Impaired Ventilatory Response Research Articles

Extreme altitude-induced central sleep apneas lasting more than 100 seconds in a healthy 23-year-old man.

Central sleep apneas (CSA) can occur de novo at high-altitude in individuals without sleep-disordered breathing at low altitude. These apneas are usually brief, lasting only 5-15 s. This report presents the first documented case of a man experiencing extreme altitude-induced CSA lasting more than 100 s in the absence of any sleep breathing disorder in normoxia. A 23-year-old male with no pre-existing health conditions was recruited for a study examining the work of breathing during sleep at a simulated altitude of 3500 m (FiO2:13%). A lowland polysomnography was first conducted to exclude moderate to severe sleep-disordered breathing and showed an apnea-hypopnea index (AHI) of 7.6/h, an oxygen desaturation index (ODI) of 4.8/h, and a mean pulse oximetry-based oxygen saturation (SpO2) of 93.9%. During the recording in the hypoxic chamber, the participant experienced prolonged CSA lasting up to 1 min and 49 s. These apneas were associated with significant oxygen desaturations (nadir: 44%). To investigate the origin of these atypical CSA, the participant underwent a new low-altitude polysomnography with transcutaneous CO2 measurement (mean PaCO2:46 mmHg) and diurnal arterial blood gas analysis (pH: 7.42, pCO2: 35.1 mmHg, pO2: 79.9 mmHg, HCO3 -: 22.4 mmol/L). These results indicated no signs of chronic hypercapnia or hypocapnia. A hypoxia tolerance test (FiO2: 11.5%) demonstrated a good ventilatory response to hypoxia during exercise (1.004 L/min/kg). A rebreathing test according to the Read protocol in hyperoxia demonstrated an impaired ventilatory response to CO2 (<0.6 L/min/mmHg). This report documents a rare form of extreme hypoxia-induced CSA, potentially caused by impaired CO2 chemoreceptor sensitivity and an increased arousal threshold.

Association of Sarcopenia and Oxygen Uptake Efficiency Slope in Male Patients With Heart Failure.

Sarcopenia, the loss of muscle mass and function, is a common comorbidity in patients with heart failure (HF). The skeletal muscle modulates the respiratory response during exercise. However, whether ventilatory behavior is affected by sarcopenia is still unknown. We enrolled 169 male patients with HF. Muscle strength was measured by a handgrip dynamometer. Body composition was measured with dual-energy X-ray absorptiometry. Sarcopenia was defined by handgrip strength <27 kg and appendicular lean mass divided by height squared (ALM/height 2 ) <7.0 kg/m 2 . Oxygen uptake efficiency slope (OUES), ventilation (VE), oxygen uptake (VO 2 ), and carbon dioxide output (VCO 2 ) were measured by a cardiopulmonary exercise test. Sarcopenia was identified in 29 patients (17%). At the first ventilatory threshold, VE/VO 2 (36.9±5.9 vs 32.7±6.5; P =.003) and VE/VCO 2 (39.8±7.2 vs 35.3±6.9; P =.004) were higher in patients with sarcopenia compared to those without sarcopenia. At the exercise peak, compared to patients without sarcopenia, patients with sarcopenia had lower OUES (1186±295 vs 1634±564; P <.001), relative VO 2 (16.2±5.0 vs 19.5±6.5 mL/kg/min; P =.01), and VE (47.3±10.1 vs 63.0±18.2L/min; P <.0001), while VE/VCO 2 (42.9±8.9 vs 38.7±8.4; P =.025) was increased. OUES was positively correlated with ALM/height 2 ( r =0.36; P <.0001) and handgrip strength ( r =0.31; P <.001). Hemoglobin (OR=1.149; 95% CI, 0.842-1.570; P =.038), ALM/height 2 (OR=2.166; 95% CI, 1.338-3.504; P =.002), and VO 2peak (OR=1.377; 95% CI, 1.218-1.557; P <.001) were independently associated with OUES adjusted by cofounders. Our results suggest that sarcopenia is related to impaired ventilatory response during exercise in patients with HF.

