Translational insights into the hormetic potential of carbon dioxide: from physiological mechanisms to innovative adjunct therapeutic potential for cancer.

Background: Carbon dioxide (CO2), traditionally viewed as a mere byproduct of cellular respiration, plays a multifaceted role in human physiology beyond simple elimination through respiration. CO2 may regulate the tumor microenvironment by significantly affecting the release of oxygen (O2) to tissues through the Bohr effect and by modulating blood pH and vasodilation. Previous studies suggest hypercapnia (elevated CO2 levels) might trigger optimized cellular mechanisms with potential therapeutic benefits. The role of CO2 in cellular stress conditions within tumor environments and its impact on O2 utilization offers a new investigative area in oncology. Objectives: This study aims to explore CO2's role in the tumor environment, particularly how its physiological properties and adaptive responses can influence therapeutic strategies. Methods: By applying a structured translational approach using the Work Breakdown Structure method, the study divided the analysis into six interconnected work packages to comprehensively analyze the interactions between carbon dioxide and the tumor microenvironment. Methods included systematic literature reviews, data analyses, data integration for identifying critical success factors and exploring extracellular environment modulation. The research used SMART criteria for assessing innovation and the applicability of results. Results: The research revealed that the human body's adaptability to hypercapnic conditions could potentially inform innovative strategies for manipulating the tumor microenvironment. This could enhance O2 utilization efficiency and manage adaptive responses to cellular stress. The study proposed that carbon dioxide's hormetic potential could induce beneficial responses in the tumor microenvironment, prompting clinical protocols for experimental validation. The research underscored the importance of pH regulation, emphasizing CO2 and carbonic acid's role in modulating metabolic and signaling pathways related to cancer. Conclusion: The study underscores CO2 as vital to our physiology and suggests potential therapeutic uses within the tumor microenvironment. pH modulation and cellular oxygenation optimization via CO2 manipulation could offer innovative strategies to enhance existing cancer therapies. These findings encourage further exploration of CO2's therapeutic potential. Future research should focus on experimental validation and exploration of clinical applications, emphasizing the need for interdisciplinary and collaborative approaches to tackle current challenges in cancer treatment.

Central and peripheral mechanisms underlying respiratory deficits in a mouse model of accelerated senescence.

Aging invariably decreases sensory and motor stimuli and affects several neuronal systems and their connectivity to key brain regions, including those involved in breathing. Nevertheless, further investigation is needed to fully comprehend the link between senescence and respiratory function. Here, we investigate whether a mouse model of accelerated senescence could develop central and peripheral respiratory abnormalities. Adult male Senescence Accelerated Mouse Prone 8 (SAMP8) and the control SAMR1 mice (10 months old) were used. Ventilatory parameters were assessed by whole-body plethysmography, and measurements of respiratory input impedance were performed. SAMP8 mice exhibited a reduction in the density of neurokinin-1 receptor immunoreactivity in the entire ventral respiratory column. Physiological experiments showed that SAMP8 mice exhibited a decreased tachypneic response to hypoxia (FiO2 = 0.08; 10 min) or hypercapnia (FiCO2 = 0.07; 10 min). Additionally, the ventilatory response to hypercapnia increased further due to higher tidal volume. Measurements of respiratory mechanics in SAMP8 mice showed decreased static compliance (Cstat), inspiratory capacity (IC), resistance (Rn), and elastance (H) at different ages (3, 6, and 10 months old). SAMP8 mice also have a decrease in contractile response to methacholine compared to SAMR1. In conclusion, our findings indicate that SAMP8 mice display a loss of the NK1-expressing neurons in the respiratory brainstem centers, along with impairments in both central and peripheral respiratory mechanisms. These observations suggest a potential impact on breathing in a senescence animal model.

Locus coeruleus noradrenaline depletion and its differential impact on CO2-induced panic and hyperventilation in male and female mice.

