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医学英语:《重症成年病人的肠外早期或晚期肠外营养干预的比较研究》

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icuer 发表于 2019-8-21 21:25:24 |阅读模式 |复制链接
摘要
背景
Controversy exists about the timing of the initiation of parenteral nutrition in critically ill adults in whom caloric targets cannot be met by enteral nutrition alone.
单用肠内营养无法满足危重症患者的能量需求时,开始肠外营养的时机一直存在争议。

方法

In this randomized, multicenter trial, we compared early initiation of parenteral nutrition (European guidelines) with late initiation (American and Canadian guidelines) in adults in the intensive care unit (ICU) to supplement insufficient enteral nutrition. In 2312 patients, parenteral nutrition was initiated within 48 hours after ICU admission(early-initiation group), whereas in 2328 patients, parenteral nutrition was not initiated before day 8 (late-initiation group). A protocol for the early initiation of enteral nutrition was applied to both groups, and insulin was infused to achieve normoglycemia.
在本次随机、多中心临床试验中,我们对比了在肠内营养摄入不足的ICU成人患者中早期(欧洲指南)和晚期开始(美国和加拿大指南)肠外营养的区别。早期组的2312例患者在入住ICU病房后的48h内开始肠外营养,而晚期组的2328例患者于入住ICU病房8天后开始肠外营养。两组均按相同方案开展早期肠内营养支持,并用胰岛素控制血糖。

结果

Patients in the late-initiation group had a relative increase of 6.3% in the likelihood of being discharged alive earlier from the ICU (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.13; P = 0.04) and from the hospital (hazard ratio, 1.06; 95% CI, 1.00 to 1.13; P = 0.04), without evidence of decreased functional status at hospital discharge. Rates of death in the ICU and in the hospital and rates of survival at 90 days were similar in the two groups. Patients in the late-initiation group, as compared with the early-initiation group, had fewer ICU infections (22.8% vs. 26.2%, P = 0.008) and a lower incidence of cholestasis (P<0.001). The late-initiation group had a relative reduction of 9.7% in the proportion of patients requiring more than 2 days of me-chanical ventilation (P = 0.006), a median reduction of 3 days in the duration of renal-replacement therapy (P = 0.008), and a mean reduction in health care costs of ?1,110 (about $1,600) (P = 0.04).
相对于较早期组,晚期组患者存活出ICU(风险比1.06,95%CI1.00~1.13,P=0.04)和出院(风险比1.06,95%CI:1.00~1.13,P=0.04)时间缩短的可能性增加6.3%;而且晚期组的出院时营养状态和生理机能并未降低。两组ICU和医院内死亡率以及90天生存率相似。与早期组相比,晚期组的患者感染率降低(22.8% vs. 26.2%,P=0.008),且胆汁淤积的发生率降低(P<0.001)。晚期组机械通气时间超过2天的患者早期组减少了9.7%(P=0.006),肾脏替代疗法持续时间较早期组缩短了3天(P=0.008),治疗成本平均降低1,110欧元(大约1,600美元)(P=0.04)。

结论
Late initiation of parenteral nutrition was associated with faster recovery and fewer complications, as compared with early initiation. (Funded by the Methusalem pro-gram of the Flemish government and others; EPaNIC ClinicalTrials.gov number, NCT00512122.)
晚期给于肠外营养的患者比早期给予者康复更快,且并发症更少。
正文

Critical illness induces anorexia and the inability to eat normally, predispos-ing patients to serious nutritional deficits, muscle wasting, weakness, and delayed recovery. Whether artificial nutritional support improves the outcome for critically ill patients is unclear. The administration route, the time until the initiation of artificial nutrition, the number of calories, and the type of nutrients may be important

危重症会引起厌食或无法正常饮食,导致患者出现严重的营养缺乏,肌肉萎缩、虚弱和康复延迟。营养支持能否改善危重患者的预后目前尚不清楚。营养支持的路径、开始的时机、目标摄入量和营养素类型都非常重要。

Enteral nutrition is associated with fewer com-plications than parenteral nutrition and is less expensive to administer.However, the use of enteral nutrition alone often does not achieve ca-loric targets.In addition, underfeeding is associ-ated with weakness, infection,an increased duration of mechanical ventilation, and death.Combining parenteral nutrition with enteral nutrition constitutes a strategy to prevent nutritional deficit but may risk overfeeding, which has been associated with liver dysfunction, infection, and prolonged ventilatory support.The increased levels of blood glucose that are associated with parenteral nutrition could contribute to such com-plications.and have been hypothesized to explain the failure of parenteral nutrition to prevent muscle wasting.

