The effect of high-flow nasal oxygen flow rate on gas exchange in apnoeic patients: a randomised controlled trial.

High-flow nasal oxygen can be administered at induction of anaesthesia for the purposes of pre-oxygenation and apnoeic oxygenation. This intervention is claimed to enhance carbon dioxide elimination during apnoea, but the extent to which this occurs remains poorly quantified. The optimal nasal oxygen flow rate for gas exchange is also unknown. In this study, 114 patients received pre-oxygenation with high-flow nasal oxygen at 50 l.min-1. At the onset of apnoea, patients were allocated randomly to receive one of three nasal oxygen flow rates: 0 l.min-1; 70 l.min-1; or 120 l.min-1. After 4 minutes of apnoea, all oxygen delivery was ceased, tracheal intubation was performed, and oxygen delivery was recommenced when SpO2 was 92%. Mean (SD) PaCO2 rise during the first minute of apnoea was 1.39 (0.39) kPa, 1.41 (0.29) kPa, and 1.26 (0.38) kPa in the 0 l.min-1, 70 l.min-1 and 120 l.min-1 groups, respectively; p = 0.16. During the second, third and fourth minutes of apnoea, mean (SD) rates of rise in PaCO2 were 0.34 (0.08) kPa.min-1, 0.36 (0.06) kPa.min-1 and 0.37 (0.07) kPa.min-1 in the 0 l.min-1, 70 l.min-1 and 120 l.min-1 groups, respectively; p = 0.17. After 4 minutes of apnoea, median (IQR [range]) arterial oxygen partial pressures in the 0 l.min-1, 70 l.min-1 and 120 l.min-1 groups were 24.5 (18.6-31.4 [12.3-48.3]) kPa; 36.6 (28.1-43.8 [9.8-56.9]) kPa; and 37.6 (26.5-45.4 [11.0-56.6]) kPa, respectively; p < 0.001. Median (IQR [range]) times to desaturate to 92% after the onset of apnoea in the 0 l.min-1, 70 l.min-1 and 120 l.min-1 groups, were 412 (347-509 [190-796]) s; 533 (467-641 [192-958]) s; and 531 (462-681 [326-1007]) s, respectively; p < 0.001. In conclusion, the rate of carbon dioxide accumulation in arterial blood did not differ significantly between apnoeic patients who received high-flow nasal oxygen and those who did not.

Alteration of monoaminergic systems in the caudal medulla and its possible link to diurnal increase of apnea in a mouse model of Rett syndrome.

PURPOSE: Methyl-CpG binding protein 2 (MeCP2)-deficient (Mecp2-/y) mice exhibit apneas that resemble respiratory abnormalities observed in Rett syndrome (RTT) patients. The present study aimed to clarify whether Mecp2-/y mice show diurnal variations in apnea as seen in RTT and how the MeCP2 deficiency affects monoaminergic systems that control breathing. METHODS: In 7-week-old Mecp2-/y mice, 24 h variation of apnea and effects of milnacipran, a serotonin/noradrenaline reuptake inhibitor, on the apnea were evaluated. The number of vesicular monoamine transporter 2 (VMAT2)-immunoreactive puncta in the caudal medulla was counted. Further, the effects of valproate (VPA) on the expression of tyrosine hydroxylase (TH) mRNA in the ventrolateral medulla of mice were assessed by RT-qPCR. RESULTS: Apnea occurred more frequently during the light phase under a 12:12 h light/dark environment in Mecp2-/y mice and milnacipran reduced apnea during the light phase but not during the dark phase. The number of VMAT2-immunoreactive puncta was reduced in Mecp2-/y mice. VPA treatment significantly increased TH mRNA expression in Mecp2-/y mice. CONCLUSION: Alteration of monoaminergic systems in the caudal medulla of Mecp2-/y mice is potentially relevant to the light-sensitive diurnal increase of apnea, and an improvement in monoaminergic neurotransmission can ameliorate the diurnal increase of apnea in Mecp2-/y mice.

Expression of p11 and TASK1 Channels in Rat Carotid Body Glomus Cells Subjected to Chronic Intermittent Hypoxia.

