and combined exposure to hypoxia and hypercapnia, as well as to correlate these changes with the neuroprotective potential previously observed for these factors. Following a 15-session course of 30-min exposures to permissive hypercapnia (PCO2 ≈ 50 mmHg) and/or normobaric hypoxia (PO2 ≈ 150 mmHg), morphometric assessment was conducted to evaluate the extent of ultrastructural changes in hippocampal neurons (mitochondria, perinuclear space, and granular endoplasmic reticulum). It was found that in hippocampal neurons from the CA1 region, permissive hypercapnia resulted in increased mitochondrial size, expansion of membranous compartments of the granular endoplasmic reticulum, and perinuclear space. Normobaric hypoxia affected only mitochondrial size, while hypercapnic hypoxia specifically widened the perinuclear space. These ultrastructural changes objectively reflect varying degrees of the influence of hypoxia and hypercapnia on organelles responsible for energy metabolism, anti-apoptotic, and synthetic functions of neurons. This confirms the effect of potentiation of their neuroprotective effects under combined exposure and highlights the dominant role of the hypercapnic component in this mechanism. [ABSTRACT FROM AUTHOR]

Chronic hypercapnia (CH) is a hallmark of respiratory-related diseases, and the level of hypercapnia can acutely or progressively become more severe. Previously, we have shown time-dependent adaptations in steady-state physiology during mild (arterial PCO2 ~55 mmHg) and moderate (~60 mmHg) CH in adult goats, including transient (mild CH) or sustained (moderate CH) suppression of acute chemosensitivity suggesting limitations in adaptive respiratory control mechanisms as the level of CH increases. Changes in specific markers of glutamate receptor plasticity, interleukin-1ß, and serotonergic modulation within key nodes of cardiorespiratory control do not fully account for the physiological adaptations to CH. Here, we used an unbiased approach (bulk tissue RNA sequencing) to test the hypothesis that mild or moderate CH elicits distinct gene expression profiles in important brain stem regions of cardiorespiratory control, which may explain the contrasting responses to CH. Gene expression profiles from the brain regions validated the accuracy of tissue biopsy methodology. Differential gene expression analyses revealed greater effects of CH on brain stem sites compared with the medial prefrontal cortex. Mild CH elicited an upregulation of predominantly immune-related genes and predicted activation of immune-related pathways and functions. In contrast, moderate CH broadly led to downregulation of genes and predicted inactivation of cellular pathways related to the immune response and vascular function. These data suggest that mild CH leads to a steady-state activation of neuroinflammatory pathways within the brain stem, whereas moderate CH drives the opposite response. Transcriptional shifts in immune-related functions may underlie the cardiorespiratory network's capability to respond to acute, more severe hypercapnia when in a state of progressively increased CH. NEW & NOTEWORTHY Mild chronic hypercapnia (CH) broadly upregulated immune-related genes and a predicted activation of biological pathways related to immune cell activity and the overall immune response. In contrast, moderate CH primarily downregulated genes related to major histocompatibility complex signaling and vasculature function that led to a predicted inactivation of pathways involving the immune response and vascular endothelial function. The severity-dependent effect on immune responses suggests that neuroinflammation has an important role in CH and may be important in the maintenance of proper ventilatory responses to acute and chronic hypercapnia. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease can lead to acute hypercapnic respiratory failure (AHRF), often treated using noninvasive ventilation (NIV). Emerging research suggests the potential utility of high flow nasal cannula (HFNC) for AHRF. This systematic review and meta‐analysis aimed to determine the effect of HFNC versus NIV on AHRF management. A search of electronic databases (CINAHL, MEDLINE, and Academic Search Complete), web sources, and trial registries was last conducted on 9 February 2023. Quality and risk of bias assessments were conducted. Meta‐analyses were used to synthesise data. Seven randomised controlled trials were included. No statistically significant differences between HFNC and NIV were found within the following outcomes of interest: (i) correction of pCO2: standardised mean difference (SMD) = −0.16, 95% confidence interval (CI) (−0.34 to 0.02), p = 0.08; (ii) correction of pH: SMD = −0.05, 95% CI (−0.25 to 0.14), p = 0.59; (iii) correction of pO2: SMD = −0.15, 95% CI (−0.40 to 0.09), p = 0.22; (iv) intubation rates: risk ratio (RR) = 0.87, 95% CI (0.41 to 1.82), p = 0.71; (v) mortality rates: RR = 0.85, 95% CI (0.47 to 1.56), p = 0.61; and (vi) treatment switch: RR = 1.30, 95% CI (0.43 to 3.94), p = 0.64. More controlled trials with large sample sizes are required to investigate the management of AHRF of various aetiologies. HFNC may be used as a final exhaustive measure for COPD‐related AHRF where NIV is not tolerated, and when it is not clinically indicated to extend to endotracheal intubation. [ABSTRACT FROM AUTHOR]

