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PubMed | University of Otago, University of British Columbia, University of New South Wales, The Good and Peninsula Sleep Laboratory
Type: Journal Article | Journal: Sleep | Year: 2014

To further our understanding of central sleep apnea (CSA) at high altitude during acclimatization, we tested the hypothesis that pharmacologically altering cerebral blood flow (CBF) would alter the severity of CSA at high altitude.The study was a randomized, placebo-controlled single-blind study.A field study at 5,050 m in Nepal.We studied 12 normal volunteers.Between days 5 to 10 at high altitude, CBF velocity (CBFv) was increased by intravenous (IV) acetazolamide (10 mg/kg) and reduced by oral indomethacin (100 mg).Arterial blood gases, hypoxic and hypercapnic ventilatory responses, and CBFv and its reactivity to carbon dioxide were measured awake. Overnight polysomnography was performed. The central apnea-hypopnea index was elevated following administration of indomethacin (89.2 43.7 to 112.5 32.9 events/h; mean standard deviation; P < 0.05) and was reduced following IV acetazolamide (89.2 43.7 to 47.1 48.1 events/h; P < 0.001). Intravenous acetazolamide elevated CBFv at high altitude by 28% (95% confidence interval [CI]: 22-34%) but did not affect ventilatory responses. The elevation in CBFv was partly mediated via a selective rise in partial pressure of arterial carbon dioxide (PaCO2) (28 4 to 31 3 mm Hg) and an associated fall in pH (P < 0.01). Oral indomethacin reduced CBFv by 23% (95% CI: 16-30%), blunted CBFv reactivity, and increased the hypercapnic ventilatory response by 66% (95% CI: 30-102%) but had no effect on PaCO2 or pH.Our findings indicate an important role for cerebral blood flow regulation in the pathophysiology of central sleep apnea at high altitude.


Ainslie P.N.,University of British Columbia | Lucas S.J.E.,University of Birmingham | Burgess K.R.,Peninsula Sleep Laboratory | Burgess K.R.,University of Sydney
Respiratory Physiology and Neurobiology | Year: 2013

We provide an updated review on the current understanding of breathing and sleep at high altitude in humans. We conclude that: (1) progressive changes in pH initiated by the respiratory alkalosis do not underlie early (<48h) ventilatory acclimatization to hypoxia (VAH) because this still proceeds in the absence of such alkalosis; (2) for VAH of longer duration (>48h), complex cellular and neurochemical re-organization occurs both in the peripheral chemoreceptors as well as within the central nervous system. The latter is likely influenced by central acid-base changes secondary to the extent of the initial respiratory responses to initial exposure to high altitude; (3) sleep at high altitude is disturbed by various factors, but principally by periodic breathing; (4) the extent of periodic breathing during sleep at altitude intensifies with duration and severity of exposure; (5) complex interactions between hypoxic-induced enhancement in peripheral and central chemoreflexes and cerebral blood flow - leading to higher loop gain and breathing instability - underpin this development of periodic breathing during sleep; (6) because periodic breathing may elevate rather than reduce mean SaO2 during sleep, this may represent an adaptive rather than maladaptive response; (7) although oral acetazolamide is an effective means to reduce periodic breathing by 50-80%, recent studies using positive airway pressure devices to increase dead space, hyponotics and theophylline are emerging but appear less practical and effective compared to acetazolamide. Finally, we suggest avenues for future research, and discuss implications for understanding sleep pathology. © 2013 Elsevier B.V.


Burgess K.R.,Peninsula Sleep Laboratory | Burgess K.R.,University of Sydney | Lucas S.J.E.,University of Otago | Shepherd K.,Peninsula Sleep Laboratory | And 9 more authors.
Sleep | Year: 2014

Study Objectives: To further our understanding of central sleep apnea (CSA) at high altitude during acclimatization, we tested the hypothesis that pharmacologically altering cerebral blood flow (CBF) would alter the severity of CSA at high altitude.Design: The study was a randomized, placebo-controlled single-blind study.Setting: A field study at 5,050 m in Nepal.Patients or Participants: We studied 12 normal volunteers.Interventions: Between days 5 to10 at high altitude, CBF velocity (CBFv) was increased by intravenous (IV) acetazolamide (10 mg/kg) and reduced by oral indomethacin (100 mg).Measurements and Results: Arterial blood gases, hypoxic and hypercapnic ventilatory responses, and CBFv and its reactivity to carbon dioxide were measured awake. Overnight polysomnography was performed. The central apnea-hypopnea index was elevated following administration of indomethacin (89.2 ± 43.7 to 112.5 ± 32.9 events/h; mean ± standard deviation; P < 0.05) and was reduced following IV acetazolamide (89.2 ± 43.7 to 47.1 ± 48.1 events/h; P < 0.001). Intravenous acetazolamide elevated CBFv at high altitude by 28% (95% confidence interval [CI]: 22-34%) but did not affect ventilatory responses. The elevation in CBFv was partly mediated via a selective rise in partial pressure of arterial carbon dioxide (PaCO2) (28 ± 4 to 31 ± 3 mm Hg) and an associated fall in pH (P < 0.01). Oral indomethacin reduced CBFv by 23% (95% CI: 16-30%), blunted CBFv reactivity, and increased the hypercapnic ventilatory response by 66% (95% CI: 30-102%) but had no effect on PaCO 2 or pH.Conclusion: Our findings indicate an important role for cerebral blood flow regulation in the pathophysiology of central sleep apnea at high altitude.