肠内营养比肠外营养的并发症少且实施成本低。但是,单用肠内营养往往不能达到目标摄入量。而且,营养摄入不足会引起虚弱、感染、延长机械通气时间,甚至导致死亡。肠内与肠外营养联合应用可以避免营养缺乏,但可能造成过度喂养,继发肝功能障碍、感染、机械通气时间延长。肠内营养导致的血糖升高,常引起多种并发症,可能是无法预防的肌肉萎缩的原因。

Current clinical practice guidelines for nutritional support in critically ill patients are largely based on expert opinion and differ substantially across continents. The guidelines of the European Society of Parenteral and Enteral Nutrition (ESPEN) recommend that practitioners consider initiating parenteral nutrition within 2 days after admis-sion to the intensive care unit (ICU) for patients who cannot be adequately fed enterally.In contrast, the American and Canadian guidelines recommend early initiation of enteral nutrition but suggest that parenteral nutrition not be initiated concomitantly, thus advising that hypocaloric nutrition be tolerated during the first week in patients who are not malnourished at baseline.

目前危重症的营养支持指南很大程度上是基于专家的观点,而且各个地区存在很大差异。欧洲肠外肠内营养协会(ESPEN)指南推荐:肠内营养摄入不足的ICU患者,入住2天后可以考虑开始联用肠外营养。相反,美国和加拿大的指南推荐早期开展肠内营养,但是不建议同时实施肠外营养,对基线期无营养不良的患者,可耐受1周的低热卡喂养。

In this study, we compared the effect of late initiation of parenteral nutrition (American and Canadian guidelines) with early initiation (ESPEN guidelines) on rates of death and complications in adults in the ICU who were nutritionally at risk but who were not chronically malnourished (body-mass index [the weight in kilograms divided by the square of the height in meters], ≥17). Since all the participating ICUs followed the guidelines for early initiation of parenteral nutrition, the ac-tive intervention was late initiation. In this study, we investigated whether preventing a caloric defi-cit during critical illness by providing parenteral nutrition to supplement enteral nutrition early in the disease course would reduce the rate of com-plications or whether withholding parenteral nu-trition for 1 week would be clinically superior

本研究比较了晚期(美国和加拿大指南)和早期(ESPEN指南)肠外营养支持对存在营养风险、但无慢性营养不良(BMI≥17)的ICU患者死亡率和并发症发生率的影响。对照组所有研究对象均按指南接受早期肠外营养,试验组接受晚期肠外营养本研究旨在调查重症患者早期肠内营养基础上,同时早期肠外营养补充能量摄入不足,与延迟1周联用肠外营养支持相比,在降低并发症方面哪个更具优越性。
方法

试验设计和质控

The Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) study was a prospective, randomized, controlled, parallel-group, multicenter trial that was initiat-ed by the investigators. The protocol and consent forms were approved by the institutional review boards at University Hospitals Leuven and Jessa Hospitals and by the Belgian authorities. The study protocol and statistical analysis plan are avail-able with the full text of this article at NEJM.org, and the methods have been reported previously.The first author and last author vouch for the fidelity of the study to the protocol..

EPaNIC研究是一项前瞻性、随机、对照、多中心平行试验,验方案和知情同意书经Leuven大学附属医院、Jessa医院和比利时政府的审查组委会审批后通过。研究设计和统计分析方案全文发表在新英格兰医学杂志,试验方法如前所述。每一位作者均保证试验严格按照方案执行。

Baxter Healthcare provided an unrestricted re-search grant that covered less than a third of the costs of the study. The company was not involved in the design of the study; in the collection, analysis, or interpretation of the data; in the preparation of the manuscript, or in the decision to submit the manuscript for publication

Baxter医疗机构提供了不到总研究经费的三分之一。试验设计,数据收集、分析和阐述,撰稿或决定投稿方向,该公司均未参与。

研究对象

From August 1, 2007, through November 8, 2010, all adults who were admitted to one of the seven participating ICUs were eligible for inclusion in the study if they had a score of 3 or more on nu-tritional risk screening (NRS) (on a scale of 1 to 7, with a score ≥3 indicating that the patient was nutritionally at risk) and did not meet any of the exclusion criteria (Fig. 1). Written informed con-sent was provided by all patients or their desig-nated representatives.

自2007年8月1日至2010年11月8日,7个ICU研究中心招募的所有患者,若NRS评分3(提示有营养风险),且不符合排除标准的均纳入本研究(图1)。所有患者或者其指定代理人均收到书面的知情同意书。

Consecutive patients were stratified according to 16 diagnostic categories (see Table 1 in the Supplementary Appendix, available at NEJM.org) and randomly assigned in a 1:1 ratio to early or late initiation of parenteral nutrition, with the use of sequentially numbered, sealed, opaque enve-lopes. Envelopes were replaced by an identical digital system at all sites after the addition of theJessa Hospitals study sites. Treatment assignments were made in permuted blocks of 10 per stratum.The treating physicians and nurses did not knowthe block size. All outcome adjudicators were un-aware of study-group assignments.

