Additional consent provisions for collection and use of participant data and biological specimens {26b}
No applicated
Interventions
Explanation for the choice of comparators {6b}
For EN[10], the current guidelines recommend the use of pumping, which is often compared to manual infusion[11]. Continuous feeding, intermittent feeding and cyclic feeding are three common feeding methods.Some studies[12-14] have demonstrated that continuous pumping does not improve blood sugar levels, stomach retention, and the occurrence of ventilator-associated pneumonia.
Intervention description {11a}
Patients were randomized into three arms: continuous feeding group, cycling feeding group, and intermittent feeding group. In the continuous group, an electric infusion feeding pump delivers EN at a constant hourly rate, 24 h/day. The critical patients randomized to the cycling feeding group received EN preparation for 16 h by continuous pumping through the stomach tube every day. The initial pumping speed of two groups was 50 mL/h, and the gastric residual volumes (GRV) was checked every 4 h. If it can be tolerated, the velocity of the pumping can be increased by half of the original speed. If it is not tolerable, the speed of the pumping is reduced by half of the original speed. GRV<500 mL was considered as a marker of adequate tolerance. Feeding intolerance was defined as GRV>500 mL. The critical patients randomized to the intermittent feeding group were administered EN preparation by four meals every day (08:00, 12:00,18:00, 22:00); each meal was pumped within 60 min through the stomach tube. In the intermittent group, the daily amount of feeding was divided into four meals, and each meal was pumped through the stomach tube within 60 min. EN preparation pumping scheme was as follows: the initial pumping speed was 250 mL/h, and the GRV was checked before each intermittent feeding. If it can be tolerated, the velocity of the pumping was increased by half of the original speed. If it was not tolerable, the speed of the pumping was reduced by half of the original speed. All feeding was started within 24 h of admission to the ICU. EN suspension ((SP, Peptisorb), Nutricia Pharmaceuticals (Wuxi, Jiangsu, China) Co. Ltd) was selected for the preparing EN. The calorie content was 1 kcal/mL and thermal nitrogen ratio was 133:1. Each bottle contains 500 mL nutrition preparation consisting of 61.5 g carbohydrate, 20.0 g protein, and 19.45 g fat (Wuxi). The treatment course was 5 days (Fig. 1).
Criteria for discontinuing or modifying allocated interventions {11b}
Withdrawal/trial discontinuation/drop-out criteria
Participants (1) who cannot tolerate the nutrition preparation, resulting in diarrhea, severe abdominal distension, and other complications; (2) or family members who request automatic withdrawal at any time.
Strategies to improve adherence to interventions {11c}
Ouyang Honglian supervised the compliance of pumping mode by checking the execution of doctors' orders. The clinical Specimen department of Guangdong Academy of Chinese Medicine carries out unified management and preservation of the collected blood specimens.
Relevant concomitant care permitted or prohibited during the trial {11d}
Relevant concomitant care is prohibited during the trial.
Provisions for post-trial care {30}
Adverse medical event (AEs) of the intervention measures in this study are rare. Any AEs that occurs in subjects during observation of a clinical study might be related to the drug of interest. The AE report form was completed during the trial. The time of occurrence, severity, duration, actions taken, and outcomes of AEs were recorded, and those occurring during follow-up were reported to the sponsor in a timely manner. Furthermore, serious AEs were reported simultaneously to the adverse drug reaction (ADR) monitoring center of the local authority within 24 h and the sponsor. The study team will give priority to unpaid examination and treatment according to the regulations of the ETHICS Committee.
Outcomes {12}
Primary outcome
The primary outcome is the mean duration (h) required to achieve the caloric goal in every group. The caloric goal of 25 kcal/kg (ideal body weight) for caloric need was calculated by a single nutritionist. The duration was the first 5 days after intervention.
