Impact of Serotonergic 5HT1A and 5HT2A Receptor Activation on the Respiratory Response to Hypercapnia in a Rat Model of Parkinson's Disease.

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

Older adults with reduced cerebrovascular reactivity exhibit high white matter hyperintensity burden.

Cerebrovascular reactivity (CVR) deficits may contribute to small vessel disease, such as white matter hyperintensities (WMH). Moreover, apolipoprotein-e4 (APOE4) carriers at genetic risk for Alzheimer's disease exhibit cerebrovascular dysfunction relative to non-carriers. We examined whether older adults, and APOE4 carriers specifically, with diminished CVR would exhibit higher WMH burden. Independently living older adults (N = 125, mean age = 69.2 years; SD = 7.6; 31.2% male) free of dementia or clinical stroke underwent brain MRI to quantify cerebral perfusion during CVR to hypercapnia and hypocapnia and determine WMH volume. Adjusting for age, sex and intracranial volume, hierarchical regression analysis revealed a significant association between whole brain CVR to hypercapnia and WMH overall [B = -.02, 95% CI (-.04, -.008), p =.003] and in APOE4 carriers [B = -.03, 95% CI (-.06, -.009), p =.009]. Findings suggest deficits in cerebral vasodilatory capacity are associated with WMH burden in older adults and future studies are warranted to further delineate the effect of APOE4 on precipitating WMH.

Tidal expiratory flow limitation during exercise is unrelated to peripheral hypercapnic chemosensitivity.

We sought to determine if peripheral hypercapnic chemosensitivity is related to expiratory flow limitation (EFL) during exercise. Twenty participants completed one testing day which consisted of peripheral hypercapnic chemosensitivity testing and a maximal exercise test to exhaustion. The chemosensitivity testing consisting of two breaths of 10% CO2 (O2∼21%) repeated 5 times during seated rest and the first 2 exercise intensities during the maximal exercise test. Following chemosensitivity testing, participants continued cycling with the intensity increasing 20 W every 1.5 minutes till exhaustion. Maximal expiratory flow-volume curves were derived from forced expiratory capacity maneuvers performed before and after exercise at varying efforts. Inspiratory capacity maneuvers were performed during each exercise stage to determine EFL. There was no difference between the EFL and non-EFL hypercapnic chemoresponse (mean response during exercise 0.96 ± 0.46 and 0.91 ± 0.33 l min-1 mmHg-1, p=0.783). Peripheral hypercapnic chemosensitivity during mild exercise does not appear to be related to the development of EFL during exercise.

Microglia modulate blood flow, neurovascular coupling, and hypoperfusion via purinergic actions.

Microglia, the main immunocompetent cells of the brain, regulate neuronal function, but their contribution to cerebral blood flow (CBF) regulation has remained elusive. Here, we identify microglia as important modulators of CBF both under physiological conditions and during hypoperfusion. Microglia establish direct, dynamic purinergic contacts with cells in the neurovascular unit that shape CBF in both mice and humans. Surprisingly, the absence of microglia or blockade of microglial P2Y12 receptor (P2Y12R) substantially impairs neurovascular coupling in mice, which is reiterated by chemogenetically induced microglial dysfunction associated with impaired ATP sensitivity. Hypercapnia induces rapid microglial calcium changes, P2Y12R-mediated formation of perivascular phylopodia, and microglial adenosine production, while depletion of microglia reduces brain pH and impairs hypercapnia-induced vasodilation. Microglial actions modulate vascular cyclic GMP levels but are partially independent of nitric oxide. Finally, microglial dysfunction markedly impairs P2Y12R-mediated cerebrovascular adaptation to common carotid artery occlusion resulting in hypoperfusion. Thus, our data reveal a previously unrecognized role for microglia in CBF regulation, with broad implications for common neurological diseases.

Clinical characterization and possible pathophysiological causes of the Deventilation Syndrome in COPD.