Impaired excitability of nucleus tractus solitarius neurons in a neonatal rat model of hyperbilirubinemia

Hyperbilirubinemia is associated with multiple morbidities including apnea of prematurity in preterm infants. Bilirubin, a byproduct of hemoglobin breakdown, is not excreted normally and results in high circulating levels giving rise to a state of hyperbilirubinemia. Free bilirubin (not bound to albumin) can cross the blood-brain barrier and be neurotoxic. Prior studies have shown that a systemic injection of bilirubin accumulates in the brainstem and is associated with an impaired ventilatory response to hypercapnia and an augmented hypoxic ventilatory depression. Here, using the Gunn rat model of endogenous hyperbilirubinemia, we investigated its effects on the excitability of neurons of the nucleus tractus solitarius (NTS). The homozygous Gunn rat (jj) model of hyperbilirubinemia lacks uridine diphosphate-glucuronosyltransferase-1A1, an enzyme which is needed to catabolize bilirubin. Heterozygous Nj Gunn rat pups were used for control. On postnatal (P) day 5, Nj and jj rat pups received either a 200mg/kg intraperitoneal injection of sulfadimethoxine (SDMX), which dissociates bilirubin from albumin resulting in increased levels of circulating free bilirubin, or an equivalent amount of saline as a vehicle control. Whole cell patch clamp was performed on NTS neurons two days later (P7) to assess characteristics of evoked excitatory postsynaptic currents (eEPSC).The amplitude of the evoked stimulus response to a 20Hz stimulus train was significantly increased in NTS neurons from jj+saline pups when compared to cells from Nj+saline and Nj+SDMX animals (p&lt;0.05). This increased amplitude was no longer present after SDMX treatment of jj pups. Additionally, jj+saline NTS neurons did not exhibit any failure to solitary tract stimulation, whereas SDMX treatment significantly increased the failure rate during a 20Hz stimulus train (jj+saline =0.0%±0.0, jj+SDMX= 18.63%±8.82, p&lt;0.05). Comparison of failure rate of jj+saline to Nj+saline (6.63%±3.12, p&lt;0.05) was also statistically significant. The hyper-responsive NTS neurons of jj+saline rats may be an adaptive response to the deleterious effects of circulating (bound and unbound) bilirubin. However, the impaired response of neurons in jj+SDMX rats may reflect neurotoxic effects of increased free bilirubin leading to impaired neurotransmission. The latter is consistent with the high failure rate of NTS neurons in jj+SDMX rats. These data may have implications for impaired respiratory control mechanisms involved in mediating essential vagally mediated ventilatory defense responses to hypoxemia and may contribute to the apnea of prematurity associated with hyperbilirubinemia in preterm infants. William and Lois Briggs Endowment. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The association of cardiorespiratory fitness with spirometric small airway obstruction.

Spirometric small airway obstruction is associated with impaired ventilatory response to exercise independently of FEV1/FVC ratio https://bit.ly/3pre4sk.

Adenylate Cyclase 3 and Cyclic Nucleotide-Gated Channel Alpha 2 Are Downstream Signaling to H2S/Olfr78 to Carotid Body Responses to Hypoxia

We previously showed that activation of Olfr78 by H 2 S as an important component of carotid body(CB) O 2 sensing. Present study delineated signaling associated with H 2 S/Olfr78 interaction. Odorant receptor activation is linked to olfactory G protein G Olf , which increases cAMP through type III adenylyl cyclase (AC3), and subsequent activation of cyclic nucleotide-gated channel alpha 2 (Cnga2). Immunohistochemistry showed that carotid body glomus cells were positive for Gα Olf , AC3, and Cnga2. Hypoxia (medium Po 2 ~40 mmHg) or H 2 S(50 μM) increased cAMP in the carotid body and these responses were absent in tyrosine hydroxylase-specific AC3 mutants. AC activators forskolin and 8-Bromo-cAMP enhanced ex vivo CB sensory response to hypoxia and H 2 S. The effects of 8-Bromo-cAMP were absent in Cnga2 mutants. Hypoxia and H 2 S stimulated ex vivo CB sensory activity and elevated intracellular calcium of glomus cells in wild type but not AC3 or Cnga2 mutants. Whole body plethysmography showed impaired ventilatory response to acute hypoxia (12%O 2 , 5 min) but not to hypercapnia in AC3 or Cnga2 mutants. The data suggest that AC3-cAMP-Cnga2 signaling contributes to H 2 S/Olfr78-dependent O 2 sensing by the CB to regulate breathing. Supported by NIH-HLBI P01-HL-44454 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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.