CO2 exposure has been used to investigate the panicogenic response in patients with panic disorder. These patients are more sensitive to CO2, and more likely to experience the "false suffocation alarm" which triggers panic attacks. Imbalances in locus coeruleus noradrenergic (LC-NA) neurotransmission are responsible for psychiatric disorders, including panic disorder. These neurons are sensitive to changes in CO2/pH. Therefore, we investigated if LC-NA neurons are differentially activated after severe hypercapnia in mice. Further, we evaluated the participation of LC-NA neurons in ventilatory and panic-like escape responses induced by 20% CO2 in male and female wild type mice and two mouse models of altered LC-NA synthesis. Hypercapnia activates the LC-NA neurons, with males presenting a heightened level of activation. Mutant males lacking or with reduced LC-NA synthesis showed hypoventilation, while animals lacking LC noradrenaline present an increased metabolic rate compared to wild type in normocapnia. When exposed to CO2, males lacking LC noradrenaline showed a lower respiratory frequency compared to control animals. On the other hand, females lacking LC noradrenaline presented a higher tidal volume. Nevertheless, no change in ventilation was observed in either sex. CO2 evoked an active escape response. Mice lacking LC noradrenaline had a blunted jumping response and an increased freezing duration compared to the other groups. They also presented fewer racing episodes compared to wild type animals, but not different from mice with reduced LC noradrenaline. These findings suggest that LC-NA has an important role in ventilatory and panic-like escape responses elicited by CO2 exposure in mice.

Disparate response of decapods to low pH: A meta-analysis of life history, physiology and behavior traits across life stages and environments.

We employed a meta-analysis to determine if the presumed resilience of decapods to ocean acidification extends to all biological aspects, environments, and life stages. Most response categories appeared unaffected by acidification. However, certain fitness-related traits (growth, survival, and, to some extent, calcification) were impacted. Acid-base balance and stress response scaled positively with reductions in pH, which maintains homeostasis, possibly at the cost of other processes. Juveniles were the only stage impacted by acidification, which is believed to reduce recruitment. We observed few differences in responses to acidification among decapods inhabiting contrasting environments. Our meta-analysis shows decapods as a group slightly to moderately sensitive to low pH, with impacts on some biological aspects rather than on all specific life stages or habitats. Although extreme pH scenarios may not occur in the open ocean, coastal and estuarine areas might experience lower pH levels in the near to medium future, posing potential challenges for decapods.

Microglial reactivity in brainstem chemosensory nuclei in response to hypercapnia.

Microglia, the resident immune cells of the CNS, surveil, detect, and respond to various extracellular signals. Depending on the nature of these signals, an integrative microglial response can be triggered, resulting in a phenotypic transformation. Here, we evaluate whether hypercapnia modifies microglia phenotype in brainstem respiratory-related nuclei. Adult C57BL/6 inbred mice were exposed to 10% CO2 enriched air (hypercapnia), or pure air (control), for 10 or 30 min and immediately processed for immunohistochemistry to detect the ubiquitous microglia marker, ionized calcium binding adaptor molecule 1 (Iba1). Hypercapnia for thirty, but not 10 min reduced the Iba1 labeling percent coverage in the ventral respiratory column (VRC), raphe nucleus (RN), and nucleus tractus solitarius (NTS) and the number of primary branches in VRC. The morphological changes persisted, at least, for 60 min breathing air after the hypercapnic challenge. No significant changes were observed in Iba1+ cells in the spinal trigeminal nucleus (Sp5) and the hippocampus. In CF-1 outbred mice, 10% CO2 followed by 60 min of breathing air, resulted in the reduction of Iba1 labeling percent coverage and the number and length of primary branches in VRC, RN, and NTS. No morphological change was observed in Iba1+ cells in Sp5 and hippocampus. Double immunofluorescence revealed that prolonged hypercapnia increased the expression of CD86, an inflammatory marker for reactive state microglia, in Iba1+ cells in VRC, RN, and NTS, but not in Sp5 and hippocampus in CF-1 mice. By contrast, the expression of CD206, a marker of regulatory state microglia, persisted unmodified. In brainstem, but not in hippocampal microglia cultures, hypercapnia increased the level of IL1ß, but not that of TGFß measured by ELISA. Our results show that microglia from respiratory-related chemosensory nuclei, are reactive to prolonged hypercapnia acquiring an inflammatory-like phenotype.

Profiles of Elderly Patients with Obesity Hypoventilation Syndrome in Martinique: A Single-Center Study.

Obesity hypoventilation syndrome (OHS) is a form of chronic respiratory insufficiency related to obesity that affects young and old people. Age appears to be associated with poorer response to treatment by nighttime ventilation. This study aimed to describe the characteristics of elderly subjects (>65 years) with OHS compared to younger patients, with a view to adapting therapy in older individuals. We conducted a retrospective study comparing socio-demographic, clinical, functional characteristics as well as treatment and outcomes between young (<65 years) and older (65 years and older) individuals with OHS at the University Hospital of Martinique. We included 143 patients (114 women), of whom 82 were 65 years or older (57%). Charlson index was higher in the older group. Patients in ≥65 years group were less frequently obese, but more frequently had diabetes mellitus, cardiac arrythmia and arterial hypertension compared to younger patients. There was no difference in the circumstances of diagnosis or arterial blood gas at diagnosis. At follow up, partial pressure of carbon dioxide (pCO2) was higher in ≥65 years group. Despite comparable NIV settings, apart from lower expiratory positive airway pressure (EPAP) with higher apnea-hypopnea index (AHI), patients in the ≥65-year-old group remained more frequently hypercapnic. In conclusion, over half (57%) of patients with OHS in our cohort were aged over 65 years. Older patients developed OHS at lower BMI levels than their younger counterparts, and more frequently, had comorbidities such as diabetes, hypertension and cardiac arrhythmia. Increased Charlson index, lower BMI and female sex were independent factors associated with OHS in the elderly.