根据16项诊断标准将患者分层(附表1),并按照1:1的比例,用随机信封法随机分为早期组和晚期组。Jessa医院加入后,各中心的随机信封被数字认证系统所替换。干预措施的分配保密进行。医生和护士不知道患者的具体干预措施。所有实验结果的评判人也不知道各组的实际干预情况。

One interim safety analysis was performed afterthe first 1500 patients had been discharged fromthe ICU. The independent data and safety monitor-ing board then advised that the study be contin-ued to completion. Because the primary efficacyend point was not analyzed, no correction of the significance level at the final analysis was required.

1500例ICU患者出院后进行中期安全性分析。独立的数据和安全监控部门认为该实验可以继续进行。由于主要的终点指标还未分析,所以最终数据分析阶段的显著性水平无需修正。

研究步骤

Patients who were assigned to the early-initiation group received intravenous 20% glucose solution; the target for total energy intake was 400 kcal per day on ICU day 1 and 800 kcal per day on day 2 (Fig. 2, and Table 2 in the Supplementary Appen-dix). On day 3, parenteral nutrition (OliClinomel or Clinimix, Baxter) was initiated, with the dose targeted to 100% of the caloric goal through com-bined enteral and parenteral nutrition (except when clinicians predicted that the patient would tolerate

sufficient enteral nutrition or oral feeding on day 3). The amount of parenteral nutrition was calculated daily as the difference between the total energy intake that was effectively delivered by enteral nutrition and the calculated caloric goal. Calculations regarding the caloric goal included protein energy and were based on corrected ideal body weight, age, and sex (Table 3 in the Supplementary Appendix). The maximum caloric goal for all patients was 2880 kcal per day. When enteral nutrition cov-ered 80% of the calculated caloric goal or when the patient was judged to be able to resume oral nutrition, parenteral nutrition was reduced and eventually stopped. Parenteral nutrition was restarted whenever enteral or oral intake fell to less than 50% of the calculated caloric needs

早期组的患者接受静脉输注20%葡萄糖溶液;总能量目标摄入量为入住ICU第一天400、第二天800 Kcal/d(图2和附表2)。第三天开始肠外营养,肠内和肠外营养联用,满足100%的目标量(除非医生认为第三天时患者完全可以耐受全肠内营养或经口摄入)。由于肠内营养支持所提供的能量与目标摄入量之间有差异,所以肠外营养用量需要每日计算。包括蛋白质在内的目标量的计算应根据理想体重、年龄和性别适当调整(附表3)。所有患者中最大的目标摄入量为2880Kcal/d。当肠内营养提供了80%的目标量或患者恢复经口摄食时,肠外营养可减量或停止。当肠内营养或经口摄入量少于目标量的50%时,应联用肠外营养支持。

Patients who were assigned to the late-initiation group received 5% glucose solution in a volume equal to that of the parenteral nutrition administered in the early-initiation group in order to provide adequate hydration, with the delivered volume of enteral nutrition taken into account. If enteral nutrition was insufficient after 7 days in the ICU, parenteral nutrition was initiated on day 8 to reach the caloric goal.

晚期组的患者静脉输注与早期组同体积的5%的葡萄糖溶液,与肠内营养的营养液一起,补充机体水分。如果7天后ICU患者的肠内营养不能满足需求,在第8天开始联用肠外营养以达到目标量。

All patients who were unable to eat by day 2 received enteral nutrition (mainly Osmolite, Abbott), while being maintained in a semirecumbent position unless medically contraindicated (Table 4 in the Supplementary Appendix). Standing orders for enteral nutrition for all patients speci-fied a twice-daily increase in the infusion rate for enteral nutrition and the use of prokinetic agents and duodenal feeding tubes. Patients in the two study groups received parenteral trace elements, minerals (potassium, phosphate, and magnesium), and vitamins early in their ICU stay24 in order to avoid problems due to micronutrient depletion on refeeding (Table 2 in the Supplementary Appendix).