Association of sarcopenia and oxygen uptake efficiency slope in male patients with heart failure: The skeletal muscle hypothesis in practice

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Background Sarcopenia, a generalized loss of muscle mass and function, is a common comorbidity in patients with heart failure (HF). The skeletal muscle, through afferent nerve pathways, modulates the respiratory response during physical efforts. However, whether ventilatory behavior is affected by the presence of sarcopenia is still unknown. Purpose To evaluate the impact of sarcopenia in ventilatory parameters of patients with HF. Methods We enrolled 169 male patients with stable chronic HF with left ventricular ejection fraction &amp;lt;40% (LVEF). Muscle strength was measured by handgrip dynamometer. Body composition was measured with dual-energy X-ray absorptiometry (DXA). Appendicular skeletal muscle (ASM) was comprised by lean muscle mass of both arms and legs. Sarcopenia was defined by handgrip strength and ASM/height2 lower than 27 kg and 7.0 kg/m2, respectively. Ventilation (VE), oxygen consumption (VO2), and carbon dioxide output (VCO2) were evaluated using breath-by-breath measurements during a cardiopulmonary exercise test performed on a cycle ergometer. Oxygen uptake efficiency slope (OUES) was calculated from data taken at exercise peak. Results Sarcopenia was identified in 29 patients (17.2%). Patients with sarcopenia had lower body mass index (BMI; 21.2±2.4 vs. 26.5±3.8 kg/m2, p&amp;lt;0.0001) with higher C-reactive protein [CRP; 12.4 (2.8-22.4) vs. 2.4 (1.0-6.3) mg/L, p&amp;lt;0.001] and brain natriuretic peptide [BNP; 949 (446-1722) vs. 374 (127-885) pg/mL, p&amp;lt;0.001] compared to patients without sarcopenia, respectively. At the first ventilatory threshold, VE/VO2 (36.9±5.9 vs. 32.7±6.5, p=0.003) and VE/VCO2 (39.8±7.2 vs. 35.3±6.9, p=0.004) were higher in sarcopenic patients compared to those without sarcopenia. At the exercise peak, comparing to patients without sarcopenia, sarcopenic patients had lower OUES (1,186±295 vs. 1,634±564, p&amp;lt;0.001), absolute VO2 (0.93±0.25 vs. 1.43±0.47 L/min, p&amp;lt;0.0001), relative VO2 (16.2±5.0 vs. 19.5±6.5 ml/kg/min, p=0.011), and VE (47.3±10.1 vs. 63.0±18.2 L/min, p&amp;lt;0.001), while VE/VCO2 (42.9±8.9 vs. 38.7±8.4, p=0.025) was increased and VE/VO2 (49.6±11.5 vs. 45.1±10.8, p=0.066) showed a tendency to be higher. OUES was positively correlated with total lean body mass (r=0.38; p&amp;lt;0.0001), ASM/height2 (r=0.36; p&amp;lt;0.0001), and handgrip strength (r=0.31; p&amp;lt;0.001). In a multivariate logistic regression model using OUES as the dependent variable, ASM/height2 (OR, 1.466; 95% CI, 1.003–2.141; p=0.048), haemoglobin (OR, 0.346; 95% CI, 0.135–0.886; p=0.027), and creatinine (OR, 0.391; 95% CI, 0.166–0.918; p=0.031) were independently associated with OUES adjusted by age, BMI, LVEF, BNP, CRP, and beta-blocker use. Conclusion Our results suggest that sarcopenia, possibly by reducing thoracic skeletal muscle mass or inefficiently modulating ventilation through afferent pathways, is related to impaired ventilatory response during exercise in patients with HF.

