Table 1.

Randomized studies evaluating probiotics in critically ill patients

	Study	Population	Methods score	Type of probiotic/intervention
				Delivery vehicle	Intervention/dose/duration	Control
1	Tempe 1983 [30]	ICU patients n = 40	C.Random: yes ITT: yes Blinding: double Score: 10 Viability (intervention): NR	EN tube	EN (unknown) + Ultra-Levure (Saccharomyces boulardii), 1010/1 L solution for 11–21 days	EN (unknown) + placebo (sterile solution)
2	Schlotterer 1987 [31]	Patients with burns n = 18	C.Random: no ITT: no Blinding: double Score: 8 Viability (intervention): NR	NG tube	EN (Polydiet or Nutrigil) + Saccharomyces boulardi 500 mg QID for 8-28 days	EN (Polydiet or Nutrigil) + placebo
3	Heimburger 1994 [32]	Mixed ICU patients: 83 % received antibiotics n = 62	C.Random: no ITT: no Blinding: double Score: 9 Viability (intervention): NR	EN tube	EN (standard) + 1 g of Lactinex (Lactobacillus acidophilus and Lactobaccilus bulgaricus) 2 × 106TID for 5–10 days	EN (standard) + placebo (0.5 g dextrose + 0.5 g lactose)
4	Bleichner 1997 [33]	Mixed ICU patients n = 128	C.Random: not sure ITT: yes Blinding: double Score: 13 Viability (intervention): NR	EN tube	EN (unknown) + Saccharomyces boulardii 500 mg QID for 21 days or until EN stopped	EN (unknown) + placebo (powder)
5	Kecskes 2003 [34]	ICU patients on antibiotics n = 45	C.Random: no ITT: no Blinding: double Score: 8 Viability (intervention): yes	NJ tube	EN (Nutrison fiber) + fermented oatmeal formula with Lactobacillus plantarum 299 10 9 BID and fiber for 7 days	EN (Nutrison fiber) + heat-killed Lactobacillus plantarum 299 BID + fiber (non-viable)
6	Jain 2004 [36]	ICU patients n = 90	C.Random: no ITT: yes Blinding: double Score: 10 Viability (intervention): NR	Oral or NG tube	EN or PN + Trevis™ 1 capsule TID + 7.5 g Raftilose (oligofructose) BID until hospital discharge	EN or PN + placebo (powdered sucrose capsules)
7	Lu 2004 [35]	Patients with burns n = 40	C.Random: no ITT: yes Blinding: double Score: 9 Viability (intervention): NR	NR	EN + synbiotics (4 types of probiotics + 4 types of unspecified prebiotics) for 21 days	EN + 4 types of prebiotics
8	Klarin 2005 [37]	Critically ill patients on antibiotics n = 17	C.Random: no ITT: no Blinding: no Score: 6 Viability (intervention): NR	Mixed in fermented oatmeal, given via NG tube	EN + Lactobacillus plantarum 299v, 109/day 50 ml every 6 h × 3 days then 25 ml every 6 h until ICU discharge	EN (Impact or Nutrodrip fiber). Some patients needed PN
9	McNaught 2005 [38]	ICU patients on antibiotics n = 130	C.Random: no ITT: yes Blinding: no Score: 7 Viability (intervention): NR	Oral, NJ tube	EN or PN + Proviva, (oatmeal and fruit drink) 5 × 107 CFU/ml of L. plantarum 299 v × 500 mls until hospital discharge or beyond	EN or PN alone
10	Kotzampassi 2006 [39]	Patients with multiple trauma from 5 ICUs n = 77	C.Random: no ITT: no Blinding: double Score: 8 Viability (intervention): NR VAP determination: clinical	Endoscopic gastrostomy or NG tube	EN or PN + Synbiotic 2000 Forte 1011, 1 sachet/day for 15 days until ICU discharge	EN or PN + placebo (maltodextrin), mixed in tap water
11	Alberda 2007 [40]	ICU patients n = 28	C.Random: no ITT: yes; Blinding: double Score: 10 Viability (intervention): No for VSL # 3; Yes for bacteria sonicates	NG tube	Jevity Plus (EN) (10 g fructooligosaccharides/1000 mL and 12 g of soluble and insoluble fiber blend) + VSL # 3, 1 package BID, 9 × 1011 /day for 7 days until ICU discharge or EN discontinuation	Jevity Plus + placebo
12	Li 2007 [41]	Patients with severe acute pancreatitis n = 25	C.Random: no ITT: yes Blinding: no Score: 7 Viability (intervention): NR	Given enterally	Jinshuangqi (bifidobacteria, lactobacillus and streptococcus) 2.0 g TID on basis of traditional treatment Duration: NR	Traditional treatment
13	Olah 2007 [42]	Patients with severe acute pancreatitis n = 83	C.Random: no ITT: no Blinding: no Score: 9 Viability (intervention): NR	NJ tube	EN (Nutricion fiber) + Synbiotic 2000, 4 × 1010 CFU for 7 days	EN (Nutricion fiber) + 10 g plant fibers ((2.5 g each of Betaglucan, inulin, pectin and resistant starch) (prebiotics) BID for at least 2 days
14	Forestier 2008 [44]	Mixed ICU patients, 50 % on antibiotics n = 208	C.Random: not sure ITT: no Blinding: double Score: 8 Viability (intervention): NR VAP determination: objective	NG tube or oral (after tube removal)	Lactobacillus casei rhamnosum, 109 CFU BID until ICU discharge	Placebo (growth medium never exposed to bacteria).