2天内无法经口摄食的所有患者,进行肠内营养支持,保持半卧位,除非有禁忌证(附表4)。明确规定所有实施肠内营养的患者,采用十二指肠喂养,每日2次增加输注速度,并联合应用胃肠动力药。两组接受肠外营养的患者在入住ICU早期即开始给予维生素矿物质,以避免微量营养素缺乏(表2

A patient-data–management system (Meta-Vision, iMDsoft) was used to calculate the daily volumes of enteral and parenteral nutrition to be administered to each patient, according to the protocol. Nutritional management after discharge from the ICU was at the discretion of the attend-ing ward physicians. Continuous insulin infusion was adjusted to obtain a blood glucose level of 80 to 110 mg per deciliter (4.4 to 6.1 mmol per liter).16,26 Arterial blood glucose levels were mon-itored, with chemical analysis performed every 1 to 4 hours on a blood gas analyzer (Radiom-eter ABL 715 and 725, Radiometer Medical) and corrected as required. Guidelines for ventilator weaning were followed in all participating ICUs. When continued intensive care was considered to be futile, two senior ICU physicians and the re-ferring specialist made end-of-life decisions by consensus.

按照实验方案,用患者数据管理系统计算每日肠内和肠外营养用量。出ICU后,普通病房的主治医生接手患者的营养管理。调整胰岛素的输注剂量,使血糖水平维持在80~110mg/dL(4.4~6.1mmol/L)。每1~4h作一次血气分析(医用辐射仪ABL715和725型号),监测动脉血糖水平,并据此调整胰岛素用量。所有ICU中心均遵守呼吸机脱机准则。当ICU治疗失败(futile),需由两名高级ICU医师和资深专家经协商达成一致后才可以做出终止生命的决定。

数据采集

Baseline demographic and clinical characteristics of the patients were well matched between the twostudy groups (Table 1, and Table 1 in the Supplementary Appendix). We quantified the severity of illness according to the score on the Acute Physiology and Chronic Health Evaluation II (APACHE II) (on a scale of 0 to 71, with higher scores indicating a greater severity of illness).The criteria of the American College of Chest Physicians–Society of Critical Care Medicine were used for the diagnosis of sepsis.Organfailure and sepsis scores were calculated by trained experts.

两组患者基线期的人口学特征和临床特征完全匹配表1和附表1)。按照“急慢性生理健康评估(APACHE Ⅱ)”(评分在0~71之间,分数越高说明疾病越严重)对疾病的严重程度量化。按照美国胸科医师学会医学的准则来诊断脓毒血症。受过培训的专家来对器官衰竭和脓毒血症评分。

Daily records were kept regarding all intensive care treatments and procedures, new bacterial or fungal infections, the results of blood and urine chemical analyses and hematologic studies, and markers of inflammation. Also recorded were the total energy intake delivered daily by means of enteral and parenteral nutrition, interruptions of delivery of enteral nutrition, and feeding-related complications. In addition, whenever practically feasible, the functional status of patients before hospital discharge was quantified. All direct health care costs were retrieved from the invoices for patients and analyzed from the perspective of the health care payer. Government and patient costs were aggregated. Vital status 90 days after randomization was obtained from the Belgian National Registry for all Belgian citizens.

所有的重症监护诊疗过程按日常记录保存,包括新出现的细菌或真菌感染、血和尿化验结果、血液学和炎性标志物的检查结果。还应记录通过肠内和肠外方式摄入的总能量、肠内营养的中断和喂养相关的并发症。此外,出院前只要条件允许,就要对患者的机能状态进行量化。所有直接的医疗费用均按发票所示予以退还,并作前瞻性分析。汇总政府和患者的开销,随机分组后90天的重要资料从比利时国家注册中心获得。

结局指标检测
安全性终点指标

Safety end points included vital status (the proportion of patients who were alive at dischargefrom the ICU in ≤8 days, the rates of death in the ICU and the hospital, and the rates of survival up to 90 days, regardless of ICU and hospital discharge status) and the rates of complications and hypoglycemia. Hypoglycemia that was resistant to parenteral glucose administration during the intervention window was considered to be a serious adverse event.

安全性终点指标包括:8天内出ICU的存活患者比例、ICU的死亡率和院内死亡率、90天生存率(无论出ICU或医院时状态如何),并发症和低血糖的发生率。低血糖是在干预窗口期,肠外营养血糖控制中的严重不良事件。
主要终点指标

The primary end point was the duration of dependency on intensive care, assessed as the number of ICU days (for survivors and nonsurvivors) and the time to discharge from the ICU. To reduce bias that might result from variability in the availability of beds on regular wards, we defined the time to discharge from the ICU as the time by which patients were ready for ICU discharge, according to prespecified objective criteria (Table 2).