Phox2b Mutation Mediated by Atoh1 Expression Impaired Respiratory Rhythm and Ventilatory Responses to Hypoxia and Hypercapnia

<i>Phox2b</i> Mutation Mediated by <i>Atoh1</i> Expression Impaired Respiratory Rhythm and Ventilatory Responses to Hypoxia and Hypercapnia

Exercise ventilatory reserve predicts survival in adult congenital heart disease associated pulmonary arterial hypertension with Eisenmenger physiology

Impaired ventilatory responses during exercise significantly contribute to breathlessness in patients with pulmonary arterial hypertension (PAH). Breathing reserve (BR) at peak exercise during cardiopulmonary exercise testing (CPET), a measure of the reserve in the ventilatory capacity, and as a PAH prognostic marker has not received wide attention. We assessed the prognostic value of a reduced BR (≤30% predicted) on survival in patients with two forms of PAH: congenital heart disease-associated PAH and Eisenmenger physiology (EIS) and idiopathic PAH (IPAH). Propensity score matched cohorts of 50 EIS and 50 IPAH patients who underwent CPET in our institution were included. Overall transplant-free survival at 5 and 10 years was assessed. Twenty-five (50.0%) EIS and 15 (33.3%) IPAH patients had a BR ​≤ ​30% at peak exercise (p ​= ​0.047). Independent predictors of a BR ​≤ ​30% across all patients included cardiothoracic ratio on chest radiograph (HR 2.2, 95% CI 1.6–3.0, p ​= ​0.01) and moderate to severe restriction on resting spirometry (HR 1.9, 95% CI 1.1–2.8, p ​= ​0.03). A BR ​≤ ​30% was associated with a significantly higher risk of mortality in the EIS group at 10 years follow-up (HR 3.4, 95% CI 1.1 to 11.4, p ​= ​0.045). Neither a BR ​≤ ​30% or >30% offered prognostic discrimination in IPAH. In summary, a BR >30% at peak exercise is associated with better survival in patients with EIS. Lung parenchymal restriction inferred from larger cardiothoracic ratios may contribute to reduced BR along with increased ventilatory drive.

Cardiorespiratory anomalies and increased brainstem microglia in a rat model of neonatal opioid withdrawal syndrome

Infants born with neonatal opioid withdrawal syndrome (NOWS) can display abnormal cardiorespiratory patterns including tachypnea, tachycardia, and impaired ventilatory responses to hypoxia (HVR) and hypercapnia (HCVR). Chronic morphine exposure is associated with increased midbrain microglial expression. Using a rat model of pre- and post-natal morphine exposure, we assessed cardiorespiratory features of NOWS (resting tachycardia and tachypnea) including the attenuated HVR and HCVR and whether they are associated with increased brainstem microglia expression. Pregnant rats (dams) received twice-daily subcutaneous injections of morphine (5 mg/kg) during the third (last) week of pregnancy to simulate 3rd trimester in utero opioid exposure. Offspring then received once-daily subcutaneous injections of morphine (0.5 mg/kg) until postnatal (P) day P10 days of age to simulate postnatal morphine therapy. Cardiorespiratory responses were assessed 24 h later (P11 days) following spontaneous withdrawal. Compared to saline-treated pups, morphine-exposed offspring exhibited tachycardia and tachypnea as well as an attenuated HVR and HCVR. Microglial cell counts were increased in the nucleus tractus solitarius (nTS), dorsal motor nucleus of the vagus (DMNV) and nucleus ambiguous (NAamb), but not the retrapezoid nucleus (RTN) or the non-cardiorespriatory region, the cuneate nucleus (CN). These data suggest that the cardiorespiratory features and autonomic dysregulation in NOWS infants may be associated with altered microglial function in specific brainstem cardiorespiratory control regions.