Carbon dioxide (CO2) is traditionally considered as metabolic waste, yet its regulation is critical for brain function. It is well accepted that hypercapnia initiates vasodilation, but its effect on neuronal activity is less clear. Distinguishing how stimulus- and CO2-induced vasodilatory responses are (dis)associated with neuronal activity has profound clinical and experimental relevance. We used an optical method in mice to simultaneously image fluorescent calcium (Ca2+) transients from neurons and reflectometric hemodynamic signals during brief sensory stimuli (i.e., hindpaw, odor) and CO2 exposure (i.e., 5%). Stimuli-induced neuronal and hemodynamic responses swiftly increased within locally activated regions exhibiting robust neurovascular coupling. However, hypercapnia produced slower global vasodilation which was temporally uncoupled to neuronal deactivation. With trends consistent across cerebral cortex and olfactory bulb as well as data from GCaMP6f/jRGECO1a mice (i.e., green/red Ca2+ fluorescence), these results unequivocally reveal that stimuli and CO2 generate comparable vasodilatory responses but contrasting neuronal responses. In summary, observations of stimuli-induced regional neurovascular coupling and CO2-induced global neurovascular uncoupling call for careful appraisal when using CO2 in gas mixtures to affect vascular tone and/or neuronal excitability, because CO2 is both a potent vasomodulator and a neuromodulator. [ABSTRACT FROM AUTHOR]

How central and peripheral chemoreceptor drives to breathe interact in humans remains contentious. We measured the peripheral chemoreflex sensitivity to hypoxia (PChS) at various isocapnic CO2 tensions (PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$) to determine the form of the relationship between PChS and central PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$. Twenty participants (10F) completed three repetitions of modified rebreathing tests with end‐tidal PO2${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ (PETO2${P_{{\mathrm{ET}}{{\mathrm{O}}_{\mathrm{2}}}}}$) clamped at 150, 70, 60 and 45 mmHg. End‐tidal PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ (PETCO2${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$), PETO2${P_{{\mathrm{ET}}{{\mathrm{O}}_{\mathrm{2}}}}}$, ventilation (V̇$\dot{V}$E) and calculated oxygen saturation (SCO2) were measured breath‐by‐breath by gas‐analyser and pneumotach. The V̇$\dot{V}$E–PETCO2${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ relationship of repeat‐trials were linear‐interpolated, combined, averaged into 1 mmHg bins, and fitted with a double‐linear function (V̇$\dot{V}$ES, L min−1mmHg−1). PChS was computed at intervals of 1 mmHg of PETCO2${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ as follows: the difference in V̇$\dot{V}$E between the three hypoxic profiles and the hyperoxic profile (∆V̇$\dot{V}$E) was calculated; three ∆V̇$\dot{V}$E values were plotted against corresponding SCO2; and linear regression determined PChS (Lmin−1mmHg−1%SCO2−1). These processing steps were repeated at each PETCO2${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ to produce the PChS vs. isocapnic PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ relationship. These were fitted with linear and polynomial functions, and Akaike information criterion identified the best‐fit model. One‐way repeated measures analysis of variance assessed between‐condition differences. V̇$\dot{V}$ES increased (P < 0.0001) with isoxic PETO2${P_{{\mathrm{ET}}{{\mathrm{O}}_{\mathrm{2}}}}}$ from 3.7 ± 1.5 L min−1mmHg−1 at 150 mmHg to 4.4 ± 1.8, 5.0 ± 1.6 and 6.0 ± 2.2 Lmin−1mmHg−1 at 70, 60 and 45 mmHg, respectively. Mean SCO2 fell progressively (99.3 ± 0%, 93.7 ± 0.1%, 90.4 ± 0.1% and 80.5 ± 0.1%; P < 0.0001). In all individuals, PChS increased with PETCO2${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$, and this relationship was best described by a linear model in 75%. Despite increasing central chemoreflex activation, PChS increased linearly with PETCO2${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ indicative of an additive central–peripheral chemoreflex response. Key points: How central and peripheral chemoreceptor drives to breathe interact in humans remains contentious.We measured peripheral chemoreflex sensitivity to hypoxia (PChS) at various isocapnic carbon dioxide tensions (PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$) to determine the form of the relationship between PChS and central PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$.Participants performed three repetitions of modified rebreathing with end‐tidal PO2${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ fixed at 150, 70, 60 and 45 mmHg. PChS was computed at intervals of 1 mmHg of end‐tidal PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ (PETCO2${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$) as follows: the difference in V̇$\dot{V}$E between the three hypoxic profiles and the hyperoxic profile (∆V̇$\dot{V}$E) was calculated; three ∆V̇$\dot{V}$E values were plotted against corresponding calculated oxygen saturation (SCO2); and linear regression determined PChS (Lmin−1mmHg−1%SCO2−1).In all individuals, PChS increased with PETCO2${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$, and this relationship was best described by a linear (rather than polynomial) model in 15 of 20.Most participants did not exhibit a hypo‐ or hyper‐additive effect of central chemoreceptors on the peripheral chemoreflex indicating that the interaction was additive. [ABSTRACT FROM AUTHOR]

