A 7-DAY MULTICENTER TRIAL OF IV SILDENAFIL FOR NEONATES WITH PPHN

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。每1000名活产儿中有1.9人被诊断为新生儿持续性肺动脉高压(PPHN)。该综合征包括肺血管收缩，通过动脉导管和/或卵圆孔从右向左分流，以及没有先天性心脏病证据的严重低氧血症。PPHN的不同潜在病理生理学早期表现为对100%氧气无反应的缺氧性呼吸衰竭。新生儿缺氧性呼吸衰竭不能通过机械通气技术、表面活性物质应用、碱化、镇静和神经肌肉阻断来控制，通常使用吸入一氧化氮(INO)治疗。这种疗法通过扩张肺部通风较好区域的肺血管，将肺血流从低通气性/灌注率较低的肺区重新分配到正常的区域，从而提高动脉血氧分压(PaO2)。它是唯一一种选择性肺血管扩张剂，可改善PPHN缺氧性阻力衰竭新生儿的氧合功能。当iNO无效时，受试者可以维持体外膜氧合(ECMO)，为功能障碍的心脏提供泵支持，为衰竭的肺提供氧合。ECMO已被描述为最具侵入性的治疗方式和最终的救援。缺氧性呼吸衰竭是新生儿ECMO转诊的最常见原因。新生儿吸入性一氧化氮研究小组(NINOS)和临床吸入性一氧化氮研究小组(CINRGI)的试验表明，iNO治疗显著减少了缺氧性呼吸衰竭和/或PPHN患者对ECMO的需求。尽管有这样的疗效，NINOS和CINRGI的试验，分别有39%和38%的接受iNO的受试者最终接受了ECMO治疗，因为iNO未能纠正他们的缺氧性呼吸衰竭。最近的数据(2000年)显示，患有PPHN的新生儿需要ECMO的存活率约为80%。在NINOS和CINRGI以及iNO的广泛应用之后，在许多新生儿中心已经成为常规的用iNO治疗缺氧性呼吸衰竭，即，在存在较轻程度的低氧血症时，比在NINOS和CINRGI(0I&>25)和没有PPHN临床证据的情况下开始治疗。背景：内皮型一氧化氮通过刺激细胞内鸟苷环化酶，进而通过升高肺动脉血管平滑肌细胞内的环鸟苷单磷酸(CGMP)来扩张肺血管。CGMP升高可降低细胞内钙离子水平，从而引起平滑肌细胞的松弛，从而降低肺动脉压(PAP)和肺血管阻力(PVR)。磷酸二酯酶5(PDE5)是一种能将细胞内CGMP代谢为无活性的5-GMP的酶，存在于人的肺动脉中。西地那非是PDE5的抑制剂，因此减缓了CGMP的降解，导致细胞内钙水平降低，最终减少了PAP和PVR。在肺动脉高压大鼠离体肺灌流中，CGMP水平较对照肺升高9倍以上。在清醒的急性肺动脉高压羔羊模型中，累积剂量西地那非(12.5、25和50 mg，间隔15分钟)分别使PAP和PVR分别降低21%、28%和42%，PVR分别降低19%、23%和45%。体动脉压仅在最大累积西地那非剂量后下降12%。在气管内滴注胎粪所致肺动脉高压的仔猪模型上，静脉注射西地非能在治疗1小时后完全逆转PVR的增加。相比之下，iNO使PVR降低了40%。在没有接受任何治疗的对照仔猪中，PVR仍然升高。西地那非没有导致全身血管扩张，表现出选择性的PDE5抑制肺血管系统。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Persistent Pulmonary Hypertension of the Newborn (PPHN) is diagnosed in 1.9 per 1,000 live births. The syndrome includes pulmonary vasoconstriction, right-to-left shunting through the ductus arteriosus and/or foramen ovale, and severe hypoxemia without evidence of congenital heart disease. The diverse underlying pathophysiologies of PPHN present early as hypoxic respiratory failure that is not responsive to 100% oxygen. Newborns with hypoxic respiratory failure who are not controlled by mechanical ventilation techniques, surfactant administration, alkalinization, sedation, and neuromuscular blockade are typically treated with inhaled Nitric Oxide (iNO). This treatment increases the partial pressure of arterial oxygen (PaO2) by dilating pulmonary vessels in better ventilation areas of the lung, redistributing pulmonary blood flow away from lung regions with low ventilation/perfusion ratios toward regions with normal ratios. It is the only selective pulmonary vasodilator that has shown to improve oxygenation in newborns with hypoxic resiratory failure of PPHN. When iNO is not effective, subjects may be maintained with extracorporeal membrane oxygenation (ECMO), which provides pump support for the dysfunctional heart and oxygenation for the failing lungs. ECMO has been described as the most invasive therapeutic modality and the ultimate rescue. Hypoxic respiratory failure is the most common reason for referral for neonatal ECMO. The Neonatal Inhaled Nitric Oxide Study Group (NINOS) and Clinical Inhaled Nitric Oxide Research Group (CINRGI) trials showed that treatment with iNO significantly reduces the need for ECMO in subjects with hypoxic respiratory failure and/or PPHN. Despite this therapeutic benefit, the NINOS and CINRGI trials, 39% and 38% of the subjects who received iNO, respectively, were eventually treated with ECMO because iNO had failed to correct their hypoxic respiratory failure. Recent data (year 2000) shows the survival rate for newborns with PPHN who require ECMO is approximately 80%. Subsequent to NINOS and CINRGI and the widespread availability of iNO, it has become routine in many neonatal centers to treat hypoxic respiratory failure with iNO earlier, ie, in the presence of lesser degrees of hypoxemia, than it was initiated in NINOS and CINRGI (0I>25) and without clinical evidence of PPHN. Background Endothelial nitric oxide dilates pulmonary blood vessels by stimulating intracellular guanylate cyclase, therby elevating intracellular cyclic guanosine monophosphate (CGMP) in pulmonary arterial vascular smooth muscle cells. Elevated CGMP reduces levels of intracellular calcium and thereby causes relaxation of smooth muscle cells, leading to reduction in pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR). Phosphodiesterase type 5 (PDE5) is an enzyme that metabolizes intracellular CGMP to inactive 5-GMP and is found in human pulmonary arteries. Sildenafil is an inhibitor of PDE5 and hence slows the degradation of CGMP, resulting in lower levels of intracellular calcium and ultimately a reduction in PAP and PVR. It has been shown in isolated perfused lung from rats with pulmonary hypertension that CGMP levels in the perfusate are elevated over 9-fold compared with control lung. In an awake lamb model of acute pulmonary hypertension, cumulative doses of sildenafil (12.5, 25, and 50 mg via nasogastric tube at 15 minute intervals) decreased the PAP 21%, 28%, and 42%, respectively, and the PVR by 19%, 23%, and 45%, respectively. Systemic arterial pressure decreased 12% only after the maximum cumulative sildenafil dose. In a piglet model of pulmonary hypertension induced by endotracheal meconium instillation, IV sildenfil was shown to completely reverse the increase in PVR after just 1 hour of treatment. In comparison, iNO reduced PVR by 40%. PVR remained elevated in control piglets that received no treatment. Sildenafil did not result in systemic vasodilation, demonstrating selective PDE5 inhibition in the pulmonary vasculature.