主要终点指标是需要重症监护的时间,对生存者和非生存者以住ICU天数计算。为减小因转出ICU时间变异造成的偏倚,当患者满足预设的转出ICU标准时,该时间点即为转出ICU病房的时间(表2)。次要有效性终点指标

Secondary end points were the number of patients with new infections; the infection site (airways or lungs, bloodstream, urinary tract, or wounds)29,30;the duration of antibiotic therapy; inflammation, as reflected by the maximum level of plasma C-reactive protein; the time to final weaning from mechanical ventilatory support and the need for tracheostomy; the rate of incident acute kidney injury, which was defined according to RIFLE criteria31 (risk of renal dysfunction, injury to the kidney, failure or loss of kidney function, and end-stage kidney disease) as at least a doubling of the serum creatinine level recorded on admission; the proportion of patients requiring renal-replacement therapy and the duration of such therapy in the ICU; and the need for and duration of pharmacologic or mechanical hemodynamic support. We compared the two study groups with respect to the proportion of patients during the study intervention and during the entire ICU stay who presented with liver dysfunction, which was defined as a total bilirubin level of more than 3 mg per deciliter (51 μmol per liter), a γ-gluta myl trans ferase level of more than 79.5 U per liter, an alkaline phosphatase level of more than 405 U per liter, or a pronounced elevation in the level of either alanine aminotransferase (>123 U per liter) or aspartate aminotransferase (>114 U per liter). Finally, we compared the duration of the hospital stay and time to discharge from the hospital between the two study groups. Before hospital discharge, we quantified functionalstatus according to the distance walked in 6 minutes32 and the proportion of patients who were independent in all activities of daily living.33 We also compared the two groups with respect to the total incremental health care costs from randomization to hospital discharge.

次要终点指标是患者的新发感染病例数、感染部位(气道、肺、血液、尿道或创口);抗生素使用时间;反应炎症水平的指标C-反应蛋白(CRP);机械通气时间和气管切开时间;急性肾损伤的发生率(按照RIFLE标准,包括肾功能障碍的危险、肾损伤、肾功能衰竭、肾功能丧失和终末期肾病,血清肌酐水平至少升高一倍作为急性肾脏损伤的诊断标准);ICU中需要接受肾脏替代疗法的患者百分比及该治疗持续的时间;需要药物维持正常血流动力学患者的百分比及持续时间。我们比较了两组患者在研究期间和整个重症监护期间发生比例,其中肝功能障碍的定义为总胆红素水平超过3g/dL(51μmol/L),γ-谷氨酰转移酶水平超过79.5U/L,碱性磷酸酶大于405U/L,或丙氨酸氨基转移酶(>123U/L)与天冬氨酸氨基转移酶(>114U/L)两者之一显著升高。最后,我们比较了两组的住院时间。出院前,我们按照患者6分钟内行走距离对生理机能进行量化评估,并记录能够独立进行日常生活的患者百分比。我们还比较了两组从随机分组一直到出院的总医疗费用。
统计分析

The sample-size calculation was based on the ability to detect a between-group change of 1 day in the ICU stay with a power of at least 80% and to concomitantly detect a change of 3% in the rate of death in the ICU with a power of at least 70%. All analyses were performed on an intention to treat basis. Variables were summarized as frequencies and percentages, means and standard deviations, or medians and interquartile ranges, as appropriate. Data were compared with the use of the chi-square test, Student’s t-test, or nonparametric testing (median test, Wilcoxon rank-sum test, or Mann–Whitney U test), as appropriate. Health care costs were reported as means with interquartile ranges and were analyzed with the use of Student’s t-test.34 We used Kaplan–Meier methods to perform time-to-event analyses, and the time-to-event effect size was estimated with the use of Cox proportional-hazards analysis. In the analysis of survival to 90 days, data for 69 of 83 non-Belgian citizens who had been discharged from the hospital before 90 days were censored at the time of discharge. For the time to dis-charge from the ICU and hospital, data for patients who died were censored at the time of death, and data for one patient who was still in the hospital 90 days after the enrollment of the last patient were censored at 90 days. For the analysis of the time to discharge alive from the ICU or hospital, data for patients who died were censored at a time point after the last surviving patient had been discharged.35 All outcomes were analyzed both with no adjustment for baseline variables and with adjustment for prespecified risk factors (type and severity of illness, age, body-mass index, and NRS score). Data for the type of illness included diagnostic categories on admission (Table 1, and Table 1 in the Supplementary Appendix) and the presence or absence of cancer.