Factors Associated with the Efficiency of Home Non-Invasive Ventilation in Patients with Obesity-Hypoventilation Syndrome in Martinique.

Obesity-hypoventilation syndrome (OHS) is a respiratory complication of obesity characterized by chronic hypercapnic respiratory failure. It is often associated with several comorbidities and is treated by positive airway pressure (PAP) therapy. This study aimed to identify factors associated with persistent hypercapnia in patients receiving home non-invasive ventilation (NIV). We performed a retrospective study including patients with documented OHS. In total, 143 patients were included (79.7% women, age 67 ± 15.5 years, body mass index 41.6 ± 8.3 kg/m2). After 4.6 ± 4.0 years of follow-up, 72 patients (50.3%) remained hypercapnic. In bivariable analysis, clinical data showed no difference in follow-up duration, number of comorbidities, comorbidities, or circumstance of discovery. Patients with persistent hypercapnia on NIV were generally older, with lower BMI and more comorbidities. (5.5 ± 1.8 versus 4.4 ± 2.1, p = 0.001), female sex (87.5% versus 71.8%), was treated by NIV (100% versus 90.1%, p < 0.01), had lower FVC (56.7 ± 17.2 versus 63.6 ± 18% of theoretical value, p = 0.04), lower TLC (69.1 ± 15.3 versus 74.5 ± 14.6% of theoretical value, p = 0.07), lower RV (88.4 ± 27.1 versus 102.5 ± 29.4% of theoretical value, p = 0.02), higher pCO2 at diagnosis (59.7 ± 11.7 versus 54.6 ± 10.1 mmHg, p = 0.01) and lower pH (7.38 ± 0.03 versus 7.40 ± 0.04, p = 0.007), higher pressure support (12.6 ± 2.6 versus 11.5 ± 2.4 cmH2O, p = 0.04) and lower EPAP (8.2 ± 1.9 versus 9 ± 2.0 cmH2O, p = 0.06). There was no difference in non-intentional leaks and daily use between patients between both groups. By multivariable analysis, sex, BMI, pCO2 at diagnosis, and TLC were independent risk factors for persistent hypercapnia on home NIV. In individuals with OHS, persistent hypercapnia on home NIV therapy is frequent. Sex, BMI, pCO2 at diagnosis, and TLC were all associated with an increased risk of persistent hypercapnia in persons treated with home NIV.

The Pedunculopontine Tegmental Nucleus is not Important for Breathing Impairments Observed in a Parkinson's Disease Model.

Parkinson's disease (PD) is a motor disorder resulting from degeneration of dopaminergic neurons of substantia nigra pars compacta (SNpc), with classical and non-classical symptoms such as respiratory instability. An important region for breathing control, the Pedunculopontine Tegmental Nucleus (PPTg), is composed of cholinergic, glutamatergic, and GABAergic neurons. We hypothesize that degenerated PPTg neurons in a PD model contribute to the blunted respiratory activity. Adult mice (40 males and 29 females) that express the fluorescent green protein in cholinergic, glutamatergic or GABAergic cells were used (Chat-cre Ai6, Vglut2-cre Ai6 and Vgat-cre Ai6) and received bilateral intrastriatal injections of vehicle or 6-hydroxydopamine (6-OHDA). Ten days later, the animals were exposed to hypercapnia or hypoxia to activate PPTg neurons. Vglut2-cre Ai6 animals also received retrograde tracer injections (cholera toxin b) into the retrotrapezoid nucleus (RTN) or preBötzinger Complex (preBötC) and anterograde tracer injections (AAV-mCherry) into the SNpc. In 6-OHDA-injected mice, there is a 77% reduction in the number of dopaminergic neurons in SNpc without changing the number of neurons in the PPTg. Hypercapnia activated fewer Vglut2 neurons in PD, and hypoxia did not activate PPTg neurons. PPTg neurons do not input RTN or preBötC regions but receive projections from SNpc. Although our results did not show a reduction in the number of glutamatergic neurons in PPTg, we observed a reduction in the number of neurons activated by hypercapnia in the PD animal model, suggesting that PPTg may participate in the hypercapnia ventilatory response.