15	Besselink 2008 [43]	Patients with severe acute pancreatitis from 15 ICUs n = 298	C.Random: not sure ITT: yes Blinding: double Score:11 Viability (intervention): NR VAP determination: clinical	NJ tube or oral	EN (Nutrison multifiber) + Ecologic 641 1010 CFU BID for 28 days	EN (Nutrison multifiber) + placebo (cornstarch + maltodextrins)
16	Klarin 2008 [45]	ICU patients from 5 ICUs, on antibiotics for C. Difficile n = 68	C.Random: yes ITT: no Blinding: double Score: 10 Viability (intervention): NR	Mixed in fermented oatmeal added to enteral feeds NG tube	299 Lactobacillus plantarum, 8 × 108 CFU/ml given as 6 × 100 ml doses every 12 h and after 50 ml given BID until ICU discharge	Same oatmeal gruel mixed with lactic acid
17	Knight 2009 [46]	General ICU patients n = 300	C.Random: yes ITT: no Blinding: double Score: 10 Viability (intervention): NR VAP determination: clinical	NJ or OG (orogastric) tube	EN (Nutrition Energy) + Synbiotic 2000 FORTE 4 × 1011 species/sachet BID for 28 days or ICU discharge	EN (Nutrison Energy) + Placebo
18	Barraud 2010 [47]	Mechanically ventilated ICU patients, 80 % on antibiotics n = 167	C.Random: yes ITT: yes; Blinding: double Score: 12 Viability (intervention): NR VAP determination: objective	NG tube	EN (Fresubin) + Ergyphilus 2 × 1010 per capsule + potato starch 5 capsules/day for 28 days	EN (fresubin) + placebo capsules (excipient of potato starch)
19	Morrow 2010 [10]	ICU patients n = 146	C.Random: no; ITT: yes; Blinding: double; Score:10 Viability (intervention): yes VAP determination: objective	Oropharynx and NG tube	EN (routine care) + Lactobacillus rhamnosus GG, 2 × 109 BID as lubricant and mixed with water until extubation	EN (routine care) + inert plant starch inulin (prebiotic) BID as lubricant and mixed with water
20	Frohmader 2010 [48]	General ICU patients on antibiotics n = 45	C.Random: yes ITT: yes Blinding: double Score: 11 Viability (intervention): yes	NG or NJ tube	EN (Standard) + VSL #3 mixed in nutritional supplement (Sustagen), BID until hospital discharge	EN (Standard) + placebo mixed in nutritional supplement (Sustagen), BID
21	Ferrie 2011 [49]	Critically ill patients with diarrhea, n = 36	C.Random: no ITT: yes Blinding: double Score: 10 Viability (intervention): yes	NG tube	EN (Standard) + Culturelle (Lactobacillus rhamnosus GG), 1010 species/capsule +280 mg inulin powder for 7 days	EN (Standard) + Raftiline, gelatin capsule with 280 mg inulin powder (prebiotic)
22	Sharma 2011 [50]	Patients with acute pancreatitis n = 50	C.Random: yes ITT: yes Blinding: double Score: 11 Viability (intervention): yes	Oral, NJ or NG	EN (standard) or oral 4 sachets each 2.5 × 109 Lactobacillus acidophilus, Bifidobacterium longus, Bifidobacterium bifidum & Bifidobacterium infantalis + 25 gms fructose for 7 days	EN (Standard) + placebo
23	Tan 2011 [51]	Patients with closed head injury n = 52	C.Random: yes ITT: yes Blinding: single Score: 10 Viability (intervention): yes VAP determination: clinical	NG tube	EN (standard) total of 109 bacteria i.e., 7 sachets each 0.5 × 108 Bifidobacterium longum, 0.5 × 1071 Lactobacillus bulgaricus and 0.5 × 107 Streptococcus thermophilus for 21 days	EN (standard)
24	Cui 2013 [20]	Patients with severe acute pancreatitis n = 70	C.Random: no ITT: yes Blinding: no Score: 9 Viability (intervention): yes	EN	EN + bifidobacterium, 4 capsules (each 210 mg, 2.604 × 109) every 12 h, given through nasal gastric tube. Total dose per day 20.832 × 109	EN
25	Tan 2013 [21]	Severe craniocerebral trauma n = 52	C.Random: no ITT: other Blinding: no Score: 11 Viability (intervention): yes	NG tube	EN + 1 × 109 bacteria of viable probiotics (Golden Bifid, 3.5 g 3 times per day) per day for 21 days.	EN (standard)
