Targeted Therapies for Selected Phenotypes of Obstructive Sleep Apnea

描述（由申请人提供）：本申请涉及广泛的挑战领域（05）比较有效性研究和特定的挑战主题（05-HL-102）阻塞性睡眠呼吸暂停治疗。大约15 - 30%的阻塞性睡眠呼吸暂停（OSA）患者对经鼻施加的持续气道正压通气（CPAP）的耐受性差，或者响应于这种标准护理而发展成有问题的中枢性呼吸暂停。虽然已经尝试了各种替代疗法，但迄今为止仍然没有针对这些难治性或困难病例的有效管理，这可能是因为大多数可用的治疗方法仅旨在降低COPD患者的上气道（UAW）可膨胀性，而不关心导致每个个体OSA的主要机制。最近的研究表明，睡眠期间的呼吸不稳定性在那些显示呼吸控制系统的高控制器增益（对PaCO2变化的呼吸反应）和/或高植物增益（正常呼吸PaCO2）的OSA患者中更显著，如通过减少的CO2储备[？（正常呼吸PaCO2-呼吸暂停阈值PaCO2）]。正如我们以前报道的，周期性呼吸和中枢性呼吸暂停经常导致上呼吸道塌陷较多的受试者在呼吸驱动的最低点发生周期性气道阻塞。因此，我们假设，纠正呼吸系统不稳定性将改善气道通畅性和呼吸的患者，其特征是呼吸运动输出显著不稳定，轻度至中度UAW可耐受性。这种方法对于那些表现出不太明显的控制不稳定性和/或具有非常严重的UAW可操作性的人来说效果较差。我们将在30名OSA患者中描述气道可扩展性和呼吸控制系统稳定性。然后，我们将检查三种不同治疗策略对这些具有广泛呼吸稳定性和UAW可接受性的患者的呼吸暂停/呼吸不足指数（AHI）和O2去饱和的影响：（1）通过独特的等碳酸再呼吸应用预防短暂性低碳酸血症;（2）通过乙酰唑胺减少植物增益;（3）在睡眠期间通过高氧抑制控制器增益。我们假设：（1）在更广泛的OSA患者中，预防短暂性低碳酸血症对AHI的所有三种治疗方法的效果最显著，因为它可以防止上气道和胸壁肌肉募集以及呼吸系统稳定性的强大决定因素（即PaCO2）降低。因此，我们希望这种治疗能显著降低AHI，即使是在中度气道阻塞和不稳定的呼吸控制的患者中。(2)通过碳酸酐酶抑制（和轻度代谢性酸中毒）增加呼吸运动输出和减少植物增益将消除中枢性呼吸暂停，并显著减少因植物或控制器增益增加而导致CO2储备变窄的受试者的阻塞性和混合性呼吸暂停，同时伴有轻度气道不稳定性，但对重度UAW不稳定性或潜在呼吸不稳定性程度不显著的受试者可能无效。(3)高氧可通过降低CO2储备减少（主要是由于控制器增益增加）伴轻度气道不稳定性的OSA患者的环路增益来改善呼吸稳定性并减少OSA，但对重度UAW不稳定性或呼吸不稳定性不明显的患者可能无效。我们预计，三种治疗方法中的任何一种都不会改善患有更严重不稳定和可塌陷UAW的患者的AHI，因为即使在睡眠期间这些扩张肌的运动输出大量增加，也不足以打开或防止这种高度可塌陷气道的关闭。这些患者的气道通畅可能需要唤醒和觉醒。拟议的研究将加深我们对每种OSA表型的异位重要性的理解，并为管理难治性OSA的个体化靶向治疗方法铺平道路。 公共卫生相关性：我们希望通过对患者与上气道可膨胀性和/或呼吸稳定性相关的特定问题进行个体化治疗，改善OSA患者睡眠期间的呼吸。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (05) Comparative Effectiveness Research and specific Challenge Topic (05-HL-102) Treatment of Obstructive Sleep Apnea. About 15-30% of obstructive sleep apnea (OSA) patients have a poor tolerance for nasally-applied continuous positive airway pressure (CPAP) or develop problematic central apneas in response to this standard care. Although various alternative therapies have been tried, there is so far still no effective management for these refractory or difficult cases, probably because most available treatments are merely aimed at reducing the upper airway (UAW) collapsibility in unselected patients without concern for the dominant mechanism causing each individual's OSA. Recent research has revealed that breathing instability during sleep is more significant in those OSA patients who show high controller gain (ventilatory response to change of PaCO2) and/or high plant gain (eupnea PaCO2) of the respiratory control system, as manifested by a reduced CO2 reserve [?(eupneic PaCO2-apneic threshold PaCO2 )]. As we reported previously, periodic breathing and central apnea often lead to cyclical airway obstruction at the nadir of the respiratory drive in subjects with more collapsible upper airways. Accordingly, we hypothesize that correcting respiratory system instability will improve airway patency and breathing for those patients who are characterized by a significantly unstable respiratory motor output with mild to moderate levels of UAW collapsibility. This approach will be less effective with those who demonstrate less significant control instability and/or have extremely severe UAW collapsibility. We will characterize airway collapsibility and respiratory control system stability in 30 OSA patients. Then we will examine the effects on apnea/hypopnea index (AHI) and O2 desaturation of three different therapeutic strategies in these patients with a wide spectrum of breathing stability and UAW collapsibility:(1) prevention of transient hypocapnia via a unique iso-capnic rebreathing application; (2) reduction of plant gain via acetazolamide; and (3) a dampening of controller gain via hyperoxia, during sleep. We hypothesize that (1) Preventing transient hypocapnia should have the most significant effect of all three treatments on AHI in a broader range of OSA patients because it will prevent reductions in such a powerful determinant (i.e. PaCO2) of both upper airway and chest wall muscle recruitment as well as of respiratory system stability. Accordingly, we would expect this treatment to significantly reduce AHI even in patients with moderate airway collapsibility and with unstable ventilatory control. (2) Increasing respiratory motor output and reducing plant gain via carbonic anhydrase inhibition (and mild metabolic acidosis) will eliminate central apneas and significantly reduce obstructed and mixed apneas in subjects with a narrowed CO2 reserve due to increased plant or controller gain combined with mild levels of airway collapsibility, but may not be effective in those with severe UAW collapsibility or insignificant degrees of underlying breathing instability. (3) Hyperoxia will improve breathing stability and reduce OSA by reducing loop gain in OSA patients with a narrowed CO2 reserve (mainly due to increased controller gain) combined with mild levels of airway collapsibility, but may not be effective in those with severe UAW collapsibility or insignificant breathing instability. We anticipate that AHI in patients with even more severely unstable and collapsible UAW will not be improved by any of the three treatments because even a substantial amount of increased motor output to these dilator muscles during sleep will not be sufficient to open or prevent closure of such high collapsible airways. Arousal and wakefulness are likely required for airway patency in these patients. The proposed studies will deepen our understanding of the importance of heteropathy for each phenotype of OSA and will pave the way for individually targeted treatment approaches for managing refractory OSA. PUBLIC HEALTH RELEVANCE: We hope to improve the breathing during sleep in patients with OSA by individualizing their treatment to the patients' specific problem(s) associated with upper airway collapsibility and/or breathing stability.