Chronic intermittent hypoxia (CIH) has been used as a model to mimic nocturnal apnea, which is associated with hypertension. One of the mechanisms for hypertension in patients with nocturnal apnea is an enhancement of the plasma membrane response to acute hypoxia in carotid body glomus cells. Hypoxia is known to induce depolarization via inhibiting TWIK-related acid-sensitive K+ (TASK) channels, one type of leak K+ channels, in glomus cells. The present experiment was undertaken to immunocytochemically investigate the effects of CIH on the expression and intracellular localization of TASK1 channels and p11 that critically affect the trafficking of TASK1 to the cell surface. The expression levels of TASK1 proteins and p11 and their intracellular localization in rat carotid body glomus cells were not noticeably affected by CIH, suggesting that the enhanced membrane response to acute hypoxia is not due to an increase in surface TASK channels.

Hypoxemia increases blood-brain barrier permeability during extreme apnea in humans.

Voluntary asphyxia imposed by static apnea challenges blood-brain barrier (BBB) integrity in humans through transient extremes of hypertension, hypoxemia and hypercapnia. In the present study, ten ultra-elite breath-hold divers performed two maximal dry apneas preceded by normoxic normoventilation (NX: severe hypoxemia and hypercapnia) and hyperoxic hyperventilation (HX: absence of hypoxemia with exacerbating hypercapnia) with measurements obtained before and immediately after apnea. Transcerebral exchange of NVU proteins (ELISA, Single Molecule Array) were calculated as the product of global cerebral blood flow (gCBF, duplex ultrasound) and radial arterial to internal jugular venous concentration gradients. Apnea duration increased from 5 m 6 s in NX to 15 m 59 s in HX (P = <0.001) resulting in marked elevations in gCBF and venous S100B, glial fibrillary acidic protein, ubiquitin carboxy-terminal hydrolase-L1 and total tau (all P < 0.05 vs. baseline). This culminated in net cerebral output reflecting mildly increased BBB permeability and increased neuronal-gliovascular reactivity that was more pronounced in NX due to more severe systemic and intracranial hypertension (P < 0.05 vs. HX). These findings identify the hemodynamic stress to which the apneic brain is exposed, highlighting the critical contribution of hypoxemia and not just hypercapnia to BBB disruption.

Changes in hormones after apneic hypoxia/hypercapnia - An investigation in voluntary apnea divers.

BACKGROUND: Prolonged apnea is characterized by hypoxia/hypercapnia. Hypoxia can be associated with hormonal dysfunction. We raised the question as to whether steroid hormonal and gonadotropin levels could be influenced by short-term hypoxia/hypercapnia in a model of dry apnea in trained apnea divers. METHODS: Adrenal, sex steroid and pituitary hormones were measured in ten trained voluntary apnea divers before, immediately after, 0.5 h and 4 h after a maximal breath-hold. Apnea was carried out under dry conditions. RESULTS: Corticosterone, progesterone, cortisol, 17-OH-progesterone, dehydroepiandrosterone and androstenedione showed a significant continuous increase with a maximum at 0.5 h after apnea, followed by a decrease back to or below baseline at 4 h after apnea. Testosterone, estradiol, cortisone and dihydrotestosterone showed a decrease 4 h after apnea. Dehydroepiandrosteronesulfate, luteinizing hormone (LH) and follicle stimulating hormone (FSH) showed no significant changes. CONCLUSION: Even a single apnea resulted in two different patterns of hormone response to apnea, with increased adrenal and reduced sex steroid levels, while LH/FSH showed no clear kinetic reaction. Apnea divers might be a suitable clinical model for hypoxic disease.

The effect of transnasal humidified rapid-insufflation ventilator exchange (THRIVE) versus nasal prongs on safe apnoea time in paralysed obese patients: a randomised controlled trial.