Effects of oxygen supplementation in ewes subjected to laparoscopic ovum pick-up under total intravenous anesthesia / Efeitos da suplementação de oxigênio em ovelhas submetidas à aspiração de folículos por laparoscopia sob anestesia intravenosa total

Laparoscopy procedures are useful tools to perform some assisted reproductive biotechnologies in ewes, it requi-res general anesthesia and manoeuvres that might result in alteration of the cardiopulmonary function. For this reason, this study aimed to investigate the effects of oxygen supplementation as a therapeutic measure to mitigate these alterations in ewes submitted to laparoscopic ovum pick-up (LOPU) under total intravenous anesthesia (TIVA). Twenty-four healthy adult ewes were submitted to two LOPUs with a 21 days interval, under ketamine-midazolam anesthesia, and receiving each of the two experimental in random order, oxygen treatment (OT) 50 mL/kg/min of oxygen via endotracheal tube and control treatment (CT) not receive any inhalation treatment. Heart rate (HR), respiratory rate (fR), peripheral oxygen saturation (SpO2), mean arterial pressure (MAP), rectal temperature (RT), end-tidal CO2 concentration (EtCO2) and recovery anesthesia time were evaluated during LOPU, arterial blood gases and electrolytes were evaluated after induction of anesthesia and at the end of the LOPU. Variables were compared between groups and moments using ANOVA. MAP, SpO2, PaO2, SaO2 and pH were higher in OT, while EtCO2, PaCO2, temperature loss and recovery time were lower. These results allow to conclude that oxy-gen supplementation in ewes submitted to LOPU under TIVA provides benefits in order to mitigate physiological alterations.(AU)

Os procedimentos de laparoscopia são ferramentas úteis para realizar algumas biotecnologias de reprodução assistida em ovelhas, requer anestesia geral e manobras que podem resultar em alteração da função cardiopulmonar. Por esse motivo, este estudo teve como objetivo investigar os efeitos da suplementação de oxigênio como medida terapêutica para atenuar as alterações em ovelhas submetidas à Aspiração Folicular guiada por Laparoscopia (LOPU) sob anestesia venosa total (TIVA). Vinte e quatro ovelhas adultas saudáveis foram submetidas a duas LOPUs com intervalo de 21 dias, sob anestesia com cetamina-midazolam, recebendo cada um dos dois experimentos em ordem aleatória, tratamento com oxigênio (OT) 50 mL/kg/min de oxigênio via tubo endotraqueal e tratamento de controle (CT) não recebem nenhum tratamento por inalação. Frequência cardíaca (FC), frequência respiratória (FR), saturação periférica de oxigênio (SpO2), pressão arterial média (PAM), temperatura retal (TR), concentração expirada de CO2 (EtCO2) e tempo de recuperação da anestesia foram avaliados durante LOPU, arterial gasometria e eletrólitos foram avaliados após a indução da anestesia e ao final da COL. As variáveis foram comparadas entre grupos e momentos por meio de ANOVA. PAM, SpO2, PaO2, SaO2 e pH foram maiores no TO, enquanto EtCO2, PaCO2, perda de temperatura e tempo de recuperação foram menores. Estes resultados permitem concluir que a suplementação de oxigênio em ovelhas submetidas a LOPU sob TIVA proporciona benefícios no sentido de atenuar as alterações fisiológicas.(AU)

Investigação da associação de dois oxigenadores em paralelo ou em série durante o suporte respiratório com oxigenação por membrana extracorpórea / Exploring the association of two oxygenators in parallel or in series during respiratory support using extracorporeal membrane oxygenation

