Targeted Therapies for Selected Phenotypes of Obstructive Sleep Apnea

描述(由申请人提供)：本申请涉及阻塞性睡眠呼吸暂停的广泛挑战领域(05)比较有效性研究和特定挑战主题(05-HL-102)治疗。大约15%-30%的阻塞性睡眠呼吸暂停(OSA)患者对鼻用持续气道正压(CPAP)的耐受性较差，或者在这种标准护理下出现有问题的中枢性呼吸暂停。尽管已经尝试了各种替代疗法，但到目前为止，仍然没有对这些难治或疑难病例进行有效的治疗，可能是因为大多数现有的治疗方法只是旨在减少未经选择的患者的上呼吸道(UAW)塌陷性，而没有考虑导致每个人OSA的主要机制。最近的研究表明，睡眠呼吸不稳定在那些表现出呼吸控制系统的高控制增益(对PaCO2变化的呼吸反应)和/或高植物增益(Eupnea PaCO2)的OSA患者中更为显著，表现为二氧化碳储备减少[？(Eupneic PaCO2-apneic Threshold PaCO2)]。正如我们之前所报道的，周期性呼吸和中枢性呼吸暂停通常会导致上呼吸道可折叠程度较高的受试者在呼吸驱动的最低点出现周期性的呼吸道阻塞。因此，我们假设，纠正呼吸系统不稳定将改善那些呼吸运动输出显著不稳定并伴有轻度至中度UAW塌陷水平的患者的呼吸道通畅性和呼吸。对于那些表现出不太明显的控制不稳定性和/或具有极严重的UAW塌陷性的人，这种方法将不太有效。我们将对30例阻塞性睡眠呼吸暂停综合征患者的呼吸道塌陷性和呼吸控制系统稳定性进行特征分析。然后，我们将考察三种不同治疗策略对呼吸暂停/低通气指数(AHI)和氧气减饱和的影响，这些患者具有广泛的呼吸稳定性和UAW崩解性：(1)通过独特的等二氧化碳重复呼吸预防一过性低碳酸血症；(2)通过乙酰唑胺减少植物增益；(3)通过睡眠中的高氧抑制控制者的增益。我们假设：(1)在更广泛的OSA患者中，预防一过性低碳酸血症在所有三种治疗方法中对AHI具有最显著的效果，因为它将防止上呼吸道和胸壁肌肉招募以及呼吸系统稳定性的如此强大的决定因素(即PaCO2)的降低。因此，我们预计这种治疗可以显著降低AHI，即使是在中度气道塌陷和呼吸控制不稳定的患者中也是如此。(2)通过抑制碳酸氢酶(和轻度代谢性酸中毒)来增加呼吸马达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二氧化碳储备减少的受试者的阻塞性和混合性呼吸暂停，但对于UAW严重塌陷或潜在呼吸不稳定程度不明显的受试者可能无效。(3)对于二氧化碳储备减少(主要是由于控制器增加)合并轻度气道塌陷的阻塞性睡眠呼吸暂停患者，高氧可以改善呼吸稳定性和降低OSA，但对UAW严重塌陷或呼吸不稳定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折叠UAW的患者的AHI，因为即使睡眠期间这些扩张肌的运动输出大量增加，也不足以打开或阻止这种高度可折叠的呼吸道的关闭。这些患者的呼吸道通畅可能需要觉醒和清醒。拟议的研究将加深我们对每种OSA表型的异位作用的重要性的理解，并将为治疗难治性OSA的个体化靶向治疗方法铺平道路。 公共卫生相关性：我们希望通过针对与上呼吸道塌陷和/或呼吸稳定相关的患者特定问题(S)的个体化治疗来改善阻塞性睡眠呼吸暂停患者的睡眠呼吸。

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.