Effects of high-flow nasal cannula oxygen therapy in bronchiectasis and hypercapnia: a retrospective observational study.

BACKGROUND: The effectiveness of high-flow nasal cannula (HFNC) therapy in patients with bronchiectasis experiencing hypercapnia remains unclear. Our aim was to retrospectively analyze the short-term outcomes of HFNC therapy in such patients, and to further explore the predictors of HFNC treatment failure in this particular patient population. METHODS: A retrospective review was conducted on patients with bronchiectasis who received HFNC (n = 70) for hypercapnia (arterial partial pressure of carbon dioxide, PaCO2 ≥ 45 mmHg) between September 2019 and September 2023. RESULTS: In the study population, 30% of patients presented with acidemia (arterial pH < 7.35) at baseline. Within 24 h of HFNC treatment, there was a significant reduction in PaCO2 levels by a mean of 4.0 ± 12.7 mmHg (95% CI -7.0 to -1.0 mmHg). Concurrently, arterial pH showed a statistically significant increase with a mean change of 0.03 ± 0.06 (95% CI 0.01 to 0.04). The overall hospital mortality rate in our study was 17.5%. The median length of hospital stay was 11.0 days (interquartile range [IQR] 8.0 to 16.0 days). Sub-analysis revealed no statistically significant differences in hospital mortality (19.0% vs. 20.4%, p = 0.896), length of hospital stay (median 14.0 days [IQR 9.0 to 18.0 days] vs. 10.0 days [IQR 7.0 to 16.0 days], p = 0.117) and duration of HFNC application (median 5.0 days [IQR 2.0 to 8.5 days] vs. 6.0 days [IQR 4.9 to 9.5 days], p = 0.076) between the acidemia group and the non-acidemia group (arterial pH ≥ 7.35). However, more patients in the non-acidemia group had do-not-intubate orders. The overall treatment failure rate for HFNC was 28.6%. Logistic regression analysis identified the APACHE II score (OR 1.24 per point) as the independent predictor of HFNC failure. CONCLUSIONS: In patients with bronchiectasis and hypercapnia, HFNC as an initial respiratory support can effectively reduce PaCO2 level within 24 h of treatment. A high APACHE II score has emerged as a prognostic indicator for HFNC treatment failure. These observations highlight randomized controlled trials to meticulously evaluate the efficacy of HFNC in this specific population.

Molecular Mechanisms of Neuroprotection after the Intermittent Exposures of Hypercapnic Hypoxia.

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.

Orphan Nuclear Receptor Family 4A (NR4A) Members NR4A2 and NR4A3 Selectively Modulate Elements of the Monocyte Response to Buffered Hypercapnia.

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.

Effects of therapeutic hypercapnia on the expression and function of γδT cells in transplanted lungs in rats.

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.

Optimizing nonintubated laryngeal microsurgery: The effectiveness and safety of superior laryngeal nerve block with high-flow nasal oxygen-A prospective cohort study.

BACKGROUND: Laryngeal microsurgery (LMS) typically requires intubated general anesthesia (ITGA). Although nonintubated general anesthesia (NIGA) with high-flow nasal oxygen (HFNO) can be applied with LMS, a muscle relaxant is required, which can cause apnea and hypercapnia. This study evaluated the effectiveness of a superior laryngeal nerve block (SLNB) in improving safety during LMS. METHODS: This prospective cohort study enrolled a cumulative total of 61 adult patients received LMS under intravenous general anesthesia and allocated to three groups: ITGA group (n = 18), which patients performed intubation; neuromuscular blocking (NMB) group (n = 21), which patients administrated muscle relaxant without intubation and superior laryngeal nerve block (NB) group (n = 22), which patients performed SLNB without intubation or muscle relaxant. RESULTS: The average (SD) values of PaCO 2 after surgery in ITGA, NMB, and NB group were 50.8 (7.5), 97.5 (24.9), and 54.8 (8.8) mmHg, respectively. The mean postoperative pH values were 7.33 (0.04), 7.14 (0.07), and 7.33 (0.04), respectively. The results were all p < 0.001, and the average pH value of the NMB group was lower than that of the ITGA and NB groups. During the LMS, the mean heart rate (HR) (93.9 [18.1] bpm) and noninvasive blood pressure systolic (NBPs) (143.5 [28.2] mmHg) in the NMB group were higher than those in the ITGA group (HR = 77.4 [13.5] bpm and NBPs = 132.7 [20.8] mmHg) and NB group (HR = 82.3 [17.4] bpm and NBPs = 120.9 [25.0] mmHg). The results of p value by HR and NBPs are p < 0.001. The PaCO 2 and pH values are similar between ITGA group and NB group. CONCLUSION: Our approach of using HFNO with SLNB was successful for performing nonintubated LMS, enabling the patients to maintain spontaneous breathing and effectively eliminate CO 2 . This approach reduces the risks of hypercapnia and acidosis even when the duration of LMS exceeds 30 minutes.

