Keith R. Burgess

Alterations in cerebral blood flow and cerebrovascular reactivity during 14 days at 5050 m

Brain blood flow increases during the first week of living at high altitude. We do not understand completely what causes the increase or how the factors that regulate brain blood flow are affected by the high‐altitude environment. Our results show that the balance of oxygen (O2) and carbon dioxide (CO2) pressures in arterial blood explains 40% of the change in brain blood flow upon arrival at high altitude (5050 m). We also show that blood vessels in the brain respond to increases and decreases in CO2 differently at high altitude compared to sea level, and that this can affect breathing responses as well. These results help us to better understand the regulation of brain blood flow at high altitude and are also relevant to diseases that are accompanied by reductions in the pressure of oxygen in the blood.

Breathing and sleep at high altitude

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 (<48 h) ventilatory acclimatization to hypoxia (VAH) because this still proceeds in the absence of such alkalosis; (2) for VAH of longer duration (>48 h), 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.

Acute mountain sickness is associated with sleep desaturation at high altitude

Objective:  This study was intended to demonstrate a biologically important association between acute mountain sickness (AMS) and sleep disordered breathing.

Central and obstructive sleep apnoea during ascent to high altitude

Objective:  The aim of the study was to investigate the relationship between central sleep apnoea (CSA) at high altitude and arterial blood gas tensions, and by inference, ventilatory responsiveness.

Influence of high altitude on cerebrovascular and ventilatory responsiveness to CO2

An altered acid–base balance following ascent to high altitude has been well established. Such changes in pH buffering could potentially account for the observed increase in ventilatory CO2 sensitivity at high altitude. Likewise, if [H+] is the main determinant of cerebrovascular tone, then an alteration in pH buffering may also enhance the cerebral blood flow (CBF) responsiveness to CO2 (termed cerebrovascular CO2 reactivity). However, the effect altered acid–base balance associated with high altitude ascent on cerebrovascular and ventilatory responsiveness to CO2 remains unclear. We measured ventilation , middle cerebral artery velocity (MCAv; index of CBF) and arterial blood gases at sea level and following ascent to 5050 m in 17 healthy participants during modified hyperoxic rebreathing. At 5050 m, resting , MCAv and pH were higher (P < 0.01), while bicarbonate concentration and partial pressures of arterial O2 and CO2 were lower (P < 0.01) compared to sea level. Ascent to 5050 m also increased the hypercapnic MCAv CO2 reactivity (2.9 ± 1.1 vs. 4.8 ± 1.4% mmHg−1; P < 0.01) and CO2 sensitivity (3.6 ± 2.3 vs. 5.1 ± 1.7 l min−1 mmHg−1; P < 0.01). Likewise, the hypocapnic MCAv CO2 reactivity was increased at 5050 m (4.2 ± 1.0 vs. 2.0 ± 0.6% mmHg−1; P < 0.01). The hypercapnic MCAv CO2 reactivity correlated with resting pH at high altitude (R2= 0.4; P < 0.01) while the central chemoreflex threshold correlated with bicarbonate concentration (R2= 0.7; P < 0.01). These findings indicate that (1) ascent to high altitude increases the ventilatory CO2 sensitivity and elevates the cerebrovascular responsiveness to hypercapnia and hypocapnia, and (2) alterations in cerebrovascular CO2 reactivity and central chemoreflex may be partly attributed to an acid–base balance associated with high altitude ascent. Collectively, our findings provide new insights into the influence of high altitude on cerebrovascular function and highlight the potential role of alterations in acid–base balance in the regulation in CBF and ventilatory control.

Sleep architecture changes during a trek from 1400 to 5000 m in the Nepal Himalaya.

The aim of this study was to examine sleep architecture at high altitude and its relationship to periodic breathing during incremental increases in altitude. Nineteen normal, sea level‐dwelling volunteers were studied at sea level and five altitudes in the Nepal Himalaya. Morning arterial blood gases and overnight polysomnography were performed in 14 subjects at altitudes: 0, 1400, 3500, 3900, 4200 and 5000 m above sea level. Subjects became progressively more hypoxic, hypocapnic and alkalinic with increasing altitude. As expected, sleep architecture was affected by increasing altitude. While time spent in Stage 1 non‐rapid eye movement sleep increased at 3500 m and higher (P < 0.001), time spent in slow‐wave sleep (SWS) decreased as altitude increased. Time spent in rapid eye movement (REM) sleep was well preserved. In subjects who developed periodic breathing during sleep at one or more altitudes (16 of 19), arousals because of periodic breathing predominated, contributing to an increase in the total arousal index. However, there were no differences in sleep architecture or sleeping oxyhaemoglobin saturation between subjects who developed periodic breathing and those who did not. As altitude increased, sleep architecture became progressively more disturbed, with Stage 1 and SWS being affected from 3500 m, while REM sleep was well preserved. Periodic breathing was commonplace at all altitudes, and while associated with increases in arousal indices, did not have any apparent effect on sleep architecture.

