Evidence Based Practice Volume Based Tube Feeding

• Research
• Open Access
• Published: 16 February 2022

Actively implementing an evidence-based feeding guideline for critically ill patients (NEED): a multicenter, cluster-randomized, controlled trial

• Jiajia Lin^{1  na1},
• Gordon S. Doig³,
• Arthur R. H. van Zanten⁴,
• Yang Wang⁵,
• Juan Xing⁶,
• Zhongheng Zhang⁷,
• Tao Chen⁸,
• Lixin Zhou⁹,
• Dongpo Jiang¹⁰,
• Qindong Shi¹¹,
• Jiandong Lin¹²,
• Jun Liu¹³,
• Aibin Cheng¹⁴,
• Yafeng Liang¹⁵,
• Peiyang Gao¹⁶,
• Junli Sun¹⁷,
• Wenming Liu¹⁸,
• Zhenyu Yang¹⁹,
• Rumin Zhang²⁰,
• Wei Xing²¹,
• An Zhang²²,
• Zhigang Zhou²³,
• Tingfa Zhou²⁴,
• Yang Liu²⁵,
• Fei Tong²⁶,
• Qiuhui Wang²⁷,
• Aijun Pan²⁸,
• Xiaobo Huang²⁹,
• Chuming Fan³⁰,
• Weihua Lu³¹,
• Dongwu Shi³²,
• Lei Wang³³,
• Wei Li³⁴,
• Liming Gu³⁵,
• Yingguang Xie³⁶,
• Rongqing Sun³⁷,
• Feng Guo³⁸,
• Lin Han³⁹,
• Lihua Zhou⁴⁰,
• Xiangde Zheng⁴¹,
• Feng Shan⁴²,
• Jianbo Liu⁴³,
• Yuhang Ai⁴⁴,
• Yan Qu⁴⁵,
• Liandi Li⁴²,
• Hailing Li⁴⁶,
• Zhiguo Pan⁴⁷,
• Donglin Xu⁴⁸,
• Zhiqiang Zou⁴⁹,
• Yan Gao⁵⁰,
• Chunli Yang⁵¹,
• Qiuye Kou⁵²,
• Xijing Zhang⁵³,
• Jinglan Wu⁵⁴,
• Chuanyun Qian⁵⁵,
• Weixing Zhang⁵⁶,
• Minjie Zhang⁵⁷,
• Yuan Zong⁵⁸,
• Bingyu Qin⁵⁹,
• Fusen Zhang⁶⁰,
• Zhe Zhai⁶¹,
• Yun Sun⁶²,
• Ping Chang⁶³,
• Bo Yu⁶⁴,
• Min Yu⁶⁵,
• Shiying Yuan⁶⁶,
• Yijun Deng⁶⁷,
• Liyun Zhao⁶⁸,
• Bin Zang⁶⁹,
• Yuanfei Li⁷⁰,
• Fachun Zhou⁷¹,
• Xiaomei Chen⁷²,
• Min Shao⁷³,
• Weidong Wu⁷⁴,
• Ming Wu⁷⁵,
• Zhaohui Zhang⁷⁶,
• Yimin Li⁷⁷,
• Qiang Guo⁷⁸,
• Zhiyong Wang⁷⁹,
• Yuanqi Gong⁸⁰,
• Yunlin Song⁸¹,
• Kejian Qian⁸²,
• Yongjian Feng⁸³,
• Baocai Fu⁸⁴,
• Xueyan Liu⁸⁵,
• Zhiping Li⁸⁶,
• Chuanyong Gong⁸⁷,
• Cheng Sun⁸⁸,
• Jian Yu⁸⁹,
• Zhongzhi Tang⁹⁰,
• Linxi Huang⁹¹,
• Biao Ma⁹²,
• Zhijie He⁹³,
• Qingshan Zhou⁹⁴,
• Rongguo Yu⁹⁵,
• Zhihui Tong¹ &
• Weiqin Li ORCID: orcid.org/0000-0002-8483-6264 ^1,2
• for the Chinese Critcal Care Nutrition Trials Group (CCCNTG)

Critical Care volume 26, Article number:46 (2022) Cite this article

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A Correction to this article was published on 21 April 2022

This article has been updated

Abstract

Background

Previous cluster-randomized controlled trials evaluating the impact of implementing evidence-based guidelines for nutrition therapy in critical illness do not consistently demonstrate patient benefits. A large-scale, sufficiently powered study is therefore warranted to ascertain the effects of guideline implementation on patient-centered outcomes.

Methods

We conducted a multicenter, cluster-randomized, parallel-controlled trial in intensive care units (ICUs) across China. We developed an evidence-based feeding guideline. ICUs randomly allocated to the guideline group formed a local "intervention team", which actively implemented the guideline using standardized educational materials, a graphical feeding protocol, and live online education outreach meetings conducted by members of the study management committee. ICUs assigned to the control group remained unaware of the guideline content. All ICUs enrolled patients who were expected to stay in the ICU longer than seven days. The primary outcome was all-cause mortality within 28 days of enrollment.

Results

Forty-eight ICUs were randomized to the guideline group and 49 to the control group. From March 2018 to July 2019, the guideline ICUs enrolled 1399 patients, and the control ICUs enrolled 1373 patients. Implementation of the guideline resulted in significantly earlier EN initiation (1.20 vs. 1.55 mean days to initiation of EN; difference − 0.40 [95% CI − 0.71 to − 0.09]; P = 0.01) and delayed PN initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI 0.44 to 1.67]; P = 0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference − 1.6% [95% CI − 4.3% to 1.2%]; P = 0.42) between groups.

Conclusions

In this large-scale, multicenter trial, active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate to a reduction in mortality from critical illness.