Lewis N.C.S.,University of British Columbia | Bailey D.M.,University of South Wales | DuManoir G.R.,University of British Columbia | Messinger L.,University of British Columbia | And 10 more authors.
Journal of Physiology | Year: 2014

Research detailing the normal vascular adaptions to high altitude is minimal and often confounded by pathology (e.g. chronic mountain sickness) and methodological issues. We examined vascular function and structure in: (1) healthy lowlanders during acute hypoxia and prolonged (~2 weeks) exposure to high altitude, and (2) high-altitude natives at 5050 m (highlanders). In 12 healthy lowlanders (aged 32 ± 7 years) and 12 highlanders (Sherpa; 33 ± 14 years) we assessed brachial endothelium-dependent flow-mediated dilatation (FMD), endothelium-independent dilatation (via glyceryl trinitrate; GTN), common carotid intima-media thickness (CIMT) and diameter (ultrasound), and arterial stiffness via pulse wave velocity (PWV; applanation tonometry). Cephalic venous biomarkers of free radical-mediated lipid peroxidation (lipid hydroperoxides, LOOH), nitrite (NO2-) and lipid soluble antioxidants were also obtained at rest. In lowlanders, measurements were performed at sea level (334 m) and between days 3-4 (acute high altitude) and 12-14 (chronic high altitude) following arrival to 5050 m. Highlanders were assessed once at 5050 m. Compared with sea level, acute high altitude reduced lowlanders' FMD (7.9 ± 0.4 vs. 6.8 ± 0.4%; P = 0.004) and GTN-induced dilatation (16.6 ± 0.9 vs. 14.5 ± 0.8%; P = 0.006), and raised central PWV (6.0 ± 0.2 vs. 6.6 ± 0.3 m s-1; P = 0.001). These changes persisted at days 12-14, and after allometrically scaling FMD to adjust for altered baseline diameter. Compared to lowlanders at sea level and high altitude, highlanders had a lower carotid wall:lumen ratio (~19%, P ≤ 0.04), attributable to a narrower CIMT and wider lumen. Although both LOOH and NO2- increased with high altitude in lowlanders, only LOOH correlated with the reduction in GTN-induced dilatation evident during acute (n = 11, r = -0.53) and chronic (n = 7, r = -0.69; P ≤ 0.01) exposure to 5050 m. In a follow-up, placebo-controlled experiment (n = 11 healthy lowlanders) conducted in a normobaric hypoxic chamber (inspired O2 fraction (F IO 2) = 0.11; 6 h), a sustained reduction in FMD was evident within 1 h of hypoxic exposure when compared to normoxic baseline (5.7 ± 1.6 vs. 8.0 ±1.3%; P < 0.01); this decline in FMD was largely reversed following α1-adrenoreceptor blockade. In conclusion, high-altitude exposure in lowlanders caused persistent impairment in vascular function, which was mediated partially via oxidative stress and sympathoexcitation. Although a lifetime of high-altitude exposure neither intensifies nor attenuates the impairments seen with short-term exposure, chronic high-altitude exposure appears to be associated with arterial remodelling. © 2013 The Physiological Society.


Burgess K.R.,Peninsula Sleep Laboratory | Burgess K.R.,University of Sydney | Fan J.-L.,University of Otago | Peebles K.,University of Otago | And 7 more authors.
Chest | Year: 2010