Effect of simulated altitude during sleep on moderate-severity OSA

Objective:  These studies were conducted to test the hypothesis that isobaric hypoxia would switch OSA to central sleep apnoea (CSA).

No Evidence of Sleep Apnea in Children with Attention Deficit Hyperactivity Disorder

Children with attention deficit hyperactivity disorder (ADHD) may have a component of sleep apnea causing arousal and contributing to ADHD behavior during the day. Twenty non-ADHD children between 4 and 16 years of age were compared with 18 children with ADHD with use of nocturnal polysomnography (PSG) and psychometric tests. The psychometric testing confirmed that the control group were normal and that the ADHD children fulfilled the diagnostic criteria for ADHD. The PSG showed normal arousal indexes for the ADHD group (9.8 ± 3.9/hr) and controls (10.2 ± 3.1/hr), and normal apnea/hypnea indexes for the ADHD group (1.0 ± 2.4/hr) and controls (0.6 ± 0.9/hr). The sleep architecture was not significantly different between groups. There were no sleep abnormalities in the ADHD children that could be responsible for, or contributing to, the disorder.

Influence of indomethacin on ventilatory and cerebrovascular responsiveness to CO2 and breathing stability: the influence of PCO2 gradients

Indomethacin (INDO), a reversible cyclooxygenase inhibitor, is a useful tool for assessing the role of cerebrovascular reactivity on ventilatory control. Despite this, the effect of INDO on breathing stability during wakefulness has yet to be examined. Although the effect of reductions in cerebrovascular CO(2) reactivity on ventilatory CO(2) sensitivity is likely dependent upon the method used, no studies have compared the effect of INDO on steady-state and modified rebreathing estimates of ventilatory CO(2) sensitivity. The latter method includes the influence of PCO(2) gradients and cerebral perfusion, whereas the former does not. We examined the hypothesis that INDO-induced reduction in cerebrovascular CO(2) reactivity would 1) cause unstable breathing in conscious humans and 2) increase ventilatory CO(2) sensitivity during the steady-state method but not during rebreathing methods. We measured arterial blood gases, ventilation (VE), and middle cerebral artery velocity (MCAv) before and 90 min following INDO ingestion (100 mg) or placebo in 12 healthy participants. There were no changes in resting arterial blood gases or Ve following either intervention. INDO increased the magnitude of Ve variability (index of breathing stability) during spontaneous air breathing (+4.3 +/- 5.2 Deltal/min, P = 0.01) and reduced MCAv (-25 +/- 19%, P < 0.01) and MCAv-CO(2) reactivity during steady-state (-47 +/- 27%, P < 0.01) and rebreathing (-32 +/- 25%, P < 0.01). The Ve-CO(2) sensitivity during the steady-state method was increased with INDO (+0.5 +/- 0.5 l x min(-1) x mmHg(-1), P < 0.01), while no changes were observed during rebreathing (P > 0.05). These data indicate that the net effect of INDO on ventilatory control is an enhanced ventilatory loop gain resulting in increased breathing instability. Our findings also highlight important methodological and physiological considerations when assessing the effect of INDO on ventilatory CO(2) sensitivity, whereby the effect of INDO-induced reduction of cerebrovascular CO(2) reactivity on ventilatory CO(2) sensitivity is unmasked with the rebreathing method.

Cardiorespiratory and cerebrovascular responses to hyperoxic and hypoxic rebreathing: effects of acclimatization to high altitude.

We examined the cardiorespiratory and cerebrovascular responses to hyperoxic and hypoxic rebreathing at low attitude and high altitude. We measured ventilation, middle cerebral artery blood flow velocity (MCAv) and arterial blood pressure in conditions of eucapnia, hypocapnia (voluntary hyperventilation) and during hyperoxic and hypoxic rebreathing firstly at low altitude (1400 m) then again at high altitude (3840 m) in five individuals, following 9 days at altitude >5000 m. High altitude was associated with elevations in the blood pressure response to hyperoxic rebreathing, whilst cerebrovascular reactivity was reduced and ventilatory sensitivity was unchanged. During hypoxic rebreathing, whilst ventilatory and blood pressure reactivity were increased (vs. low altitude and hyperoxic rebreathing), cerebrovascular reactivity was preserved. In conclusion, at high altitude there was an enhancement in peripheral but not central chemosensitivity to CO(2); and during hypoxic rebreathing, marked elevations in blood pressure may restore some of the reduction in cerebrovascular CO(2) reactivity, potentially reflecting a pressure-passive relationship in the brain offsetting sympathetic-induced cerebral vasoconstriction.