Attenuating Inflammation via Protein-Calorie Restriction

描述(由申请人提供)： 这项建议的目的是培养托德·W·赖斯博士在设计和进行临床试验方面的科学发展和提升技能，使他可以成为进行临床研究的独立研究员。范德比尔特大学医学中心将通过其几个重症监护病房，为赖斯博士提供必要的患者群体，以进行一项前瞻性、随机的临床试验，比较机械通气危重患者中营养营养与先进营养的效果，以及全卡路里比率。实验室资源可用于研究生化反应的变化，包括促炎和抗炎细胞因子反应。将评估临床结果的差异，包括患者脱离呼吸机的情况。通过与他的临床导师Arthur P.Wheeler博士的合作，赖斯博士将擅长试验设计、生物统计学、流行病学、患者招募以及向科学界报告结果。这些技能将为赖斯博士在重症监护研究领域追求独立的学术生涯奠定基础。许多机械通气的患者无法自我营养，只能通过肠内或肠外的方式获得营养。肠内营养已被证明可以通过保护肠道粘膜、减少细菌易位和减少全身感染来减少炎症和改善临床结果。尽管在完全肠道喂养的情况下观察到了这些改善，但非常低的肠道喂养率在动物身上显示了类似的保护作用。我们假设，这些低水平的喂养也保护了机械通气患者的肠道粘膜，同时减少了这些患者的促炎和抗炎细胞因子反应以及胃肠道并发症，与全热量喂养相比，结果是改善了临床结果。这项建议的具体目的是证明，与全热量肠内喂养相比，低水平的肠道喂养将：1)减少早期的促炎和代偿性抗炎细胞因子反应；2)减少喂养并发症的发生率，从而，3) 改善临床结果，如无呼吸机日和其他器官衰竭日。老龄化 人口增加、免疫抑制增加以及侵入性手术的使用增加将导致危重护理的持续增长。许多机械通气的危重病人需要肠内营养支持。尽管广泛使用，但缺乏向此类患者提供最佳肠内营养的数据。这项建议将有助于权衡好处和风险，建立一种降低喂养并发症的经济高效的方法，并为未来研究需要机械通气的急性呼吸衰竭患者的肠内喂养奠定基础。

DESCRIPTION (provided by applicant): The purpose of this proposal is to cultivate the scientific development and advance the skills of Dr. Todd W. Rice in the design and conduct of clinical trials, so that he may become an independent investigator in conducting clinical research. Vanderbilt University Medical Center, through its several intensive care units, will provide Dr. Rice with the necessary patient population to conduct a prospective, randomized clinical trial comparing the effects of trophic nutrition versus advancement to full-calorie rates in mechanically ventilated, critically ill patients. Laboratory resources are available to investigate changes in biochemical responses, including pro- and anti-inflammatory cytokine responses. Differences in clinical outcomes, including weaning patients from the ventilator, will be assessed. Through collaboration with his clinical mentor, Dr. Arthur P. Wheeler, Dr. Rice will become adept at trial design, biostatistics, epidemiology, patient recruitment, and reporting of results to the scientific community. These skills will provide the foundation for Dr. Rice to pursue an independent academic career in critical care research. Many mechanically ventilated patients, unable to nourish themselves, are provided with nutrition, either enterally or parenterally. Enteral nutrition has been shown to reduce inflammation and improve clinical outcomes by preserving the intestinal mucosa, decreasing bacterial translocation, and reducing systemic infections. Although these improvements have been observed with full enteral feedings, very low rates of enteral feedings show similar protection in animals. We hypothesize that these low-level feedings also preserve the intestinal mucosa in ventilated patients, while reducing the pro- and anti-inflammatory cytokine responses seen in these patients along with the gastrointestinal complications, resulting in improved clinical outcomes compared to full-calorie feeds. The specific aims of this proposal are to demonstrate that low-level as compared to full-calorie enteral feedings will: 1) decrease the early pro-inflammatory and compensatory anti-inflammatory cytokine responses; 2) decrease the incidence of feeding complications, and thus, 3) improve clinical outcomes, such as ventilator-free days and other organ-failure free days. The aging population, increasing immunosuppression, and rising use of invasive procedures will result in the continued growth of critical care. Many mechanically ventilated, critically ill patients are supported with enteral nutrition. Despite widespread use, data on optimal delivery of enteral nutrition to such patients is lacking. This proposal will help weigh the benefits and risks, establish a cost-efficient means of reducing feeding complications, and provide the foundation for future studies of enteral feeds in patients with acute respiratory failure requiring mechanical ventilation.