TABLE 1

Characteristics and designs of the included studies

First author year [ref.]Study designMale/patientsAge yearsInclusion criteriaDefinition of VAPProbiotics interventionPrimary outcomesSecondary outcomes
Mahmoodpoor 2019 [32]Prospective, double-blind, randomise, controlled trial55/102Probiotics:
59.1±12.9/
Control:
57.5±14.5
Patients ≥18 years old and had been undergoing MV for >48 hA new or persistent infiltration on chest radiography with 2 of the 3 criteria of 1) temperature >38°C or <36°C; 2) leukocytosis or leukopenia; 3) purulent sputum underwent BAL 4) the quantitative BAL cultures had at least 104 CFU·mL−1Lac+Bif+Str: 1 capsule every 12 h daily for 14 days. Each capsule contained 1010 bacteria consisting of Lactobacillus species (casei, acidophilus, rhamnosus, bulgaricus), Bifidobacterium species (breve, longum) and Streptococcus thermophilusVAP frequencyICU and hospital length of stay, duration of MV, complications
Klarin 2018 [30]A multicentre, prospective, randomised controlled open trial76/137Probiotics:
66 (57–76)/
Control:
65.5 (54–75)
Patients ≥18 years old, critically ill with an anticipated need for MV of at least 24 h, not moribund, not having pneumonia, no fractures in the facial skeleton or the base of the skull, no oral ulcers, not immune deficient, not a carrier of HIV or viral hepatitis, not being tracheotomised, and no standard oral care beforeA new, persistent or progressive infiltrate on chest radiograph combined with at least 3 of the other 4 criteria: 1) a purulent tracheal aspirate; 2) positive culture of tracheal aspirates occurring after 48 h of MV; 3) rectal or urine bladder temperature >38.0°C or <35.5°C; 4) WBC>12×103 or <3×103·mm−3 or a rapid increase in WBC count without suspicion of infection in another organLac: Lp299 (Lactobacillus plantarum 299) were applied to the mucosal surface of the oral cavity twice a day, the subsequent cleansing was performed with gauze swabs soaked in carbonated bottled waterVAP frequency, Duration of ICU stay, duration of MVNumber of patients with findings of emerging microorganisms, positive findings of bacteria and fungi species
Shimizu 2018 [24]Single-blind, randomised, controlled trial47/72Probiotics:
74 (64–82)/
Control:
74 (64–81)
Patients >16 years old and had been undergoing MV for >72 h after admission to the ICU, diagnosed as sepsisNot mentionedLac+Bif: Yakult BL Seichoyaku (3 g·day−1) contained 1×108 living bacteria of the B. breve strain Yakult/g and 1×108 living bacteria of the L. casei strain Shirota/g and galactooligo-saccharides (10 g·day−1) were administered via nasal tube and were continued until oral intake was initiatedInfectious complications including enteritis, VAP, and bacteraemia within 4 weeks from admissionMortality within 4 weeks, faecal bacterial counts, organic acid concentration
Zeng 2016 [25]Prospective, open-label, randomised, controlled multicentre trial138/235Probiotics:
50.2±18.2/
Control:
54.6±17.9
Patients ≥18 years with an expected need of MV for at least 48 hA new, persistent or progressive infiltrate on chest radiographs that persisted for at least 48 h combined with at least 2 of the 3 criteria: 1) temperature >38.0°C or <35.5°C; 2) WBC>12×103 or <3×103·mm−3 and/or left shift; 3) purulent tracheal aspiratesBac+Ent: Capsules containing active Bacillus subtilis and Enterococcus faecalis (4.5×109/0.25 g and 0.5×109/0.25 g, respectively) 0.5 g three times daily, for a maximum of 14 daysMicrobiologically confirmed VAP incidence, the proportions eradication of colonisation, acquired colonisation with PPMOs in the oropharynx and stomachDays on MV, days in the ICU and in the hospital after ICU admission, mortality (in ICU, in hospital), days of antibiotic use for VAP, antibiotic-free days at day 28, carbapenem-free days at day 28 and glycopeptide or linezolid-free days at day 28
Rongrungruang 2015 [21]Prospective, randomised, open-label, controlled trial62/150Probiotics:
73±13.16
(30–94)/
Control:
69±18.45
(20–97)
Adult patients who were expected to receive MV at least 72 h and had no VAP at enrolmentA new, persistent, or progressive infiltrate visible on a chest radiograph in combination with at least 3 of the 4 criteria: 1) temperature >38 °C or <35.5°C; 2) WBC >12×103 or <3×103·mm−3; 3) purulent tracheal aspirate; 4) semi-quantitative culture of tracheal aspirate samples positive for pathogenic bacteriaLac: 80 mL of commercially- available fermented dairy product containing 8×109 CFU of Lactobacillus casei, oral care after the standard oral care once daily, additional 80 mL of the aforementioned fermented dairy product was given once daily for 28 daysIncidence of VAP, incidence rate of VAP episodes per 1000 ventilator daysLength of hospital stay, mortality at day 28 and 90, incidence of diarrhoea, presence of resistant bacteria in oropharyngeal and rectal swab samples on day 0, 7 and 28
