- Study identification and selection
A total of 93 relevant articles were identified through database search and a review of reference lists of related articles. We excluded 78 articles due to the following reasons: 21 were conference abstracts or the full text was not available, 17 were not RCTs, 13 did not exclusively enroll ICU patients, 6 were not in English, 8 did not report relevant outcomes, 5 had multiple interventions, 2 did not include exclusive EN, 1 did not have a placebo receiving control group, 5 due to other reasons. Finally, 15 RCTs, with a total of 1139 patients, were included (Figure 1). The mean JADAD score of all trials was 4.2. The minimum JADED score was 1 point for randomization. A summary of the findings of the studies is presented in Table 2.
Table 2 Randomized controlled trials evaluating the effect of pre, pro or synbiotics on feeding tolerance of enterally-fed critically ill patients
Abbreviations: NR, not reported; NGT, nasogastric tube; EN, enteral nutrition; ICU, intensive care unit; OGT, orogastric tube; GRV, gastric residual volume; VSL#3, a single daily high dose probiotic preparation.
Six trials examined the effect of pre, pro or synbiotics on energy intake. In one trial in 2000, 44 critically ill patients receiving EN and antibiotics were randomized to receive fiber-containing or fiber-free formula and pectin or placebo for 6 days. Mean energy intake ranged from 1200 Kcal on day 1 to 1563 Kcal on day 5. Mean energy or protein intake was not significantly different in the four study groups (18). Rushdi et al. also evaluated the effect of guar gum enriched formula in 20 critically ill tube-fed patients with persistent diarrhea for 4 days. They showed that patients in the intervention group tolerated significantly higher formula volumes on days 1, 2 and 4. On the fourth day, the feed volume was 1775±450 ml in the intervention group compared to 1070±604 ml in the controls (p<0.01) (20). In 2018, Fazilaty et al. evaluated the effect of EN containing β-glucan on inflammatory markers and clinical outcomes. They reported no significant difference in the mean tolerated calories between study groups (1710.5±17.03 Kcal vs. 1718.2±182.4 Kcal, p=0.6) (29). Tuncay et al. compared the effect of an enteral formula enriched with prebiotic versus standard EN on nutritional parameters among 46 neurocritically ill patients. Results showed that feed volume and mean energy intake significantly increased from baseline to day 21 in both groups. Patients in the intervention group tolerated a significantly higher amount of energy and feed volume on day 1 and 21 (31). Knight et al. investigated the effect of enteral synbiotic on ventilator-associated pneumonia in critically ill patients. They also reported an increase in the daily tolerated feed volume from day 1 to 7 in both groups. The feed volume ranged from 488.9± 622.8 on day 1 to 1055.6±722.6 on day 7 in the synbiotic group and from 360±431.7 to 1243.9±810.3 in the placebo group. There was no significant difference between the two groups regarding the mean tolerated enteral feed volume (21). In another trial conducted in 2014, 40 critically ill patients were randomly assigned to receive a multi-strain probiotic or placebo for 7 days. Results showed no significant difference between groups in terms of the mean energy intake (1503.75±231.6 vs. 1617.5±185.51, p= 0.09). The percentage of patients who met energy requirements in the synbiotic and placebo groups was 84.98±3.6 and 87.24±3.92 respectively (p=0.06) (26).
Four trials assessed the effect of pre or probiotics on prevalence or time to receive the target calorie. In a trial conducted in 2001, severe sepsis or septic shock patients were randomly assigned to receive EN supplemented with partially hydrolyzed guar or fiber-free EN. All patients were on mechanical ventilation, antibiotic and catecholamine therapy. The time to reach the preconceived protein/ calorie goals was 5±3 days in prebiotic and 6±3 days in the control group. The difference was not statistically significant (19). Malik et al. also investigated the effect of 7-days microbial cell preparation administration on the return of gut function. Time to return to normal gut function was defined as the time taken to receive a minimum of 80% of estimated calorie for a consecutive 48-hour period. They reported that patients in the treatment group achieved a faster return of gut function (3±1.75 days vs. 7±1.7 days, p<0.001) (28). Ferrie et al. investigated the effect of Lactobacillus rhamnosus GG in critically ill patients with established diarrhea on feeding intolerance. The frequency of patients with feeding intolerance (tolerate less than 80% of calorie goal for 2 consecutive days) was 11.1% in the probiotic group and 16.6% in the control group (p= 0.63) (25). Tuncay et al. also reported the prevalence of target dose achievement in 21 days intervention, as 95.7% in prebiotic supplemented and 78.3% in standard EN groups. The difference was not significant (31).
