Supplemental Parenteral Nutrition to Reduce Death in Malnourished ICU Patients

描述(由申请人提供)： 这项申请涉及国家心肺血液研究所临床试验试点研究(R34)。背景：危重患者应该摄入多少卡路里和蛋白质以减少发病率和死亡率，目前尚不清楚，也仍存在争议。对ICU患者目前做法的审查表明，标准医院营养方案提供的肠道能量和蛋白质的实际数量远低于处方。美国的ICU在提供规定的卡路里和蛋白质方面是世界上最不成功的。尽管在过去的几年里，在指导方针和质量改进倡议方面做出了积极的、反复的努力，但通过肠道途径输送的卡路里数量并没有显著改善。因此，如果我们要成功地改善因热量供应不足而有死亡风险的患者的能量和蛋白质供应，我们将不得不通过静脉肠外营养(PN)途径供应热量。不同的国家指南对PN在ICU中的作用提出了不同的建议，国际审计显示实践差异很大，现有的临床试验数据尽管薄弱和过时，但关于在危重疾病的早期阶段使用PN的情况存在分歧(一些显示出死亡率益处，一些显示没有死亡率益处或PN可能增加感染风险)。然而，最近的一项大型观察性研究表明，在ICU入院的早期阶段接受的能量和蛋白质的数量影响患者死亡率，与递送途径无关。这项国际多中心观察性研究对165个ICU的2772名ICU患者进行了为期72小时的机械通气，结果发现死亡几率与每日摄入的总卡路里之间存在显著的线性反比关系。关键的发现是，增加卡路里摄入量显著降低了BMI 25和BMI 35患者的死亡率，而BMI 25和35组患者的卡路里摄入量增加并没有带来任何好处。在体重指数为25或35的患者中，额外喂养1000千卡的人60天死亡的几率几乎减半。每天额外喂食30克蛋白质也观察到了类似的结果。因此，我们的假设是，增加对患有ARF(身体质量指数[BMI]25或35)的体重不足和超重的危重患者的卡路里和蛋白质供应将导致与常规护理相比，改善60天的存活率。我们的具体目标是进行一项跨国、多中心的随机双盲对照试验，研究EN加补充PN与EN和肠外安慰剂溶液(标准护理)对消瘦和肥胖的急性呼吸衰竭(ARF)危重患者的影响。这样一项能够显示60天死亡率差异的试验需要大约2000名患者。然而，由于我们不确定进行这样一项大型研究的可行性和安全性，因此在这项申请中，我们建议最初将对6个中心的160名患者进行试点研究。试点研究的主要目的是确认我们可以安全地实现两个研究组之间热量摄入量的临床显著差异，而不会因补充PN而增加任何风险。研究设计：先导性研究为6中心、双盲、安慰剂对照、随机试验。患者将被随机分为EN+安慰剂PN液组或EN+PN组。研究人群：160名患有ARF的危重患者(定义为需要机械通气和72小时)在ICU入院后48小时内开始进行EN治疗，这些患者病前体重指数为25和35。研究干预：符合条件的患者将在入院后48小时内随机分组。在两组中，EN将根据标准喂养方案和标准1.2千卡/毫升配方启动并进行到目标剂量。干预组将通过PN获得额外的蛋白质/能量。该注射液含1.2卡/毫升，与EN液相似。对照组将使用含有1/2生理盐水的安慰剂溶液来维持失明。每天将监测和调整PN和EN的相对量，以确保患者每天摄入100%的处方卡路里。补充PN液或安慰剂PN将持续7天。在本研究结束时，研究干预将停止，临床医生可以按照两组的临床指示开出营养处方(PN或EN)。结果：这项拟议的试点研究将衡量所有临床结果(例如死亡率)。这项初步研究的主要目的是在对照组和干预组之间实现30%的热量和蛋白质输送差异(600-100千卡/天和20-30克蛋白质/天)。研究患者在ICU期间也将被前瞻性地跟踪，以记录对研究干预、维持失明和不良事件的遵从性。这将使我们能够评估进行更大规模、决定性试验的可行性。这项全面的权威性研究的结果将有助于回答以下基本问题 为营养高危ICU患者提供的能量和蛋白质数量的影响，并将在多年来第一次告知目前在ICU中使用PN的做法。

DESCRIPTION (provided by applicant): This application addresses the National Heart, Lung, and Blood Institutes Clinical Trial Pilot Studies (R34). Background: The optimal amount of calories and protein a critically ill patient should receive to reduce morbidity and mortality is unclear and remains controversial. Review of current practice in ICU patients indicates the actual amounts of enteral energy and protein delivered by standard hospital nutrition protocols is well below what is prescribed. U.S. ICU's were the least successful worldwide in delivering prescribed calories and protein. Despite aggressive, repeated efforts with guidelines and quality improvement initiatives over past years the amount of calories delivered via the enteral route has not significantly improved. Thus, if we are to successfully improve provision of energy and protein to patients at-risk of death from insufficient caloric delivery, we will have to supply calories via the intravenous parenteral nutrition (PN) route. Various national guidelines make different recommendations on the role of PN in the ICU, international audits show considerable practice variations, and existing clinical trial data, albeit it weak and outdated, are split on the use of PN in the early phase of critical illness (with some showing a mortality benefit and some showing no mortality benefit or possible increased infection risk from PN). However, a large recent observational research shows the amount of energy and protein received during the early stages of ICU admission impacts patient mortality, independent of route of delivery. This data from an international multicenter observational study of 2772 ICU patients in 165 ICUs who were expected to require mechanical ventilation for > 72 h found a significant inverse linear relationship between the odds of