Patients with obstructive sleep apnea (OSA) are predisposed to instability in central ventilatory control during sleep. Increased instability, as reflected in an enhanced expired volume in per unit time loop gain, has been associated with a greater predisposition to upper airway collapse. Here, in an otherwise healthy patient with untreated mild OSA, we describe the further exacerbation of OSA after oral indomethacin administration. The subject was a control subject in part of a study to investigate the effects of altering cerebral blood flow (CBF) on ventilatory responses and sleep. He was administered either placebo or 100 mg of indomethacin orally with 20 mL of antacid 2.5 h before sleep on different days. He was studied overnight by polysomnography, arterial blood gases, and transcranial Doppler ultrasound. Administration of 100 mg of oral indomethacin prior to sleep resulted in an almost doubling of the apneahypopnea index (14 to 24/h), compared with placebo. This was due to an increase in apneas, rather than hypopneas. Following the indomethacin, changes in arterial blood gases were unremarkable, but both CBF as indexed using transcranial Doppler ultrasound and CBF reactivity to a steady-state change in CO2 (CBF-CO2) reactivity were reduced, and the ventilatory response to CO2 was elevated. CBF was also further reduced during nonrapid eye movement sleep following the indomethacin when compared with the control night. Indomethacin-induced reductions in CBF and CBF-CO2 reactivity and related increases in ventilatory instability may lead to a greater predisposition to upper airway collapse and related apnea; these factors may partly explain the exacerbation of OSA. © 2010 American College of Chest Physicians.


Burgess K.R.,Peninsula Sleep Laboratory | Burgess K.R.,University of Sydney | Lucas S.J.E.,University of Otago | Shepherd K.,Peninsula Sleep Laboratory | And 9 more authors.
Journal of Applied Physiology | Year: 2013

Although periodic breathing during sleep at high altitude occurs almost universally, the likely mechanisms and independent effects of altitude and acclimatization have not been clearly reported. Data from 2005 demonstrated a significant relationship between decline in cerebral blood flow (CBF) at sleep onset and subsequent severity of central sleep apnea that night. We suspected that CBF would decline during partial acclimatization. We hypothesized therefore that reductions in CBF and its reactivity would worsen periodic breathing during sleep following partial acclimatization. Repeated measures of awake ventilatory and CBF responsiveness, arterial blood gases during wakefulness. and overnight polysomnography at sea level, upon arrival (days 2-4), and following partial acclimatization (days 12-15) to 5,050 m were made on 12 subjects. The apnea-hypopnea index (AHI) increased from to 77 ± 49 on days 2-4 to 116 ± 21 on days 12-15 (P = 0.01). The AHI upon initial arrival was associated with marked elevations in CBF (+28%, 68 ± 11 to 87 ± 17 cm/s; P < 0.05) and its reactivity to changes in PaCO2 [>90%, 2.0 ± 0.6 to 3.8 ± 1.5 cm·s -1·mmHg-1 hypercapnia and 1.9 ± 0.4 to 4.1 ± 0.9 cm·s-1·mmHg-1 for hypocapnia (P < 0.05)]. Over 10 days, the increases resolved and AHI worsened. During sleep at high altitude large oscillations in mean CBF velocity (CBFv) occurred, which were 35% higher initially (peak CBFv = 96 cm/s vs. peak CBFv = 71 cm/s) than at days 12-15. Our novel findings suggest that elevations in CBF and its reactivity to CO2 upon initial ascent to high altitude may provide a protective effect on the development of periodic breathing during sleep (likely via moderating changes in central PCO2). Copyright © 2013 the American Physiological Society.


PubMed | Peninsula Sleep Laboratory
Type: Journal Article | Journal: Journal of applied physiology (Bethesda, Md. : 1985) | Year: 2013

Although periodic breathing during sleep at high altitude occurs almost universally, the likely mechanisms and independent effects of altitude and acclimatization have not been clearly reported. Data from 2005 demonstrated a significant relationship between decline in cerebral blood flow (CBF) at sleep onset and subsequent severity of central sleep apnea that night. We suspected that CBF would decline during partial acclimatization. We hypothesized therefore that reductions in CBF and its reactivity would worsen periodic breathing during sleep following partial acclimatization. Repeated measures of awake ventilatory and CBF responsiveness, arterial blood gases during wakefulness. and overnight polysomnography at sea level, upon arrival (days 2-4), and following partial acclimatization (days 12-15) to 5,050 m were made on 12 subjects. The apnea-hypopnea index (AHI) increased from to 77 49 on days 2-4 to 116 21 on days 12-15 (P = 0.01). The AHI upon initial arrival was associated with marked elevations in CBF (+28%, 68 11 to 87 17 cm/s; P < 0.05) and its reactivity to changes in PaCO2 [>90%, 2.0 0.6 to 3.8 1.5 cms(-1)mmHg(-1) hypercapnia and 1.9 0.4 to 4.1 0.9 cms(-1)mmHg(-1) for hypocapnia (P < 0.05)]. Over 10 days, the increases resolved and AHI worsened. During sleep at high altitude large oscillations in mean CBF velocity (CBFv) occurred, which were 35% higher initially (peak CBFv = 96 cm/s vs. peak CBFv = 71 cm/s) than at days 12-15. Our novel findings suggest that elevations in CBF and its reactivity to CO(2) upon initial ascent to high altitude may provide a protective effect on the development of periodic breathing during sleep (likely via moderating changes in central Pco2).

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