BACKGROUND: Evidence is lacking regarding the efficacy of Optiflow transnasal humidified rapid-insufflation ventilator exchange (THRIVE™) in obese patients. We compared the impact of this technique at 70 L min-1 with 4 L min-1 oxygen via nasal prongs on safe apnoea times of paralysed obese patients. METHODS: We randomised adults with a BMI >35 kg m-2 undergoing elective bariatric surgery. While apnoeic and paralysed, Group T received 70 L min-1 oxygen via Optiflow THRIVE™. Group N received nasal prong oxygen at 4 L min-1. The primary outcome was time to SpO2 ≤95% while apnoeic, with a 360 s cut-off. This was analysed by applying a time-to-event analysis. RESULTS: Forty-two patients were included. The median (inter-quartile range) BMI was 44.8 kg m-2 (40.0-50.0) in Group T and 42.0 kg m-2 (39.3-45.1) in Group N. Median (inter-quartile range) time to SpO2 ≤95% in Group T was 356 (165 to ≥360) s and in Group N, 210 (160-270) s. Using a survival analysis framework, median time-to-event in Group T was 356 s (95% confidence interval 165 s-upper limit not defined) and 210 s (95% confidence interval 160-242 s) (P=0.049) in Group N. CONCLUSIONS: Compared with oxygen delivered via nasal prongs at 4 L min-1, oxygen delivery via Optiflow THRIVE™ at a flow rate of 70 L min-1 can prolong safe apnoea time, however, the results are statistically inconclusive. Optiflow THRIVE™ did decrease the rate of reduction in Pao2 during apnoea. CLINICAL TRIAL REGISTRATION: ANZCTR 12618000445279.

Prediction of pharmacokinetic values of two various dosages of caffeine in premature neonates with apnea.

OBJECTIVES: Despite extensive caffeine use in preterm infants, the pharmacokinetics (PKs) data are limited because of the studies are complicated to do in these patients. This research was investigated the PK profile of two various dosages of caffeine in premature neonates. MATERIALS AND METHODS: The PK values of caffeine in premature neonates with Apnea were predicted by using all of computer-based simulation (Simcyp®), population-based PK, and modeling (P-Pharm®). We assayed the plasma levels of caffeine in two groups. The information was analyzed utilizing nonlinear mixed-effects modeling approach. The PK parameters were assessed simulating virtual clinical considers with subjects got 20 mg. kg-1 of caffeine in both groups, which was followed by a 5 mg. kg-1 once daily in Group 1 or 2.5 mg. kg-1 twice daily in Group 2. All statistical analysis was executed utilizing SSPS issue 19 and a P value of 0.05 was chosen significance. RESULTS: In the present study, the means CL, volume of distribution, and T1/2 of caffeine in preterm infants were 0.0476 L. h-1, 1.1081 L, 16.2284 h, respectively. Whereas our simulated means by Simcyp were 0.090 L. h-1, 1.841 L, and 14.653 h in Group 1 and 16.223 h in Group 2, respectively. CONCLUSIONS: There was overall good agreement between predicted and measured PK values in our study. This study provides an initial demonstration of Simcyp simulation advantage on anticipating of PK parameters.

Five repeated maximal efforts of apneas increase the time to exhaustion in subsequent high-intensity exercise.

Ten subjects were tested on a cycle ergometer to exhaustion with intensity corresponding to 150 % of their peak power output (TF150) under three conditions [C: base line measurement; PRE: after five repeated breath hold maneuvers (BH); and POST: after 5BH, preceded by two weeks of BH training]. Respiratory and blood measurements were carried out. Upon cessation of 5BH, subjects compared to C condition started TF150 with reduced arterialized blood pH (C:7.428±0.023, PRE:7.419±0.016, POST:7.398±0.021) and elevated bicarbonate concentration (mmol/l), ventilation (l/min) and oxygen uptake (ml/min) (C:28.4±1.5, PRE:29.9±1.2, POST:30.0±1.8; C:10.4±2.5, PRE:13.3±3.3, POST:15.6±5.6; C:333.0±113.8, PRE:550.1±131.1, POST:585.1±192.8, respectively). After TF150, subjects had significantly reduced pH and elevated ventilation, and oxygen uptake in PRE and POST, in comparison to the C condition. TF150 (sec) significantly improved after 5BH without being further affected by BH training (C:44.8±8.1, PRE:49.2±4.8, POST:49.3±8.2). Priming breath holds prior to middle-distance racing may improve performance.

The role of NADPH oxidase in chronic intermittent hypoxia-induced respiratory plasticity in adult male mice.

