Increasing cerebral blood flow reduces the severity of central sleep apnea at high altitude

Earlier studies have indicated an important role for cerebral blood flow in the pathophysiology of central sleep apnea (CSA) at high altitude, but were not decisive. To test the hypothesis that pharmacologically altering cerebral blood flow (CBF) without altering arterial blood gas (ABGs) values would alter the severity of CSA at high altitude, we studied 11 healthy volunteers (8M, 3F; 31 ± 7 yr) in a randomized placebo-controlled single-blind study at 5,050 m in Nepal. CBF was increased by intravenous (iv) acetazolamide (Az; 10 mg/kg) plus intravenous dobutamine (Dob) infusion (2–5 μg·kg−1·min−1) and reduced by oral indomethacin (Indo; 100 mg). ABG samples were collected and ventilatory responses to hypercapnia (HCVR) and hypoxia (HVR) were measured by rebreathing and steady-state techniques before and after drug/placebo. Duplex ultrasound of blood flow in the internal carotid and vertebral arteries was used to measure global CBF. The initial 3–4 h of sleep were recorded by full polysomnography. Intravenous Az + Dob increased global CBF by 37 ± 15% compared with placebo ( P < 0.001), whereas it was reduced by 21 ± 8% by oral Indo ( P < 0.001). ABGs and HVR were unchanged in both interventions. HCVR was reduced by 28% ± 43% ( P = 0.1) during intravenous Az ± Dob administration and was elevated by 23% ± 30% ( P = 0.05) by Indo. During intravenous Az + Dob, the CSA index fell from 140 ± 45 (control night) to 48 ± 37 events/h of sleep ( P < 0.001). Oral Indo had no significant effect on CSA. We conclude that increasing cerebral blood flow reduced the severity of CSA at high altitude; the likely mechanism is via a reduction in the background stimulation of central chemoreceptors.NEW & NOTEWORTHY This work is significant because it shows convincingly for the first time in healthy volunteers that increasing cerebral blood flow will reduce the severity of central sleep apnea in a high-altitude model, without the potentially confounding effects of altering partial pressure of arterial carbon dioxide or the ventilatory response to hypoxia. The proposed mechanism of action is that of increasing the removal of locally produced CO2from the central chemoreceptors, causing the reduction in hypercapnic ventilatory response, hence reducing loop gain.

The respiratory system

The respiratory system in relation to dentistry is the topic of this chapter. Gaseous exchange in the lungs is mainly controlled by central chemoreceptors sensing a change in the pH of the cerebrospinal fluid. These receptors then activate a respiratory response which returns the blood and cerebrospinal fluid pH to normal. Localized airway obstruction, obstructive sleep apnoea, and lung disease can cause hypoxaemia (a low arterial oxygen oncentration) and hypercapnia (a raised carbon dioxide concentration in the blood). We emphasize the specific dental issues in patients with asthma, i.e. the dry mouth when taking β‎‎2-adrenergic agonists and the management of an acute asthmatic attack. Specific points of relevance to the dentist are summarized in sections throughout the chapter.

Mechanisms of the deep, slow-wave, sleep-related increase of upper airway muscle tone in healthy humans

Upper airway muscle activity is reportedly elevated during slow-wave sleep (SWS) when compared with lighter sleep stages. To uncover the possible mechanisms underlying this elevation, we explored the correlation between different indices of central and reflex inspiratory drive, such as the changes in airway pressure and end-expiratory CO2and the changes in the genioglossus (GG) and tensor palatini (TP) muscle activity accompanying transitions from the lighter N2 to the deeper N3 stage of non-rapid eye movement (NREM) sleep in healthy young adult men. Forty-six GG and 38 TP continuous electromyographic recordings were obtained from 16 men [age: 20 ± 2.5 (SD) yr; body mass index: 22.5 ± 1.8 kg/m2] during 32 transitions from NREM stages N2 to N3. GG but not TP activity increased following transition into N3 sleep, and the increase was positively correlated with more negative airway pressure, increased end-tidal CO2, increased peak inspiratory flow, and increased minute ventilation. None of these correlations was statistically significant for TP. Complementary GG and TP single motor unit analysis revealed a mild recruitment of GG units and derecruitment of TP units during the N2 to N3 transitions. These findings suggest that, in healthy individuals, the increased GG activity during SWS is driven primarily by reflex stimulation of airway mechanoreceptors and central chemoreceptors.NEW & NOTEWORTHY The characteristic increase in the activity of the upper airway dilator muscle genioglossus during slow-wave sleep (SWS) in young healthy individuals was found to be related to increased stimulation of airway mechanoreceptors and central chemoreceptors. No evidence was found for the presence of a central SWS-specific drive stimulating genioglossus activity in young healthy individuals. However, it remains to be determined whether a central drive exists in obstructive sleep apnea patients.

Medullary serotonin neurons are CO2 sensitive in situ

Brainstem central chemoreceptors are critical to the hypercapnic ventilatory response, but their location and identity are poorly understood. When studied in vitro, serotonin-synthesizing (5-HT) neurons within the rat medullary raphé are intrinsically stimulated by CO2/acidosis. The contributions of these neurons to central chemosensitivity in vivo, however, are controversial. Lacking is documentation of CO2-sensitive 5-HT neurons in intact experimental preparations and understanding of their spatial and proportional distribution. Here we test the hypothesis that 5-HT neurons in the rat medullary raphé are sensitive to arterial hypercapnia. We use extracellular recording and hypercapnic challenge of spontaneously active medullary raphé neurons in the unanesthetized in situ perfused decerebrate brainstem preparation to assess chemosensitivity of individual cells. Juxtacellular labeling of a subset of recorded neurons and subsequent immunohistochemistry for the 5-HT-synthesizing enzyme tryptophan hydroxylase (TPH) identify or exclude this neurotransmitter phenotype in electrophysiologically characterized chemosensitive and insensitive cells. We show that the medullary raphé houses a heterogeneous population, including chemosensitive and insensitive 5-HT neurons. Of 124 recorded cells, 16 cells were juxtacellularly filled, visualized, and immunohistochemically identified as 5-HT synthesizing, based on TPH-immunoreactivity. Forty-four percent of 5-HT cells were CO2 stimulated (increased firing rate with hypercapnia), while 56% were unstimulated. Our results demonstrate that medullary raphé neurons are heterogeneous and clearly include a subset of 5-HT neurons that are excited by arterial hypercapnia. Together with data identifying intrinsically CO2-sensitive 5-HT neurons in vitro, these results support a role for such cells as central chemoreceptors in the intact system.