Comparative study of ventilation techniques with supraglottic airway devices in cats: volume-controlled vs pressure-controlled techniques.

OBJECTIVES: This study compared the effectiveness of a new supraglottic airway device (SGAD) in cats undergoing anaesthesia using two types of mechanical ventilation: volume-controlled ventilation (VCV) and pressure-controlled ventilation (PCV). METHODS: A total of 13 healthy cats (five male, eight female; median age 2 years [range 1-3]) were randomly allocated to either VCV or PCV. Five tidal volumes (6, 8, 10, 12 and 14 ml/kg) and five peak inspiratory pressures (4, 5, 6, 7 and 8 cmH2O) were randomly applied with a minute ventilation of 100 ml/kg/min. Various parameters, such as blood pressure, gas leakage, end-tidal CO2 (ETCO2) and work of breathing (WOB), were measured while using VCV or PCV. RESULTS: The occurrence of hypotension (mean arterial blood pressure <60 mmHg) was slightly less frequent with VCV (38 events, 65 ventilating sessions) than with PCV (40 events, 65 ventilating sessions), but this difference did not reach statistical significance (P = 0.429). The number of leakages did not differ between the VCV group (3 events, 65 ventilating sessions) and the PCV group (3 events, 65 ventilating sessions) (P = 1.000). Hypercapnia was identified when using VCV (10 events, 65 ventilating sessions) less frequently than when using PCV (17 events, 65 ventilating sessions), but this difference did not reach statistical significance (P = 0.194). The study found a significantly higher WOB in the PCV group compared with the VCV group (P <0.034). CONCLUSIONS AND RELEVANCE: The present results suggested that both VCV and PCV can be used with an SGAD during anaesthesia, with VCV preferred for prolonged mechanical ventilation due to its lower workload. Adjusting tidal volume or inspiratory pressure corrects hypercapnia.

Myeloid Zfhx3 deficiency protects against hypercapnia-induced suppression of host defense against influenza A virus.

Hypercapnia, elevation of the partial pressure of CO2 in blood and tissues, is a risk factor for mortality in patients with severe acute and chronic lung diseases. We previously showed that hypercapnia inhibits multiple macrophage and neutrophil antimicrobial functions and that elevated CO2 increases the mortality of bacterial and viral pneumonia in mice. Here, we show that normoxic hypercapnia downregulates innate immune and antiviral gene programs in alveolar macrophages (AMØs). We also show that zinc finger homeobox 3 (Zfhx3) - a mammalian ortholog of zfh2, which mediates hypercapnic immune suppression in Drosophila - is expressed in mouse and human macrophages. Deletion of Zfhx3 in the myeloid lineage blocked the suppressive effect of hypercapnia on immune gene expression in AMØs and decreased viral replication, inflammatory lung injury, and mortality in hypercapnic mice infected with influenza A virus. To our knowledge, our results establish Zfhx3 as the first known mammalian mediator of CO2 effects on immune gene expression and lay the basis for future studies to identify therapeutic targets to interrupt hypercapnic immunosuppression in patients with advanced lung disease.

Assessing cerebrovascular reactivity (CVR) in rhesus macaques (Macaca mulatta) using a hypercapnic challenge and pseudo-continuous arterial spin labeling (pCASL).