样本量的计算基于两组间ICU住院时间有1天显著性差异的把握度至少为80%,以及两组间死亡率有3%显著性差异的把握度至少70%。所有分析均基于意向治疗。变量包括:频率、百分率、均数和标准差、中位数和四分位数,视情况而定。采用卡方检验、t检验或非参数检验。医疗成本以四分位数间距的均数形式分析,采用t检验。采用Kaplan-Meier法用作时间发生事件分析,采用Cox模型估计时间发生事件效应的样本量。在90天生存分析中,83例非比利时居民中的69例患者提前出院,在分析过程中剔除这些人的数据。ICU转出或出院分析中,剔除死亡病例的数据,纳入最后一名患者90天后有一例患者在仍然住院,该患者的数据也被剔除。在ICU存活出院或医院存活出院的病例分析中,在最后一名存活患者出院后,剔除死亡病例的数据。对基线期未校正的变量和根据预设危险因素校正的变量(疾病类型和严重程度、年龄、BMI和NRS评分)均作相应分析。疾病资料包括诊断(表1和附图1)和有无癌症。

We performed prespecified subgroup analyses for patients at increased risk as indicated by the body-mass index (<25 or ≥40)11,36-38 or NRS score (≥5), those who had undergone cardiac surgery, and those with sepsis on admission. These subgroup analyses were performed for the primary outcome and one safety end point. Interactions in the fully adjusted models were tested at a significance level of less than 0.10. For all end points, a two-sided P value of less than 0.05 was considered to indicate statistical significance, without correction for multiple testing. All analyses were performed with the use of JMP software, version 8.0.1 (SAS Institute)

BMI<25、>40或NRS 2002评分≥5、接受心脏外科手术或存在脓毒血症往往会使风险增加,按照试验预先设计我们据此进行亚组分析。亚组分析中包括主要结果和安全性终点指标。在校正了所有因素的模型中以小于0.10的显著性水平来检验交互作用。所有终点指标以双侧检验P小于0.05表示统计学差异,无需修正多重检验。所有分析采用8.0.1版本JMP软件(SAS公司)。

结果

干预措施

A total of 4640 patients underwent randomization and were included in the analysis (Fig. 1). Details regarding the patients’ nutrition, which was administered according to the study protocol, are shown in Figure 2 (also Fig. 1 in the Supplementary Appendix). Patients in the late-initiation group required a median of 31 IU of insulin (interquartile range, 19 to 48) per day to reach the target blood glucose level, with a mean (±SD) blood glucose level of 102±14 mg per deciliter (5.7±0.8 mmol per liter), as compared with a median of 58 IU of insulin (interquartile range, 40 to 85) for a mean blood glucose level of 107±18 mg per deciliter (5.9±1.0 mmol per liter) in the early-initiation group (P<0.001 for both comparisons). Levels of serum potassium, phosphorus, and magnesium were similar in the two study groups (data not shown).

本研究总共包括随机纳入的4640例患者(图1)。按照研究设计严格(Details)给予营养支持(图2或附图1)。晚期组患者每天需要中位数为31IU的胰岛素(四分位数间距为19~48)来维持目标血糖水平,血糖维持在102±14 mg/dL(5.7 ±0.8 mmol/L);而早期组患者每天需要中位数为58IU/d的胰岛素(四分位数间距为40~85)将血糖维持在107±18 mg/dL(5.9±1.0 mmol/L),胰岛素给予量和血糖水平两组都有显著性区别(P<0.001)。两组人血清钾、磷、镁水平相近(数据未列出)。

安全性结果

The two study groups had similar rates of death in the ICU and the hospital and at 90 days (Table 2, and Fig. 2 in the Supplementary Appendix). However, the proportion of patients who were discharged alive from the ICU within 8 days was higher in the late-initiation group, even though hypoglycemia developed in more patients in this group. The rates of nutrition-related complications were similar in the two groups, and there were no serious adverse events that could be attributed to the study interventions

两组的ICU死亡率、医院死亡率和90天死亡率相似(表2,附图2)。晚期组有较多患者出现低血糖症状,但从ICU病房8天内存活转出患者比率较高。两组的营养相关性并发症的发生率相似,未因试验干预而发生任何严重不良事件。

主要结果

The median stay in the ICU was 1 day shorter in the late-initiation group than in the early-initiation group, which was reflected in a relative increase of 6.3% in the likelihood of earlier discharge alive from the ICU (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.13; P = 0.04)(Table 2 and Fig. 3). This effect size was similar (an increase in likelihood of 6.9%) after adjustment for hypoglycemia.

晚期组患者住ICU时间中位数比早期组短一天,同时早期存活出ICU的比例晚期组较早期组高6.3%(HR=1.06, 95%CI:1.00~1.13;P=0.04)(表2,图3)。校正低血糖因素后,该结果仍相似(6.9%)。

次要结果

Fewer patients in the late-initiation group acquired a new infection (in the airways or lungs, bloodstream, or wound) in the ICU, but the acute inflammatory response was more pronounced than in the early-initiation group (Table 2). The duration of mechanical ventilation and the course of renal-replacement therapy were shorter in the late-initiation group. More patients in the late-initiation group had hyperbilirubinemia (>3 mg per deciliter), and fewer had a clinically important increase in levels of γ-glutamyltransferase or alkaline phosphatase. The numbers of patients with pronounced elevations in aminotransferaselevels were similar in the two groups (Table 5 in the Supplementary Appendix).

