Central Journal of Human Nutrition & Food Science

Cite this article: Ogasawara T, Matsuda S, Kato S, Tanaka K, Yano T, et al. (2014) Early Enteral Nutrition Using Oligomeric Formula in Mechanically Venti-lated, Critically Ill Patients: A Randomized Control Trial. J Hum Nutr Food Sci 2(4): 1046.

*Corresponding authorTakashi Ogasawara, MD, PhD, Department of Respiratory Medicine, Hamamatsu Medical Center, 328 Tomitsuka, Hamamatsu, Shizuoka 432-8580, Japan, E-mail:

Submitted: 11 May2014

Accepted: 12 October 2014

Published: 15 October 2014

ISSN: 2333-6706

Copyright© 2014 Ogasawara et al.

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Research Article

Early Enteral Nutrition Using Oligomeric Formula in Mechanically Ventilated, Critically Ill Patients: A Randomized Control TrialTakashi Ogasawara1*, Syuichi Matsuda1, Shinpei Kato1, Kazuki Tanaka1, Toshiaki Yano1, Shiori Marui2, Takako Nihashi2, Yasuko Okamoto2, Masahito Ohgiku3, Norio Kasamatsu1 and Yoshito Ikematsu3

1Department of Respiratory Medicine, Hamamatsu Medical Center, Japan2Nutrition Department, Hamamatsu Medical Center, Japan3Department of Surgery, Hamamatsu Medical Center, Japan

ABBREVIATIONSICU: Intensive Care Unit; MV: Mechanical Ventilation;

GRV: Gastric Residual Volume; APACHE: Acute Physiology and Chronic Health Evaluation; SOFA score: Sequential Organ Failure Assessment score; IQR: Inter Quartile Rage; BMI: Body Mass Index; COPD: Chronic Obstructive Pulmonary Disease; P/F: PaO2/Fraction of Inspired Oxygen; SD: Standard Deviation; BUN: Blood Urea Nitrogen; n.s.: not significant; CTCAE: Common Terminology Criteria for Adverse Events; AST: Aspartate Amino Transferase; ALT: Alanine Amino Transferase; LDL: Low Density Lipoprotein.

INTRODUCTIONIn recent years, early enteral nutrition has played an

important role in treating critically ill patients receiving mechanical ventilation (MV). For example, enteral nutrition decreases the incidence of infectious complications in critically ill patients [1]. In addition, although the mechanism is unclear, early enteral nutrition helps preserve gut immune function and reduce inflammation [2,3].

A polymeric protein formula, composed mostly of easily available casein or soybean protein, is used as the enteral feeding formulation in Japan. Several nutritional guidelines recommend

Abstract

Purpose: The aim of this study was to evaluate whether oligomeric formula decreases gastrointestinal intolerance in critically ill respiratory patients receiving early enteral nutrition.

Materials and Methods: This was a prospective randomized controlled trial in respiratory patients admitted to the intensive care unit (ICU) in our hospital between December 2012 and January 2014. Twenty-four patients were randomly assigned in a 1:1 ratio to the oligomeric formula group or polymeric group; enteral feeding was initiated within 48 hours after ICU admission. The primary endpoint was the incidence of gastrointestinal complications. The secondary outcome was changes in nutritional indicators from baseline to day 3.

Results: Baseline characteristics were similar between the oligomeric (n = 11) and polymeric (n = 9) groups. There was no significant difference in diarrhea incidence (0% vs. 11%; p = 0.45), vomiting, or constipation. Although serum potassium levels increased in the oligomeric group (4.3 to 4.8 mEq/L; p = 0.04), there were no significant changes in other laboratory values in either group.

Conclusions: An oligomeric formula for early enteral feeding in critically ill respiratory patients did not decrease gastrointestinal intolerance compared with a polymeric formula.

Keywords•Enteral nutrition•Oligomeric formula•Critical care medicine•Mechanical ventilation

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that polymeric protein formula should be considered when initiating enteral feeding [1,4-6]. However, a peptide-based (oligomeric) formula may be used if there is evidence of diarrhea or intolerance to enteral nutrition [1,7]. Although patients with gastrointestinal complications such as short bowel syndrome and pancreatitis may also benefit from an oligomeric formula [1,4,7], there is no evidence supporting the use of higher-cost oligomeric formula in critical care. The use of oligomeric formula instead of polymeric formula in mechanically ventilated, critically ill patients is also not recommended [1,5]; however, if enteral nutrition with oligomeric formula contributes to improved gastrointestinal tolerance, physicians who treat patients receiving MV may be able to focus on intensive respiratory management and disease treatment without taking additional measures for gastrointestinal complications such as diarrhea or vomiting.