Trial registration: ISRCTN, ISRCTN12233792. Registered November 20th, 2017.

Introduction

Major international evidence-based guidelines consistently recommend that early targeted nutrition therapy should be provided to critically ill patients [1, 2]. However, multicenter cluster-randomized controlled trials (cRCTs) evaluating the impact of implementing evidence-based guidelines for early targeted nutrition therapy do not consistently show patient benefits [3,4,5]. Therefore, a considerable gap exists between international guideline recommendations and actual clinical practice [6, 7].

We developed an evidence-based practical feeding guideline to overcome barriers and enhance nutrition therapy in Chinese intensive care units (ICUs) [8]. A pilot before-and-after study (N = 410) showed that active implementation of the guideline was effective in increasing enteral nutrition (EN) delivery, thus warranting a large-scale, sufficiently powered study to ascertain effects on patient-centered outcomes [9].

The purpose of this study was to determine the effect of actively implementing an evidence-based feeding guideline on patient outcomes. Using a cluster-randomized design, participating ICUs were randomized to receive the active implementation package or remain as controls. We hypothesized that successful implementation of this guideline could enhance nutrition delivery, and therefore reduce 28-day mortality.

Methods

Trial design and oversight

This investigator-initiated, cluster-randomized, parallel-controlled trial assessed the effects of an actively implemented evidence-based guideline for nutrition therapy to control usual care on patient outcomes. The study was approved by the ethics committee of Jinling Hospital (trial sponsor) and registered in the ISRCTN registry before enrollment commenced (Ethical Number: 22017NZKY-019-02; ISRCTN Registry Identifier: ISRCTN12233792). The local hospital ethics committees of all the participating sites also approved the trial. At each site, informed consent was obtained from the patients or their next of kin before enrollment. Patients were enrolled from March 26th, 2018 (the first recruitment) to July 4th, 2019 (the last recruitment). The last patient's follow-up was completed on July 31st, 2019.

The study was funded by the Key Research and Development Program Foundation of Jiangsu Province of China (no. BE2015685) and Nutricia, Wuxi, China, which supported meetings and training during the study period. The funders had no role in the study's design, data collection, analysis, or preparation of the manuscript. Representatives from Nutricia received copies of the paper before submission for publication but had no influence over content. The trial protocol and statistical analysis plan are available in Additional file 1. The dates of each protocol version, the changes made during each update, and the other details are also provided in Additional file 1.

Participants

Patients admitted to the participating ICUs were eligible for inclusion if they were 18 years or older, were in the ICU less than 24 h, had one or more organ system failures (sequential organ failure assessment (SOFA) score for any individual organ system ≥ 2), were expected to stay in ICU for more than seven days, and were judged not likely to resume oral diet within three days. Patients who received EN in the past three days, were receiving palliative treatment, were expected to die within 48 h, were pregnant, had a long-term history of steroid use or other immunosuppressive agents, or were receiving radiotherapy or chemotherapy due to malignant diseases were not eligible for inclusion.

Randomization and masking

Randomization was performed at ICU level. All the participating sites were stratified within province/state based on the type of ICU (emergency, medical, surgical, neurosurgery, and general). Randomization occurred in a 1:1 fashion (guideline group and control group) for the participating ICUs within the same strata using computer-generated random numbers. Allocation concealment was maintained by conducting randomization after hospital consent to participate was obtained.

Implementation of the feeding guideline

An up-to-date, evidence-based feeding guideline was developed by reviewing major international guidelines and conducting an updated literature search to include Chinese language publications[1, 10]. The guideline was finalized in April 2016 and tested in a small before-and-after study (N = 410) [9]. The graphical feeding protocol representing the guideline recommendations is presented in Fig. 1 (see the adjunct table in Additional file 2: Table S1). Briefly, the protocol includes when to start EN, when to adjust feeding rate, when to start parenteral nutrition and how to manage feeding intolerance. The major aims of this protocol include promoting early EN, standardizing the application of PN (avoiding universal early PN), and increasing target-reaching rate in the first week of ICU admission, as to address the major issues shown in our cross-sectional study [7].

Fig. 1

Evidence-based feeding guideline. A algorithm of the evidence-based feeding guideline. Feeding intolerance evaluation was implemented using the feeding intolerance score (Additional file 2: Table S1). GI denotes gastrointestinal, AGI denotes acute gastrointestinal injury, PN denotes parenteral nutrition, EN denotes enteral nutrition, and FIS denotes feeding intolerance score. B treatment of feeding intolerance. WBC denotes white blood cells, RBC denotes red blood cells, CD denotes Clostridium difficile, and D/C denotes discontinue

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Standardized educational materials were developed to facilitate the implementation of the feeding guideline in ICUs assigned to the study group [9]. A series of educational meetings were organized for all primary site investigators. The primary site investigators were responsible for the distribution, detailing, training, and implementation of the guideline at each center. Each center formed an "intervention team" led by the investigator, including local physicians, nurses, and dietitians. Paper materials, including the graphic feeding protocol and a checklist, were developed and distributed to all intervention sites. The intervention team was responsible for placing these materials at the bedside and in highly visible locations in the ICUs as passive reminders. Live online educational outreach meetings were arranged at request to maintain communication among the management committee and the local investigators. Members of the management committee were required to reply to any queries raised by a site investigator within 24 h.

ICUs assigned to the control group collected data but remained unaware of the contents of the feeding guideline throughout the study period.

Data collection

A web-based database (Unimed Scientific Inc., Wuxi, China) was developed for data collection. Before enrollment, a start-up meeting for data entry and storage training was organized for all site investigators and research coordinators on March 20^th, 2018.