RESUMO Objetivo: Caracterizar as pressões, as resistências, a oxigenação e a eficácia da descarboxilação de dois oxigenadores associados em série ou em paralelo durante o suporte com oxigenação veno-venosa por membrana extracorpórea. Métodos: Usando os resultados de insuficiência respiratória grave em suínos associada à disfunção de múltiplos órgãos, ao modelo de suporte com oxigenação por membrana extracorpórea veno-venosa e à modelagem matemática, exploramos os efeitos na oxigenação, descarboxilação e pressões do circuito de associações de oxigenadores em paralelo e em série. Resultados: Testaram-se cinco animais com peso mediano de 80kg. Ambas as configurações aumentaram a pressão parcial de oxigênio após os oxigenadores. O teor de oxigênio da cânula de retorno também foi ligeiramente maior, mas o efeito na oxigenação sistêmica foi mínimo, usando oxigenadores com alto fluxo nominal (~ 7L/minuto). Ambas as configurações reduziram significativamente a pressão parcial de dióxido de carbono sistêmico. Como o fluxo sanguíneo na oxigenação por membrana extracorpórea aumentou, a resistência do oxigenador diminuiu inicialmente, com aumento posterior, com fluxos sanguíneos mais altos, mas pouco efeito clínico. Conclusão: A associação de oxigenadores em paralelo ou em série durante o suporte com oxigenação veno-venosa por membrana extracorpórea proporciona um modesto aumento na depuração da pressão parcial de dióxido de carbono, com leve melhora na oxigenação. O efeito das associações de oxigenadores nas pressões de circuitos extracorpóreos é mínimo.

ABSTRACT Objective: To characterize the pressures, resistances, oxygenation, and decarboxylation efficacy of two oxygenators associated in series or in parallel during venous-venous extracorporeal membrane oxygenation support. Methods: Using the results of a swine severe respiratory failure associated with multiple organ dysfunction venous-venous extracorporeal membrane oxygenation support model and mathematical modeling, we explored the effects on oxygenation, decarboxylation and circuit pressures of in-parallel and in-series associations of oxygenators. Results: Five animals with a median weight of 80kg were tested. Both configurations increased the oxygen partial pressure after the oxygenators. The return cannula oxygen content was also slightly higher, but the impact on systemic oxygenation was minimal using oxygenators with a high rated flow (~ 7L/minute). Both configurations significantly reduced the systemic carbon dioxide partial pressure. As the extracorporeal membrane oxygenation blood flow increased, the oxygenator resistance decreased initially with a further increase with higher blood flows but with a small clinical impact. Conclusion: Association of oxygenators in parallel or in series during venous-venous extracorporeal membrane oxygenation support provides a modest increase in carbon dioxide partial pressure removal with a slight improvement in oxygenation. The effect of oxygenator associations on extracorporeal circuit pressures is minimal.

Phox2b mutation mediated by Atoh1 expression impaired respiratory rhythm and ventilatory responses to hypoxia and hypercapnia.

Mutations in the transcription factor Phox2b cause congenital central hypoventilation syndrome (CCHS). The syndrome is characterized by hypoventilation and inability to regulate breathing to maintain adequate O2 and CO2 levels. The mechanism by which CCHS impact respiratory control is incompletely understood, and even less is known about the impact of the non-polyalanine repeat expansion mutations (NPARM) form. Our goal was to investigate the extent by which NPARM Phox2b mutation affect (a) respiratory rhythm; (b) ventilatory responses to hypercapnia (HCVR) and hypoxia (HVR); and (c) number of chemosensitive neurons in mice. We used a transgenic mouse line carrying a conditional Phox2bΔ8 mutation (same found in humans with NPARM CCHS). We crossed them with Atoh1cre mice to introduce mutation in regions involved with respiratory function and central chemoreflex control. Ventilation was measured by plethysmograph during neonatal and adult life. In room air, mutation in neonates and adult did not greatly impact basal ventilation. However, Phox2bΔ8, Atoh1cre increased breath irregularity in adults. The HVR and HCVR were impaired in neonates. The HVR, but not HCVR, was still partially compromised in adults. The mutation reduced the number of Phox2b+/TH--expressing neurons as well as the number of fos-activated cells within the ventral parafacial region (also named retrotrapezoid nucleus [RTN] region) induced by hypercapnia. Our data indicates that Phox2bΔ8 mutation in Atoh1-expressing cells impaired RTN neurons, as well as chemoreflex under hypoxia and hypercapnia specially early in life. This study provided new evidence for mechanisms related to NPARM form of CCHS neuropathology.

Metabolic and respiratory chemosensitivity and brain monoaminergic responses to cold exposure in chicks subjected to thermal manipulation during incubation.