Increased brainstem microglia is associated with an attenuated hypercarbic ventilatory response in a rat model of neonatal opioid withdrawal syndrome

Background Infants born with neonatal opioid withdrawal syndrome (NOWS) display abnormal respiratory patterns including tachypnea, apnea and impaired ventilatory responses to hypoxia and hypercarbia challenges. Infants with NOWS are also at an increased risk of sudden infant death syndrome (SIDS), which is associated with impairments in respiratory control and increased gliosis in key brainstem respiratory control regions including the nucleus tractus solitarius (nTS). Objective Use a rat model of neonatal opioid withdrawal syndrome to assess whether pre- and postnatal morphine exposure attenuates the ventilatory responses to hypoxia and hypercarbia challenges in the offspring and whether they are associated with increased nTS microglia expression. Design/Methods Pregnant female rats (dams) received twice-daily subcutaneous injections of morphine (5mg/kg) during the third (last) week of pregnancy to simulate 3rd trimester in utero opioid exposure. After birth, the pups received once-daily subcutaneous injections of morphine (1mg/kg), through postnatal day 10 to simulate postnatal morphine therapy. Whole-body plethysmography was used precisely 24 hours later to assess ventilatory defense responses to acute hypoxia (HVR) and hypercapnia (HCVR) challenge (5 minutes at 10% O2 and 5% CO2, respectively). Brainstems were removed to assess nTS microglia expression using immunohistochemistry and a glial (Iba-1) marker. Results Compared to saline-treated pups, morphine exposure attenuated the HCVR, but not the HVR (Fig. 1A). Morphine-exposed offspring also expressed increased number of microglia in the nTS (Fig. 1B). Conclusion The disturbances in neonatal hypercarbia challenge are associated with increased brainstem microglia expression, which could contribute to the etiology underlying the increased risk of SIDS in infants with NOWS.

Disordered Leptin signaling in the retrotrapezoid nucleus is associated with the impaired hypercapnic ventilatory response in obesity

Sleep-disordered breathing is characterized by disruptions of normal breathing patterns during sleep. Obesity is closely related to hypoventilation or apnea and becomes a primary risk factor for sleep-disordered breathing. Leptin, a peptide secreted by adipose tissue, has been implicated in central control of breathing. Activation of the retrotrapezoid nucleus (RTN) neurons, a critical central respiratory chemoreceptor candidate, potentiates a central drive to breathing. Here, we ask whether the disordered leptin signaling in the RTN is responsible for obesity-related hypoventilation. In a diet induced obesity (DIO) mouse model, the hypercapnic ventilatory response (HCVR) was assessed and the cellular leptin signaling in the RTN was examined. Our main findings demonstrate that DIO mice exhibit overweight, hypercapnia, high levels of serum and cerebrospinal leptin. During exposure to room air, DIO mice manifest basal hypoventilation with a rapid and shallow breathing pattern. Exposure to CO2 elicits the impaired HCVR in DIO mice. In addition, both the number of CO2-activated neurons and expression of TASK-2 channels in the RTN are dramatically reduced in DIO mice. Moreover, there is leptin signaling disorder in RTN neurons in DIO mice, including a significant decrease in leptin-activated RTN neurons, downregulation of phosphorylated STAT3 and upregulation of SOCS3. Altogether, we suggest that the disordered leptin/STAT3/SOCS3 signaling pathway in the RTN plays a role in obesity-related hypoventilation.

Respiratory Control by Phox2b-expressing Neurons in a Locus Coeruleus-preBötzinger Complex Circuit.