Trial outcomes

The primary study outcome was all-cause mortality within 28 days of enrollment; the secondary outcomes included: process measures of guideline uptake, organ failure related outcomes and corresponding therapies, ICU-free days within 28 days, the incidence of new infections. Detailed definitions of all outcome measures are provided in the study protocol (Additional file 1).

Statistical analysis

In the previous cluster-randomized trials evaluating the effect of the use of a nutrition guideline on mortality, the 95% CI reported in the ACCEPT nutrition guidelines trial ranges from a 21% to a 0.002% reduction [5]. The ANZ guidelines trial 95% CI ranges from a 6.3% reduction to a 12% increase [3], and another guidelines cRCT conducted in Canada, 95% CI, ranged from a 14% reduction to 13% increase [4]. Simple pooling of the upper estimates of mortality benefit [(21 + 6.3 + 14)/3] reveals it could be reasonable to expect a 13.7% absolute (45% relative) reduction in mortality. Assuming 20% [7] mortality in the control group, a conservative 40% relative (8% absolute) treatment effect was assumed possible with an inter-class correlation of 0.1 [5]. Under these assumptions, a trial with 2,250 participants from 90 ICUs would achieve 80% power to detect the anticipated 8% mortality reduction (CRTSize, Rotondi 2009, version 1.0).

All analyses followed the intention-to-treat principle and were adjusted for clustering. Comparisons between the two groups were made using a mixed-effect model for the primary outcome and key secondary outcomes (ICU-free days within 28 days and the incidence of new infections), adjusting for the clustered nature of the data. Other secondary outcomes and baseline characteristics were compared by Chi-square test or t-test as appropriate, with the adjustment for the effects of clustering. Baseline imbalances in potentially confounding variables (P < 0.10) were addressed using an appropriately adjusted multivariable model for the primary outcome in additional sensitivity analysis. Two-sided 5% significance levels were used to identify statistically significant results. Analyses were conducted using SAS 9.4®.

Results

Results of recruitment

In total, 118 ICUs from 22 provinces/states were contacted for participation: 15 ICUs declined to participate in the trial, three failed to obtain ethics approval in time, and three were excluded because they had recently implemented a similar feeding guideline. We randomized 97 ICUs, as shown in the CONSORT flow (Fig. 2). After randomization, seven ICUs (three in the intervention group and four in the control group) withdrew from the study before enrolling any patients. Overall, 2,772 patients were enrolled from 90 ICUs (Additional file 2: Table S2). Twenty-eight day mortality was unavailable in 3.6% of patients (100/2,772, Fig. 2).

Fig. 2

The flow of clusters (ICUs) and participants (patients) through the trial. ICU denotes intensive care unit

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Baseline characteristics

The baseline patient-level clinical characteristics were well balanced, except for SOFA score, abdominal infections, and proportion of patients with Acute Gastrointestinal Injury (AGI) score grade III. (Table 1, See Additional file 3 for additional information of baseline characteristics).

Table 1 Baseline ICU and Patient-Level Characteristics

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Process measures

In ICUs allocated to guideline implementation, EN was initiated significantly earlier than in control ICUs (1.20 vs. 1.55 mean days to initiation of EN; difference − 0.40 [95% CI − 0.71 to − 0.09]; P = 0.01) with significantly more patients receiving EN within 48 h of ICU admission (772/1,399 vs. 451/1,373 patients, P < 0.001). Furthermore, PN initiation was significantly delayed in guideline ICUs (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI, 0.44 to 1.67]; P = 0.001) with significantly fewer patients receiving PN during the first 48 h after enrollment (250/1342 vs. 555/1336 patients, P = 0.005). See Table 2 for additional process measures.

Table 2 Process measures of nutrition therapy

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During the first seven days of enrollment, significantly more patients in the guideline ICUs received EN from day 2 to day 7 (Fig. 3b). Correspondingly, fewer patients received PN on each day of the first seven days of enrollment (Fig. 3c). The proportion of total daily energy delivered by EN was significantly higher in the guideline ICUs on each day of the first seven days after enrollment (Additional file 2: Figure S1). Details (rates, means, P values, etc.) for each day are reported in Table S3-S6 (Additional file 2). For the proportion of patients reaching 70% of the estimated energy target and daily protein intake from day 1 to day 7 after enrollment, there is no difference between groups (Additional file 2: Tables S7–S8, Figure S2–S3).

Fig. 3

Nutritional support within the first seven days after enrollment. Error bars indicate test-based 95% confidence intervals (adjusted for cluster effect). a Proportion of patients receiving enteral and/or parenteral nutrition. P > 0.05 (adjusted for cluster effect) between feeding protocol and control groups at each day from day 1 to day 7. b Proportion of patients receiving enteral nutrition. P < 0.05 (adjusted for cluster effect) between feeding protocol and control groups at each day within seven days of enrollment except day 1. c Proportion of patients receiving parenteral nutrition P < 0.05 (adjusted for cluster effect) between feeding protocol and control groups at each day within seven days of enrollment

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Primary outcome and other clinical outcomes

On crude analysis there was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference − 1.6% [95%CI − 4.3% to 1.2%]; P = 0.42) between study groups. Multivariable analysis controlling for the stratification factors (province/state and type of ICUs) and potentially confounding factors (SOFA score, abdominal infections, and AGI score) did not alter the overall interpretation of the primary outcome (difference, − 0.4% [95% CI  − 5.6% to 4.8%]; P = 0.76).