Cerebrovascular reactivity (CVR) is a measure of cerebral small vessels' ability to respond to changes in metabolic demand and can be quantified using magnetic resonance imaging (MRI) coupled with a vasoactive stimulus. Reduced CVR occurs with neurodegeneration and is associated with cognitive decline. While commonly measured in humans, few studies have evaluated CVR in animal models. Herein, we describe methods to induce hypercapnia in rhesus macaques (Macaca mulatta) under gas anesthesia to measure cerebral blood flow (CBF) and CVR using pseudo-continuous arterial spin labeling (pCASL). Fifteen (13 M, 2 F) adult rhesus macaques underwent pCASL imaging that included a baseline segment (100% O2) followed by a hypercapnic challenge (isoflurane anesthesia with 5% CO2, 95% O2 mixed gas). Relative hypercapnia was defined as an end-tidal CO2 (ETCO2) ≥5 mmHg above baseline ETCO2. The mean ETCO2 during the baseline segment of the pCASL sequence was 34 mmHg (range: 23-48 mmHg). During this segment, mean whole-brain CBF was 51.48 ml/100g/min (range: 21.47-77.23 ml/100g/min). Significant increases (p<0.0001) in ETCO2 were seen upon inspiration of the mixed gas (5% CO2, 95% O2). The mean increase in ETCO2 was 8.5 mmHg and corresponded with a mean increase in CBF of 37.1% (p<0.0001). The mean CVR measured was 4.3%/mmHg. No anesthetic complications occurred as a result of the CO2 challenge. Our methods were effective at inducing a state of relative hypercapnia that corresponds with a detectable increase in whole brain CBF using pCASL MRI. Using these methods, a CO2 challenge can be performed in conjunction with pCASL imaging to evaluate CBF and CVR in rhesus macaques. The measured CVR in rhesus macaques is comparable to human CVR highlighting the translational utility of rhesus macaques in neuroscience research. These methods present a feasible means to measure CVR in comparative models of neurodegeneration and cerebrovascular dysfunction.

The Effects of Hypocapnia and Hypercapnia on Intraoperative Bleeding, Surgical Field Quality, and Surgeon Satisfaction Level in Septorhinoplasty: A Prospective Randomized Clinical Study.

BACKGROUND: Septorhinoplasty (SRP) is one of the most commonly performed procedures in the world for functional and aesthetic purposes. The present study was aimed to compare the effects of hypocapnia and hypercapnia regarding the total amount of intraoperative bleeding, surgical field quality, and surgeon satisfaction level. METHODS: In this randomized prospective clinical study, eighty patients with American Society of Anesthesiologists I-II and were 18-45 years old scheduled for septorhinoplasty were randomly allocated to group hypocapnia [end-tidal carbon dioxide (EtCO2) 30 ± 2 mmHg] and group hypercapnia (EtCO2 40 ± 2 mmHg). We evaluated the total amount of intraoperative bleeding, the surgical field quality, surgeon satisfaction level, hemodynamics and peri- and postoperative adverse events. RESULTS: Group hypocapnia significantly reduced the total amount of intraoperative bleeding (p < 0.001). The surgical field quality and surgeon satisfaction level in group hypocapnia were significantly better than group hypercapnia (p < 0.001). EtCO2 levels of group hypocapnia were significantly lower than group hypercapnia at all time points (p < 0.001 for all time points). There were no significant differences between the groups in terms of heart rate and mean arterial pressure at all time points. There were no significant differences between the groups in terms of adverse events CONCLUSIONS: The results of this double-blind randomized clinical trial showed that reducing the amount of intraoperative bleeding for patients with hypocapnia undergoing SRP through known methods (e.g., reverse Trendelenburg head-up position, positive end-expiratory pressure limiting, controlled hypotension, and use of topical vasoconstrictors, corticosteroids, and tranexamic acid) would improve the quality of the surgical field and raise the surgeon satisfaction level. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Comparison of Two Dexmedetomidine Administration Strategies on the Incidence of Postoperative Respiratory Complications: A Retrospective, Inverse Probability of Treatment Weighted Study.

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.

Intraoperative partial pressure of arterial carbon dioxide levels and adverse outcomes in patients undergoing lung transplantation.