We conducted a prospective randomized controlled trial to determine whether oligomeric formula decreases gastrointestinal intolerance in critically ill respiratory patients receiving early enteral nutrition.

MATERIALS AND METHODSA prospective, randomized controlled trial was conducted

during December 2012–January 2014. This trial was approved by the institutional review board at our hospital (approval date: December 3, 2012, #, 26/2012) and registered on the university hospital medical information network (registration date: December 15, 2012, ID: UMIN000009552). Eligible patients and their families provided written informed consent.

Patients were eligible if they were admitted to the intensive care unit because of respiratory disorders and their physicians intended to administer enteral nutrition within 48 hours. Patients were included if they received MV, non-invasive positive pressure ventilation, or high-concentration oxygen therapy. Patients were excluded if they had severe intolerance for enteral nutrition or formula, problems with the administration of their enteral nutrition, problems with evaluating their intolerance due to complicated diseases during the study, or who were judged by their physicians as inadequate cases for inclusion.

Consecutive patients were randomly assigned in a 1:1 ratio to either the oligomeric formula group or the polymeric formula group. In both groups, enteral nutrition via a nasogastric tube was initiated within 48 hours after intensive care unit (ICU) admission at 20 ml/hour (300 kcal/day) using an enteral feeding pump, increasing to 40 ml/hour (600 kcal/day) on day 3 (Table 1). After day 5, all patients requiring continued enteral feeding received polymeric formula-based enteral nutrition adequate for their medical condition at 60 ml/L. Gastric residual volume (GRV) was measured before administration of enteral feeding on each day (once on days 1 and 2; twice; on day 3) by aspiration through a nasogastric tube using a 20-mL syringe. If GRV was >200 mL, initiation of enteral feeding was delayed.

The primary endpoint was the incidence of gastrointestinal complications during enteral nutrition such as diarrhea, vomiting/regurgitation of gastric contents, abdominal distention, and GRV on days 1–3. Diarrhea was defined as 5 or more stools of type 6 (muddy) or 7 (watery) on the Bristol stool scale [8]. Vomiting/regurgitation was defined as gastric contents detected in the

oropharynx or outside the mouth. Diarrhea and constipation were evaluated according to the Common Terminology Criteria for Adverse Events, Version 4.0 [9]. The secondary outcome was changes in laboratory values and nutritional indicators from baseline to day 3. Furthermore, clinical outcomes for the 2 groups were compared, including duration of MV, ICU length of stay, hospital length of stay, 28-day mortality, and in-hospital mortality.

According to prior patient data from our hospital, the incidence of diarrhea in the oligomeric group was estimated to be 5% [10], diarrhea would occur in 2–95% of patients treated with enteral nutrition [11,12], and the incidence of diarrhea in the polymeric group was assumed to be 60%. To assess the tolerability of oligomeric formula with 80% power and a 2-sided 5% type I error probability, 10 patients were needed in each group. Baseline age, body weight, body mass index, and severity indices (Acute Physiology and Chronic Health Evaluation II [APACHE II], sequential organ failure assessment [SOFA] score, and PaO2/FiO2 ratio) are reported as medians and inter quartile ranges (IQR), while categorical variables are reported as percentages, with differences assessed using the Mann–Whitney U test and Fisher’s exact test, respectively. Laboratory findings are indicated as means and standard deviations, and these changes were assessed using a paired t-test. For primary endpoints, gastrointestinal intolerance is reported as a percentage of patients. Defecation frequency is reported as the number of times per patient, and GRV is reported as median and IQR, with differences assessed using the Mann–Whitney U test. For duration of MV, ICU length of stay, and hospital length of stay, patients who died before day 28 were assigned 28 days for the duration of MV and ICU length of stay. Differences were considered significant at p< 0.05.

STAT VIEW version 5.0 (SAS Institute, Cary, NC, USA) was used for the statistical calculations.

RESULTS AND DISCUSSIONThe trial enrolled 24 patients; 2 patients were able to recover

oral intake within 3 days, 1 patient was excluded because of death within 3 days, and 1 patient with a fatal condition was excluded because of the physician’s decision (Figure 1). Thus, the intention-to-treatment population comprised 20 patients: 11 in the oligomeric group and 9 in the polymeric group. The groups were comparable at baseline (Table 2). The severity scores were quite high for both populations based on APACHE II scores (median 23 [IQR 20–24] in the oligomeric group versus

Nutrient

Oligomeric group Polymeric groupday 1 – 2(200 mL)20 mL/h

day 3 – 4(400 mL)40 mL/h

day 1 – 2(300 mL)20 mL/h

day 3 – 4(400 mL)40 mL/h

Energy, kcal 300 600 300 600Protein, g 19 38 16.5 23.2Carbohydrate, g 26.4 52.8 48 88.6Fat, g 13.2 26.4 6.7 20.2

n-3, g 0.86 1.72 0.42 1.24Mineral

Na, mg 240 480 540 716K, mg 464 928 390 738

Table 1: Composition of oligomeric and polymeric formula.