26	Wang 2013 [22]	Severe acute pancreatitis with intestinal ileus or abdominal distention. n = 183	C.Random: no ITT: yes Blinding: no Score: 6 Viability (intervention): NR	SBFT	EN (standard) + capsules 0.5 g TID containing Bacillus subtilis and Enterococcus faecium (5.0 × 107Bacillus subtilis and 4.5 × 108 Enterococcus faecium per 250 g capsule). Unclear timeframe.	EN (standard)
27	Lopez de Toro 2014 [23]	Medical and surgical ICU patients with multi-organ failure n = 89	C.Random: yes ITT: yes Blinding: no Score: 11 Viability (intervention): NR	EN	EN + symbiotic drink with streptococcus Thermophilus, lactobacillus bulgaricus, Lactobacillus casei, lactobacillus acidophilus, bifidobacterium, Escherichia coli, coliformes × 7 days (max 4.8 × 109 UFC/ml).	EN and PN
28	Sanaie 2014 [24]	Critically ill pts, SIRS, expected length of stay ≥7 days n = 40	C.Random: yes ITT: yes Blinding: double Score: 9 Viability (intervention): yes	NG tube	EN (standard) + 2 sachets VSL#3 BID × 7 days.	EN (standard) + placebo
29	Rongrungruang 2015 [25]	Critically ill patients, expected to receive mechanical ventilation at least 72 h and had no VAP at enrollment n = 150	C.Random: no ITT: no Blinding: no Score: 6 Viability (intervention): yes	EN	80 ml of 8 × 109 cfu of Lactobacillus casei (Shirota strain) (Yakult) for oral care after the standard oral care once daily An additional 80 ml of the product was given via enteral feeding once daily for 28 days or when their endotracheal tubes were removed	EN (standard) + oral care with 2 % chlorhexidine solution 4 times per day
30	Zeng 2016 [26]	Critically ill patients, expected to receive mechanical ventilation at least 48 h n = 235	C.Random: yes ITT: no Blinding: no Score: 5 Viability (intervention): yes	NG tube	1 capsule (Medilac-S, China) 0.5 g three times daily. Each probiotic capsule contained active Bacillus subtilis and Enterococcus faecalis at a concentration of 4.5 × 109 /0.25 g and 0.5 × 109/0.25 g, respectively	EN (standard)

CFU colony forming units, C.Random concealed randomization, EN enteral nutrition, FOS fructooligosaccharides, NG nasogastric, NJ nasojejunal, NR not reported, OG orogastric, ITT intention to treat, SIRS, systemic inflammatory response syndrome, VAP ventilator-associated pneumonia, BID twice daily. Trevis™: 1 capsule = Lactobacillus acidophilus La5, Bifidobacterium lactis Bb12, Streptococcus thermophilus, Lactobacillus bulgaricus, 4 × 10 ⁹ /total; Synbiotic 2000 Forte: 10¹¹ CFU each of Pediococcus pentoseceus 5-33:3, Leuconostoc mesenteroides 32-77:1, L. paracasei ssp paracasei 19, L. plantarum 2362, and 2.5 g each of inulin, oat bran, pectin and resistant starch; Ergyphilus: 10¹⁰ Lactobaccilus rhamnosus GG, Lactobacillus casei, L. acidophilus, Bifidobacterium bifidus; VSL # 3: >10¹⁰ Bifidobacterium longum, Bifidobacterium breve, >10 ^10/g Bifidobacterium infantis, >10 ^11/g L. acidophulus, L. plantarum, L. casei, L. bulgaris, and Streptococcus thermophiles; Jinshuangqi: B. longum >10 ^{7 CFU} , L. bulgaricus >10 ^{6 CFU}, and S. Thermophilus >10 ^{6 CFU}; Ecologic 641: L. acidophilus, Lactobacillus salivarius, Lactococcus lactis, B. bifidus, and Bifidobacterium lactis; Synbiotic 2000: 10 ¹⁰  CFU each of P. pentoseceus 5-33:3, Leuconostoc mesenteroides 32-77:1, L. paracasei ssp paracasei 19, L. plantarum 2362, and 2.5 g each of betaglucan, inulin, pectin and resistant starch; Golden Bifid: B. bifidum, L. bulgaricus, and S. thermophilus triple-human probiotic-supplemented oligosaccharides FOS (bifidus factor)