1/2 Ganciclovir to Prevent Reactivation of Cytomegalovirus in Patients with Acute Respiratory Failure and Sepsis

项目总结 脓毒症相关的急性呼吸衰竭是导致发病率、死亡率和医疗费用的主要原因。 在世界范围内，而且发病率正在增加。尽管进行了深入的研究，但很少有药理方面的研究 干预措施，护理在很大程度上是支持性的。巨细胞病毒(CMV)是一种人类疱疹病毒，可感染50- 80%的健康成年人并在肺部建立终生潜伏期，通常仅在 严重免疫抑制的病人。约40%的CMV会从潜伏期重新激活(病毒复制) 在危重疾病期间血清阳性，其他免疫能力强的人，并与较差的临床相关 结果包括死亡率增加、机械通气时间延长和ICU住院时间延长。 令人信服的证据表明，CMV重新激活是导致脓毒症发病率和死亡率的原因之一。 相关的呼吸衰竭来自动物模型和我们最近完成的NHLBI资助的第二阶段 更昔洛韦预防的随机安慰剂对照试验。在这项试验中，在CMV血清阳性的成年人中 对于脓毒症相关的呼吸衰竭，更昔洛韦有效地抑制了CMV的复制，具有可接受的 安全状况，并与改善临床结果有关，包括增加无呼吸机天数 (VFD)，幸存者更短的机械通气时间，更短的ICU住院时间，以及改善 第7天存活者的PaO2/FiO2比值。我们假设危重疾病早期静脉注射更昔洛韦将 有效抑制巨细胞病毒血清阳性成人脓毒症相关急性呼吸道巨细胞病毒再激活 失败，从而减少肺损伤，加快康复，并导致改善临床结果。 我们建议进行3期随机对照试验，以确定给予的抗病毒药物更昔洛韦是否具有预防作用。 在ICU入院后5天内给药可改善VFD和其他临床相关结果 败血症相关急性呼吸衰竭的CMV血清免疫活性阳性成人。我们将衡量 研究干预对主要试验结果(VFD)和次要结果(28岁死亡率)的影响 天数、存活者机械通气持续时间、氧合、静态呼吸系统顺应性、CMV 血浆和肺重新激活，以及在6个月时的一套核心长期结果)。在探索性分析中，我们 将评估基线因素作为CMV重新激活的预测因素，并表征CMV病毒之间的关系 VFD的负荷动力学和其他临床结果。 我们的跨学科团队在成功协调多站点多PI ICU方面拥有独特的经验 RCT。我们在美国建立了一个由19个临床站点组成的网络，所有这些站点都拥有强大的基础设施 ICU临床试验和已证明的招募患者进入随机对照试验的能力。如果它是有效的，这是廉价和可行的 干预有可能显著改善脓毒症相关性呼吸衰竭患者的护理， 极大地改变了临床实践，并为脓毒症与CMV重新激活的关系提供了新的见解。

PROJECT SUMMARY Sepsis-associated acute respiratory failure is a leading cause of morbidity, mortality and health care expenditure world-wide, and is increasing in incidence. Despite intensive investigation, there are few pharmacologic interventions, and care is largely supportive. Cytomegalovirus (CMV) is a human herpesvirus that infects 50- 80% of healthy adults and establishes lifelong latency in the lung, generally causing overt disease only in severely immunosuppressed patients. CMV reactivation (viral replication) from latency occurs in ~40% of CMV seropositive, otherwise immunocompetent persons during critical illness and is associated with worse clinical outcomes including increased mortality, prolonged mechanical ventilation, and increased ICU length of stay. Compelling evidence implicating CMV reactivation as a causal contributor to morbidity and mortality in sepsis- associated respiratory failure comes from animal models and our recently completed NHLBI-funded phase 2 randomized placebo-controlled trial (RCT) of ganciclovir prophylaxis. In this trial, among CMV seropositive adults with sepsis-associated respiratory failure, ganciclovir effectively suppressed CMV replication, had an acceptable safety profile, and was associated with improved clinical outcomes, including increased ventilator-free days (VFD), shorter duration of mechanical ventilation among survivors, shorter ICU length of stay, and improved PaO2/FiO2 ratio in day-7 survivors. We hypothesize that IV ganciclovir administered early in critical illness will effectively suppress CMV reactivation in CMV seropositive adults with sepsis-associated acute respiratory failure, thereby reducing lung damage, accelerating recovery, and leading to improved clinical outcomes. We propose to conduct a phase 3 RCT to determine whether the antiviral drug ganciclovir given as prophylaxis improves VFDs and other clinically relevant outcomes when administered within 5 days of ICU admission to CMV seropositive immunocompetent adults with sepsis-associated acute respiratory failure. We will measure the effect of the study intervention on the primary trial outcome (VFDs) and secondary outcomes (mortality at 28 days, duration of mechanical ventilation in survivors, oxygenation, static respiratory system compliance, CMV plasma and lung reactivation, and a core set of longer-term outcomes at 6 months). In exploratory analyses, we will assess baseline factors as predictors for CMV reactivation, and characterize the relationship of CMV viral load kinetics with VFDs and other clinical outcomes. Our interdisciplinary team has unique experience in successfully coordinating multi-site multi-PI ICU-based RCTs. We have established a network of 19 clinical sites in the US, all of which have robust infrastructure for ICU clinical trials and proven ability to recruit patients into RCTs. If it is effective, this inexpensive and feasible intervention has the potential to significantly improve care of patients with sepsis-associated respiratory failure, substantially change clinical practice, and offer new insights into the sepsis-CMV reactivation relationship.