• Carbon dioxide (CO 2) levels are important in managing neurologic conditions. • Spreading depolarizations (SD) are a pathologic mechanism of cerebral cortex. • CO 2 levels did not impact SD characteristics in normoxic or hypoxic rat brain. • Mean arterial pressure negatively correlated with SD duration. • The role of CO 2 warrants investigation in conditions of acute focal brain injury. Patients with traumatic brain injury are typically maintained at low-normal levels of arterial partial pressure of carbon dioxide (P a CO 2) to counteract the risk of elevated intracranial pressure during intensive care. However, several studies suggest that management at hypercarbic levels may have therapeutic benefit. Here we examined the impact of CO 2 levels on spreading depolarizations (SD), a mechanism and marker of acute lesion development in stroke and brain trauma. In an acute preparation of mechanically ventilated (30/70 O 2 /N 2) female rats, SDs were evoked by cortical KCl application and monitored by electrophysiology and laser doppler flowmetry; CO 2 levels were adjusted by ventilator settings and supplemental CO 2. During 90 min of KCl application, rats were maintained at hypocapnia (end-tidal CO 2 22 ± 2 mmHg) or hypercapnia (57 ± 4 mmHg) but did not differ significantly in arterial pH (7.31 ± 0.10 vs. 7.22 ± 0.08, p = 0.31) or other variables. Surprisingly, there was no difference between groups in the number of SDs recorded (10.7 ± 4.2 vs. 11.7 ± 3.1; n = 3 rats/group; p = 0.75) nor in SD durations (64 ± 27 vs. 69 ± 37 sec, p = 0.54). In separate experiments (n = 3), hypoxia was induced by decreasing inhaled O 2 to 10% and single SDs were induced under interleaved conditions of hypo-, normo-, and hypercapnia. No differences in SD duration were observed. In both normoxia and hypoxia experiments, however, mean arterial pressures were negatively correlated with SD durations (normoxia R2 = −0.29; hypoxia R2 = −0.61, p 's < 0.001). Our results suggest that any therapeutic benefit of elevated CO 2 therapy may be dependent on an acidic shift in pH or may only be observed in conditions of focal brain injury. [ABSTRACT FROM AUTHOR]

Inflammation, although necessary to fight infections, becomes a threat when it exceeds the capability of the immune system to control it. In addition, inflammation is a cause and/or symptom of many different disorders, including metabolic, neurodegenerative, autoimmune and cardiovascular diseases. Comorbidities and advanced age are typical predictors of more severe cases of seasonal viral infection, with COVID-19 a clear example. The primary importance of mitogen-activated protein kinases (MAPKs) in the course of COVID-19 is evident in the mechanisms by which cells are infected with SARS-CoV-2; the cytokine storm that profoundly worsens a patient's condition; the pathogenesis of diseases, such as diabetes, obesity, and hypertension, that contribute to a worsened prognosis; and post-COVID-19 complications, such as brain fog and thrombosis. An increasing number of reports have revealed that MAPKs are regulated by carbon dioxide (CO2); hence, we reviewed the literature to identify associations between CO2 and MAPKs and possible therapeutic benefits resulting from the elevation of CO2 levels. CO2 regulates key processes leading to and resulting from inflammation, and the therapeutic effects of CO2 (or bicarbonate, HCO3−) have been documented in all of the abovementioned comorbidities and complications of COVID-19 in which MAPKs play roles. The overlapping MAPK and CO2 signalling pathways in the contexts of allergy, apoptosis and cell survival, pulmonary oedema (alveolar fluid resorption), and mechanical ventilation–induced responses in lungs and related to mitochondria are also discussed. F1FfzyNebiAnmgfybRMuY1 Video Abstract [ABSTRACT FROM AUTHOR]