We evaluated ventilation (V˙E), body temperature (TB), oxygen consumption (V˙ O2), respiratory equivalent (V˙E/ V˙ O2), and monoamine concentrations of 14-day-old (14d) male and female chicks from eggs incubated at low (LT, 36 °C), control (CT, 37.5 °C) and high (HT, 39 °C) temperature during the early embryonic phase, to normoxia, hypercapnia and hypoxia under exposure to cold environment (20 °C). At normoxia, acute cold exposure did not affect the ventilatory variables, with the exception of HT males, in which cold prevented the reduced V˙E observed under thermoneutral conditions. Exposure to 20 °C caused a decrease in TB in both sexes, and LT and HT females presented a greater hypothermic response. Hypercapnia combined with cold did not alter the ventilatory variables, but LT females and CT males and females showed a blunted CO2-induced hyperventilation due to a higher V˙ O2, compared to the same groups in thermoneutral conditions. Unlike with thermoneutral conditions, the blunted hypercapnic hyperventilation observed in the HT groups was not observed during cold challenge. CO2 exposure promoted a similar decrease in TB in the thermoneutral and acutely cold exposed groups, while LT females under cold condition presented a blunted hypothermic response. During hypoxia, cold challenge attenuated the increase in V˙E in LT females and HT males, due to changes in VT. Hypoxic metabolic depression was greater in LT females and males and HT males during cold exposure, while no change in V˙E/ V˙ O2 was observed. The only alteration in monoaminergic concentration under cold challenge was an increase in brainstem 5-HIAA and 5-HIAA/5-HT ratio in HT females, and an enhanced 5-HT concentration in HT males. In summary, thermal manipulation during embryogenesis induces 14d old chicks to respond differently to cold stress with LT females and HT males being more sensitive.

CO2 exposure enhances Fos expression in hypothalamic neurons in rats during the light and dark phases of the diurnal cycle.

Orexinergic (OX) neurons in the lateral hypothalamus (LH), perifornical area (PFA) and dorsomedial hypothalamus (DMH) play a role in the hypercapnic ventilatory response, presumably through direct inputs to central pattern generator sites and/or through interactions with other chemosensitive regions. OX neurons can produce and release orexins, excitatory neuropeptides involved in many functions, including physiological responses to changes in CO2/pH. Thus, in the present study, we tested the hypothesis that different nuclei (LH, PFA and DMH) where the orexinergic neurons are located, show distinct activation by CO2 during the light-dark cycle phases. For this purpose, we evaluated the Fos and OXA expression by immunohistochemistry to identify neurons that co-localize Fos + OXA in the LH, LPeF, MPeF and DMH in the light-inactive and dark-active phase in Wistar rats subjected to 3 h of normocapnia or hypercapnia (7% CO2). Quantitative analyses of immunoreactive neurons show that hypercapnia caused an increase in the number of neurons expressing Fos in the LH, LPeF, MPeF and DMH in the light and dark phases. In addition, the number of Fos + OXA neurons increased in the LPeF and DMH independently of the phases of the diurnal cycle; whereas in the MPeF, this increase was observed exclusively in the light phase. Thus, we suggest that OX neurons are selectively activated by hypercapnia throughout the diurnal cycle, reinforcing the differential role of nuclei in the hypothalamus during central chemosensitivity.

Respiratory deficits in a female rat model of Parkinson's disease.

NEW FINDINGS: What is the central question of this study? How does the 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease model affect the respiratory response in female rats? What effect does ovariectomy have on that response? What is the main finding and its importance? The results suggest a protective effect of ovarian hormones in maintaining normal neuroanatomical integrity of the medullary respiratory nucleus in females. It was observed that ovariectomy alone reduced neurokinin-1 density in the pre-Bötzinger complex and Bötzinger complex, and there was an incremental effect of 6-OHDA and ovariectomy on retrotrapezoid nucleus neurons. ABSTRACT: Emerging evidence indicates that the course of Parkinson's disease (PD) includes autonomic and respiratory deficiencies in addition to the classical motor symptoms. The prevalence of PD is lower in women, and it has been hypothesized that neuroprotection by ovarian hormones can explain this difference. While male PD animal models present changes in the central respiratory control areas, as well as ventilatory parameters under normoxia and hypercapnia, little is known about sex differences regarding respiratory deficits in this disease background. This study aimed to explore the neuroanatomical and functional respiratory changes in intact and ovariectomized (OVX) female rats subjected to chemically induced PD via a bilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA). The respiratory parameters were evaluated by whole-body plethysmography, and the neuroanatomy was monitored using immunohistochemistry. It was found that dopaminergic neurons in the substantia nigra and neurokinin-1 receptor density in the rostral ventrolateral respiratory group, Bötzinger and pre-Bötzinger complex were reduced in the chemically induced PD animals. Additionally, reduced numbers of Phox2b neurons were only observed in the retrotrapezoid nucleus of PD-OVX rats. Concerning respiratory parameters, in OVX rats, the resting and hypercapnia-induced tidal volume (VT ) is reduced, and ventilation ( V ̇ E ${\dot V_{\rm{E}}}$ ) changes independently of 6-OHDA administration. Notably, there is a reduction in the number of retrotrapezoid nucleus Phox2b neurons and hypercapnia-induced respiratory changes in PD-OVX animals due to a 6-OHDA and OVX interaction. These results suggest a protective effect induced by ovarian hormones in neuroanatomical changes observed in a female experimental PD model.