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median 24 [IQR 23–27] in the polymeric group) and SOFA scores (median 4 [IQR 3.5–5.5] in the oligomeric group versus median 5 [IQR 3–7] in the polymeric group).

There was no significant difference in the primary endpoint between groups (Table 3). Only one patient (11%) in the polymeric group had a defined diarrhea episode (5 or more times of muddy or watery stool per day) within 3 days after starting enteral nutrition, but it was not significant (p = 0.45). This patient participated twice in this trial and had diarrhea of grade 2,only when assigned to the polymeric group. Two patients (18%) in the oligomeric group and 2 patients (22%) in the polymeric group had diarrhea of grade 1. Vomiting and abdominal distention were not detected in either group. The incidence of constipation did not differ between groups. GRV before initiating enteral feeding each day was mostly 0 ml, and discontinuation of enteral feeding due to >200 ml of GRV was observed just once in the oligomeric group.

According to the laboratory results, there were no changes in nutritional status during the 3 days in either group (Table 4). The mean serum prealbumin level in the oligomeric group increased from 8.8 to 11.1 mg/dL, and the level in the polymeric group edged up slightly from 10.1 to 11.6 mg/dL; however, these changes were not significant (p = 0.11 and 0.39, respectively). The potassium level in the oligomeric group significantly increased from 4.3 to 4.8 mEq/L (p = 0.04).

There was no significant difference in the clinical outcomes between groups (Table 5). The calories of supplemental parenteral nutrition during the study period and the total calories administered with enteral nutrition did not differ between groups. Both the duration of MV and the ICU length of stay in the oligomeric group were not significantly longer than those in the polymeric group. In-hospital mortality in the oligomeric group was higher than in the polymeric group, though it did not reach significance (p = 0.37).

This randomized controlled trial did not show a beneficial effect of oligomeric formula for decreasing gastrointestinal intolerance in critically ill respiratory patients receiving early enteral nutrition. The use of oligomeric formula did not improve nutritional parameters observed during the first 3 days after

Figure 1 CONSORT diagram of the present trial.

CharacteristicsOligomeric-

Group(n = 11)

Polymeric Group(n = 9)

P value

Age, y, median (IQR) 76 (67 – 83) 78 (77 – 80) 0.65Men, n (%) 8 (73) 7 (78) 0.99Body weight, kg, median (IQR) 53 (42 – 57) 50 (42 – 59) 0.79

BMI, kg/m2, median (IQR) 20.6 (17.7 – 21.7)

19.1 (14.3 – 21.0) 0.47

IPPV, n (%) 7 (64) 5 (56) 0.99Underlying disorder, n (%)

Acute exacerbation of interstitial pneumonia 3 (27) 1 (11) 0.59

Exacerbation of COPD 0 (0) 2 (22) 0.19CO2 narcosis 3 (27) 2 (22) 0.99Diffuse alveolar hemorrhage 2 (18) 1 (11) 0.99Aspiration pneumonia 1 (9) 0 (0) 0.99Others 2 (18) 3 (33) 0.62

APACHE II score, median (IQR) 23 (20 – 24) 24 (23 – 27) 0.18SOFA score, median (IQR) 4 (3.5 – 5.5) 5 (3 – 7) 0.65

P/F ratio, median (IQR) 166 (108 – 229)

154 (123 – 219) 0.91

Pre albumin, mg/dl, mean (SD) 8.8 (4.5) 10.1 (4.2) 0.53Albumin, g/dl, mean (SD) 2.6 (0.5) 2.5 (0.8) 0.76BUN, mg/dl, mean (SD) 26 (11) 27 (17) 0.91Creatinine, mg/dl, mean (SD) 1.1 (1.2) 1.1 (0.8) 0.84Glucose, mg/dl, mean (SD) 149 (63) 148 (43) 0.98

Table 2: Baseline patient characteristics.