The locus coeruleus (LC) has been implicated in the control of breathing. Congenital central hypoventilation syndrome results from mutation of the paired-like homeobox 2b (Phox2b) gene that is expressed in LC neurons. The present study was designed to address whether stimulation of Phox2b-expressing LC (Phox2bLC) neurons affects breathing and to reveal the putative circuit mechanism. A Cre-dependent viral vector encoding a Gq-coupled human M3 muscarinic receptor (hM3Dq) was delivered into the LC of Phox2b-Cre mice. The hM3Dq-transduced neurons were pharmacologically activated while respiratory function was measured by plethysmography. We demonstrated that selective stimulation of Phox2bLC neurons significantly increased basal ventilation in conscious mice. Genetic ablation of these neurons markedly impaired hypercapnic ventilatory responses. Moreover, stimulation of Phox2bLC neurons enhanced the activity of preBötzinger complex neurons. Finally, axons of Phox2bLC neurons projected to the preBötzinger complex. Collectively, Phox2bLC neurons contribute to the control of breathing most likely via an LC-preBötzinger complex circuit.

Role of melanocortin 4 receptor in hypertension induced by chronic intermittent hypoxia.

We previously demonstrated that central nervous system (CNS) melanocortin 4 receptors (MC4R) play a key role in regulating blood pressure (BP) in some conditions associated with increased SNS activity, including obesity. In this study, we examined whether activation of CNS MC4R contributes to chronic intermittent hypoxia (CIH)-induced hypertension and ventilatory responses to hypercapnia. Rats were instrumented with an intracerebroventricular (ICV) cannula in the lateral cerebral ventricle for continuous infusion of MC4R antagonist (SHU-9119) and telemetry probes for measuring mean arterial pressure (MAP) and heart rate (HR). Untreated and SHU-9119-treated rats as well as obese and lean MC4R-deficient rats were exposed to CIH for 7-18 consecutive days. Chronic intermittent hypoxia reduced cumulative food intake by 18±5g while MAP and HR increased by 10±3mmHg and 9±5bpm in untreated rats. SHU-9119 increased food intake (from 15±1 to 46±3g) and prevented CIH-induced reduction in food intake. CIH-induced hypertension was not attenuated by MC4R antagonism (average increase of 10±1 vs 9±1mmHg for untreated and SHU-9119 treated rats). In obese MC4R-deficient rats, CIH for 7days raised BP by 11±4mmHg. However, when MC4R-deficient rats were food restricted to prevent obesity, CIH-induced hypertension was attenuated by 32%. We also found that MC4R deficiency was associated with impaired ventilatory responses to hypercapnia independently of obesity. These results show that obesity and the CNS melanocortin system interact in complex ways to elevate BP during CIH and that MC4R may be important in the ventilatory responses to hypercapnia.

Antioxidant treatment for impaired hypoxic ventilatory responses in experimental diabetes in the rat

Inflammation, tissue hypoxia, and impaired hypoxic ventilatory response (HVR) are the intricately entwined features of diabetes which perpetuate the disease and its sequelae. Hyperglycemia, notably, is an oxygen consuming process due to enhanced cellular metabolism. Oxidative stress underlies diabetic pathogenesis and also is a crucial modulator of the hypoxic chemoreflex. The present study seeks to determine if suppressed ventilation in diabetes could be improved by antioxidant treatment. The study was performed in streptozotocin-induced diabetes in awake rats. Two weeks into full-fledged diabetes, the rats were divided into mangiferin (potent natural antioxidant)-treated and untreated, with the observation continued for another two weeks. The HVR was investigated plethysmographically and compared with the pre-diabetic baseline in the same animal. Thiobarbituric acid reactive substances, superoxide dismutase, and tumor necrosis factor-α were assayed in the serum. We demonstrate that mangiferin reversed the suppressed HVR and acted toward normalization of oxidative and inflammatory stress. In conclusion, mangiferin holds a therapeutic promise in breaking the mesh of chronic tissue hypoxia, inflammation, and oxidative stress in diabetes by enhancing ventilation.