Reactive oxygen species (ROS) are proposed as mediators of chronic intermittent hypoxia (CIH)-induced respiratory plasticity. We sought to determine if NADPH oxidase 2 (NOX2)-derived ROS underpin CIH-induced maladaptive changes in respiratory control. Adult male mice (C57BL/6 J) were assigned to one of three groups: normoxic controls (sham); chronic intermittent hypoxia-exposed (CIH, 12 cycles/hour, 8 h/day for 14 days); and CIH + apocynin (NOX2 inhibitor, 2 mM) given in the drinking water throughout exposure to CIH. In addition, we studied sham and CIH-exposed NOX2-null mice (B6.129S-CybbTM1Din/J). Whole-body plethysmography was used to measure breathing and metabolic parameters. Ventilation (V̇I/V̇CO2) during normoxia was unaffected by CIH, but apnoea index was increased, which was prevented by apocynin, but not by NOX2 deletion. The ventilatory response to hypercapnia following exposure to CIH was potentiated in NOX2-null mice. Our results reveal ROS-dependent influences on the control of breathing and point to antioxidant intervention as a potential adjunctive therapeutic strategy in respiratory control disorders.

Effect of variable pre-oxygenation endpoints on safe apnoea time using high flow nasal oxygen for women in labour: a modelling investigation.

BACKGROUND: Studies of pulmonary denitrogenation (pre-oxygenation) in obstetric populations have shown high flow nasal oxygen therapy (HFNO) is inferior to facemask techniques. HFNO achieves median end-tidal oxygen fraction (FE'O2) of 0.87 after 3 min. As HFNO prolongs safe apnoea times through apnoeic oxygenation, we postulated that HFNO would still extend safe apnoeic times despite the lower FE'O2 after pre-oxygenation. METHODS: The Interdisciplinary Collaboration in Systems Medicine simulation suite, a highly integrated, high-fidelity model of the human respiratory and cardiovascular systems, was used to study the effect of varying FE'O2 (60%, 70%, 80%, and 90%) on the duration of safe apnoea times using HFNO and facemask techniques (with the airway open and obstructed). The study population consisted of validated models of pregnant women in active labour and not in labour with BMI of 24, 35, 40, 45, and 50 kg m-2. RESULTS: HFNO provided longer safe apnoeic times in all models, with all FE'O2 values. Labour and increased BMI reduced this effect, in particular a BMI of 50 kg m-2 reduced the improvement in apnoea time to 1.8-8.5 min (depending on the FE'O2), compared with an improvement of more than 60 min in the subject with BMI 24 kg m-2. CONCLUSIONS: Despite generating lower FE'O2, HFNO provides longer safe apnoea times in pregnant subjects in labour. Care should be taken when used in patients with BMI ≥50 kg m-2 as the extension of the safe apnoea time is limited.

Cardiac hypoxic resistance and decreasing lactate during maximum apnea in elite breath hold divers.

Breath-hold divers (BHD) enduring apnea for more than 4 min are characterized by resistance to release of reactive oxygen species, reduced sensitivity to hypoxia, and low mitochondrial oxygen consumption in their skeletal muscles similar to northern elephant seals. The muscles and myocardium of harbor seals also exhibit metabolic adaptations including increased cardiac lactate-dehydrogenase-activity, exceeding their hypoxic limit. We hypothesized that the myocardium of BHD possesses similar adaptive mechanisms. During maximum apnea 15O-H2O-PET/CT (n = 6) revealed no myocardial perfusion deficits but increased myocardial blood flow (MBF). Cardiac MRI determined blood oxygen level dependence oxygenation (n = 8) after 4 min of apnea was unaltered compared to rest, whereas cine-MRI demonstrated increased left ventricular wall thickness (LVWT). Arterial blood gases were collected after warm-up and maximum apnea in a pool. At the end of the maximum pool apnea (5 min), arterial saturation decreased to 52%, and lactate decreased 20%. Our findings contrast with previous MR studies of BHD, that reported elevated cardiac troponins and decreased myocardial perfusion after 4 min of apnea. In conclusion, we demonstrated for the first time with 15O-H2O-PET/CT and MRI in elite BHD during maximum apnea, that MBF and LVWT increases while lactate decreases, indicating anaerobic/fat-based cardiac-metabolism similar to diving mammals.

Ablation of Zfhx4 results in early postnatal lethality by disrupting the respiratory center in mice.

