PROtecting Maternal brains from Injury and Stroke (PROMIS): a Single-center Phase 2 Clinical Trial

项目摘要/摘要 先兆子痫(PEC)影响每20个孕妇中就有一个，是严重孕产妇发病率和 死亡率。PEC的危及生命的神经并发症包括脑出血、脑出血、脑出血 浮肿、脑血管痉挛和缺血性中风。大多数孕产妇死于与PEC相关的疾病 脑血管并发症发生在产后。尽管如此，临床研究主要集中在 产前血压(BP)治疗，而不是产后。目前的BP管理指南 产后患者建议治疗的绝对阈值，不考虑以下因素 较患者基线血压变化的程度或速度。临床医生迫切需要更好的方法来1)识别 这些产后并发症的风险人群，以及2)指导BP治疗 针对脑保护进行了优化的个性化、精确靶点。正常的大脑功能需要恒定的大脑 血流量(CBF)。大脑小动脉对血压波动做出积极反应，保护大脑 由低或高灌注量引起的急性损伤，这种现象被称为大脑自动调节。变化 脑自身调节参与产后脑血管并发症的病理生理过程。在……里面 自我调节受损的个体，以血压参数为目标优化脑血流灌注可能会有所帮助 降低脑缺血、颅内压升高、脑水肿和脑出血的风险。 近红外光谱(NIRS)是一种测量脑组织的非侵入性床边监测方式 氧合作为CBF的代用品。使用基于NIRS的自动调节引导的血压靶点改善临床 神经损伤患者的预后。我们建议将这一新方法应用于管理 产后PEC(分娩后6周内)单中心第二阶段临床试验，PROMIS(保护 母亲的大脑因损伤和中风而死亡)。我们将使用NIRS监测来计算个性化限制 20名有严重症状的产后先兆子痫患者的脑自我调节(目标1)； 产后重度子痫前期患者应用自动调节引导的血压目标治疗 20人(目标2)。我们假设：1)基于标准指南的产后PEC血压管理 超过24小时将导致≥在10%的时间内BP超过个性化上限或下限 自动调节；2)在自动调节的个性化限制之外使用BP的时间越长，将与a) 神经症状增加和b)NIRS脑部低或高血流灌注的客观证据；以及 3)使用自动调节引导目标的有针对性的BP管理将导致较少的神经症状和 与根据当前指南治疗的患者相比，在自动调节限制之外花费的时间更少。 这项新颖、高风险、高回报的试验将是第一个旨在 预防因神经原因导致的产后产妇死亡和残疾。

PROJECT SUMMARY/ABSTRACT Preeclampsia (PEC) affects 1 in 20 pregnancies and is a leading cause of severe maternal morbidity and mortality. Life-threatening neurological complications of PEC include intracerebral hemorrhage, cerebral edema, cerebral vasospasm, and ischemic stroke. Most maternal deaths due to PEC-associated cerebrovascular complications occur postpartum. Despite this, clinical research has primarily focused on antepartum blood pressure (BP) treatment, rather than postpartum. Current BP management guidelines for postpartum patients recommend absolute thresholds for treatment, without accounting for factors such as degree or rapidity of change from patients’ baseline BP. Clinicians urgently need better methods to 1) identify individuals at risk for these devastating postpartum complications, and 2) guide BP management using personalized, precise targets optimized for brain protection. Normal brain function requires constant cerebral blood flow (CBF). Cerebral arterioles respond actively in response to fluctuations in BP, protecting the brain from acute injury due to hypo- or hyper-perfusion, a phenomenon known as cerebral autoregulation. Changes in cerebral autoregulation contribute to the pathophysiology of postpartum cerebrovascular complications. In individuals with impaired autoregulation, targeting BP parameters to optimize cerebral perfusion could help reduce the risk of ischemia, elevated intracranial pressure, cerebral edema and intracerebral hemorrhage. Near-infrared spectroscopy (NIRS) is a non-invasive bedside monitoring modality that measures brain tissue oxygenation as a proxy for CBF. The use of NIRS-based autoregulation-guided BP targets improves clinical outcomes in neurologically injured patients. We propose to apply this novel approach to the management of postpartum PEC (within 6 weeks of delivery) in a single-center, Phase II clinical trial, PROMIS (PROtecting Maternal brains from Injury and Stroke). We will use NIRS monitoring to calculate personalized limits of cerebral autoregulation in 20 individuals with postpartum preeclampsia with severe features (Aim 1); and pilot the use of autoregulation-guided BP goals for postpartum preeclampsia with severe features in an additional 20 individuals (Aim 2). We hypothesize that: 1) standard guideline-based BP management for postpartum PEC over 24 hours will result in ≥ 10% of time during which BP exceeds personalized upper or lower limits of autoregulation; 2) more time with BP outside personalized limits of autoregulation will be associated with a) increased neurological symptoms and b) objective evidence of cerebral hypo- or hyper-perfusion by NIRS; and 3) targeted BP management using autoregulation-guided goals will result in fewer neurological symptoms and less time spent outside limits of autoregulation, compared with patients treated according to current guidelines. This novel, high-risk, high-reward trial will be the first early phase interventional neuro-obstetric trial aimed at preventing postpartum maternal death and disability due to neurological causes.