晚期组ICU患者较早期组新发感染(气道、肺、血液或创口)者少,但是急性炎症反应更显著(表2)。晚期组机械通气时间和肾脏替代治疗时间缩短。晚期组患者胆红素水平(>3mg/dL)较高、但具有重要临床意义的γ-谷氨酰转移酶和碱性磷酸酶未升高。转氨酶显著升高的患者数两组相近(附表5)。

The median duration of hospitalization was 2 days shorter in the late-initiation group than in the early-initiation group, which was reflected in a relative increase of 6.4% in the likelihood of earlier discharge from the hospital (hazard ratio, 1.06; 95% CI, 1.00 to 1.13; P = 0.04) (Table 2). Functional status, as assessed by the 6-minute walk distance and activities of daily living at the time of imminent hospital discharge, was similar in the two study groups. Late initiation of parenteral nutrition resulted in a mean reduction in total health care costs of ?1,110 (about $1,600) per patient (Table 2).

晚期组的中位数住院时间比早期组缩短两天,早出院的可能性比早期组增加6.4%(HR=1.06;95%CI:1.00-1.13;P=0.04)(表2)。反应功能状态的6分钟步行距离和出院后日常生活能力两组相似。晚期组的总治疗成本每例患者下降1,110欧元(大约1,600美元)(表2)。

亚组分析

Predefined subgroup analyses revealed no het-erogeneity for the primary outcome or for the safety outcomes (Table 6 in the Supplementary Appendix). In post hoc subgroup analyses, we compared late initiation of parenteral nutrition with early initiation in patients for whom early enteral nutrition was surgically contraindicated (517 patients who had undergone complicated pulmonary, esophageal, abdominal, or pelvic surgery and who had a mean APACHE II score of 27±11). Together, these high-risk subgroups predictably received a median of 0 kcal (interquartile range, 0 to 163) per day of enteral nutrition by day 7. Among these patients, the rate of infection was lower in the late-initiation group (29.9%) than in the early-initiation group (40.2%, P = 0.01). In the late-initiation group, there was a relative increase of 20% in the likelihood of earlier discharge alive from the ICU (hazard ratio, 1.20; 95% CI, 1.00 to 1.44; P = 0.05; P = 0.11 for interaction) (Table 6 in the Supplementary Appendix).

预设的亚组分析在主要结局和安全性指标上无异质性(附表6)。在后期亚组分析比较晚期组和早期组中存在肠内营养禁忌症的患者(517例患者出现肺、食管、腹部、盆腔手术并发症,APACHE Ⅱ评分为27±11)。这些高危亚组患者在7天内接受中位数为0 (四分位数间距0~163 kcal/d)的肠内营养。这些患者中,晚期组的感染率(29.9 %)显著低于早期组(40.2 %)(P=0.01);晚期组提前存活出ICU的可能性较早期组升高20 %(HR=1.20;95%CI:1.00~1.44;P=0.05;交互作用显著性:P=0.11)(附表6)。

讨论

We found that there was no significant difference in mortality between late initiation and early initiation of parenteral nutrition among patients in the ICU who were at risk for malnutrition, despite the use of early enteral feeding plus micronutrients in a protocol that prevented hyperglycemia. However, withholding of parenteral nutrition until day 8 was associated with fewer ICU infections but a higher degree of acute inflammation. Late initiation of parenteral nutrition was also associated with a shorter duration of mechanical ventilation and a shorter course of renal-replacement therapy, a shorter ICU stay despite a slight increase in hypoglycemic episodes, a shorter hospital stay without a decrease in functional status, and reduced health care costs.

尽管早期添加微量营养素的肠内营养支持方案防止了高血糖的发生,但是存在营养不良风险的两组ICU患者之间的死亡率无显著差异。第8天后开始肠外营养支持的患者ICU感染率更低,但是急性炎症反应更严重。尽管较晚开始肠外营养发生低血糖的患者稍多,但是在缩短机械通气时间、肾脏替代治疗时间,及住ICU时间,缩短住院时间且无功能障碍,降低治疗成本等方面较早开始肠外营养者更具优势。

Our results do not support the conclusions from previous observational studies that earlier achievement of nutritional targets improves the outcome for critically ill patients. Such observational studies could not differentiate between cause and consequence, since the sickest patients were often those who could not tolerate enteral nutrition. Such associations also formed the basis of the recommendation that critically ill patients should undergo early initiation of enteral tube feeding and that patients with insufficient enteral nutrition should receive early parenteral supplementation. In our study, although patients’vital status was unaffected, all primary and secondary morbidity end points indicated that early parenteral nutrition was not beneficial. Such factors as the body-mass index, severity of nutritional risk, and presence or absence of sepsis on admission did not influence the results, indicating that our findings have general application. Furthermore, the effect of late initiation of parenteral nutrition in the large cohort of patients who had undergone cardiac surgery was identical to that in other diagnostic groups.