Impaired hypoxic ventilatory response and related factors in Han and Uygur patients with obstructive sleep apnea-hypopnea syndrome

Objective: To investigate the respiratory central hypoxia response and its related factors in Han and Uygur patients with obstructive sleep apnea hypopnea syndrome (OSAHS). Methods: One hundred and sixty six OSAHS patients were selected from Jan. 2016 to Dec. 2016 in Department of Respiratory and Critical Care Medicine, Kelamayi Central Hospital, including 69 cases of Han nationality and 97 cases of Uygur nationality. Seventy-three healthy subjects of Uygur nationality were enrolled as the control group. All of them under went sleep monitoring, nocturnal oxygen saturation (SaO(2)), pulmonary function and respiratory central hypoxia response. Results: The 3 groups were matched for age, gender, body mass index(BMI) and apnea-hypopnea index(AHI). The Uygur patients had a higher oxygen desaturation index (ODI4) [(30±22) per hour vs (18±17) per hour ] than Han patients of the same age and BMI. Compared to Han patients, Uygur patients had weaker hypoxic responsiveness [(-0.41±0.23) L·min(-1)·%(-1) vs (-0.36±0.22) L·min(-1)·%(-1,) P<0.05], and the difference still existed after adjusting for AHI [(-0.31±0.21) L·min(-1)·%(-1) vs (-0.41±0.22) L·min(-1)·%(-1,) P<0.05] in mild OSAHS, but this difference was not significant in severe OSAHS. Conclusions: The central hypoxic response in Uygur OSAHS patients was lower than that in Han OSAHS patients and normal controls.

Ventilatory Responses During Submaximal Exercise in Children With Prader-Willi Syndrome.

Prader-Willi syndrome (PWS) is a genetic neurobehavioral disorder presenting hypothalamic dysfunction and adiposity. At rest, PWS exhibits hypoventilation with hypercapnia. We characterized ventilatory responses in children with PWS during exercise. Participants were children aged 7-12 years with PWS (n = 8) and without PWS with normal weight (NW; n = 9, body mass index ≤ 85th percentile) or obesity (n = 9, body mass index ≥ 95th percentile). Participants completed three 5-minute ambulatory bouts at 3.2, 4.0, and 4.8km/h. Oxygen uptake, carbon dioxide output, ventilation, breathing frequency, and tidal volume were recorded. PWS had slightly higher oxygen uptake (L/min) at 3.2km/h [0.65 (0.46-1.01) vs 0.49 (0.34-0.83)] and at 4.8km/h [0.89 (0.62-1.20) vs 0.63 (0.45-0.97)] than NW. PWS had higher ventilation (L/min) at 3.2km/h [16.2 (13.0-26.5) vs 11.5 (8.4-17.5)], at 4.0km/h [16.4 (13.9-27.9) vs 12.7 (10.3-19.5)], and at 4.8km/h [19.7 (17.4-31.8) vs 15.2 (9.5-21.6)] than NW. PWS had greater breathing frequency (breaths/min) at 3.2km/h [38 (29-53) vs 29 (22-35)], at 4.0km/h [39 (29-58) vs 29 (23-39)], and at 4.8km/h [39 (33-58) vs 32 (23-42)], but similar tidal volume and ventilation/carbon dioxide output to NW. PWS did not show impaired ventilatory responses to exercise. Hyperventilation in PWS may relate to excessive neural stimulation and metabolic cost.

Chemosensitive Phox2b‐expressing neurons are crucial for hypercapnic ventilatory response in the nucleus tractus solitarius