In daily routine, many COPD patients report early onset augmented dyspnea following use of NIV (Deventilation Syndrome, DVS) as a negative side-effect. The aim of this study is the clinical characterization and concrete definition of DVS. This monocenter prospective observational study collected demographic, physiologic and symptomatic data from 67 in-patients with severe COPD Gold III-IV and chronic hypercapnic failure before, during and after use of an established NIV. During their inpatient follow-up, we examined patients during the first hour after termination of nocturnal NIV. DVS was defined by the authors as an increase of ≥ 2 points on the Borg scale during the first 30 min in patients who reported repeated dyspnea after the use of NIV. We monitored cardiovascular and respiratory data and measured diaphragm excursion. Subjective dyspnea was documented by use of the Borg scale and questionnaires. In addition, respirator and demographic data were collected. DVS occurred in 58% of our COPD patient collective, showing predominant emphysema phenotype. Patients with DVS were more severely ill than non-DVS concerning bronchial obstruction (FEV1 0.6 vs. 0.8 l, p < 0.05) and hypercapnia during spontaneous breathing (pre NIV pCO2: 54.5 vs. 49.3 mmHg, p < 0.02). DVS patients showed significantly higher respiratory rates (RR) (20.1 vs. 18.1/min p < 0.05) after termination of NIV. This trial characterizes and defines early onset augmented dyspnea after the use of NIV, referred to as DVS. It is hereby brought to attention as a frequent side effect of long-term home ventilation and possible pathophysiologic mechanisms are elucidated.

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.

Enhancement of self-sustained muscle activity through external dead space ventilation appears to be associated with hypercapnia.

We reported that external dead space ventilation (EDSV) enhanced self-sustained muscle activity (SSMA) of the human soleus muscle, which is an indirect observation of plateau potentials. However, the main factor for EDSV to enhance SSMA remains unclear. The purpose of the present study was to examine the effects of EDSV-induced hypercapnia, hypoxia, and hyperventilation on SSMA. In Experiment 1 (n = 11; normal breathing [NB], EDSV, hypoxia, and voluntary hyperventilation conditions) and Experiment 2 (n = 9; NB and normoxic hypercapnia [NH] conditions), SSMA was evoked by electrical train stimulations of the right tibial nerve and measured using surface electromyography under each respiratory condition. In Experiment 1, SSMA was significantly higher than that in the NB condition only in the EDSV condition (P < 0.05). In Experiment 2, SSMA was higher in the NH condition than in the NB condition (P < 0.05). These results suggest that the EDSV-enhanced SSMA is due to hypercapnia, not hypoxia or increased ventilation.

Evaluation of fNIRS signal components elicited by cognitive and hypercapnic stimuli.

Functional near infrared spectroscopy (fNIRS) measurements are confounded by signal components originating from multiple physiological causes, whose activities may vary temporally and spatially (across tissue layers, and regions of the cortex). Furthermore, the stimuli can induce evoked effects, which may lead to over or underestimation of the actual effect of interest. Here, we conducted a temporal, spectral, and spatial analysis of fNIRS signals collected during cognitive and hypercapnic stimuli to characterize effects of functional versus systemic responses. We utilized wavelet analysis to discriminate physiological causes and employed long and short source-detector separation (SDS) channels to differentiate tissue layers. Multi-channel measures were analyzed further to distinguish hemispheric differences. The results highlight cardiac, respiratory, myogenic, and very low frequency (VLF) activities within fNIRS signals. Regardless of stimuli, activity within the VLF band had the largest contribution to the overall signal. The systemic activities dominated the measurements from the short SDS channels during cognitive stimulus, but not hypercapnic stimulus. Importantly, results indicate that characteristics of fNIRS signals vary with type of the stimuli administered as cognitive stimulus elicited variable responses between hemispheres in VLF band and task-evoked temporal effect in VLF, myogenic and respiratory bands, while hypercapnic stimulus induced a global response across both hemispheres.

[Non-invasive Home-Ventilation: Pathophysiology, Initiation and Follow up]. / Nichtinvasive außerklinische Beatmung: Pathophysiologie, Einstellung, Kontrolle.

COPD is the most common reason for hypercapnia. However, it is -by far- not the only reason. In fact, numerous neuromuscular disorders (not only ALS) as well as restrictive thoracic disorders do also lead to clinically highly relevant hypercapnia. Early diagnosis of hypercapnic ventilatory failure usually takes place at nighttime. NIV devices work with a periodic interplay of alternating IPAP and EPAP which results in a ventilation of the lungs, thereby elimination CO2 to treat hypercapnic respiratory failure. Firstline settings for a NIV therapy to treat "stable hypercapnia" are as follows: Pressure Support Ventilation Modus, EPAP 5 cmH2O, IPAP 15 cmH2O, Back Up rate 15/Minute. The overall goal of NIV treatment is a successful reduction in CO2. This can be achieved by changing the following variables of the ventilator settings: increase in IPAP ± increase in back up respiratory rate ± use of assisted pressure controlled ventilation mode (APCV).

Extremes of cerebral blood flow during hypercapnic squat-stand maneuvers.