Abbreviations: IQR: Inter Quartile Range; BMI: Body Mass Index; COPD: Chronic Obstructive Pulmonary Disease; APACHE II: Acute Physiology and Chronic Hearth Evaluation II, SOFA: Sequential Organ Failure Assessment; P/F: PaO2/Fraction of Inspired Oxygen; SD: Standard Deviation; BUN: Blood Urea Nitrogen.

VariablesOligomeric-

Group(n = 11)

Polymeric Group(n = 9)

P value

Vomiting, n (%) 0 (0) 0 (0) n.s.Diarrhea from day1 to day3, n (%) 0 (0) 1 (11) 0.45Diarrhea defined by CTCAE Version 4.0

Grade 1 2 (18) 2 (22)Grade 2 0 (0) 1 (11)

Bristol stool scale of first defecation, median (range) 6 (2 - 7) 5.5 (4 – 7) 0.55

Frequency of defecation, times / one patientday1 0.27 0.56

n.s.day2 0.64 0.89day3 0.45 0.56

Constipation, n (%) 3 (27) 4 (44) 0.39Grade 1 1 (9) 2 (22)Grade 3 2 (18) 2 (22)

Abdominal distention, n (%) 0 (0) 0 (0) n.s.Gastric residual volume, ml, median (IQR)

day1 0 (0 – 2.5) 0 (0 – 0)n.s.day2 0 (0 – 3) 0 (0 – 0)

day3 0 ( 0 – 9) 0 (0 – 0)

Table 3: Gastrointestinal complications.

Abbreviations: n.s.: not significant; CTCAE: Common Terminology Criteria for Adverse Events; IQR: Inter Quartile Range.

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Variables

Oligomeric group(n = 11)

Polymeric group(n = 9)

day1 day3 p value day1 day3 p valueAlbumin, g/dl 2.6 (0.5) 2.5 (0.5) 0.37 2.5 (0.2) 2.6 (0.4) 0.80Pre albumin, mg/dL 8.8 (4.5) 11.1 (3.8) 0.11 10.1 (4.2) 11.6 (6.5) 0.39Hemoglobin, g/dL 11.2 (1.3) 11.4 (1.5) 0.66 10.5 (2.6) 10.9 (2.1) 0.56Total lymphocyte count, /µL 650 (380) 574 (273) 0.64 1031 (753) 981 (579) 0.98AST, IU/L 44 (36) 40 (24) 0.99 37 (45) 38 (29) 0.89ALT, IU/L 28 (20) 34 (22) 0.09 57 (117) 40 (17) 0.66BUN, mg/dL 26 (11) 30 (12) 0.12 27 (17) 36 (21) 0.18Creatinine, mg/dL 1.1 (1.2) 1.1 (1.4) 0.50 1.1 (0.8) 1.1 (1.8) 0.72Na, mEq/L 140 (4.8) 140 (5.4) 0.92 137 (1.9) 136 (4.4) 0.43K, mEq/L 4.3 (0.8) 4.8 (0.7) 0.04 4.6 (1.2) 4.6 (1.3) 0.77Cl, mEq/L 105(5.3) 103 (5.9) 0.47 100 (5.0) 98 (6.0) 0.08Glucose, mg/dL 149 (63) 153 (41) 0.83 148 (43) 131 (54) 0.32Total cholesterol, mg/dL 135 (20) 132 (22) 0.35 139 (42) 142 (47) 0.30LDL-cholesterol, mg/dL 82 (14) 81 (19) 0.36 84 (29) 81 (33) 0.74Triglycerides, mg/dL 100 (44) 91 (48) 0.70 71 (22) 91 (52) 0.18

Table 4: Laboratory results at baseline and at day 3 after initiating enteral nutrition.

Abbreviations: AST: Aspartate Amino Transferase; ALT: Alanine Amino Transferase; BUN: Blood Urea Nitrogen; LDL: Low Density Lipoprotein. Data presented as mean (standard deviation).

Outcomes OligomericGroup(n = 11)

Polymeric Group(n = 9) P value

Supplemental parenteral nutrition, kcal/day, median (IQR) 420 (215 – 420) 420 (210 – 420) 0.91

Final daily calories, kcal/kg, median (IQR) 22.8 (18.3 – 25.4) 22.5 (16.0 – 32.0) 0.97

Duration of mechanical ventilation, d, median (IQR) 28 (4.5 – 30) 10 (5 – 23) 0.44

ICU length of stay, d, median (IQR) 19 (9 – 28) 9 (5 – 13) 0.18

Hospital length of stay, d, median (IQR) 32 (28 – 53) 28 (18 – 30) 0.34

28 -d mortality, n (%) 3 (27) 2 (22) 0.99

In-hospital mortality, n (%) 5 (45) 2 (22) 0.37

Table 5: Clinical outcomes.