Key points Pre‐term birth is associated with physiological sequelae that persist into adulthood. In particular, modulated ventilatory responsiveness to hypoxia and hypercapnia has been observed in this population. Whether pre‐term birth per se causes these effects remains unclear. Therefore, we aimed to assess pulmonary ventilation and blood gases under various environmental conditions, comparing 17 healthy prematurely born individuals (mean ± SD; gestational age, 28 ± 2 weeks; age, 21 ± 4 years; peak oxygen uptake, 48.1 ± 11.2 ml kg−1 min−1) with 16 well‐matched adults born at term (gestational age, 40 ± 1 weeks; age, 22 ± 2 years; peak oxygen uptake, 51.2 ± 7.7 ml kg−1 min−1). Participants were exposed to seven combinations of hypoxia/hypobaria (equivalent to ∼3375 m) and/or hypercapnia (3% CO2), at rest for 6 min. Pulmonary ventilation, pulse oxygen saturation and the arterial partial pressures of O2 and CO2 were similar in pre‐term and full‐term individuals under all conditions. Higher ventilation in hypoxia compared to normoxia was only observed at terrestrial altitude, despite an equivalent (normobaric) hypoxic stimulus administered at sea level (0.138 FiO2${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$). Assessment of oscillations in key variables revealed that combined hypoxic hypercapnia induced greater underlying fluctuations in ventilation in pre‐term individuals only. In general, higher pulse oxygen saturation fluctuations were observed with hypoxia, and lower fluctuations in end‐tidal CO2 with hypercapnia, despite similar ventilatory oscillations observed between conditions. These findings suggest that healthy prematurely born adults display similar overall ventilation to their term‐born counterparts under various environmental stressors, but that combined ventilatory stimuli could induce an irregular underlying ventilatory pattern. Moreover, barometric pressure may be an important factor when assessing ventilatory responsiveness to moderate hypoxic stimuli. Evidence exists for unique pulmonary and respiratory function under hypoxic conditions in adult survivors of pre‐term birth. Whether pre‐term birth per se causes these differences requires a comparison of conventionally healthy prematurely born adults with an appropriately matched sample of term‐born individuals. According to the present data, there is no difference between healthy pre‐term and well‐matched term‐born individuals in the magnitude of pulmonary ventilation or arterial blood gases during independent and combined hypobaria, hypoxia and hypercapnia. Terrestrial altitude (hypobaria) was necessary to induce differences in ventilation between normoxia and a hypoxic stimulus equivalent to ∼3375 m of altitude. Furthermore, peak power in pulse oxygen saturation was similar between hypobaric normoxia and normobaric hypoxia. The observed similarities between groups suggest that ventilatory regulation under various environmental stimuli is not impaired by pre‐term birth per se. Instead, an integrated combination of neonatal treatment strategies and cardiorespiratory fitness/disease status might underlie previously observed chemosensitivity impairments. [ABSTRACT FROM AUTHOR]

Human spaceflight is entering a time of markedly increased activity fueled by collaboration between governmental and private industry entities. This has resulted in successful mission planning for destinations in low Earth orbit, lunar destinations (Artemis program, Gateway station) as well as exploration to Mars. The planned construction of additional commercial space stations will ensure continued low Earth orbit presence and destinations for science but also commercial spaceflight participants. The human in the journey to space is exposed to numerous environmental challenges including increased gravitational forces, microgravity, altered human physiology during adaptation to weightlessness in space, altered ambient pressure, as well as other important stressors contingent on the type of mission and destination. This chapter will cover clinically important aspects relevant to lung function in a normally proceeding mission; emergency scenarios such as decompression, fire, etc., will not be covered as these are beyond the scope of this review. To date, participation in commercial spaceflight by those with pre-existing chronic medical conditions is very limited, and hence, close collaboration between practicing pulmonary specialists and aerospace medicine specialists is of critical importance to guarantee safety, proper clinical management, and hence success in these important endeavors. [ABSTRACT FROM AUTHOR]