There were no differences in new-onset organ failure within the first seven days after enrollment between groups (Additional file 2: Table S9). ICUs assigned to implement the feeding guideline reported a significantly reduced need for renal replacement therapy (0.97 vs. 1.46 days/10 patient-days; difference − 0.48 days [95%CI − 0.88 to − 0.08 days]; P = 0.02) and vasoactive agent use within the first seven days of enrollment (2.19 vs. 2.98 days/10 patient-days; difference − 0.73 days [95%CI − 1.34 to − 0.12 days]; P = 0.02).

There was no difference in ICU-free days (9.1 vs. 8.7 days; difference 0.5 [95%CI − 1.0 to 2.0]; P = 0.53) or incidence of new infections (6.9% vs. 6.7%; difference 0.1% [95%CI − 1.9% to 2.1%]; P = 0.93) between groups. The intracluster correlation coefficient (ICC) and design effects for the primary and key secondary outcomes are shown in Table 3. Serious Adverse Events were reported in one patient from the guideline group and three patients (1/1399 vs. 3/1373, P = 0.38) in the control group (Table 3).

Table 3 Patient-centered outcomes and adverse events for all enrolled patients

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Discussion

We evaluated the effectiveness of an active implementation package supporting an evidence-based feeding guideline for nutrition therapy in critical illness in this 90 ICU cluster-randomized trial. Overall, the successful implementation of the feeding guideline significantly increased early EN delivery and significantly reduced PN use. However, these changes in practice did not influence our primary outcome, 28-day mortality.

Active implementation of an evidence-based feeding guideline has been reported to improve nutrition performance [3,4,5]. However, the impact on clinical outcomes has been variable in previous cRCTs [3,4,5], with only one of the three studies showing an improvement in mortality. This study was conducted in 1997–1998 and contained a key recommendation that early EN should commence within 24 h [5]. However, a second larger cRCT undertaken in 2003 that also recommended EN should commence within 24 h of ICU admission failed to duplicate this mortality effect [3]. The third cRCT on this topic recommended early EN should commence within 48 h, like our guideline, however this third cRCT failed to demonstrate a significant effect on any clinical outcomes[4]. Given our current cRCT was powered to detect a meaningful 8% absolute reduction in mortality, the 95% CIs around our estimate of mortality effectively rule out any mortality reduction greater than 4.3% (5.6% after adjustment). None of the previous three cRCTs were adequately powered to detect an effect of this magnitude (Ex. 4.3%).

A previous multicenter cRCT evaluating the active implementation of an evidence-based protocol for nutrition therapy in critical illness demonstrated a significant reduction in the duration of renal failure [3]. This is consistent with our finding of a reduced need for renal replacement therapy, which may be attributed to the renal protective effects of protein administration through maintenance of renal blood flow [11]. However, the overall protein intake in both groups did not achieve the latest threshold recommended by the ESPEN2019(> 1.3 g/kg/d) [12]. Given that secondary endpoints are not adjusted for multiplicity of testing, and the need for organ support are not pre-specified secondary outcomes, these findings should be interpreted with caution. Further trials should be undertaken to investigate the relationship between protein intake and kidney injury.

Practice change

Implementation of our feeding guideline resulted in comprehensive practice changes across the participating ICUs, marked by significantly earlier EN delivery and reduced PN use. The benefits of early EN have been well addressed in multiple critically ill populations [2], and achieving earlier EN commencement is one of the primary aims of this feeding guideline. A discrepancy between our feeding guideline and those used in the previous cRCTs [3,4,5] is that we clearly discouraged early initiation of PN if EN was not feasible in patients with low nutrition risk, according to the recommendations made by the ASPEN/SCCM guidelines [1]. Early initiation of PN is costly and may result in worse outcomes, as shown in the EPaNIC trial [13]. However, the overall improvement in early EN and reduction in PN use achieved in our study was modest and did not translate into improvements in mortality or a reduction of new infections. This failure to impact the onset of new infections is consistent with the results of the previous large trials, which also found no impact of PN on infectious complications [14, 15].

The most recent ESPEN guidelines recommend that clinicians should strive to provide more than 70% of a patient's calculated energy targets by ICU day 4 [12]. In our study, active implementation of the feeding guideline did not result in significantly more patients achieving this goal, although the proportion of EN-delivered energy did increase. Feeding intolerance is a significant concern impeding the early achievement of energy targets worldwide [16]. Our feeding guideline incorporated a self-developed feeding intolerance score for repeated gastrointestinal function assessment [17]. The feeding intolerance score includes key gastrointestinal symptoms and intra-abdominal pressure, both associated with ICU mortality [18, 19], and we categorized them into four grades of severity for quantitive measurement. Our results suggest that applying this score as a tool for repeated feeding tolerance assessment may have effectively facilitated EN delivery without additional feeding intolerance. We recommend additional individual patient RCTs to evaluate the effectiveness of this intolerance score.

Limitations

Our study was adequately powered to detect a meaningful difference in the primary outcome, mortality. However, previous studies, including our own before-and-after study (N = 410) [9], which investigated nutrition in ICUs, showed that the likeliness of nutrition practice to reduce mortality is very limited [20], which means an estimation of an 8% reduction in mortality might be overoptimistic. Besides, the mortality in the control group is lower than expected (15.2% vs. 20% for sample size estimation), which might make our trial underpowered. Regarding the guideline, we recommend using semi-elemental products to initiate EN in patients with AGI II-III, which is not a common practice and only recommended by a few international nutrition guidelines [4]. This practice may impact the generalizability of our results to come countries. Moreover, although 32% of patients at standard care hospitals received PN on the first day of enrollment, this was reduced to 15% of patients under guideline care. This level of PN use in our guideline hospitals appears to be similar to standard care in other countries around the world [6, 21]. Furthermore, large-scale clinical trials randomizing critically ill patients to commence EN first vs. PN first establish there is no impact on clinical outcomes or infectious complications [14, 15]. Therefore we suggest that PN use in our participating ICUs does not affect the generalizability of our results.