Breathing is an integrated motor behavior that is driven and controlled by a network of brainstem neurons. Zfhx4 is a zinc finger transcription factor and our results showed that it was specifically expressed in several regions of the mouse brainstem. Mice lacking Zfhx4 died shortly after birth from an apparent inability to initiate respiration. We also found that the electrical rhythm of brainstem‒spinal cord preparations was significantly depressed in Zfhx4-null mice compared to wild-type mice. Immunofluorescence staining revealed that Zfhx4 was coexpressed with Phox2b and Math1 in the brainstem and that Zfhx4 ablation greatly decreased the expression of these proteins, especially in the retrotrapezoid nucleus. Combined ChIP‒seq and mRNA expression microarray analysis identified Phox2b as the direct downstream target gene of Zfhx4, and this finding was validated by ChIP‒qPCR. Previous studies have reported that both Phox2b and Math1 play key roles in the development of the respiratory center, and Phox2b and Math1 knockout mice are neonatal lethal due to severe central apnea. On top of this, our study revealed that Zfhx4 is a critical regulator of Phox2b expression and essential for perinatal breathing.

A brainstem peptide system activated at birth protects postnatal breathing.

Among numerous challenges encountered at the beginning of extrauterine life, the most celebrated is the first breath that initiates a life-sustaining motor activity1. The neural systems that regulate breathing are fragile early in development, and it is not clear how they adjust to support breathing at birth. Here we identify a neuropeptide system that becomes activated immediately after birth and supports breathing. Mice that lack PACAP selectively in neurons of the retrotrapezoid nucleus (RTN) displayed increased apnoeas and blunted CO2-stimulated breathing; re-expression of PACAP in RTN neurons corrected these breathing deficits. Deletion of the PACAP receptor PAC1 from the pre-Bötzinger complex-an RTN target region responsible for generating the respiratory rhythm-phenocopied the breathing deficits observed after RTN deletion of PACAP, and suppressed PACAP-evoked respiratory stimulation in the pre-Bötzinger complex. Notably, a postnatal burst of PACAP expression occurred in RTN neurons precisely at the time of birth, coinciding with exposure to the external environment. Neonatal mice with deletion of PACAP in RTN neurons displayed increased apnoeas that were further exacerbated by changes in ambient temperature. Our findings demonstrate that well-timed PACAP expression by RTN neurons provides an important supplementary respiratory drive immediately after birth and reveal key molecular components of a peptidergic neural circuit that supports breathing at a particularly vulnerable period in life.

Six weeks of dynamic apnoeic training stimulates erythropoiesis but does not increase splenic volume.

PURPOSE: This study examined the influence of dynamic apnoea training on splenic volume and haematological responses in non-breath-hold divers (BHD). METHODS: Eight non-BHD performed ten maximal dynamic apnoeas, four times a week for  six weeks. Splenic volumes were assessed ultrasonically, and blood samples were drawn for full blood count analysis, erythropoietin, iron, ferritin, albumin, protein and osmolality at baseline, 24 h post the completion of each week's training sessions and seven days post the completion of the training programme. Additionally, blood samples were drawn for haematology at 30, 90, and 180 min post session one, twelve and twenty-four. RESULTS: Erythropoietin was only higher than baseline (6.62 ± 3.03 mlU/mL) post session one, at 90 (9.20 ± 1.88 mlU/mL, p = 0.048) and 180 min (9.04 ± 2.35 mlU/mL, p = 0.046). Iron increased from baseline (18 ± 3 µmol/L) post week five (23 ± 2 µmol/L, p = 0.033) and six (21 ± 6 µmol/L; p = 0.041), whereas ferritin was observed to be lower than baseline (111 ± 82 µg/L) post week five (95 ± 75 µg/L; p = 0.016), six (84 ± 74 µg/L; p = 0.012) and one week post-training (81 ± 63 µg/L; p = 0.008). Reticulocytes increased from baseline (57 ± 12 × 109/L) post week one (72 ± 17 × 109/L, p = 0.037) and six (71 ± 17 × 109/L, p = 0.021) while no changes were recorded in erythrocytes (p = 0.336), haemoglobin (p = 0.124) and splenic volumes (p = 0.357). CONCLUSIONS: Six weeks of dynamic apnoeic training increase reticulocytes without altering mature erythrocyte concentration and splenic volume.

Baroreflex responses during dry resting and exercise apnoeas in air and pure oxygen.