Squat-stand maneuvers (SSMs) are a popular method of inducing blood pressure (BP) oscillations to reliably assess dynamic cerebral autoregulation (dCA), but their effects on the cerebral circulation remain controversial. We designed a protocol whereby participants would perform SSMs under hypercapnic conditions. Alarmingly high values of cerebral blood flow velocity (CBFV) were recorded, leading to early study termination after the recruitment of a single participant. One healthy subject underwent recordings at rest (5 min sitting, 5 min standing) and during two SSMs (fixed and random frequency). Two sets of recordings were collected; one while breathing room air, one while breathing 5% CO2 . Continuous recordings of bilateral CBFV (transcranial Doppler), heart rate (ECG), BP (Finometer), and end-tidal CO2 (capnography) were collected. Peak values of systolic CBFV were significantly higher during hypercapnia (p < 0.01), and maximal values exceeded 200 cm.s-1 . Estimates of dCA (ARI) during hypercapnia were impaired relative to poikilocapnia (p = 0.03). The phase was significantly reduced under hypercapnic conditions (p = 0.03). Here we report extremely high values of CBFV in response to repeated SSMs during induced hypercapnia, in an otherwise healthy subject. Our findings suggest that protocols performing hypercapnic SSMs are potentially dangerous. We, therefore, urge caution if other research groups plan to undertake similar protocols.

Ventilatory responses during and following hypercapnic gas challenge are impaired in male but not female endothelial NOS knock-out mice.

The roles of endothelial nitric oxide synthase (eNOS) in the ventilatory responses during and after a hypercapnic gas challenge (HCC, 5% CO2, 21% O2, 74% N2) were assessed in freely-moving female and male wild-type (WT) C57BL6 mice and eNOS knock-out (eNOS-/-) mice of C57BL6 background using whole body plethysmography. HCC elicited an array of ventilatory responses that were similar in male and female WT mice, such as increases in breathing frequency (with falls in inspiratory and expiratory times), and increases in tidal volume, minute ventilation, peak inspiratory and expiratory flows, and inspiratory and expiratory drives. eNOS-/- male mice had smaller increases in minute ventilation, peak inspiratory flow and inspiratory drive, and smaller decreases in inspiratory time than WT males. Ventilatory responses in female eNOS-/- mice were similar to those in female WT mice. The ventilatory excitatory phase upon return to room-air was similar in both male and female WT mice. However, the post-HCC increases in frequency of breathing (with decreases in inspiratory times), and increases in tidal volume, minute ventilation, inspiratory drive (i.e., tidal volume/inspiratory time) and expiratory drive (i.e., tidal volume/expiratory time), and peak inspiratory and expiratory flows in male eNOS-/- mice were smaller than in male WT mice. In contrast, the post-HCC responses in female eNOS-/- mice were equal to those of the female WT mice. These findings provide the first evidence that the loss of eNOS affects the ventilatory responses during and after HCC in male C57BL6 mice, whereas female C57BL6 mice can compensate for the loss of eNOS, at least in respect to triggering ventilatory responses to HCC.

Intraocular pressure during handgrip exercise: The effect of posture and hypercapnia in young males.

PURPOSE: As part of our investigations of intraocular pressure (IOP) as a potential contributing factor to the spaceflight-associated neuro-ocular syndrome using the 6° head-down tilt (6°HDT) bed rest experimental model, we compared the effect of rest and isometric exercise in prone and supine 6°HDT positions on IOP with that observed in the seated position. METHODS: Ten male volunteers (age = 22.5 ± 3.1 yrs) participated in six interventions. All trials comprised a 10-min rest period, a 3-min isometric handgrip exercise at 30% of participant's maximum, and a 10-min recovery period. The trials were conducted under normocapnic (NCAP) or hypercapnic (FI CO2  = 0.01; HCAP) conditions, the latter mimicking the ambient conditions on the International Space Station. IOP, systolic and diastolic pressures, and heart rate (HR) were measured during the trials. RESULTS: Isometric exercise-induced elevations in HR and mean arterial blood pressure. IOP in the prone 6°HDT position was significantly higher (p < 0.001) compared to IOP in supine 6°HDT position and seated trials at all time points. IOP increased with exercise only in a seated HCAP trial (p = 0.042). No difference was observed between trials in NCAP and HCAP. IOP in the prone 6°HDT position was constantly elevated above 21 mmHg, the lower limit for clinical ocular hypertension. CONCLUSIONS: IOP in the prone 6°HDT position was similar to IOP reported in astronauts upon entering microgravity, potentially indicating that prone, rather than supine 6°HDT position might be a more suitable experimental analog for investigating the acute ocular changes that occur in microgravity.