From a technical perspective, although the active implementation package supporting the feeding guideline resulted in measurable and meaningful differences in practice, the guidelines are complex and make multiple clinical recommendations. Because of this complexity, we cannot attribute specific changes in clinical outcomes to any specific guideline recommendation, we can only hypothesize such a relationship may exist. Any such hypothesis must be tested in an individual patient RCT evaluating specific clinical outcomes and specific clinical recommendations.

Conclusions

In conclusion, successful active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate into a reduction in our primary outcome, 28-day all-cause mortality. Additional research is warranted to investigate the impact of enhanced nutrition, especially protein, on other outcomes.

Availability of data and materials

The datasets generated and analyzed in this article are not publicly available due to health privacy concerns but are available from the corresponding author on reasonable request.

Change history

• 21 April 2022

  A Correction to this paper has been published: https://doi.org/10.1186/s13054-022-03982-6

Abbreviations

cRCT:

Cluster-randomized controlled trials

ICU:

Intensive care unit

EN:

Enteral nutrition

PN:

Parenteral nutrition

SOFA:

Sequential organ failure assessment

AGI:

Acute gastrointestinal injury

ICC:

Intracluster correlation coefficient

FIS:

Feeding intolerance score

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Acknowledgements

The authors would like to acknowledge all the patients and health staffs who participated in this trial. A full list of members of the Chinese Critcal Care Nutrition Trials Group (CCCNTG): Lu Ke, Jiajia Lin, Zhihui Tong, Weiqin Li (Jinling Hospital); Yang Wang (Fuwai Hospital); Juan Xing (BenQ Medical Center); Zhongheng Zhang, Feng Guo (Sir Run Run Shaw Hospital); Tao Chen (Liverpool School of Tropical Medicine); Lixin Zhou (First People's Hospital of Foshan); Dongpo Jiang (Daping Hospital); Qindong Shi (First Affiliated Hospital of Xi'an Jiao Tong University); Jiandong Lin (First Affiliated Hospital of Fujian Medical University); Jun Liu (Suzhou Municipal Hospital); Aibin Cheng (North China University of Science and Technology Affiliated Hospital); Yafeng Liang (Yantai Yuhuangding Hospital); Peiyang Gao (Chengdu University of Traditional Chinese Medicine Affiliated Hospital); Junli Sun (Luoyang Central Hospital); Wenming Liu (Changzhou No.2 People's Hospital); Zhenyu Yang (The Second Affiliated Hospital of Harbin Medical University); Rumin Zhang (Zibo Central Hospital); Wei Xing (The Third Xiangya Hospital of Central South University); An Zhang (The Second Affiliated Hospital of Chongqing Medical University); Zhigang Zhou (First People's Hospital of Kunming); Tingfa Zhou (Linyi City People Hospital); Yang Liu (Tangshan Gongren Hospital); Fei Tong (Hebei Medical University Second Affiliated Hospital); Qiuhui Wang (Wuxi People's Hospital); Aijun Pan (Anhui Provincial Hospital); Xiaobo Huang (Sichuan Provincial People's Hospital); Chuming Fan (First People's Hospital of Yunnan); Weihua Lu (Yijishan Hospital); Dongwu Shi (Shanxi Provincial People's Hospital); Lei Wang (Shanxi Medical University First Affiliated Hospital); Wei Li (The People's Hospital of Fujian Province); Liming Gu (People's Hospital of Yuxi City); Yingguang Xie (Jining First People's Hospital); Rongqing Sun (The First Affiliated Hospital of Zhengzhou University); Lin Han (People's Hospital of Guangxi Zhuang Autonomous Region); Lihua Zhou (Affiliated Hospital of Inner Mongolia Medical College); Xiangde Zheng (Dazhou Central Hospital); Feng Shan, Liandi Li (Qindao University Medical College Affiliated Hospital); Jianbo Liu (Inner Mongolia People's Hospital); Yuhang Ai (Xiangya Hospital Central South University); Yan Qu (Qingdao Municipal Hospital Group); Hailing Li (No.971 hospital of People's Liberation Army Navy); Zhiguo Pan (General Hospital of Southern Theatre Command); Donglin Xu (Guangzhou First People's Hospital); Zhiqiang Zou (Union Hospital of Fujian Medical University); Yan Gao (The General Hospital of Shenyang Military); Chunli Yang (Jiangxi Provincial People's Hospital); Qiuye Kou (The Sixth Affiliated Hospital, Sun Yat-Sen University); Xijing Zhang (Xijing Hospital); Jinglan Wu (Shenzhen Nanshan People's Hospital); Chuanyun Qian (Kuming Medical University First Affiliated Hospital); Weixing Zhang (Peking University Shenzhen Hospital); Minjie Zhang, Yongjian Feng (Jinan University First Affiliated Hospital); Yuan Zong (Shaanxi Provincial People's Hospital); Bingyu Qin (Henan Provincial People's Hospital); Fusen Zhang (Tai'an City Central Hospital); Zhe Zhai (The Fourth Hospital of Harbin Medical University); Yun Sun (Anhui Medical University Second Affiliated Hospital); Ping Chang (Southern Medical University Zhujiang Hospital); Bo Yu (the Second Xiangya Hospital of Central South University); Min Yu (First People's Hospital of Yichang); Shiying Yuan (Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology); Yijun Deng (Yancheng First People's Hospital); Liyun Zhao (Guangdong Second Traditional Chinese Medicine Hospital); Bin Zang (China Medical University Affiliated Shengjing Hospital); Yuanfei Li (Changsha Central Hospital affiliated to University of South China); Fachun Zhou (Chongqing Medical University First Affiliated Hospital); Xiaomei Chen (Qilu Hospital); Min Shao (The First Affiliated Hospital of Anhui Medical University); Weidong Wu (Shanxi Bethune Hospital); Ming Wu (First Affiliated Hospital of Shenzhen University); Zhaohui Zhang (Yichang Central People's Hospital); Yimin Li (First Affiliated Hospital of Guangzhou Medical University); Qiang Guo (First Affiliated Hospital of Soochow University); Zhiyong Wang (Hebei Medical University Third Affiliated Hospital); Yuanqi Gong (The Second Affiliated Hospital of Nanchang University); Yunlin Song (The First Affiliated Hospital of Xinjiang Medical University); Kejian Qian (The First Affiliated Hospital of Nanchang University); Baocai Fu (Yantai Mountain Hospital); Xueyan Liu (Shenzhen People's Hospital); Zhiping Li (Hunan Provincial People's Hospital); Chuanyong Gong (Tianjing Hospital of Integration of Chinese and Western Medicine); Cheng Sun (Guangdong Provincial People's Hospital); Jian Yu (The Second Hospital of Dalian Medical University); Zhongzhi Tang (Wuhan General Hospital of Guangzhou Military Region); Linxi Huang (Shantou University Medical College First Affiliated Hospital); Biao Ma (Jining Medical College Affiliated Hospital); Zhijie He (Sun Yat-sen Memorial Hospital); Qingshan Zhou (Hubei Provincial People's Hospital); Rongguo Yu (Fujian Provincial Hospital).