Banupriya 2015 [34]Open-label, randomised, controlled trial91/150Probiotics:
2.9±3.41/
Control:
2.93±3.77
Aged 12 years or less, likely to need MV>48 hA new, persisting radiographical infiltrate combined with radiographical evidence of pulmonary abscess formation, or 2 of the 3 criteria: 1) fever (increase in the temperature of at least 1°C and a core temperature >38.3°C); 2) leukocytosis (25% increase in circulating leukocytes from baseline or WBC>10×103·mm−3); 3) purulent tracheal aspirate, a positive blood or pleural fluid culture with the microorganismsLac+Bif+Str: One capsule containing 2 billion CFU of Lactobacillus, 1 billion CFU of Bifidobacterium, and 300 million CFU of Streptococcus thermophilus were used twice a dayIncidence of VAPDuration of hospital stay, mortality
Li 2012 [33]Randomised, control trail92/165Probiotics:
32.3±1.5/
Control:
31.6±1.4
(weeks)
MV≥48 h, no respiratory tract infection before orotracheal intubation, no history of using a large number of adrenal cortex hormone and immunosuppressive agents within 48 h before orotracheal intubation, no immune deficiency diseaseAfter 48 h of MV, airway secretion culture was positive or new pathogenic bacteria appeared, new infiltration shadow appeared on chest radiography accompanied by increased pulmonary, clinical fever, WBC >10.0×109·L−1Bif: Probiotics (Bifidobacterium triple viable powder, Shanghai Xinyi Pharmaceutical) at a dose of 0.33 g·day−1 after the start of micro feeding and continued until the end of the study, if feeding intolerance occurs, immediately fast and stop oral probiotics, and continue oral probiotics when milk is reopened, probiotics fed for 3 days before blood bacterial cultureThe number of the bacterial strain of VAPThe time of bacterial colonisation, VAP occurrence
Tan 2011 [22]Prospective, randomised, single-blind study40/52Probiotics:
40.5±13.0/
Control:
40.8±12.8
Closed head injury alone, admission within 24 h after trauma, GCS score between 5 and 8, aged 18 to 60 years old, able to be fed via nasogastric tube within 48 h after admissionPneumonia occurring ≥48 h after endotracheal intubation, a new or progressive radiographic infiltrate, at least two clinical features: 1) temperature >38.0°C; 2) WBC>12×109·L−1 or WBC count <4×109·L−1; 3) purulent tracheobronchial secretions and positive cultures of tracheobronchial secretionBif+Lac+Str: Seven sachets of viable probiotics (each sachet containing 0.5×108 Bifidobacterium longum, 0.5×107 Lactobacillus bulgaricus, and 0.5×107 Streptococcus thermophilus) three times a day, which provided a total of 109 bacteriaMultiple infections in the same patientThe use of antibiotics, length of ICU stay and the 28-day, mortality rate
Morrow 2010 [23]Prospective, randomised, double-blind, placebo-controlled trial86/146Probiotics:
52.5±19.3/
Control:
54.6±16.3
Adults ≥19 years old require MV with an endotracheal tube ≥72 hA new and persistent infiltrate on chest radiographs with 2 of 3 criteria:1) temperature >38.5°C or <35.0°C; 2) WBC>10 000·mm−3 or <3000·mm−3; 3) purulent sputum 4) quantitative BAL culture with at least 104 CFU·mL−1 in patients intubated for 48 h or longerLac: 2×109 CFU of Lactobacillus rhamnosus GG on a twice-daily basis, the contents of one capsule containing 109 CFU of Lactobacillus were suspended in sterile, water-based surgical lubricant and administered as a slurry to the oropharynx, the contents of a second capsule containing 109 of CFU Lactobacillus were suspended in sterile water and given through the nasogastric tubeMicrobiologically confirmed VAP incidenceMortality, the time to occurrence of VAP, durations of MV, ICU stay and hospital stay, clostridium difficile-associated diarrhoea and another ICU-associated diarrhoea, antibiotic consumption, and hospital charges
Barraud 2010 [28]Double-blind, concealed randomised, placebo-controlled trial68/16760.7±15.8Adult patients under MV for a predicted period of at least 48 hA new and persistent infiltrate on chest radiograph associated with at least one of the following: 1) purulent tracheal secretions, temperature ≥38.3°C and WBC count ≥10×103·μL−1; 2) positive quantitative cultures of distal pulmonary secretions obtained from BAL (significant threshold more than 104 CFU·mL−1)Lac+Bif: 2×1010 of revivable bacteria (mainly Lactobacillus rhamnosus GG, but also Lactobacillus casei, Lactobacillus acidophilus, and Bifidobacterium bifidum) once a day until successful weaning28-day mortalityInfection and diarrhoea, length of stay in ICU of hospital, resolution of organ failure at 28 days