Quantitative myocardial first-pass perfusion imaging of CO2 -induced vasodilation in rats.

Inducible hypercapnia is an alternative for increasing the coronary blood flow necessary to facilitate the quantification of myocardial blood flow during hyperemia. The current study aimed to quantify the pharmacokinetic effect of a CO2 gas challenge on myocardial perfusion in rats using high-resolution, first-pass perfusion CMR and compared it with pharmacologically induced hyperemia using regadenoson. A dual-contrast, saturation-recovery, gradient-echo sequence with a Cartesian readout was used on a small-animal 9.4-T scanner; additional cine images during hyperemia/rest were recorded with an ultrashort echo time sequence. The mean myocardial blood flow value at rest was 6.1 ± 1.4 versus 13.9 ± 3.7 and 14.3 ± 4 mL/g/min during vasodilation with hypercapnia and regadenoson, respectively. Accordingly, the myocardial flow reserve value was 2.6 ± 1.1 for the gas challenge and 2.5 ± 1.4 for regadenoson. During hyperemia with both protocols, a significantly increased cardiac output was found. It was concluded that hypercapnia leads to significantly increased coronary flow and yields similar myocardial flow reserves in healthy rats as compared with pharmacological stimulation. Accordingly, inducible hypercapnia can be selected as an alternative stressor in CMR studies of myocardial blood flow in small animals.

Orexin contributes to eupnea within a critical period of postnatal development.

Orexin neurons are active in wakefulness and mostly silent in sleep. In adult rats and humans, orexin facilitates the hypercapnic ventilatory response but has little effect on resting ventilation. The influence of orexin on breathing in the early postnatal period, and across states of vigilance, have not been investigated. This is relevant as the orexin system may be impaired in Sudden Infant Death Syndrome (SIDS) cases. We addressed three hypotheses: 1) orexin provides a drive to breathe in infancy; 2) the effect of orexin depends on stage of postnatal development; and 3) orexin has a greater influence on breathing in wakefulness compared with sleep. Whole body plethysmography was used to monitor breathing of infant rats at three ages: postnatal days (P) 7-8, 12-14, and 17-19. Respiratory variables were analyzed in wakefulness (W), quiet sleep (QS), and active sleep (AS), following suvorexant (5 mg/kg ip), a dual orexin receptor antagonist, or vehicle (DMSO). Effects of suvorexant on ventilatory responses to graded hypercapnia ([Formula: see text] = 0.02, 0.04, 0.06), hypoxia ([Formula: see text] = 0.10), and hyperoxia ([Formula: see text] = 1.0) at P12-14 were also tested. At P12-14, but not at other ages, suvorexant significantly reduced respiratory frequency in all states, reduced the ventilatory equivalent in QW and QS, and increased [Formula: see text] to ∼5 mmHg. Suvorexant had no effect on ventilatory responses to graded hypercapnia or hypoxia. Hyperoxia eliminated the effects of suvorexant on respiratory frequency at P12-14. Our data suggest that orexin preserves eupneic frequency and ventilation in rats, specifically at ∼2 wk of age, perhaps by facilitating tonic peripheral chemoreflex activity.

Acute Beetroot Juice Ingestion Does Not Alter Renal Hemodynamics during Normoxia and Mild Hypercapnia in Healthy Young Adults.

Arterial hypercapnia reduces renal perfusion. Beetroot juice (BRJ) increases nitric oxide bioavailability and may improve renal blood flow. We tested the hypothesis that acute consumption of BRJ attenuates both decreases in blood velocity and increases in vascular resistance in the renal and segmental arteries during acute hypercapnia. In fourteen healthy young adults, blood velocity and vascular resistance were measured with Doppler ultrasound in the renal and segmental arteries during five minutes of breathing a carbon dioxide gas mixture (CO2) before and three hours after consuming 500 mL of BRJ. There was no difference between pre- and post-BRJ consumption in the increase in the partial pressure of end-tidal CO2 during CO2 breathing (pre: +4 ± 1 mmHg; post: +4 ± 2 mmHg, p = 0.4281). Segmental artery blood velocity decreased during CO2 breathing in both pre- (by -1.8 ± 1.9 cm/s, p = 0.0193) and post-BRJ (by -2.1 ± 1.9 cm/s, p = 0.0079), but there were no differences between pre- and post-consumption (p = 0.7633). Segmental artery vascular resistance increased from room air baseline during CO2 at pre-BRJ consumption (by 0.4 ± 0.4 mmHg/cm/s, p = 0.0153) but not post-BRJ (p = 0.1336), with no differences between pre- and post-consumption (p = 0.7407). These findings indicate that BRJ consumption does not attenuate reductions in renal perfusion during acute mild hypercapnia in healthy young adults.