Central hypercapnic hypoventilation is highly prevalent in children suffering from congenital central hypoventilation syndrome (CCHS). Mutations of the gene for paired-like homeobox 2b (Phox2b) are aetiologically associated with CCHS and Phox2b is present in central components of respiratory chemoreflex, such as the nucleus tractus solitarius (NTS). Injection of the neurotoxin substance P-saporin into NTS destroys Phox2b-expressing neurons. Impaired hypercapnic ventilatory response caused by this neurotoxin is attributable to a loss of CO2 -sensitive Phox2b-expressing NTS neurons. A subgroup of Phox2b-expressing neurons exhibits intrinsic chemosensitivity. A background K+ channel-like current is partially responsible for such chemosensitivity in Phox2b-expressing neurons. The present study helps us better understand the mechanism of respiratory deficits in CCHS and potentially locates a brainstem site for development of precise clinical intervention. The nucleus tractus solitarius (NTS) neurons have been considered to function as central respiratory chemoreceptors. However, the common molecular marker defined for these neurons remains unknown. The present study investigated whether paired-like homeobox 2b (Phox2b)-expressing NTS neurons are recruited in hypercapnic ventilatory response (HCVR) and whether these neurons exhibit intrinsic chemosensitivity. HCVR was assessed using whole body plethysmography and neuronal chemosensitivity was examined by patch clamp recordings in brainstem slices or dissociated neurons from Phox2b-EGFP transgenic mice. Injection of the neurotoxin substance P-saporin (SSP-SAP) into NTS destroyed Phox2b-expressing neurons. Minute ventilation and tidal volume were both reduced by 13% during exposure to 8% CO2 in inspired air when ∼13% of the Phox2b-expressing neurons were eliminated. However, a loss of ∼18% of these neurons was associated with considerable decreases in minute ventilation by ≥18% and in tidal volume by≥22% when challenged by ≥4% CO2 . In both cases, breathing frequency was unaffected. Most CO2 -activated neurons were immunoreactive to Phox2b. In brainstem slices, ∼43% of Phox2b-expressing neurons from Phox2b-EGFP mice displayed a sustained or transient increase in firing rate during physiological acidification (pH7.0 or 8% CO2 ). Such a response was also present in dissociated neurons in favour of an intrinsic property. In voltage clamp recordings, a background K+ channel-like current was found in a subgroup of Phox2b-expressing neurons. Thus, the respiratory deficits caused by injection of SSP-SAP into the NTS are attributable to proportional lesions of CO2 /H+ -sensitive Phox2b-expressing neurons.

Incidence of postoperative residual paralysis in a nigerian teaching hospital.

Postoperative residual paralysis (PORP) is a known risk factor after general anesthesia (GA) for critical respiratory events and increased postoperative morbidity. PORP is defined as a train-of-four ratio (TOFR) of <0.9 using acceleromyography (AMG). TOFR <0.9 has been associated with increased risk of aspiration, obstruction of the upper airway and an impaired hypoxic ventilatory response. The aim of this study was to determine the incidence of PORP, associated factors related with its occurrence and critical respiratory events in the postanesthesia recovery room (PAR) at our institution. Forty-one adult patients were scheduled for elective surgeries requiring GA with the use of at least 1 dose of a nondepolarizing neuromuscular blocking drug (NMBD). An independent anesthetist quantitatively measured TOFR of recruited patients postoperatively in the recovery room using the TOF-watch SX acceleromyograph (Organon Teknika) 5 min after arrival. The incidence of PORP was 75.6% (n = 31), with severe PORP (TOFR <0.7) seen in 41.5% (n = 17) of patients. Median time to full recovery in the PAR was 33 min (range 5-164 min). There was no statistical difference in the incidence of PORP related to the choice of NMBD (P = 0.186) or duration of surgery (P = 0.175). No respiratory complications or events were observed in patients with residual blockade. The incidence of PORP is quite high and undetected in our environment. Quantitative monitoring for residual paralysis is advocated as part of routine monitoring with the use of NMBDs for improved patient safety.

The research development of congenital central hypoventilation syndrome

Congenital central hypoventilation syndrome, also known as Ondine's curse , is characterized by hypoventilation during sleep and impaired ventilatory responses to hypercapnia and hypoxemia.This disorder is associated with a malfunction of the nerves that control involuntary body functions and abnormal development of early embryonic cells that form the spinal cord.This review summarized the latest progression in the pathogenesis, clinical symptoms, diagnosis, treatment and prognosis. Key words: Congenital central hypoventilation syndrome; Pathogenesis; Clinical symptoms; Diagnosis; Treatment; Prognosis