PURPOSE: We analysed the characteristics of arterial baroreflexes during the first phase of apnoea (φ1). METHODS: 12 divers performed rest and exercise (30 W) apnoeas (air and oxygen). We measured beat-by-beat R-to-R interval (RRi) and mean arterial pressure (MAP). Mean RRi and MAP values defined the operating point (OP) before (PRE-ss) and in the second phase (φ2) of apnoea. Baroreflex sensitivity (BRS, ms·mmHg-1) was calculated with the sequence method. RESULTS: In PRE-ss, BRS was (median [IQR]): at rest, 20.3 [10.0-28.6] in air and 18.8 [13.8-25.2] in O2; at exercise 9.2[8.4-13.2] in air and 10.1[8.4-13.6] in O2. In φ1, during MAP decrease, BRS was lower than in PRE-ss at rest (6.6 [5.3-11.4] in air and 7.7 [4.9-14.3] in O2, p < 0.05). At exercise, BRS in φ1 was 6.4 [3.9-13.1] in air and 6.7 [4.1-9.5] in O2. After attainment of minimum MAP (MAPmin), baroreflex resetting started. After attainment of minimum RRi, baroreflex sequences reappeared. In φ2, BRS at rest was 12.1 [9.6-16.2] in air, 12.9 [9.2-15.8] in O2. At exercise (no φ2 in air), it was 7.9 [5.4-10.7] in O2. In φ2, OP acts at higher MAP values. CONCLUSION: In apnoea φ1, there is a sudden correction of MAP fall via baroreflex. The lower BRS in the earliest φ1 suggests a possible parasympathetic mechanism underpinning this reduction. After MAPmin, baroreflex resets, displacing its OP at higher MAP level; thus, resetting may not be due to central command. After resetting, restoration of BRS suggests re-establishment of vagal drive.

Laryngeal Chemoreflex in Health and Disease: A Review.

The larynx plays a key role in airway protection via the laryngeal chemoreflex (LCR). This involuntary reflex can be evoked when hazardous substances activate mucosal receptors, which send signals to be processed within the brainstem. Although the LCR is meant to be protective, the reflex can become hyperstimulated, even to benign stimuli, which can result in pathological disorders, such as chronic cough and inducible laryngeal obstruction. In this review, we will outline the mechanism of the LCR and its associated pathological disorders.

Heat Shock Protein HSP70 in Oxidative Stress in Apnea Patients.

We studied the level of heat shock protein HSP70 under conditions of oxidative stress in 47 patients with apnea. The control group included 13 healthy subjects without verified apnea. Blood serum, plasma, and erythrocyte hemolysate were used to determine LPO and anti-oxidant protection components by spectrophotometrical and spectrofluorometrical methods. HSP70 was assayed by ELISA. A direct relationship was established between the intensity of oxidative stress and HSP70 expression in patients with apnea. Quantitative determination of HSP70 can be used as a molecular marker in the early diagnosis and prognosis of the development of various pathological conditions in hypoxia.

Prebiotic administration modulates gut microbiota and faecal short-chain fatty acid concentrations but does not prevent chronic intermittent hypoxia-induced apnoea and hypertension in adult rats.

BACKGROUND: Evidence is accruing to suggest that microbiota-gut-brain signalling plays a regulatory role in cardiorespiratory physiology. Chronic intermittent hypoxia (CIH), modelling human sleep apnoea, affects gut microbiota composition and elicits cardiorespiratory morbidity. We investigated if treatment with prebiotics ameliorates cardiorespiratory dysfunction in CIH-exposed rats. METHODS: Adult male rats were exposed to CIH (96 cycles/day, 6.0% O2 at nadir) for 14 consecutive days with and without prebiotic supplementation (fructo- and galacto-oligosaccharides) beginning two weeks prior to gas exposures. FINDINGS: CIH increased apnoea index and caused hypertension. CIH exposure had modest effects on the gut microbiota, decreasing the relative abundance of Lactobacilli species, but had no effect on microbial functional characteristics. Faecal short-chain fatty acid (SCFA) concentrations, plasma and brainstem pro-inflammatory cytokine concentrations and brainstem neurochemistry were unaffected by exposure to CIH. Prebiotic administration modulated gut microbiota composition and diversity, altering gut-metabolic (GMMs) and gut-brain (GBMs) modules and increased faecal acetic and propionic acid concentrations, but did not prevent adverse CIH-induced cardiorespiratory phenotypes. INTERPRETATION: CIH-induced cardiorespiratory dysfunction is not dependant upon changes in microbial functional characteristics and decreased faecal SCFA concentrations. Prebiotic-related modulation of microbial function and resultant increases in faecal SCFAs were not sufficient to prevent CIH-induced apnoea and hypertension in our model. Our results do not exclude the potential for microbiota-gut-brain axis involvement in OSA-related cardiorespiratory morbidity, but they demonstrate that in a relatively mild model of CIH, sufficient to evoke classic cardiorespiratory dysfunction, such changes are not obligatory for the development of morbidity, but may become relevant in the elaboration and maintenance of cardiorespiratory morbidity with progressive disease. FUNDING: Department of Physiology and APC Microbiome Ireland, University College Cork, Ireland. APC Microbiome Ireland is funded by Science Foundation Ireland, through the Government's National Development Plan.