Funding

The study was funded partly by the Key Research and Development Program Foundation of Jiangsu Province of China (no. BE2015685) and partly by the Nutricia Research. The funders had no role in the study's design, data collection, and analysis, or preparation of the manuscript. Representatives from Nutricia,Wuxi, China received copies of the paper before submission for publication but had no influence over content.

Author information

Author notes

1. Lu Ke and Jiajia Lin contributed equally to this work.

Authors and Affiliations

1. Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, No. 305 Zhongshan East Road, Nanjing, 210000, Jiangsu Province, China

   Lu Ke, Jiajia Lin, Zhihui Tong, Weiqin Li & Weiqin Li

2. National Institute of Healthcare Data Science, Nanjing University, Nanjing, China

   Lu Ke & Weiqin Li

3. Northern Clinical School, Royal North Shore Hospital, University of Sydney, Sydney, Australia

   Gordon S. Doig

4. Department of Intensive Care Medicine, Gelderse Vallei Hospital, Willy Brandtlaan 10, 6716 RP, Ede, The Netherlands

   Arthur R. H. van Zanten

5. Department of Medical Research and Biometrics Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

   Yang Wang

6. Benq Medical Center, Nanjing, China

   Juan Xing

7. Department of Emergency Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

   Zhongheng Zhang

8. Tropical Clinical Trials Unit, Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, L3 5QA, UK

   Tao Chen

9. First People's Hospital of Foshan, Foshan, China

   Lixin Zhou

10. Daping Hospital, Army Medical University, Chongqing, China

    Dongpo Jiang

11. First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China

    Qindong Shi

12. First Affiliated Hospital of Fujian Medical University, Fuzhou, China

    Jiandong Lin

13. Suzhou Municipal Hospital, Suzhou, China

    Jun Liu

14. North China University of Science and Technology Affiliated Hospital, Tangshan, China

    Aibin Cheng

15. Qindao University Medical College Affiliated Yantai Yuhuangding Hospital, Yantai, China

    Yafeng Liang

16. Chengdu University of Traditional Chinese Medicine Affiliated Hospital, Chengdu, China

    Peiyang Gao

17. Luoyang Central Hospital Affiliated To Zhengzhou University, Luoyang, China

    Junli Sun

18. Changzhou No. 2 People's Hospital Affiliated to Nanjing Medical University, Changzhou, China

    Wenming Liu

19. The Second Affiliated Hospital of Harbin Medical University, Harbin, China

    Zhenyu Yang

20. Zibo Central Hospital, Zibo, China

    Rumin Zhang

21. Department of Intensive Care Medicine, The Third Xiangya Hospital of Central South University, Changsha, China

    Wei Xing

22. The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

    An Zhang

23. First People's Hospital of Kunming, Kunming, China

    Zhigang Zhou

24. Linyi City People Hospital, Shandong, China

    Tingfa Zhou

25. Tangshan Gongren Hospital, Tangshan, China

    Yang Liu

26. Hebei Medical University Second Affiliated Hospital, Shijiazhuang, China

    Fei Tong

27. Wuxi People's Hospital, Wuxi, China

    Qiuhui Wang

28. Anhui Provincial Hospital, Hefei, China

    Aijun Pan

29. Department of Critical Care Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China

    Xiaobo Huang

30. First People's Hospital of Yunnan, Kunming, China

    Chuming Fan

31. Yijishan Hospital of Wannan Medical College, Wuhu, China

    Weihua Lu

32. Shanxi Provincial People's Hospital, Taiyuan, China

    Dongwu Shi

33. Shanxi Medical University First Affiliated Hospital, Taiyuan, China

    Lei Wang

34. The People's Hospital of Fujian Province, Fuzhou, China

    Wei Li

35. People's Hospital of Yuxi City, Yuxi, China

    Liming Gu

36. Jining First People's Hospital, Jining, China

    Yingguang Xie

37. The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Rongqing Sun

38. Department of Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Feng Guo

39. People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China

    Lin Han

40. Affiliated Hospital of Inner Mongolia Medical College, Huhehaote, China

    Lihua Zhou

41. Dazhou Central Hospital, Dazhou, China

    Xiangde Zheng

42. Qindao University Medical College Affiliated Hospital, Qindao, China

    Feng Shan & Liandi Li

43. Inner Mongolia People's Hospital, Huhehaote, China

    Jianbo Liu

44. Xiangya Hospital Central South University, Changsha, China