Abbreviations: IQR: Inter Quartile Range; ICU: Intensive Care Unit.

initiation of enteral nutrition compared to a polymeric formula. The duration of MV and 28-day mortality did not differ between groups.

Guidelines for several countries recommend enteral nutrition in critically ill patients should be initiated within 24–48 hours after ICU admission [1, 4-7]. Early initiation of enteral nutrition in critically ill respiratory patients is associated with modulated stress and systemic immune responses, attenuated disease severity, decreased complications, and decreased length of ICU stay [13]. A catabolic stress state in which patients commonly demonstrate a systemic inflammatory response leads to a significant nutritional deficit.

The best formulation, timing, and amount of enteral feeding remain unknown. Because a meta-analysis showed no significant benefit of an oligomeric formula for diarrhea [4], nutritional guidelines recommend the use of a polymeric formula when initiating enteral feeding in critically ill patients [1, 4-6]. In the present study, the oligomeric formula also showed no significant decrease of gastrointestinal complications compared with the polymeric formula. On the other hand, an adequate procedure for increasing calories with enteral feeding remains controversial.

In the EDEN trial, initial trophic enteral feeding for up to 6 days did not improve the length of MV or 60-day mortality compared with full enteral feeding, but did show decreased gastrointestinal intolerance (diarrhea, aspiration, and abdominal distention) [14]. Therefore, the present study initiated 300 kcal of enteral feeding at 20 mL/hour for the first 2 days and increased enteral feeding every 2 days until the caloric requirement was met. Using this approach, the incidence of diarrhea and other gastrointestinal complications was suppressed with both the oligomeric or polymeric formula, with no difference observed between groups.

The present study demonstrated a trend for increased serum pre albumin levels in the oligomeric group. Although the oligomeric formula might be superior for digestion and absorption compared with the polymeric formula, there was a greater amount of protein administered with enteral nutrition in the oligomeric group than in the polymeric group. On the other hand, serum potassium levels, while remaining within the normal range, increased significantly in the oligomeric group. The amount of potassium in the oligomeric formula was higher than that in the polymeric formula. When this oligomeric formula was used in critically ill patients with renal failure, care was taken for elevated serum potassium levels.

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The clinical outcomes (duration of MV, ICU length of stay, and in-hospital mortality) in the polymeric group were not significantly higher than the oligomeric group, consistent with previous studies [15-17]. The total calories administered with enteral feeding did not differ between groups, and no weakness of the oligomeric formula in nutritional therapy was detected; therefore, the poor outcomes in the oligomeric group might result from more patients with steroid therapy-resistant exacerbation of interstitial pneumonia or diffuse alveolar hemorrhage. In the present trial, 5 of 6 patients with those fatal diseases died without improvement of respiratory failure during hospitalization; thus, the clinical outcomes may have been highly influenced by the proportion of those patients in each group (45% in the oligomeric group vs. 22% in the polymeric group)

There are some important limitations of the present trial. First, this study was a single-institution trial with a small number of patients. The sample size was determined on the basis of a hypothesis that the incidence of diarrhea in the polymeric group would be 60% as previously reported [11, 12]. Our step-up enteral feeding procedure might have suppressed the incidence of diarrhea as it was detected in only 11% of the polymeric group. The beneficial effect of oligomeric formula during continuous feeding or bolus administration in respiratory critically ill patients was unclear from the results of the present study. Second, stool weight was not measured. Small amounts of muddy or watery stool were counted as one time of stool, but diarrhea should have been evaluated after measuring stool weight. Third, the total amount of formula from day 1 to 2 was different in the oligomeric and polymeric formula, because 1.5 kcal/mL of polymeric formula was not used in our hospital. In addition, the administration time of enteral feeding on days 1 and 2 differed between groups.

CONCLUSIONResults from this single-institution trial suggest that

oligomeric formula does not decrease gastrointestinal intolerability in critically ill respiratory patients compared to the polymeric formula, using a step-up procedure of early enteral feeding by initiating a small amount of formula. A multicenter study would provide greater power to detect the beneficial effects of oligomeric formula in respiratory critical care medicine.

ACKNOWLEDGEMENTSWe would like to thank the intensive care nurses in our

hospital for providing medical support for patients participating in this trial.

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Ogasawara T, Matsuda S, Kato S, Tanaka K, Yano T, et al. (2014) Early Enteral Nutrition Using Oligomeric Formula in Mechanically Ventilated, Critically Ill Patients: A Randomized Control Trial. J Hum Nutr Food Sci 2(4): 1046.

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