Secondary outcome
Secondary outcomes included the following: (1) The rate of onset of gastric residual (%) (defined as volume >500 mL) among three groups. (2) Abdominal pressure (mmHg) was measured through the indirect bladder pressure; first in the supine position, emptying the bladder urine, second pouring 50 mL saline into the balloon catheter to the pubic symphysis as the base point, keeping the piezometric tube perpendicular to the ground to obtain indirect abdominal pressure. (3) The rate of onset of pneumonia was evaluated in each group (%). It was defined by two of the following clinical criteria: fever (>38.3 °C) or hypothermia (≤36.0 °C); leukocytosis (>10×109 cells/L) or leukopenia (≤4×109 cells/L); purulent tracheal aspirate or sputum. These factors were associated with the appearance of a new infiltrate or changes in the existing infiltrate on the chest X-ray.[15] (4) The proportion (%) of individuals who achieved the caloric goal. The caloric goals using 25 kcal/kg (ideal body weight) for caloric need were calculated by a single nutritionist. (5) Motilin levels before and 5 days after intervention. (6)The length of the ICU stay (in days) up to 12 weeks. (7) The ICU mortality rate (%) at 28 days after intervention and survival analysis up to 12 weeks.
Participant timeline {13}
Sample size {14}
The sample size was calculated based on the incidence of gastric retention and aspiration size (P=0.05, P=-0.20, respectively). Compared to the continuous group, Patients in the intermittent and cycling groups did not reduce the percentage of patients who met the target calories, which was 80 percent. A standard deviation of the outcome variable of 70% power and a significance level of 0.05 (two-sided) was set, ratio of patients in continuous group and in the intermittent, cycling groups with continuous group is 0.5. So a sample size of 26 patients in each group was required; however, the total sample size was 84. Based on the sample size in previous studies, and assuming that the withdrawal rate is <8–10% [16], we expected that 30 patients to be enrolled in each arm and that the total sample size was at least 90.
Recruitment {15}
Recruitment advertisements will be posted in the department to facilitate recruitment.Guang Yang or Yi Yu is responsible for talking to the patient or his statutory agent and obtaining informed consent.
Assignment of interventions: allocation
Sequence generation {16a}
A random number table generated by SPSS 20.0 software (IBM Co., Armonk, NY, USA), using the randomization method, was employed to assign the participants to each group in a ratio of 1:1:1. Patients were enrolled in allocated accordance with the sequence of admission to ICU.
Concealment mechanism {16b}
Center randomization/Envelopes containing random sequences and groups are sealed and opaque.
Implementation {16c}
Jian Li will generate the allocation sequence, Guang Yang will enrol participants and assign participants to interventions.
Assignment of interventions: Blinding
Who will be blinded {17a}
Since this study was a comparative assessment of treatment modalities, blinding was not feasible. Masking was applied to the assessment team, data manager, and statistician related to the participant treatment arm allocation and to the treatment team for the baseline and follow-up assessments.
Procedure for unblinding if needed {17b}
No
Data collection and management
Plans for assessment and collection of outcomes {18a}
The Second Affiliated Hospital of Guangzhou University of Chinese Medicine was in charge of data management and statistical analysis in this study. The statistical analysts were not involved in clinical observation. Study personnel will undergo training sessions on data collection and are individually tested on data entry as well as outcomes assessments before trial initiation. Study data is collected and managed using SPSS 20.0.
Plans to promote participant retention and complete follow-up {18b}
Follow-up or telephone follow-up was conducted 28 days after the intervention.
Data management {19}
An independent data safety monitoring board (DSMB) will receive trial data from the biostatistician and choose to continue the study as planned, change the study protocol, or stop the trial early for harm. Double data entry is carried out by special persons and reported to DSMB.