OBJECTIVE: Patients undergoing lung transplantation (LTx) often experience abnormal hypercapnia or hypocapnia. This study aimed to investigate the association between intraoperative PaCO2 and postoperative adverse outcomes in patients undergoing LTx. METHODS: We retrospectively reviewed the medical records of 151 patients undergoing LTx. Patients' demographics, perioperative clinical factors, and pre- and intraoperative PaCO2 data after reperfusion were collected and analyzed. Based on the PaCO2 levels, patients were classified into three groups: hypocapnia (≤35 mmHg), normocapnia (35.1-55 mmHg), and hypercapnia (>55 mmHg). Univariate and multivariable logistic regressions were used to identify independent risk factors for postoperative composite adverse events and in-hospital mortality. RESULTS: Intraoperative hypercapnia occurred in 69 (45.7%) patients, and hypocapnia in 17 (11.2%). Patients with intraoperative PaCO2 of 35.1-45 mmHg showed a lower incidence of composite adverse events (53.3%) and mortality (6.2%) (P < 0.001). There was no significant difference in composite adverse events and mortality among preoperative PaCO2 groups (P > 0.05). Compared with intraoperative PaCO2 at 35.1-45 mmHg, the risk of composite adverse events in hypercapnia group increased: the adjusted OR was 3.07 (95% confidence interval [CI]: 1.36-6.94; P = 0.007). The risk of death was significantly higher in hypocapnia group than normocapnia group, the adjusted OR was 7.69 (95% CI: 1.68-35.24; P = 0.009). Over ascending ranges of PaCO2, PaCO2 at 55.1-65 mmHg had the strongest association with composite adverse events, the adjusted OR was 6.40 (95% CI: 1.18-34.65; P = 0.031). CONCLUSION: These results demonstrate that intraoperative hypercapnia independently predicts postoperative adverse outcomes in patients undergoing LTx. Intraoperative hypocapnia shows predictive value for postoperative in-hospital mortality in LTx.

Subclinical respiratory dysfunction and impaired ventilatory adaptation in degenerative cervical myelopathy.

Degenerative cervical myelopathy (DCM) is a debilitating neurological condition characterized by chronic compression of the cervical spinal cord leading to impaired upper and lower limb function. Despite damage to areas of the cervical spinal cord that house the respiratory network, respiratory dysfunction is not a common symptom of DCM. However, DCM may be associated with respiratory dysfunction, and this can affect the ventilatory response to respiratory challenges during emergence from anesthesia, exercise, or pulmonary disease. Surgical spinal cord decompression, which is the primary treatment for DCM, leads to improved sensorimotor function in DCM; yet its impact on respiratory function is unknown. Here, using a clinically relevant model of DCM, we evaluate respiratory function during disease progression and assess adaptive ventilation to hypercapnic challenge before and after surgical intervention. We show that despite significant and progressive forelimb and locomotor deficits, there was no significant decline in eupneic ventilation from the early to late phases of spinal cord compression. Additionally, for the first time, we demonstrate that despite normal ventilation under resting conditions, DCM impairs acute adaptive ventilatory ability in response to hypercapnia. Remarkably, akin to DCM patients, surgical decompression treatment improved sensorimotor function in a subset of mice. In contrast, none of the mice that underwent surgical decompression recovered their ability to respond to hypercapnic ventilatory challenge. These findings underscore the impact of chronic spinal cord compression on respiratory function, highlighting the challenges associated with ventilatory response to respiratory challenges in individuals with DCM. This research highlights the impact of cervical spinal cord compression on respiratory dysfunction in DCM, as well as the persistence of adaptive ventilatory dysfunction after surgical spinal cord decompression. These results indicate the need for additional interventions to enhance recovery of respiratory function after surgery for DCM.

Hypercapnia increases ACE2 expression and pseudo-SARS-CoV-2 entry in bronchial epithelial cells by augmenting cellular cholesterol.

Patients with chronic lung disease, obesity, and other co-morbid conditions are at increased risk of severe illness and death when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hypercapnia, the elevation of CO2 in blood and tissue, commonly occurs in patients with severe acute and chronic lung disease, including those with pulmonary infections, and is also associated with high mortality risk. We previously reported that hypercapnia increases viral replication and mortality of influenza A virus infection in mice. We have also shown that culture in elevated CO2 upregulates expression of cholesterol synthesis genes in primary human bronchial epithelial cells. Interestingly, factors that increase the cholesterol content of lipid rafts and lipid droplets, platforms for viral entry and assembly, enhance SARS-CoV-2 infection. In the current study, we investigated the effects of hypercapnia on ACE2 expression and entry of SARS-CoV-2 pseudovirus (p-SARS-CoV-2) into airway epithelial cells. We found that hypercapnia increased ACE2 expression and p-SARS-CoV-2 uptake by airway epithelium in mice, and in cultured VERO and human bronchial epithelial cells. Hypercapnia also increased total cellular and lipid raft-associated cholesterol in epithelial cells. Moreover, reducing cholesterol synthesis with inhibitors of sterol regulatory element binding protein 2 (SREBP2) or statins, and depletion of cellular cholesterol, each blocked the hypercapnia-induced increases in ACE2 expression and p-SARS-CoV-2 entry into epithelial cells. Cigarette smoke extract (CSE) also increased ACE2 expression, p-SARS-CoV-2 entry and cholesterol accumulation in epithelial cells, an effect not additive to that of hypercapnia, but also inhibited by statins. These findings reveal a mechanism that may account, in part, for poor clinical outcomes of SARS-CoV-2 infection in patients with advanced lung disease and hypercapnia, and in those who smoke cigarettes. Further, our results suggest the possibility that cholesterol-lowering therapies may be of particular benefit in patients with hypercapnia when exposed to or infected with SARS-CoV-2.