mortalit and total daily calories received. The key finding is that increased amounts of calories significantly reduced mortality for the patients with a BMI<25 and a BMI>35 with no benefit of increased calorie intake for patients in the BMI 25-<35 group. Feeding an additional 1000 kcals almost halved the odds of 60-day mortality in patients with a BMI <25 or >35. Similar results were observed for feeding an additional 30 grams of protein per day. Thus, Our Hypothesis is increased calorie and protein delivery to underweight and overweight critically ill patients with ARF (Body Mass Index [BMI] <25 or >35) will result in improved 60 day survival compared to usual care Our Specific Aim is to conduct a multinational, multicenter double-blind randomized controlled trial of EN plus supplemental PN vs EN and a parenteral placebo solution (standard care) in lean and obese critically ill patients with acute respiratory failure (ARF). Such a trial powered to show differences in 60-day mortality would require approximately 2000 patients. However, as we are uncertain of the feasibility and safety of conducting such a large study, thus in this application we propose pilot study of 160 patients in 6 centers will be conducted initially The main aim of the pilot study is to confirm we can safely achieve a clinically significant difference in caloric intake between the two study groups, without any increased risk from the supplemental PN. Study Design: The pilot study is a 6-center, double-blinded, placebo-controlled, randomized trial. Patients will be randomized to either: EN plus placebo PN solution or EN plus PN. Study Population: 160 critically ill patients with ARF (defined as expected to require mechanical ventilation > 72 h) to be initiated on EN within 48 h of ICU admission who have a pre-illness BMI < 25 and >35. Study Intervention: Eligible patients will be randomized within 48 h of ICU admission. In both groups, EN will be initiated and progressed to target dose according to a standard feeding protocol with a standard 1.2 kcal/ml formula. The intervention group will receive additional protein/energy via PN. This parenteral solution contains 1.2 cal/ml, similar to the EN solution. A placebo solution containing 1/2 normal saline will be used to maintain blinding in the control group. The relative amount of PN and EN will be monitored and adjusted daily to ensure that the patient receives 100% of prescribed calories daily. The supplemental PN solution or placebo PN will continue for 7 days. At the end of this study period, the study intervention will be stopped and clinicians can prescribe nutrition (PN or EN) as clinically indicated in both groups. Outcomes: This proposed pilot study will measure all clinical outcomes (e.g. mortality). The primary aim of this pilot study is to achieve a 30% difference in caloric and protein delivery difference (600-100 kcal/d and 20-30 g protein/d) between the control and intervention groups. Study patients will also be followed prospectively while in the ICU, to document compliance with the study intervention, maintenance of blinding, and adverse events. This will enable us to assess the feasibility of conducting the larger, definitive trial. Te results of this full-scale definitive study will serve to answer fundamental questions with regards to impact of amount of energy and protein delivered to nutritionally at-risk ICU patients and will for the first time in many years inform current practice on the use PN in the ICU.