    Yuhang Ai

45. Qingdao Municipal Hospital Group, Qingdao, China

    Yan Qu

46. No.971 Hospital of People's Liberation Army Navy, Qingdao, China

    Hailing Li

47. General Hospital of Southern Theatre Command, Guangzhou, China

    Zhiguo Pan

48. Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China

    Donglin Xu

49. Union Hospital of Fujian Medical University, Fuzhou, China

    Zhiqiang Zou

50. The General Hospital of Shenyang Military, Shenyan, China

    Yan Gao

51. Jiangxi Provincial People's Hospital, Nanchang, China

    Chunli Yang

52. The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China

    Qiuye Kou

53. Department of Anaesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, China

    Xijing Zhang

54. Shenzhen Nanshan People's Hospital, Shenzhen, China

    Jinglan Wu

55. Kuming Medical University First Affiliated Hospital, Kuming, China

    Chuanyun Qian

56. Peking University Shenzhen Hospital, Guandong, China

    Weixing Zhang

57. General ICU, Jinan University First Affiliated Hospital, Jinan, China

    Minjie Zhang

58. Shaanxi Provincial People's Hospital, Xi'an, China

    Yuan Zong

59. Henan Provincial People's Hospital, Zhengzhou, China

    Bingyu Qin

60. Tai'an City Central Hospital, Tai'an, China

    Fusen Zhang

61. The Fourth Hospital of Harbin Medical University, Harbin, China

    Zhe Zhai

62. Anhui Medical University Second Affiliated Hospital, Hefei, China

    Yun Sun

63. Southern Medical University Zhujiang Hospital, Guangzhou, China

    Ping Chang

64. Department of Critical Care Medicine, the Second Xiangya Hospital of Central South University, Changsha, 410000, Hunan, China

    Bo Yu

65. First People's Hospital of Yichang, Yichang, China

    Min Yu

66. Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China

    Shiying Yuan

67. Yancheng First People's Hospital, Yancheng, China

    Yijun Deng

68. Guangdong Second Traditional Chinese Medicine Hospital, Guangzhou, China

    Liyun Zhao

69. China Medical University Affiliated Shengjing Hospital, Shenyang, China

    Bin Zang

70. Changsha Central Hospital Affiliated to University of South China, Changsha, China

    Yuanfei Li

71. Chongqing Medical University First Affiliated Hospital, Chongqing, China

    Fachun Zhou

72. Department of Critical Care Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China

    Xiaomei Chen

73. The First Affiliated Hospital of Anhui Medical University, Hefei, China

    Min Shao

74. Shanxi Bethune Hospital, Taiyuan, China

    Weidong Wu

75. Health Science Center, The Second People's Hospital of Shenzhen, First Affiliated Hospital of Shenzhen University, Shenzhen, China

    Ming Wu

76. Yichang Central People's Hospital, Yichang, China

    Zhaohui Zhang

77. First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Yimin Li

78. First Affiliated Hospital of Soochow University, Suzhou, China

    Qiang Guo

79. Hebei Medical University, Third Affiliated Hospital, Shijiazhuang, China

    Zhiyong Wang

80. The Second Affiliated Hospital of Nanchang University, Jiangxi, China

    Yuanqi Gong

81. The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China

    Yunlin Song

82. The First Affiliated Hospital of Nanchang University, Jiangxi, China

    Kejian Qian

83. Neurosurgical ICU, Jinan University First Affiliated Hospital, Jinan, China

    Yongjian Feng

84. Yantai Mountain Hospital, Yantai, China

    Baocai Fu

85. Shenzhen People's Hospital, Shenzhen, China

    Xueyan Liu

86. Hunan Provincial People's Hospital, Changsha, China

    Zhiping Li

87. Tianjing Hospital of Integration of Chinese and Western Medicine, Tianjing, China

    Chuanyong Gong

88. Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China

    Cheng Sun

89. The Second Hospital of Dalian Medical University, Liaoning, China

    Jian Yu

90. Wuhan General Hospital of Guangzhou Military Region, Wuhan, China

    Zhongzhi Tang

91. Shantou University Medical College First Affiliated Hospital, Shantou, China

    Linxi Huang

92. Jining Medical College Affiliated Hospital, Jining, China

    Biao Ma

93. Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Zhijie He

94. Hubei Provincial People's Hospital, Wuhan, China

    Qingshan Zhou

95. Fujian Provincial Hospital, Fujian, China

    Rongguo Yu

Consortia

for the Chinese Critcal Care Nutrition Trials Group (CCCNTG)