Cerebral blood flow and cerebrovascular reactivity are modified by maturational stage and exercise training status during youth.

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. ABSTRACT: Global cerebral blood flow (gCBF) and cerebrovascular reactivity to hypercapnia ( CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) 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 CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ is currently unknown. Therefore, we used duplex ultrasound to assess gCBF and CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ 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 CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ . Data are reported as group means (SD). Pre-PHV youth demonstrated elevated gCBF and slower CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ 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, CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ 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 CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ 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.

Effects of permissive hypercapnia on intraoperative cerebral oxygenation and early postoperative cognitive function in older patients with non-acute fragile brain function undergoing laparoscopic colorectal surgery: protocol study.

BACKGROUND: Perioperative brain protection in older patients has been the focus of research recently; meanwhile, exploring the relationship between regional cerebral oxygen saturation (rSO2) and brain function in the perioperative period has been an emerging and challenging area-the difficulties related to the real-time monitoring of rSO2 and the choice of feasible interventions. As an advanced instrument for intraoperative rSO2 monitoring, the clinical application of near-infrared spectrum (NIRS) cerebral oxygen monitoring has gradually increased in popularity and is being recognized for its beneficial clinical outcomes in patients undergoing cardiac and noncardiac surgery. In addition, although sufficient evidence to support this hypothesis is still lacking, the effect of permissive hypercapnia (PHC) on rSO2 has expanded from basic research to clinical exploration. Therefore, monitoring intraoperative rSO2 in older patients with NIRS technology and exploring possible interventions that may change rSO2 and even improve postoperative cognitive performance is significant and clinically valuable. METHODS: This study is a single-center randomized controlled trial (RCT). 76 older patients are enrolled as subjects. Patients who meet the screening criteria will be randomly assigned 1:1 to the control and intervention groups. PHC-based mechanical ventilation will be regarded as an intervention. The primary outcome is the absolute change in the percent change in rSO2 from baseline to the completion of surgery in the intervention and control groups. Secondary outcomes mainly include observations of intraoperative cerebral oxygenation and metabolism, markers of brain injury, and assessments of patients' cognitive function using scale through postoperative follow-up. DISCUSSION: The findings of this RCT will reveal the effect of PHC on intraoperative rSO2 in older patients with nonacute fragile brain function (NFBF) and the approximate trends over time, and differences in postoperative cognitive function outcomes. We anticipate that the trial results will inform clinical policy decision-makers in clinical practice, enhance the management of intraoperative cerebral oxygen monitoring in older patients with comorbid NFBF, and provide guidance for clinical brain protection and improved postoperative cognitive function outcomes. TRIAL REGISTRATION: ChiCTR, ChiCTR2200062093, Registered 9/15/2022.

Impact of Remimazolam versus Sevoflurane Anesthesia on Cerebral Oxygenation and Intracranial Pressure during Gynecological Laparoscopy with Mild Hypercapnia.

BACKGROUND Remimazolam has the advantage of better hemodynamic stability compared with other anesthetics. We compared the effects of remimazolam and sevoflurane on cerebral oxygenation, intracranial pressure, and intraoperative hemodynamic parameters during mild hypercapnia in patients undergoing laparoscopy in the Trendelenburg position. MATERIAL AND METHODS Sixty-two patients (20-65 years old) scheduled for gynecological laparoscopy were randomly allocated to either the remimazolam (n=31) or sevoflurane (n=31) group. Respiratory and hemodynamic parameters and regional cerebral oxygen saturation (rSO2) were recorded. Intracranial pressure was measured using the optic nerve sheath diameter (ONSD). RESULTS The change over time in rSO2 did not differ between groups (P=0.056). The change in ONSD over time showed a significant intergroup difference (P=0.002). ONSD significantly changed over time (P=0.034) in the sevoflurane group but not in the remimazolam group (P=0.115). The changes in mean arterial pressure and heart rate over time showed significant intergroup differences (P=0.045 and 0.031, respectively). The length of stay and the use of rescue antiemetics and analgesics in the postanesthetic care unit were significantly lower in the remimazolam group than in the sevoflurane group (P=0.023, 0.038, and 0.018, respectively). CONCLUSIONS Remimazolam can provide a favorable hemodynamic profile and attenuate the increase in ONSD during gynecological laparoscopy compared with sevoflurane anesthesia during lung-protective ventilation with mild hypercapnia. Remimazolam can provide faster and better postoperative recovery than sevoflurane anesthesia.

