Table 1.

Summary of high-power studies supporting the benefit of probiotics in the pediatriac intensive care unit (PICU).

	Authors	Study and Period	Patient Group	Administrations	Main Results
1	Singhi S. et al.	1991–1996, 1999–2000, 2002–2003 High statistical power	861 episodes of nosocomial bloodstream infection were documented in 841 patients	___	-Increase of frequency of nosocomial infection in the PICU -Increasing trend of resistance to the commonly used cephalosporins.
2	Petrof et al.	Sistemic review 1980–2011 High statistical power	23 randomized controlled trials enrolling critically ill adults, which evaluated probiotics compared with a placebo and reported clinically important outcomes	Probiotics with the conventional prescribed therapy set in the ICU leads	-Using probiotics in preventing systemic diseases leads to a reduction in complications related to infections.
3	Honeycutt TC et al.	Randomized, double-blind, placebo-controlled trial, April 2004–December 200 Low statistical power	61 total pediatric ICU patients: 31 of treatment group vs. 30 of placebo group	One capsule of Lactobacillus rhamnosus strain ones a day vs. one capsule of insulin once a day	-No results in support of the usage of probiotics.
4	Angurana SK et al.	Randomized, double-blind, placebo-controlled trial, November 2014–October 2015 High statistical power	100 children 3 months to 12 years old with severe sepsis in the ICUs (probiotic group n = 50 vs. placebo group n = 50)	Probiotic group received a multistrain, high-dose probiotic product VSL#3, which contained Lactobacillus paracasei, L. plantarum, L. acidophilus, L. delbrueckii, Bifidobacterium longum, B. infantis, B. breve, Streptococcus salium, B. infantis and B. delbrueckii. breve, and Streptococcus salivarius	-Using probiotics leads to a decrease of proinflammatory cytokines and an increase of anti-inflammatory cytokines.
5	Wang Y. et al.	Systematic review and meta-analysis, from the earliest available date to 30 April 2016. High statistical power	23 trials involving 6269 children in the PICUs, probiotics groups vs. placebo groups	___	-Probiotics lead to lower probability of developing complication and fast healing.
6	Banupriya et al.	Open-label randomized controlled trial, November 2011 and July 2013 High statistical power	150 pediatric patients requiring mechanical ventilation for more than 48 h in the PICU (75 vs. 75 patients)	Mix of Lactobacillus acidophilus, L. rhamnosus, Lactobacillus plantarum, L. casei, Lactobacillus bulgaricus, Bifidobacterium longum, B. infantis, Bifidobacterium breve, and Streptococcus thermophilus for 7 days or until discharge	-Probiotics lead to a decrease in the incidence of VAP and a decrease in the ICU stay; -Probiotics lead to lower colonisation by potentially pathogenic organisms, Klebsiella, and Pseudomonas.
7	Shimizu et al.	Randomized controlled trial, November 2011–September 2016 Intermediate statistical power	72 patients in the PICUs (35 patients receiving synbiotics and 37 patients not receiving synbiotics)	A daily symbiotics administration (in particular, bifidobacterium breve strain yakult, lactobacillus casei strain Shirota, and galacto-oligosaccharides).	-Probiotic lead to decrease of the incidence of VAP and of the incidence of enteritis.
8	Szajewska H. et al.	Recommendations, developed by the Working Group (WG) on Probiotics of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition, for the use of probiotics for the prevention of antibiotic-associated diarrhea (AAD) in children based on systematic review, 2016			-The incidence of ICU-acquired diarrhoea episodes decreased in children treated with Lactobacillus rhamnosus GG.
9	Kumar S. et al.	Prospective double-blinded, randomised controlled trial, November 2007–October 2008 High statistical power	150 PICU children aged between 3 months and 12 years: placebo group (n = 75) and probiotics group (n = 75)	Probiotics contained Lactobacillus acidophillus, L. rhamnosum, Bifidobacterium longum, B. bifidum, Saccharomyces boulardi, and S. thermophilus.	-Probiotics lead to less Candida colonisation and reduce a pathological growth of Candida; -Candiduria was less common in the probiotic group.
10	Manzoni et al.	Retrospective study, 2003–2008 Very high statistical power	743 VLBW infants	Lactobacillus GG as a single dose of 3 × 109 CFU/day from the fourth day of life for 4 to 6 weeks	-Probiotics were well tolerated without any adverse effects and did not lead to bacteremia or sepsis episode attributable to Lactobacillus GG.
11	Simakachorn N. et al.	Controlled, double-blind, randomised clinical trial, August 2006–May 2009 Intermediate statistical power	94 patients between 1 and 3 years old under mechanical ventilation requiring enteral feeding	Synbiotic blend composed of two probiotic strains, Lactobacillus paracasei NCC 2461 and Bifidobacterium longum NCC 3001	-Probiotic’s formula was as well tolerated as the currently used formula and that it was safe.

High statistical power 0.8–0.9; intermediate statistical power 0.7–0.6; low statistical power < 0.5.