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

Abstract

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·min) 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 CO from the central chemoreceptors, causing the reduction in hypercapnic ventilatory response, hence reducing loop gain.

Cerebral blood flow, cerebrovascular reactivity and their influence on ventilatory sensitivity

“…without changing P aCO 2 in the short term, reduced the severity of CSA from 140 ± 45 to 48 ± 37 events/h of sleep (Burgess et al, 2018). These results are consistent with modelling studies and suggest that CBF -through its influence on the central chemoreceptorsaids not only in shapingV E -CO 2 but also in stabilizing breathing in challenging environments such as sleeping at altitude.…”

Neurophysiologic Profiling of At-Risk Low and Very Low Birth-Weight Infants Using Magnetic Resonance Imaging

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A New Kid on the Block? Carbonic Anhydrases as Possible New Targets in Alzheimer’s Disease

“…However, clearance of brain products is driven by both CSF movements and vascular pulsatility [86,87]. AAZ is clinically used to increase cerebral blood flow and vasoreactivity [88,89]. This effect, promoting perivascular clearance through increased vascular flow and pulsatility, which drives movement of perivascular fluids, may be beneficial for brain clearance of waste products such as Aβ [78,86].…”

“…Recently, a series of observations are shedding light on the potential involvement of CAs on neurodegenerative disorders, particularly in AD—(i) increased CA II was found in the mitochondria during aging and neurodegeneration as revealed by proteomic studies [17]; (ii) CAs inhibition prevented Aβ-induced mitochondrial dysfunction related to neuronal and microvascular toxicity in vitro and in the mouse brain [19,66,67]; (iii) CA II is found in amyloid plaques in the AD human brain [16]; (iv) CA II expression is increased in hippocampus and in plasma of AD patients [13,18]; (v) alterations of CA catalytic activity were reported in the temporal lobe and hippocampus of AD post-mortem samples [36,37]; (vi) CA inhibition is used as a strategy to increase cerebral blood flow and vasoreactivity in multiple clinical trials [88,89]. Even if these findings may seem apparently easily interconnected, is clear that at this point many pieces are still missing to complete the puzzle.…”