Nocturnal Hypoventilation in the Patients Submitted to Thoracic Surgery.

Introduction: Nocturnal hypoventilation may occur due to obesity, concomitant chronic obstructive pulmonary disease (COPD), obstructive sleep apnea, and/or the use of narcotic analgesics. The aim of the study was to evaluate the risk and severity of nocturnal hypoventilation as assessed by transcutaneous continuous capnography in the patients submitted to thoracic surgery. Materials and Methods: The material of the study consisted of 45 obese (BMI 34.8 ± 3.7 kg/m2) and 23 nonobese (25.5 ± 3.6 kg/m2) patients, who underwent thoracic surgery because of malignant (57 patients) and nonmalignant tumors. All the patients received routine analgesic treatment after surgery including intravenous morphine sulfate. Overnight transcutaneous measurements of CO2 partial pressure (tcpCO2) were performed before and after surgery in search of nocturnal hypoventilation, i.e., the periods lasting at least 10 minutes with tcpCO2 above 55 mmHg. Results: Nocturnal hypoventilation during the first night after thoracic surgery was detected in 10 patients (15%), all obese, three of them with COPD, four with high suspicion of moderate-to-severe OSA syndrome, and one with chronic daytime hypercapnia. In the patients with nocturnal hypoventilation, the mean tcpCO2 was 53.4 ± 6.1 mmHg, maximal tcpCO2 was 59.9 ± 8.4 mmHg, and minimal tcpCO2 was 46.4 ± 6.7 mmHg during the first night after surgery. In these patients, there were higher values of minimal, mean, and maximal tcpCO2 in the preoperative period. Nocturnal hypoventilation in the postoperative period did not influence the duration of hospitalization. Among 12 patients with primary lung cancer who died during the first two years of observation, there were 11 patients without nocturnal hypoventilation in the early postoperative period. Conclusion: Nocturnal hypoventilation may occur in the patients after thoracic surgery, especially in obese patients with bronchial obstruction, obstructive sleep apnea, or chronic daytime hypercapnia, and does not influence the duration of hospitalization.

Mild and moderate chronic hypercapnia elicit distinct transcriptomic responses of immune function in cardiorespiratory nuclei.

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.

Hemodynamic imaging parameters in brain metastases patients - Agreement between multi-delay ASL and hypercapnic BOLD.

Arterial spin labeling (ASL) MRI is a routine clinical imaging technique that provides quantitative cerebral blood flow (CBF) information. A related technique is blood oxygenation level-dependent (BOLD) MRI during hypercapnia, which can assess cerebrovascular reactivity (CVR). ASL is weighted towards arteries, whereas BOLD is weighted towards veins. Their associated parameters in heterogeneous tissue types or under different hemodynamic conditions remains unclear. Baseline multi-delay ASL MRI and BOLD MRI during hypercapnia were performed in fourteen patients with brain metastases. In the ROI analysis, the CBF and CVR values were positively correlated in regions showing sufficient reserve capacity (i.e. non-steal regions, rrm = 0.792). Additionally, longer hemodynamic lag times were related to lower baseline CBF (rrm = -0.822) and longer arterial arrival time (AAT; rrm = 0.712). In contrast, in regions exhibiting vascular steal an inverse relationship was found with higher baseline CBF related to more negative CVR (rrm = -0.273). These associations were confirmed in voxelwise analyses. The relationship between CBF, AAT and CVR measures seems to be dependent on the vascular status of the underlying tissue. Healthy tissue relationships do not hold in tissues experiencing impaired or exhausted autoregulation. CVR metrics can possibly identify at-risk areas before perfusion deficiencies become visible on ASL MRI, specifically within vascular steal regions.