Mohamad El-Chami

Intermittent hypoxia: a low-risk research tool with therapeutic value in humans.

Intermittent hypoxia has generally been perceived as a high-risk stimulus, particularly in the field of sleep medicine, because it is thought to initiate detrimental cardiovascular, respiratory, cognitive, and metabolic outcomes. In contrast, the link between intermittent hypoxia and beneficial outcomes has received less attention, perhaps because it is not universally understood that outcome measures following exposure to intermittent hypoxia may be linked to the administered dose. The present review is designed to emphasize the less recognized beneficial outcomes associated with intermittent hypoxia. The review will consider the role intermittent hypoxia has in cardiovascular and autonomic adaptations, respiratory motor plasticity, and cognitive function. Each section will highlight the literature that contributed to the belief that intermittent hypoxia leads primarily to detrimental outcomes. The second segment of each section will consider the possible risks associated with experimentally rather than naturally induced intermittent hypoxia. Finally, the body of literature indicating that intermittent hypoxia initiates primarily beneficial outcomes will be considered. The overarching theme of the review is that the use of intermittent hypoxia in research investigations, coupled with reasonable safeguards, should be encouraged because of the potential benefits linked to the administration of a variety of low-risk intermittent hypoxia protocols.

Time of day affects the frequency and duration of breathing events and the critical closing pressure during NREM sleep in participants with sleep apnea

We investigated if the number and duration of breathing events coupled to upper airway collapsibility were affected by the time of day. Male participants with obstructive sleep apnea completed a constant routine protocol that consisted of sleep sessions in the evening (10 PM to 1 AM), morning (6 AM to 9 AM), and afternoon (2 PM to 5 PM). On one occasion the number and duration of breathing events was ascertained for each sleep session. On a second occasion the critical closing pressure that demarcated upper airway collapsibility was determined. The duration of breathing events was consistently greater in the morning compared with the evening and afternoon during N1 and N2, while an increase in event frequency was evident during N1. The critical closing pressure was increased in the morning (2.68 ± 0.98 cmH2O) compared with the evening (1.29 ± 0.91 cmH2O; P ≤ 0.02) and afternoon (1.25 ± 0.79; P ≤ 0.01). The increase in the critical closing pressure was correlated to the decrease in the baseline partial pressure of carbon dioxide in the morning compared with the afternoon and evening (r = -0.73, P ≤ 0.005). Our findings indicate that time of day affects the duration and frequency of events, coupled with alterations in upper airway collapsibility. We propose that increases in airway collapsibility in the morning may be linked to an endogenous modulation of baseline carbon dioxide levels and chemoreflex sensitivity (12), which are independent of the consequences of sleep apnea.

Time of day affects chemoreflex sensitivity and the carbon dioxide reserve during NREM sleep in participants with sleep apnea

Our investigation was designed to determine whether the time of day affects the carbon dioxide reserve and chemoreflex sensitivity during non-rapid eye movement (NREM) sleep. Ten healthy men with obstructive sleep apnea completed a constant routine protocol that consisted of sleep sessions in the evening (10 PM to 1 AM), morning (6 AM to 9 AM), and afternoon (2 PM to 5 PM). Between sleep sessions, the participants were awake. During each sleep session, core body temperature, baseline levels of carbon dioxide (PET(CO2)) and minute ventilation, as well as the PET(CO2) that demarcated the apneic threshold and hypocapnic ventilatory response, were measured. The nadir of core body temperature during sleep occurred in the morning and was accompanied by reductions in minute ventilation and PetCO2 compared with the evening and afternoon (minute ventilation: 5.3 ± 0.3 vs. 6.2 ± 0.2 vs. 6.1 ± 0.2 l/min, P < 0.02; PET(CO2): 39.7 ± 0.4 vs. 41.4 ± 0.6 vs. 40.4 ± 0.6 Torr, P < 0.02). The carbon dioxide reserve was reduced, and the hypocapnic ventilatory response increased in the morning compared with the evening and afternoon (carbon dioxide reserve: 2.1 ± 0.3 vs. 3.6 ± 0.5 vs. 3.5 ± 0.3 Torr, P < 0.002; hypocapnic ventilatory response: 2.3 ± 0.3 vs. 1.6 ± 0.2 vs. 1.8 ± 0.2 l·min(-1)·mmHg(-1), P < 0.001). We conclude that time of day affects chemoreflex properties during sleep, which may contribute to increases in breathing instability in the morning compared with other periods throughout the day/night cycle in individuals with sleep apnea.

