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Date of Award
Jason H. Mateika
Purpose: Our project was designed to determine the effect of time of day on multiple mechanisms influencing breathing stability and respiratory plasticity. We investigated if the number and duration of breathing events coupled to upper airway collapsibility, as well as the carbon dioxide reserve, chemoreflex sensitivity and arousal threshold during non-rapid eye movement (NREM) sleep were affected by the time of day. In addition, we examined if mild intermittent hypoxia (IH) initiates long-term facilitation of upper airway muscle activity leading to a reduction in the therapeutic continuous positive airway pressure required to eliminate breathing events.
Methods: 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. 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 Participants then completed the same protocol on two additional occasions, where the critical closing pressure that demarcated upper airway collapsibility was determined on one, and 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 on the other (the order of these 2 visits was randomized). In the second aim of the study, male participants with obstructive sleep apnea were treated with twelve 2-minute episodes of hypoxia (PETO2 ≈ 50 mmHg) separated by 2-minute intervals of normoxia in the presence of PETCO2 that was sustained 3 mmHg above baseline. During recovery from the last episode the positive airway pressure was reduced in a step-wise fashion until flow limitation was evident. The participants also completed a sham protocol under normocapnic conditions, which mimicked the timeframe of the IH protocol.
Results: 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).. 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 lt; 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). 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 ± 1.0 cmH2O/s, P < 0.05). Likewise, tidal volume was increased (1169 ± 105 vs. 1082 ± 100 ml, P < 0.05) and PETCO2 was decreased (37.0 ± 0.8 vs. 37.7 ± 0.8 mmHg 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. After exposure to IH the therapeutic pressure was significantly reduced (Δ CPAP = - 4.95 ± 0.5 cmH2O, p < 0.001) without evidence of flow limitation (P > 0.2) or increases in upper airway resistance (P > 0.4). In contrast, a similar decrease in pressure was accompanied by significant flow limitation (P < 0.003) and an increase in upper airway resistance (P < 0.01) following completion of the sham protocol.
Conclusion: Our findings indicate that time of day affects the duration and frequency of events, coupled with alterations in upper airway collapsibility and 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. 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, which are independent of the consequences of sleep apnea. We also 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. In addition, Exposure to IH decreases the therapeutic pressure required to eliminate apneic events which could improve treatment compliance. This possibility coupled with the direct beneficial effects of IH on co-morbidities linked to sleep apnea suggests that IH may have a multipronged therapeutic effect on sleep apnea.
El Chami, Mohamad, "Circadian Modulation Of Breathing Stability And Respiratory Plasticity" (2017). Wayne State University Dissertations. 1800.