Melanin-concentrating hormone regulates the hypercapnic chemoreflex by acting in the lateral hypothalamic area.

NEW FINDINGS: What is the central question of this study? Melanin-concentrating hormone (MCH) suppresses the hypercapnic chemoreflex: what is the mechanism by which this effect is produced? What is the main finding and its importance? MCH acting in the lateral hypothalamic area but not in the locus coeruleus in rats, in the light period, attenuates the hypercapnic chemoreflex. The data provide new insight into the role of MCH in the modulation of the hypercapnic ventilatory response. ABSTRACT: Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide involved in a broad range of homeostatic functions including regulation of the hypercapnic chemoreflex. We evaluated whether MCH modulates the hypercapnic ventilatory response by acting in the lateral hypothalamic area (LHA) and/or in the locus coeruleus (LC). Here, we measured pulmonary ventilation ( V ̇ E ${\dot V_{\rm{E}}}$ ), body temperature, electroencephalogram (EEG) and electromyogram (EMG) of unanaesthetized adult male Wistar rats before and after microinjection of MCH (0.4 mM) or MCH receptor 1 (MCH1-R) antagonist (SNAP-94847; 63 mM) into the LHA and LC, in room air and 7% CO2 conditions during wakefulness and sleep in the dark and light periods. MCH intra-LHA caused a decreased CO2 ventilatory response during wakefulness and sleep in the light period, while SNAP-94847 intra-LHA increased this response, during wakefulness in the light period. In the LC, MCH or the MCH1-R antagonist caused no change in the hypercapnic ventilatory response. Our results suggest that MCH, in the LHA, exerts an inhibitory modulation of the hypercapnic ventilatory response during the light-inactive period in rats.

Prenatal fluoxetine has long-lasting, differential effects on respiratory control in male and female rats.

Serotonin (5-HT) is an important modulator of brain networks that control breathing. The selective serotonin reuptake inhibitor fluoxetine (FLX) is the first-line antidepressant drug prescribed during pregnancy. We investigated the effects of prenatal FLX exposure on baseline breathing, ventilatory and metabolic responses to hypercapnia and hypoxia as well as number of brainstem 5-HT and tyrosine hydroxylase (TH) neurons of rats during postnatal development (P0-82). Prenatal FLX exposure of males showed a lower baseline V̇e that appeared in juveniles and remained in adulthood, with no sleep-wake state dependency. Prenatal FLX exposure of females did not affect baseline breathing. Juvenile male FLX showed increased CO2 and hypoxic ventilatory responses, normalizing by adulthood. Alterations in juvenile FLX-treated males were associated with a greater number of 5-HT neurons in the raphe obscurus (ROB) and raphe magnus (RMAG). Adult FLX-exposed males showed greater number of 5-HT neurons in the raphe pallidus (RPA) and TH neurons in the A5, whereas reduced number of TH neurons in A7. Prenatal FLX exposure of female rats was associated with greater hyperventilation induced by hypercapnia at P0-2 and juveniles, whereas P12-14 and adult FLX (non-rapid eye movement, NREM sleep) rats showed an attenuation of the hyperventilation induced by CO2. FLX-exposed females had fewer 5-HT neurons in the RPA and reduced TH A6 density at P0-2; and greater number of TH neurons in the A7 at P12-14. These data indicate that prenatal FLX exposure affects the number of some monoaminergic regions in the brain and results in long-lasting, sex-specific changes in baseline breathing pattern and ventilatory responses to respiratory challenges.NEW & NOTEWORTHY Selective serotonin reuptake inhibitors (SSRIs) readily cross the placental and the fetal blood-brain barrier where it will affect 5-HT levels in the developing brain. Although SSRI is used during pregnancy, there are no studies showing SSRI exposure during late pregnancy and postnatal effects on breathing control in males and females. We demonstrated that fluoxetine exposure during late pregnancy in rats was associated with long-lasting, sex-specific effects on breathing and brainstem monoaminergic groups.

Effects of hypercapnia versus normocapnia during general anesthesia on outcomes: a systematic review and meta-analysis.