In the study by Bleichner et al., 128 critically ill patients were randomized to receive Saccharomyces
Boulardii or placebo capsules. The prevalence of diarrhea was not significantly different between the two groups. However, treatment with S. boulardii reduced the mean frequency of diarrhea days per feeding days from 18.9 to 14.2% (p= 0.006) (17). Schultz et al. investigated the effect of pectin on the prevalence of diarrhea in a critical care setting. Diarrhea was more prevalent in the placebo group compared to the intervention group (36% vs. 9%, respectively) (18). In another trial, the mean frequency of diarrhea days was significantly lower in the fiber group. Furthermore, in the fiber group diarrhea occurred in 10.8% of feeding days, compared to 31.5% in the controls (p<0.001) (19). Rushdi et al. also investigated the effect of soluble guar gum on the number of liquid stools during the 4 days of intervention. The number of liquid stools was significantly lower at day 4 compared to day 1 in the intervention group, while it was significantly higher in the control group. The number of liquid stools on the fourth day was 1.2±0.7 in the intervention group, compared to 2.1±0.8 in the control group (p<0.01) (20). Knight et al. also reported the overall prevalence of diarrhea to be 5% in the synbiotic group, and 7% in the controls (21). Another trial in 2010, examined the effect of probiotic VSL#3 on diarrhea among 45 critically ill patients. The mean frequency of diarrhea in the probiotic and placebo groups was 0.53±0.54 and 1.05±1.08 episodes per patient per day, respectively (p=0.03) (22). Barraud et al. also investigated the effect of lactic acid bacteria on the prevalence of diarrhea. They demonstrated no significant effect of probiotic therapy on diarrhea (23). In another RCT, Morrow et al. demonstrated that probiotic administration had no significant effect on the incidence of ICU associated diarrhea. However, the number of days with ICU-associated diarrhea was significantly higher in the probiotic group compared to the placebo group (5.9±3.8 vs. 4.1±3.7, p=0.03) (24). Ferrie et al. also reported that critically ill patients who received probiotic had more diarrhea episodes compared to the control group, although the difference was not statistically significant (25). Majid et al. also demonstrated that fiber-enriched EN with additional prebiotic had no significant effect on the incidence of diarrhea or length of ICU stay (27). Shimizu et al. also investigated the effect of daily synbiotic therapy on infectious complications, including enteritis in the intensive care unit. Enteritis was defined as acute onset of continuous liquid stool for more than 12 hours. The results showed that the incidence of enteritis was significantly lower in the synbiotic group (30). Tuncay et al. also reported that the administration of prebiotic-enriched EN was associated with a non-significant tendency toward lower rate (8.7% vs. 56.5%) and faster amelioration of diarrhea (none vs. 52.2% diarrhea on day 7) (31).
- Effect on length of stay (LOS)
The effect of pre, pro or synbiotics on ICU and hospital LOS was reported in 10 and 5 trials, respectively (Table 3). Malik et al. demonstrated that probiotic administration was associated with significantly lower ICU LOS (28). Other studies found no significant difference between groups, regarding ICU or hospital LOS (18, 21, 22, 24, 25, 29-32).
Table 3 Reported fedding tolerance-related outcomes in RCTs evaluating the effect of pre, pro or synbiotics on feeding tolerance of enterally-fed critically ill patients
Abbreviations: NR, not reported; ICU, intensive care unit.
ǂ Mean energy intake was reported for the entire intervention duration