Ethanol's disruptive effects upon early breathing plasticity and blood parameters associated with hypoxia and hypercapnia.

Early ethanol exposure affects respiratory neuroplasticity; a risk factor associated with the Sudden Infant Death Syndrome. High and chronic ethanol doses exert long-lasting effects upon respiratory rates, apneic episodes and ventilatory processes triggered by hypoxia. The present study was performed in 3-9-day-old rat pups. Respiratory processes under normoxic and hypoxic conditions were analyzed in pups intoxicated with different ethanol doses which were pre-exposed or not to the drug. A second major goal was to examine if acute and/or chronic early ethanol exposure affects blood parameters related with hypercapnic or hypoxic states. In Experiment 1, at postnatal day 9, animals previously treated with ethanol (2.0 g/kg) or vehicle (0.0 g/kg) were tested sober or intoxicated with 0.75, 1.37 or 2.00 g/kg ethanol. The test involved sequential air conditions defined as initial normoxia, hypoxia and recovery normoxia. Motor activity was also evaluated. In Experiment 2, blood parameters indicative of possible hypoxic and hypercapnic states were assessed as a function of early chronic or acute experiences with the drug. The main results of Experiment 1 were as follows: i) ethanol's depressant effects upon respiratory rates increased as a function of sequential treatment with the drug (sensitization); ii) ethanol inhibited apneic episodes even when employing the lowest dose at test (0.75 g/kg); iii) the hyperventilatory response caused by hypoxia negatively correlated with the ethanol dose administered at test; iv) ventilatory long-term facilitation (LTF) during recovery normoxia was observed in pups pre-exposed to the drug and in pups that received the different ethanol doses at test; v) self-grooming increased in pups treated with either 1.37 or 2.00 g/kg ethanol. The main result of Experiment 2 indicated that acute as well as chronic ethanol exposure results in acidosis-hypercapnia. The results indicate that early and brief experiences with ethanol are sufficient to affect different respiratory plasticity processes as well as blood biomarkers indicative of acidosis-hypercapnia. An association between the LTF process and the acidosis-hypercapnic state caused by ethanol seems to exist. The mentioned experiences with the drug are sufficient to result in an anomalous programming of respiratory patterns and metabolic conditions.

Mortality and ventilatory effects of central serotonin deficiency during postnatal development depend on age but not sex.

Serotonin (5-HT) influences brain development and has predominantly excitatory neuromodulatory effects on the neural respiratory control circuitry. Infants that succumb to sudden infant death syndrome (SIDS) have reduced brainstem 5-HT levels and Tryptophan hydroxylase 2 (Tph2). Furthermore, there are age- and sex-dependent risk factors associated with SIDS. Here we utilized our established Dark Agouti transgenic rat lacking central serotonin KO to test the hypotheses that CNS 5-HT deficiency leads to: (1) high mortality in a sex-independent manner, (2) age-dependent alterations in other CNS aminergic systems, and (3) age-dependent impairment of chemoreflexes during post-natal development. KO rat pups showed high neonatal mortality but not in a sex-dependent manner and did not show altered hypoxic or hypercapnic ventilatory chemoreflexes. However, KO rat pups had increased apnea-related metrics during a specific developmental age (P12-16), which were preceded by transient increases in dopaminergic system activity (P7-8). These results support and extend the concept that 5-HT per se is a critical factor in supporting respiratory control during post-natal development.

Effects of different levels of hypoxia and hypercarbia on ventilation and gas exchange in Boa constrictor amaralis and Crotalus durissus (Squamata: Serpentes).