Exposure to intermittent hypoxia and sustained hypercapnia reduces therapeutic CPAP in participants with obstructive sleep apnea

Our purpose was to determine whether exposure to mild intermittent hypoxia leads to a reduction in the therapeutic continuous positive airway pressure required to eliminate breathing events. Ten male participants were treated with twelve 2-min episodes of hypoxia ([Formula: see text] ≈50 mmHg) separated by 2-min intervals of normoxia in the presence of [Formula: see text] that was sustained 3 mmHg above baseline. During recovery from the last episode, the positive airway pressure was reduced in a stepwise fashion until flow limitation was evident. The participants also completed a sham protocol under normocapnic conditions, which mimicked the time frame of the intermittent hypoxia protocol. After exposure to intermittent hypoxia, the therapeutic pressure was significantly reduced (i.e., 5 cmH2O) without evidence of flow limitation (103.4 ± 6.3% of baseline, P = 0.5) or increases in upper airway resistance (95.6 ± 15.0% of baseline, P = 0.6). In contrast, a similar decrease in pressure was accompanied by flow limitation (77.0 ± 1.8% of baseline, P = 0.001) and an increase in upper airway resistance (167.2 ± 17.5% of baseline, P = 0.01) after the sham protocol. Consistent with the initiation of long-term facilitation of upper airway muscle activity, exposure to intermittent hypoxia reduced the therapeutic pressure required to eliminate apneic events that could improve treatment compliance. This possibility, coupled with the potentially beneficial effects of intermittent hypoxia on comorbidities linked to sleep apnea, suggests that mild intermittent hypoxia may have a multipronged therapeutic effect on sleep apnea.NEW & NOTEWORTHY Our new finding is that exposure to mild intermittent hypoxia reduced the therapeutic pressure required to treat sleep apnea. These findings are consistent with previous results, which have shown that long-term facilitation of upper muscle activity can be initiated following exposure to intermittent hypoxia in humans.

Impact of arousal threshold and respiratory effort on the duration of breathing events across sleep stage and time of night

PURPOSE The frequency and duration of breathing events are influenced by sleep stage and time of day. In the present study we examined if these modifications are linked to adaptations in the arousal threshold and/or the magnitude of respiratory effort during and immediately after breathing events. METHODS Participants with sleep apnea slept for 3h in the evening and morning. For breathing events detected during these sessions the rate of change of respiratory effort, maximum respiratory effort immediately prior to termination of an event, and the maximum tidal volume and the minimum partial pressure of end-tidal carbon dioxide (PETCO2) immediately following an event were measured. RESULTS The rate of change of respiratory effort was similar in N2 compared to N1 but the maximum respiratory effort immediately prior to event termination was greater (-10.7±1.2 vs. -9.6±1.0cmH2O/s, P<0.05). Likewise, tidal volume was increased (1169±105 vs. 1082±100ml, P<0.05) and PETCO2 was decreased (37.0±0.8 vs. 37.7±0.8mmHg P<0.05) following events in N2 compared to N1. A similar tidal volume and PETCO2 response was evident following events in the morning compared to the evening independent of sleep stage. CONCLUSIONS We conclude that alterations in the arousal threshold, reflected by an increase in respiratory effort at event termination, coupled to increases in tidal volume and reductions in PETCO2 contribute to modifications in event duration and frequency associated with variations in sleep state or time of night.

The impact of intermittent or sustained carbon dioxide on intermittent hypoxia initiated respiratory plasticity. What is the effect of these combined stimuli on apnea severity

The following review explores the effect that intermittent or sustained hypercapnia coupled to intermittent hypoxia has on respiratory plasticity. The review explores published work which suggests that intermittent hypercapnia leads to long-term depression of respiration when administered in isolation and prevents the initiation of long-term facilitation when administered in combination with intermittent hypoxia. The review also explores the impact that sustained hypercapnia alone and in combination with intermittent hypoxia has on the magnitude of long-term facilitation. After exploring the outcomes linked to intermittent hypoxia/hypercapnia and intermittent hypoxia/sustained hypercapnia the translational relevance of the outcomes as it relates to breathing stability during sleep is addressed. The likelihood that naturally induced cycles of intermittent hypoxia, coupled to oscillations in carbon dioxide that range between hypocapnia and hypercapnia, do not initiate long-term facilitation is addressed. Moreover, the conditions under which intermittent hypoxia/sustained hypercapnia could serve to improve breathing stability and mitigate co-morbidities associated with sleep apnea are considered.