BACKGROUND: The effect of mild changes in CO2 levels to organ perfusion and tissue inflammation are well known, whereas an influence of hypercapnia under general anesthesia on adverse events as nausea and vomiting, or length of hospital stay is barely examined. The goal of our meta-analysis was to identify possibly positive effects of hypercapnia versus normocapnia in general anesthesia in adult patients. METHODS: We conducted a systematic review of parallel-arm randomised controlled trials comparing hypercapnia versus normocapnia in adult patients undergoing general anesthesia. In July 2018 and September 2019 we searched "CENTRAL‿, "MEDLINE‿, and "Embase‿, checked reference lists of all included studies and relevant systematic reviews for additional references to trials. Two review authors independently assessed trials for inclusion, extracted data, and completed a "Risk of bias‿ assessment for all included studies. RESULTS: Our search identified 297 records after abstract screening 30 full-text papers remained for further examination. Ten publications met our inclusion criteria and were used for narrative description of this systematic review. Three studies were eligible for the meta-analysis normocapnia versus hypercapnia with the outcomes: time to extubation and adverse events. On average, time to extubation was significantly reduced in the hypercapnia group with a mean difference 3.78 (95% CI 0.85 to 6.71). No difference was found regarding adverse events. CONCLUSIONS: The findings of our study do not enable us to produce evidence of a positive influence of increased CO2 partial pressure levels during general anesthesia. A well-planned, adequately powered randomized controlled trial would be desirable in the future.

Estrategia ventilatoria para el aclaramiento de dióxido de carbono en un lactante con hipercapnia incontrolable / Ventilatory strategy for carbon dioxide clearance in an infant with persistent hypercapnia / Estratégia ventilatória para depuração de dióxido de carbono em uma criança com hipercapnia incontrolável

Resumen Se presenta la experiencia de combinar la ventilación convencional y una técnica modificada de insuflación de gas paratraqueal para evitar complicaciones de la insuflación traqueal directa en un lactante con hipercapnia refractaria, quien ingresó con falla respiratoria aguda secundaria a neumonía multilobar. Al iniciar la ventilación mecánica presentó neumotórax, fístulas broncopleurales y acidemia hipercápnica refractaria a tratamiento convencional. Se inició insuflación de gas paratraqueal en ventilación convencional en modo de presión control, con 10 L/min de aire humidificado con una presión control máxima sostenida de 20 cmH2O. Tres horas después se observó una mejoría de la gasometría arterial y pasadas 72 horas se logró retirar el dispositivo paratraqueal sin complicaciones, con adecuada evolución clínica. Al no incluir un catéter intratraqueal se evitaron complicaciones conservando los mecanismos que mejoran la oxigenación e hipercapnia. La técnica presentada es prometedora; sin embargo, se deben realizar estudios con un mayor número de individuos.

Abstract The experience of combining conventional ventilation and a modified paratracheal gas insufflation technique to avoid complications is presented. An infant with acute respiratory failure secondary to multilobar pneumonia who after start off mechanical ventilation developed pneumothorax, bronchopleural fistulas, and persistent hypercapnic acidemia refractory to conventional ventilatory strategies. It was decided to initiate paratracheal gas insufflation in conventional ventilation in pressure control mode, with 10 L/min of humidified air with a maximum sustained control pressure of 20 cmH2O. Three hours after an improvement in arterial blood gas was recorded and after 72 hours the paratracheal device was removed without complications, with adequate clinical evolution. By not incorporate an intratracheal catheter some complications are avoided, preserving the mechanisms that improve oxygenation and CO2 elimination. Paratracheal gas insufflation is a promising technique, although more studies are required with a greater number of individuals.

Resumo Apresenta-se a experiência de combinar ventilação convencional e técnica modificada de insuflação de gás paratraqueal para evitar complicações da insuflação traqueal direta em uma criança com hipercapnia refratária que foi admitido com insuficiência respiratória aguda secundária a pneumonia multilobar. Ao iniciar ventilação mecânica, apresentou pneumotórax, fístulas broncopleurais e acidemia hipercápnica refratária ao tratamento convencional. A insuflação de gás paratraqueal foi iniciada em ventilação convencional no modo de controle de pressão, com 10 L/min de ar umidificado com pressão de controle máxima sustentada de 20 cmH2O. Três horas após, observou-se melhora da gasometria arterial e após 72 horas o dispositivo paratraqueal foi retirado sem intercorrências, com evolução clínica adequada. Ao não incluir um cateter intratraqueal, as complicações foram evitadas, preservando os mecanismos que melhoram a oxigenação e a hipercapnia. A técnica apresentada é promissora, porém, estudos com um número maior de indivíduos devem ser realizados.