Ventilation and gas exchange have been studied in relatively few species of snakes, especially regarding their response to environmental hypoxia or hypercarbia. We exposed Crotalus durissus (N = 6) and Boa constrictor (N = 6) to decreasing levels of oxygen (12, 9, 6, 3 % O2) and increasing levels of carbon dioxide (1.5, 3.0, 4.5, 6.0 % CO2) and analyzed the effect of the different gas mixtures on ventilation and gas exchange using open-flow respirometry. Neither hypoxia nor hypercarbia significantly altered the duration of expiration or inspiration, nor their proportions. Both hypoxia and hypercarbia increased minute ventilation, but the decrease in oxygen had a less pronounced effect on ventilation. Gas exchange under normoxic conditions was low and was not significantly affected by hypoxia, but hypercarbia decreased gas exchange significantly in both species. While B. constrictor maintained its respiratory exchange ratio (RER) under hypercarbia between 0.5 and 1.0, C. durissus showed a RER above 1.0 during hypercarbia, due to a significantly greater CO2 excretion. The overall responses of both species to hypercarbia and especially to hypoxia were very similar, which could be associated to similar lifestyles as ambush hunting sit-and-wait predators that are able to ingest large prey items. The observed differences in gas exchange could be related to respiratory systems with macroscopically different structures, possessing only a tracheal lung in C. durissus, but two functional lungs in B. constrictor.

Carotid body chemosensitivity is not attenuated during cold water diving.

Tonic carotid body (CB) activity is reduced during exposure to cold and hyperoxia. We tested the hypotheses that cold water diving lowers CB chemosensitivity and augments CO2 retention more than thermoneutral diving. Thirteen subjects [age: 26 ± 4 yr; body mass index (BMI): 26 ± 2 kg/m2) completed two 4-h head-out water immersion protocols in a hyperbaric chamber (1.6 ATA) in cold (15°C) and thermoneutral (25°C) water. CB chemosensitivity was assessed with brief hypercapnic ventilatory response ([Formula: see text]) and hypoxic ventilatory response ([Formula: see text]) tests before dive, 80 and 160 min into the dive (D80 and D160, respectively), and immediately after and 60 min after dive. Data are reported as an absolute mean (SD) change from predive. End-tidal CO2 pressure increased during both the thermoneutral water dive [D160: +2 (3) mmHg; P = 0.02] and the cold water dive [D160: +1 (2) mmHg; P = 0.03]. Ventilation increased during the cold water dive [D80: 4.13 (4.38) and D160: 7.75 (5.23) L·min-1; both P < 0.01] and was greater than the thermoneutral water dive at both time points (both P < 0.01). [Formula: see text] was unchanged during the dive (P = 0.24) and was not different between conditions (P = 0.23). [Formula: see text] decreased during the thermoneutral water dive [D80: -3.45 (3.61) and D160: -2.76 (4.04) L·min·mmHg-1; P < 0.01 and P = 0.03, respectively] but not the cold water dive. However, [Formula: see text] was not different between conditions (P = 0.17). In conclusion, CB chemosensitivity was not attenuated during the cold stress diving condition and does not appear to contribute to changes in ventilation or CO2 retention.

Breath-holding as a novel approach to risk stratification in COVID-19.

BACKGROUND: Despite considerable progress, it remains unclear why some patients admitted for COVID-19 develop adverse outcomes while others recover spontaneously. Clues may lie with the predisposition to hypoxemia or unexpected absence of dyspnea ('silent hypoxemia') in some patients who later develop respiratory failure. Using a recently-validated breath-holding technique, we sought to test the hypothesis that gas exchange and ventilatory control deficits observed at admission are associated with subsequent adverse COVID-19 outcomes (composite primary outcome: non-invasive ventilatory support, intensive care admission, or death). METHODS: Patients with COVID-19 (N = 50) performed breath-holds to obtain measurements reflecting the predisposition to oxygen desaturation (mean desaturation after 20-s) and reduced chemosensitivity to hypoxic-hypercapnia (including maximal breath-hold duration). Associations with the primary composite outcome were modeled adjusting for baseline oxygen saturation, obesity, sex, age, and prior cardiovascular disease. Healthy controls (N = 23) provided a normative comparison. RESULTS: The adverse composite outcome (observed in N = 11/50) was associated with breath-holding measures at admission (likelihood ratio test, p = 0.020); specifically, greater mean desaturation (12-fold greater odds of adverse composite outcome with 4% compared with 2% desaturation, p = 0.002) and greater maximal breath-holding duration (2.7-fold greater odds per 10-s increase, p = 0.036). COVID-19 patients who did not develop the adverse composite outcome had similar mean desaturation to healthy controls. CONCLUSIONS: Breath-holding offers a novel method to identify patients with high risk of respiratory failure in COVID-19. Greater breath-hold induced desaturation (gas exchange deficit) and greater breath-holding tolerance (ventilatory control deficit) may be independent harbingers of progression to severe disease.