July 22, 2024

Study design

This prospective, randomized, double-blind, multicenter trial was conducted in the ICUs and respiratory care units (RCU) at Songklanagarind Hospital, Songkhla; Phramongkutklao Hospital Bangkok; and Vajira Hospital, Bangkok between January 2019 and June 2022.

Study populations

All mechanically ventilated patients who were admitted to the ICU or RCU during the study period (January 2019 to June 2022) were screened based on the inclusion criteria: (1) age ≥ 18 years; (2) body mass index (BMI) 18–30 kg/m2, (3) anticipated mechanical ventilation for ≥ 2 days; (4) risk of malnutrition, indicating a requirement for nutritional support [based on mNUTRIC Score ≥ 5 points]; (5) hemodynamically stable and indicated to receive enteral feeding via nasogastric tube within the first 48 h of ICU admission; and (6) anticipated exclusive nasogastric feeding duration ≥ 5 days.

We excluded patients: (1) with a risk or diagnosis of aspiration pneumonia; (2) with thyroid disorders; (3) with severe hepatic impairment (Child–Pugh Score, Class C); (4) on renal replacement therapy; (5) with suspected or diagnosed abdominal hypertension; (6) with HIV infection or autoimmune diseases; (7) with uncontrolled cancer or terminal disease; (8) who received chemotherapy or radiotherapy in the preceding 6 months; (9) continuously received any immunosuppressants for ≥ 2 weeks within the 4 months prior to ICU admission; (10) documented history of hypersensitivity to any ingredients of the feeding formula; (11) patients requiring additional calorie and nutrient supplementation, besides EN through nasogastric feeding, to achieve caloric goals during the trial (e.g. parenteral nutrition). Furthermore, patients who required fentanyl > 2 μg/kg/h, morphine > 0.05 mg/kg/h, or norepinephrine > 0.3 μg/kg/min were excluded.

Ethical approval

The trial protocol was developed in accordance with the ethical principles outlined in the Declaration of Helsinki and ICH Good Clinical Practice guideline for medical research involving human subjects. The trial protocol and informed consent form was approved by all participating institutes, including the Human Research Ethics Committee (HREC) Faculty of Medicine, Prince of Songkla University (REC.61–124-14–1), the Institutional Review Board (IRB) of the Royal Thai Army Medical Department (IRB no. P003h/61), and the Research Ethics Committee of the Faculty of Medicine Vajira Hospital, Navamindradhiraj University (IRB no. 036/61).

This study was registered in the Thai Clinical Trials Registry (reg. no. TCTR20220221006). All participants or their legally authorized representatives provided written informed consent before enrollment in the study.

Study protocol

Block randomization was conducted via a computerized system sponsored by the funding entity, with stratification by study site location. Participants were assigned in equal numbers to either the PBF or the SPF. Subsequent to patient recruitment and randomization, each study site accessed the randomization sequence through a secured telephone system. The trial was designed to be double-blind; as such, all involved parties—including treating clinicians, caregivers, participants, researchers, and the sponsor—were kept unaware of the specific enteral formulas administered throughout the study period. The formulas were provided as powders labeled ‘Product A’ or ‘Product B’, with packaging that was intentionally made indistinguishable to preserve the integrity of the blind. These powders were then prepared with a caloric density of 1 kcal/mL by hospital dietitians or nurses. The comprehensive biochemical compositions of PBF and SPF are presented in Table 1.

Table 1 The study formula at the specific concentration of 1 kcal/1 mL.

Based on the estimated or actual body weight, the target energy requirement for the first 3 days post-randomization was set at 25 kcal/kg/day, which was then increased to 30 kcal/kg/day from the fourth day until the 14th day or the end of the study period. No alternative routes of nutritional support or dietary supplementation for participants were permitted during the trial.

Enteral feeding protocol

Enteral nutrition (EN) was administered via a continuous infusion starting at an initial rate of 20 mL/hour, employing an infusion pump to deliver the enteral formula through a nasogastric tube. Gastric residual volumes (GRVs) were manually aspirated every six hours to monitor for signs of feeding intolerance. In instances where the GRV was below 250 mL, the infusion rate was escalated by 20 mL/hour at each six-hour interval until the prescribed caloric intake was achieved. Conversely, for patients exhibiting elevated GRVs exceeding 250 mL, the infusion rate was either halved or maintained at the minimal rate of 20 mL/hour, in conjunction with the intravenous administration of metoclopramide at a dose of 10 mg every six to eight hours. This regimen was continued until GRV levels were reduced to acceptable thresholds, upon which the rate of EN was progressively increased towards the target rate. It is noteworthy that, owing to the lack of available intravenous erythromycin within the country, intravenous metoclopramide constituted the conventional therapeutic approach for managing elevated GRVs in critically ill patients demonstrating feeding intolerance. This treatment protocol was maintained for the duration of the study.