Gas exchange in the lung depends on tidal breathing, which brings new oxygen to and removes carbon dioxide from alveolar gas. This maintains alveolar partial pressures that promote passive diffusion to add oxygen and remove carbon dioxide from blood in alveolar capillaries. In a lung model without ventilation and perfusion (V̇ A Q̇) mismatch, alveolar partial pressures of oxygen and carbon dioxide are primarily determined by inspiratory pressures and alveolar ventilation. Regions with shunt or low ratios worsen arterial oxygenation while alveolar dead space and high lung units lessen CO 2 elimination efficiency. Although less common, diffusion limitation might cause hypoxemia in some situations. This review covers the principles of lung gas exchange and therefore mechanisms of hypoxemia or hypercapnia. In addition, we discuss different metrics that quantify the deviation from ideal gas exchange. [ABSTRACT FROM AUTHOR]

Introduction: Acute hypercapnic respiratory failure has a poor prognosis in patients with interstitial lung disease (ILD). Recent data demonstrated a positive effect of nasal high-flow (NHF) in patients with acute hypoxemic respiratory failure. Preliminary data also show benefits in several hypercapnic chronic lung diseases. Objectives: The aim of this study was to characterize flow-dependent changes in mean airway pressure, breathing volumes, and breathing frequency and decreases in PCO2. Methods: Mean airway pressure was measured in the nasopharyngeal space. To evaluate breathing volumes, a polysomnographic device was used (16 patients). All subjects received 20, 30, 40, and 50 L/min and—to illustrate the effects—nCPAP and nBiPAP. Capillary blood gas analyses were performed in 25 hypercapnic ILD subjects before and 5 h after the use of NHF. Additionally, comfort and dyspnea during the use of NHF were surveyed. Results: NHF resulted in a small flow-dependent increase in mean airway pressure. Tidal volume was unchanged and breathing rate decreased. The calculated minute volume decreased by 20 and 30 L/min NHF breathing. In spite of this fact, hypercapnia decreased at a flow rate of 24 L/min. Additionally, an improvement in dyspnea was observed. Conclusions: NHF leads to a reduction in paCO2. This is most likely achieved by a washout of the respiratory tract and a reduction in functional dead space. NHF enhances the effectiveness of breathing in ILD patients by the reduction in respiratory rate. In summary, NHF works as an effective ventilatory support device in hypercapnic ILD patients. [ABSTRACT FROM AUTHOR]

Objective: Severe respiratory dysfunction induced by generalized convulsive seizures (GCS) is now thought to be a common mechanism for sudden unexpected death in epilepsy (SUDEP). In a mouse model of seizure‐induced death, increased interictal respiratory variability was reported in mice that later died of respiratory arrest after GCS. We studied respiratory variability in epilepsy patients as a predictive tool for severity of postictal hypoxemia, a potential biomarker for SUDEP risk. We then explored the relationship between respiratory variability and central CO2 drive, measured by the hypercapnic ventilatory response (HCVR). Methods: We reviewed clinical, video‐electroencephalography, and respiratory (belts, airflow, pulse oximeter, and HCVR) data of epilepsy patients. Mean, SD, and coefficient of variation (CV) of interbreath interval (IBI) were calculated. Primary outcomes were: (1) nadir of capillary oxygen saturation (SpO2) and (2) duration of oxygen desaturation. Poincaré plots of IBI were created. Covariates were evaluated in univariate models, then, based on Akaike information criteria (AIC), multivariate regression models were created. Results: Of 66 GCS recorded in 131 subjects, 30 had interpretable respiratory data. In the multivariate model with the lowest AIC value, duration of epilepsy was a significant predictor of duration of oxygen desaturation. Duration of tonic phase and CV of IBI during the third postictal minute correlated with SpO2 nadir, whereas CV of IBI during non‐rapid eye movement sleep had a negative correlation. Poincaré plots showed that long‐term variability was significantly greater in subjects with ≥200 s of postictal oxygen desaturation after GCS compared to those with <200 s desaturation. Finally, HCVR slope showed a negative correlation with measures of respiratory variability. Significance: These results indicate that interictal respiratory variability predicts severity of postictal oxygen desaturation, suggesting its utility as a potential biomarker. They also suggest that interictal respiratory control may be abnormal in some patients with epilepsy. [ABSTRACT FROM AUTHOR]