Hold your breath: peripheral and cerebral oxygenation during dry static apnea.

PURPOSE: Acute breath-holding deprives the human body from oxygen. In an effort to protect the brain, the diving response is initiated, coupling several physiological responses. The aim of this study was to describe the physiological responses to apnea at the cardiac, peripheral and cerebral level. METHODS: 31 physically active subjects (17 male, 14 female, 23.3 ± 1.8 years old) performed a maximal static breath-hold in a seated position. Heart rate (HR), muscle and cerebral oxygenation (by means of near-infrared spectroscopy, NIRS) were continuously measured. RM MANOVA's were used to identify changes in HR, peripheral (mTOI) and cerebral (cTOI) tissue oxygenation and oxygenated (O2Hb) and deoxygenated (HHb) hemoglobin during apnea. RESULTS: Average apnea duration was 157 ± 41 s. HR started decreasing after 10 s (p < 0.001) and dropped on average by 27 ± 14 bpm from baseline (p < 0.001). mTOI started decreasing 10 s after apnea (p < 0.001) and fell by 8.6 ± 4.0% (p < 0.001). Following an immediate drop after 5 s (p < 0.001), cTOI increased continuously, reaching a maximal increase of 3.7 ± 2.4% followed by a steady decrease until the end of apnea. cTOI fell on average 5.4 ± 8.3% below baseline (p < 0.001). CONCLUSION: During apnea, the human body elicits several protective mechanisms to protect itself against the deprivation of oxygen. HR slows down, decreasing O2 demand of the cardiac muscle. The decrease in mTOI and increase in cTOI imply a redistribution of blood flow prioritizing the brain. However, this mechanism is not sufficient to maintain cTOI until the end of apnea.

Liquiritin apioside attenuates laryngeal chemoreflex but not mechanoreflex in rat pups.

Liquiritin apioside (LA), a main flavonoid component of licorice, reportedly suppresses cough responses to inhalation of aerosolized capsaicin [CAP; a stimulant to transient receptor potential vanilloid 1 (TRPV1)] in conscious guinea pigs via acting on peripheral nerves. However, the evidence of LA having a direct effect on airway sensory fibers is lacking. Considering the important role laryngeal chemoreceptors and mechanoreceptors play in triggering apnea and cough, we studied whether LA suppressed the apneic responses to stimulation of these receptors via directly acting on the superior laryngeal nerve (SLN). Intralaryngeal delivery of chemical [CAP, HCl, and distilled water (DW)] and mechanical [an air-pulse (AP)] stimulations was applied in anesthetized rat pups to evoke the apnea. These stimuli were repeated after intralaryngeal LA treatment or peri-SLN LA treatment to determine the direct effect of LA on the SLN. Our results showed that all stimuli triggered an immediate apnea. Intralaryngeal LA treatment significantly attenuated the apneic response to chemical but not mechanical stimulations. The same attenuation was observed after peri-SLN LA treatment. Owing that TRPV1 receptors of laryngeal C fibers are responsible for the CAP-triggered apneas, the LA impact on the activity of laryngeal C neurons retrogradely traced by DiI was subsequently studied using a patch-clamp approach. LA pretreatment significantly altered the electrophysiological kinetics of CAP-induced currents in laryngeal C neurons by reducing their amplitudes, increasing the rise times, and prolonging the decay times. In conclusion, our results, for the first time, reveal that LA suppresses the laryngeal chemoreceptor-mediated apnea by directly acting on the SLN (TRPV1 receptors of laryngeal C fibers).