Data collection

At enrollment, demographic data, including age, sex, underlying medical conditions, reasons for admission, body weight, and height, were recorded. Biochemical parameters, including blood urea nitrogen (BUN) and creatinine (Cr), liver function tests, and blood electrolyte levels, along with a complete blood count (CBC) and coagulogram, were performed. Using biochemical tests, nutritional status, including measurements of prealbumin, retinol-binding protein, albumin, and 24-h urinary nitrogen, was assessed. Moreover, the levels of inflammatory biomarkers, such as C-reactive protein (CRP), interleukin-6 (IL-6), and procalcitonin, were determined. Illness severity was evaluated at ICU admission using the Acute Physiology and Chronic Health Evaluation II (APACHE II) and Simplified Organ Failure Assessment (SOFA) scores.

The Bhumibol Adulyadej Hospital Nutrition Triage (BNT) was employed for the subjective assessment of the patients’ nutritional status. The BNT incorporates aspects such as caloric intake history; unintentional weight loss; edema signs; subcutaneous fat and muscle loss examination; functional status; and the presence of acute, subacute, or chronic diseases that may cause inflammatory processes or metabolic derangements and is a validated tool for the nutritional evaluation of Thai adult patients. Based on the overall BNT score, nutritional status can be categorized into four strata: NT-1 (no risk of malnutrition; 0–4 points), NT-2 (mild malnutrition; 5–7 points), NT-3 (moderate malnutrition; 8–10 points), and NT-4 (severe malnutrition; > 10 points)26.

Clinical and BNT evaluations were performed daily. The total daily caloric and protein supplementation, as well as total and average daily GRV, were recorded. Biochemical parameters, including CBC, serum electrolytes, liver, and renal function tests (BUN and Cr), retinol-binding protein, prealbumin, albumin, CRP, procalcitonin, and IL-6 levels, were analyzed at baseline and every other day for 14 days.

The 24-h urinary collection for nitrogen and creatinine measurements was undertaken on days 1, 3, 5, and 14. The nitrogen balance was calculated using a standard formula described previously27.

Safety profile

All signs and symptoms of GI intolerance, such as vomiting, diarrhea, constipation, abdominal distention, and aspiration, were daily monitored and documented by researchers as adverse events (AE). Diarrhea assessment employed the Hart and Dobb score based on stool consistency and volume, wherein a score ≥ 12 indicates diarrhea28.

The incidence of diarrhea was calculated by dividing the number of days that the patient had a Hart and Dobb score ≥ 12 by the patient’s total duration (days) of study participation. All AEs were recorded in an AE report form, and the researchers adjusted the relationship between these events and the study formula. AEs were continuously monitored and followed-up during the study and for 28 days after study completion. The institutional ethics committee was notified of these records per standard regulations.

Study outcomes

The primary endpoint of this study was the duration required to meet the established caloric goals between both enteral formulations. Secondary predefined endpoints encompassed the mean daily GRV, the rate and total dose of administration of intravenous metoclopramide as a prokinetic therapy, the number of days on mechanical ventilation, the incidence rate of infections acquired in the ICU, the total duration of ICU stay, the mortality rate within the ICU, and the fluctuations in serum markers indicative of inflammation and nutritional status. Additionally, the study monitored the frequency of adverse events (AEs) and the occurrence of diarrhea within the respective groups.

Statistical analysis

In a prior retrospective study of patients with acute gastrointestinal injury, a significant difference of 31 h was observed in the time to achieve caloric goals between the PBF and SPF groups29 This discrepancy guided our calculation of sample size, which was designed to accommodate a type I error (alpha) of 0.1 and a type II error (beta) of 0.2, yielding a requirement of 39 participants for each group.

Continuous variables were presented as the mean and standard deviation (SD), whereas categorical variables were expressed as the frequency and proportion. Intergroup differences in patient characteristics and outcomes of interest were assessed using the student’s t-test, Wilcoxon rank-sum test, Fisher’s exact test, and chi-square test, as appropriate.

For repeated-measure analysis, intergroup comparison of variables was undertaken using generalized estimating equations (GEE) with a population-average model. The working correlation matrix for GEE analysis was selected based on the lowest quasi-likelihood under the independent model criterion (QIC). Interactions between the group and time were quantified as β-coefficients with 95% Wald confidence intervals (CI).

The proportion of patients achieving the caloric goal was depicted using a Kaplan–Meier curve and compared between the groups via the Logrank test. Concerning nutritional status, which was determined daily by the BNT score, we categorized the BNT score into four strata as previously described. We then conducted pairwise comparisons within the groups for three-time intervals: between day 1 and day 7, day 1 and day 14, and day 7 and day 14. These comparisons aimed to determine changes in BNT score strata using the chi-square test. Additionally, pairwise comparisons of BNT score classification on days 1, 7, and 14 were analyzed using the chi-square test to assess differences between the groups.

Data were analyzed on an intention-to-treat basis. No imputation was made for missing data; P < 0.05 was considered statistically significant. Data analyses were performed using the IBM SPSS Statistics for Macintosh (version 27.0; IBM Corp., Armonk, NY), and MedCalc® Statistical Software version 22.017 (MedCalc Software Ltd, Ostend, Belgium; https://www.medcalc.org; 2024).

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