After an individual experiences a cervical cord injury, the cell body's adaptation to the smaller size of phrenic motoneurons occurs within several weeks. It is not known whether a routine hypercapnic load can alter this adaptation of phrenic motoneurons. We investigated this question by using rats with high cervical cord hemisection. The rats were divided into four groups: control, hypercapnia, sham, and sham hypercapnia. Within 72 h post-hemisection, the hypercapnia groups began a hypercapnic challenge (20 min/day, 4 times/week for 3 weeks) with 7% CO2 under awake conditions. After the 3-week challenge, the phrenic motoneurons in all of the rats were retrogradely labeled with horseradish peroxidase, and the motoneuron sizes in each group were compared. The average diameter, cross-sectional area, and somal surface area of stained phrenic motoneurons as analyzed by software were significantly smaller in only the control group compared to the other groups. The histogram distribution was unimodal, with larger between-group size differences for motoneurons in the horizontal plane than in the transverse plane. Our findings indicate that a routine hypercapnic challenge may increase the input to phrenic motoneurons and alter the propensity for motoneuron adaptations. [ABSTRACT FROM AUTHOR]

Background: The RAM cannula® consists of nasal prongs that can be used to administer oxygen, continuous, and bilevel positive airway pressure therapies. Studies have reported the efficacy and utility of the RAM cannula in inpatients requiring noninvasive ventilation (NIV); however, there is limited literature on the use of the RAM cannula to provide NIV in the outpatient setting. Objectives: This study aimed to describe the clinical features and outcomes of children who used NIV via RAM cannula in the outpatient setting. Design: Retrospective review. Methods: We conducted a retrospective review of children treated with outpatient NIV via RAM cannula at our institution between January 2010 and March 2023. The analyzed data included age, diagnoses, indications for NIV, duration of RAM cannula use, complications, and outcomes at 6 months. Results: We identified 20 patients who used outpatient NIV via RAM cannula during the study period. The median age at initiation of NIV via RAM cannula was 5.8 months (IQR 2.4-9.9 months). Indications for NIV included sleep-related hypoventilation (15%), restrictive lung disease (25%), obstructive sleep apnea (45%), and chronic respiratory failure (50%), with 6 patients having ⩾2 indications for NIV. RAM cannula was utilized for inability to tolerate conventional NIV interfaces (80%), to alleviate dyspnea (60%), and to avoid tracheostomy (55%). Patients used NIV via RAM cannula for a median duration of 7.7 months (IQR 3.7-20.6 months). Patient outcomes included ongoing usage of RAM cannula (55%), changing to conventional NIV interfaces (15%) or oxygen (10%), weaning off respiratory support (5%), and death (15%). There were no complications related to using the RAM cannula. Conclusion: Our study demonstrates the utility of outpatient NIV via RAM cannula in children with a variety of diagnoses until clinical improvement or tolerance of conventional interfaces, and for avoidance of tracheostomy. [ABSTRACT FROM AUTHOR]

The wavelet spectral characteristics of three respiratory muscle signals (scalenus (SC), parasternal intercostal (IC), and rectus abdominis (RA)) and one locomotor muscle (brachioradialis (BR)) were analyzed in the time–frequency (T-F) domain during voluntary breath-holding (BH), with a focus on the physiological breakpoint that is commonly considered the first involuntary breathing movement (IBM) that signals the end of the easy-going phase of BH. The study was performed for an end-expiratory BH physiological breaking point maneuver on twelve healthy, physically active, naive breath-holders/apneists (six professional athletes; six recreational athletes, and two individuals in the post-COVID-19 period) using surface electromyography (sEMG). We observed individual effects that were dependent on muscle oxygenation and each person's fitness, which were consistent with the mechanism of motor unit (MU) recruitment and the transition of slow-twitch oxidative (type 1) to fast-twitch glycolytic (type 2) muscle fibers. Professional athletes had longer BH durations (BHDs) and strong hypercapnic responses regarding the expiratory RA muscle, which is activated abruptly at higher BHDs in a person-specific range below 250 Hz and is dependent on the BHD. This is in contrast with recreational athletes, who had strong hypoxic responses regarding inspiratory IC muscle, which is activated faster and gradually in the frequency range of 250–450 Hz (independent of the person and BHD). This pilot study preliminarily indicates that it is possible to noninvasively assess the physiological characteristics of skeletal muscles, especially oxygenation, and improve physical fitness tests by determining the T-F features of elevated myoelectric IC and RA activity during BH. [ABSTRACT FROM AUTHOR]