• Lu Ke
• , Jiajia Lin
• , Zhihui Tong
• , Weiqin Li
• , Yang Wang
• , Juan Xing
• , Zhongheng Zhang
• , Feng Guo
• , Tao Chen
• , Lixin Zhou
• , Dongpo Jiang
• , Qindong Shi
• , Jiandong Lin
• , Jun Liu
• , Aibin Cheng
• , Yafeng Liang
• , Peiyang Gao
• , Junli Sun
• , Wenming Liu
• , Zhenyu Yang
• , Rumin Zhang
• , Wei Xing
• , An Zhang
• , Zhigang Zhou
• , Tingfa Zhou
• , Yang Liu
• , Fei Tong
• , Qiuhui Wang
• , Aijun Pan
• , Xiaobo Huang
• , Chuming Fan
• , Weihua Lu
• , Dongwu Shi
• , Lei Wang
• , Wei Li
• , Liming Gu
• , Yingguang Xie
• , Rongqing Sun
• , Lin Han
• , Lihua Zhou
• , Xiangde Zheng
• , Feng Shan
• , Liandi Li
• , Jianbo Liu
• , Yuhang Ai
• , Yan Qu
• , Hailing Li
• , Zhiguo Pan
• , Donglin Xu
• , Zhiqiang Zou
• , Yan Gao
• , Chunli Yang
• , Qiuye Kou
• , Xijing Zhang
• , Jinglan Wu
• , Chuanyun Qian
• , Weixing Zhang
• , Minjie Zhang
• , Yongjian Feng
• , Yuan Zong
• , Bingyu Qin
• , Fusen Zhang
• , Zhe Zhai
• , Yun Sun
• , Ping Chang
• , Bo Yu
• , Min Yu
• , Shiying Yuan
• , Yijun Deng
• , Liyun Zhao
• , Bin Zang
• , Yuanfei Li
• , Fachun Zhou
• , Xiaomei Chen
• , Min Shao
• , Weidong Wu
• , Ming Wu
• , Zhaohui Zhang
• , Yimin Li
• , Qiang Guo
• , Zhiyong Wang
• , Yuanqi Gong
• , Yunlin Song
• , Kejian Qian
• , Baocai Fu
• , Xueyan Liu
• , Zhiping Li
• , Chuanyong Gong
• , Cheng Sun
• , Jian Yu
• , Zhongzhi Tang
• , Linxi Huang
• , Biao Ma
• , Zhijie He
• , Qingshan Zhou
•  & Rongguo Yu

Contributions

WQL, LK and ZHT were involved with study conception and design. LK, JJL, GSD and AVZ were involved in interpreting the data and writing the manuscript. YW, JX, ZHZ, TC, LXZ, DPJ, QDS, JDL, JL, ABC, YFL, PYG, JLS, WML, ZYY, RMZ, WX, AZ, ZGZ, TFZ, YL, FT, QHW, AIP, XBH, CMF, WHL, DWS, LW, WL, LMG, YGX, RQS, FG, LH, LHZ, XDZ, FS, JBL, YHA, YQ, LDL, HLL, ZGP, DLX, ZQZ, YG, CLY, QYK, XJZ, JLW, CYQ, WXZ, MJZ, YZ, BYQ, FSZ, ZZ, YS, PC, GBW, MY, SYY, YJD, LYZ, BZ, YFL, FCZ, XMC, HYL, WDW, MW, ZHZ, YML, QG, ZYW, YQG, YLS, KJQ, YJF, BCF, XYL, ZPL, CYG, CS, JY, ZZT, LXH, BM, ZJH, QSZ, RGY participated in acquisition, analysis, or interpretation of data. ZHT and WQL provided critical edits to the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Zhihui Tong or Weiqin Li.

Ethics declarations

Ethics approval and consent to participate

The study protocol was approved by the ethics committee of Jinling Hospital (trial sponsor) (Ethical Number: 22017NZKY-019-02) and by the local ethics committee of all the study centers.

Consent for publication

Consent for publication was obtained for this report.

Competing interests

Dr. Gordon S. Doig reported receiving academic research grants related to nutrition in critical illness from the Australian National Health and Medical Research Council, Fresenius Kabi Deutschland GmbH and Baxter Healthcare Pty Ltd and speakers honoraria from Fresenius Kabi Deutschland GmbH, Baxter Healthcare Australia, Pty Ltd, Nestle Healthcare, Vevy, Switzerland and Nutricia Pharmaceutical (Wuxi) Co., Ltd. China. Dr. van Zanten reports personal fees from Baxter, personal fees from Nestle, personal fees from Fresenius Kabi, grants and personal fees from Nutricia, grants from Cardinal Health, grants from Mermaid, grants from Lyric, outside the submitted work. Dr. Weiqin Li reported receiving speakers honoraria from Nutricia Pharmaceutical (Wuxi) Co., Ltd. China. The remaining authors have disclosed that they do not have any conflicts of interest.

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Supplementary Information

Additional file 1

. Protocol and Statistical Analysis Plan.

Additional file 2

. Table S1. Feeding intolerance score. Table S2. Recruitment of patients. Table S3. Proportion of patients receiving enteral and/or parenteral nutrition. Table S4. Proportion of patients receiving enteral nutrition. Table S5. Proportion of patients receiving parenteral nutrition. Table S6. Proportion of enteral nutrition delivered energy in daily energy delivery. Table S7. Target-reaching rate in fed patients from day1 to day7 after enrollment. Table S8. Protein intake from day1 to day7 after enrollment. Table S9. Organ failure-related outcomes. Figure S1. Proportion of enteral nutrition delivered energy in daily energy delivery within the first seven days after enrollment. Figure S2. Target-reaching (more than 70% of the estimated energy target) rate in fed patients for energy delivery from day1 to day7 after enrollment. Figure S3. Daily protein intake from day1 to day7 after enrollment.

Additional file 3

. Continued Table 1. Baseline ICU and Patient-Level Characteristics..

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Ke, L., Lin, J., Doig, G.S. et al. Actively implementing an evidence-based feeding guideline for critically ill patients (NEED): a multicenter, cluster-randomized, controlled trial. Crit Care 26, 46 (2022). https://doi.org/10.1186/s13054-022-03921-5

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• Received: 14 December 2021

• Accepted: 31 January 2022

• Published: 16 February 2022

• DOI : https://doi.org/10.1186/s13054-022-03921-5

Keywords

• Intensive care unit
• Cluster-randomized trial
• Nutrition therapy
• Evidence-based guideline

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