本研究结果与以前的观察性研究所发现的尽早达到目标摄入量可改善危重症患者预后的结果不一致。这些观察性研究无法得到这一因果关系的结论,因为越严重的患者越不能耐受肠内营养。这似乎促成了一种基本的观点:危重患者应早期行肠内营养,在肠内营养不足时应尽早补充肠外营养。本研究中尽管患者的生命状态没有受到影响,但是所有主要和次要的终点指标结果均显示早期肠外营养并无益处。BMI、营养风险的严重度、脓毒血症的发生与否并不影响试验结果,说明本研究结果具有普遍适用性。而且,在心脏外科患者中进行的晚期肠外营养干预的大型队列研究也得到同样结论。

The subgroup of patients for whom early enteral nutrition was surgically contraindicated appeared to have a greater benefit from late initiation of parenteral nutrition than did other patients, perhaps because such patients in the early-initiation group received the largest amount of parenteral nutrition. Alternatively, withholding of macronutrients in the early stages of a critical illness, regardless of the route of nutrition, may enhance recovery. We speculate that the increased rates of infection and delayed recovery from organ failure that are associated with the early administration of parenteral nutrition may be explained by a suppression of autophagy, with inadequate clearance of cell damage and microorganisms.The protocol for our study targeted normoglycemia. Whether an increased blood glucose target would have affected the outcome of the trial remains speculative. However, the expected increase in blood glucose levels could add to the risk of early parenteral nutrition.

与其他患者相比,早期肠内营养存在禁忌的亚组患者开展晚期肠外营养获益更多,可能是由于早期组患者早期接受了大量肠外营养的原因。另一方面,在重症疾病早期阶段控制宏量营养素的摄入,不管采用哪种营养支持途径,均可加速康复。推测早期肠外营养导致感染率增加和器官衰竭延迟康复,可能的解释为单核巨噬细胞作用抑制,不能及时清除损伤的细胞和微生物。本研究方案要求血糖水平正常。提高血糖目标值是否会影响本研究结果,尚需进一步探讨。但血糖目标值升高可能会增加早期肠外营养的危险性。

Our study has certain limitations. First, the parenteral nutrition that we used contained neither glutamine nor specific immune-modulating compounds,but rather reflected the parenteral nutrition given in common daily practice.The data favoring the administration of glutamine remain controversial.Second, the use of standardized, premixed parenteral-nutrition products resulted in a relatively low protein-to-energy ratio (Fig. 1 in the Supplementary Appendix). However, high-level evidence of an improved outcome with increased protein doses is currently lacking. Third, the amount of nutrition was calculated without measurement of energy expenditure with the use of indirect calorimetry, a technique that is not recommended by evidence-based guidelines.Finally, because of the nature of the study, patients or their designated representatives and their ICU providers were aware of study-group assignments.

本研究也存在局限性。首先,我们所用的肠外营养不包括谷氨酰胺,也非免疫增强型配方,仅只给予普通的肠外营养。首先,谷氨酰胺的研究结果仍然存在争议。第二,标准、预混型的肠外营养产品中蛋白能量比较低(附图1)。然而,目前仍缺乏通过增加蛋白来改善预后的高质量研究证据。第三,在计算营养素用量时没有使用间接热量测定法来确定能量消耗量,因为以循证医学为基础的指南并不推荐该技术。最后,由于研究性质,患者或其指定的代理人和ICU医生知道研究分组情况。

In conclusion, the early initiation of parenteral nutrition to supplement insufficient enteral nutrition during the first week after ICU admission in severely ill patients at risk for malnutrition appears to be inferior to the strategy of withholding parenteral nutrition until day 8 while providing vitamins, trace elements, and minerals. Late parenteral nutrition was associated with fewer infections, enhanced recovery, and lower health care costs.

综上所述,存在营养不良风险的重症患者在早期肠内营养的同时,早期开始肠外营养支持来补充肠内营养的摄入不足,不如第8天以后再开始肠外营养。晚期肠外营养可以降低感染率、加速康复和降低治疗成本。

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