Confidentiality {27}
The participants’ medical records were maintained at the hospital, and the investigator, research authority, and the ethics committee were allowed access to this information. Any public report on the results of this study did not disclose the participants’ personal identities. Every effort was made to protect the privacy of participants’ personal medical data, according to the law. Personal and medical information was kept confidential in a safe and reliable place. At any time, the participants may request access to their personal information (such as address and contact information) and may modify the same if necessary.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
The clinical Specimen department of Guangdong Academy of Chinese Medicine carries out unified management and preservation of the collected blood specimens. Motilin levels were determined by elisa in the laboratory of critical care Medicine of Guangdong Academy of Chinese Medicine.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
All statistical analyses were performed using SPSS 20.0 software. Measurement data were expressed as mean ± standard deviation. Normality test and homogeneity test of variance were also performed. In case of normal distribution and homogeneity of variance, a t-test was conducted, otherwise a non-parametric test was used. If the measurement data conforms to normal distribution, then independent sample t-test was applied between the two groups and one-way analysis of variance (ANOVA) was utilized between three groups. In the case of non-normal distribution, the two groups were compared using the Mann–Whitney U test, while Kruskal–Wallis test was utilized between three groups. The enumeration data between two and three groups were compared using chi-square/crosstab statistical analysis and expressed as frequency constituent ratio (%). P<0.05 indicated statistical significance.
Interim analyses {21b}
The trial can be prematurely paused or closed by the DSMB in order to evaluate safety information from the study, or if there is evidence of harm in the study. Principal investigator(PI) can access to these interim result.
Methods for additional analyses (e.g. subgroup analyses) {20b}
Not Applicable
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Patients who died or were lost to follow-up will have their observation time censored at the time of death or date of last contact. For patients with early withdrawal and lost to follow-up, intentional analysis was used. For all primary and secondary endpoints, we will consider a repeated measurement approach based on mixed models which contain both fixed effects (eg, Abdominal pressure measurement technique) and random effects (eg, patient). These models are likelihood-based approaches in the presence of ignorable missing data (ie, missing at random) and are a proper way to accommodate information on a patient with outcomes, even when such a patient’s profile is incomplete. For second endpoint (6), cumulative proportion surviving curves according Kaplan-Meier will be obtained for each group and compared with the method of log-rank test. In order to explore the group effect on the time to event of composite outcome adjusting for baseline covariates, the Cox regression model will be fitted.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
Granting full access to the protocol is intended, but participant-level dataset and statistical code is not intended
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
The coordinating centre, steering committee and endpoint adjudication committee 's responsibilities shall be assumed by the Ethics Committee of Guangdong Hospital of Chinese Medicine, reviewing the data for at least half a year.
Composition of the data monitoring committee, its role and reporting structure {21a}
Monitoring will be performed by an independent data safety monitoring board (DSMB) consisting of three members with expertise in critical care, clinical trial methodology, and biostatistics. The DSMB will receive trial data from the biostatistician and choose to continue the study as planned, change the study protocol, or stop the trial early for harm. The DSMB will submit The experimental data to The Ethics Committee of Guangdong Hospital of Traditional Chinese Medicine for review at least once every 6 months. Related data from each DSMB meeting will be retained in a secured file for inspection by regulatory authorities.
Adverse event reporting and harms {22}
Any adverse medical event (AEs) that occurs in subjects during observation of a clinical study might be related to the interventions of interest. The AE report form was completed during the trial. The time of occurrence, severity, duration, actions taken, and outcomes of AEs were recorded, and those occurring during follow-up were reported to the sponsor in a timely manner. Furthermore, serious AEs were reported simultaneously to the adverse drug reaction (ADR) monitoring center of the local authority within 24 h and the sponsor.
Frequency and plans for auditing trial conduct {23}
auditing trial conduct is once a year. The process will be independent from investigators and the sponsor.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
If the research plan needs to be modified, it shall provide relevant explanatory materials and application to the ethical Committee, and the modification can only be made after approval.
Dissemination plans {31a}
Access to the final dataset will be retained with the study investigators. Compensation for the trial, including harm, is not intended. Results of the trial are intended for publication in a peer-reviewed journal by the authors, and assistance of professional writers is not expected.