Knight 2009 [27]Prospective, randomised, double-blind, placebo-controlled trial161/259Probiotics:
49.5±19.6/
Control:
50.0±18.5
Expected to require MV for at least 48 h, no contraindications to enteral nutritionA new progressive, or persistent infiltration on chest radiograph plus at least two of the following: 1) temperature >38.0°C; 2) WBC>12×103·μL−1 or <4 ×103·μL−1; 3) purulent tracheobronchial secretionsSynbiotic 2000 FORTE: At least 2 days of either Synbiotic 2000 FORTE twice a day, or a crystalline cellulose based placebo, Synbiotic 2000 FORTE contains Pediococcus pentosaceus, Leuconostoc mesenteroides, Lactobacillus paracasei subsp. paracasei and Lactobacillus plantarum as probioticsIncidence of VAPOropharyngeal flora, duration of MV and VAP rates per 1000 ventilator days, length of ICU stay, mortality in ICU and hospital
Giamarellos-Bourboulis 2009 [26]Double-blind, placebo-controlled, multicentre, randomised clinical trial?/72Probiotics:
52.9/
Control:
55.9
Patients with severe multiple organ injuries necessitating emergency tracheal intubation and ventilation support and subsequent hospitalisation in ICUPatients presenting with all of the following: 1) new or persistent consolidation in lung radiograph; 2) purulent TBS; 3) clinical pulmonary infection score (CPIS)>6Synbiotic 2000 FORTE: The formula Synbiotic 2000FORTE was diluted in 100 mL of tap water and administered by a nasogastric tube or through gastrostomy once daily for 15 consecutive days after admissionIncidence of VAPIncidence of bloodstream infections, incidence and comparative time of primary bacteraemia, comparative serum levels of WBCs and CRP of patients with primary bacteraemia and with VAP
Forestier 2008 [29]Prospective, randomised, double-blind, placebo-controlled pilot study146/208Probiotics:
60 (18–91)/
Control:
57 (18–80)
Patients ≥18 years with a stay longer than 48 h and a nasogastric feeding tubeAccording mostly to CDC's NHSN criteria: 1) at least one positive sample (bronchoalveolar mini-lavage >103 CFUs·mL−1 or endotracheal aspirate with >105 CFUs·mL−1) 2) the presence of one or several new abnormal radiographical and progressive parenchymatous infiltrates; 3) one of the following signs: purulent sputum production, fever (temperature >38.5°C), pathogenic bacteria in blood culture without other infection source, and BAL>5% cells with intracellular bacteriaLac: L. casei rhamnosus (109 CFU), twice dailyThe time of first P. aeruginosa acquisitionWhether respiratory tract infection or colonisation due to P. aeruginosa, to evaluate the ability of L. casei rhamnosus to persist in the stomach
Klarin 2008 [9]Randomised, controlled, open pilot study22/44Probiotics:
70 (20–87)/
Control:
70 (43–81)
Patients ≥18 years, critically ill with an anticipated need for MV of at least 24 h, not moribund, not suffering from pneumonia at admission, no fractures in the facial skeleton or the base of the skull, no oral ulcers, not immune deficient, not a carrier of HIV or viral hepatitisA new, persistent or progressive infiltrate on chest radiograph combined with at least 3 of the other 4 criteria: 1) a purulent tracheal aspirate; 2) positive culture of tracheal aspirates occurring after 48 h of MV; 3) rectal or urine bladder temperature >38.0°C or <35.5°C; 4) WBC >12×109·L−1 or <3×109·L−1Lac: Lp299 (Lactobacillus plantarum 299) twice a day, subsequent cleansing was performed with gauze swabs soaked in carbonated bottled waterPathogenic bacteria analysis in oropharynx and trachea
Spindler-Vesel 2007 [31]Prospective, randomised, double-blind study88/11341±18.9Multiple injured patients with an ISS of >18 and at least a 4-day ICU stayNot mentionedSynbiotic 2000 FORTE: The contents of the sachets (1010 Pediococcus pentosaceus 5–33:3, 1010 Lactococcus raffinolactis 32–77:1, 1010 Lactobacillus paracasei subsp. paracasei 19, 1010 Lactobacillus plantarum 2362 and the fibres) were dissolved in 100 mL of lukewarm sterile waterIncidence of infection (such as VAP), duration of MV, multiple organ failure scores, length of ICU stay
  • VAP: ventilation-associated pneumonia; MV: mechanical ventilation; BAL: bronchoalveolar lavage; Lac: Lactobacillus (casei, plantarum, rhamnosus, bulgaricus; acidophilus); Bif: Bifidobacterium (breve, longum, bifidum); Str: Streptococcus thermophilus; ICU: intensive care unit; WBC: white blood cell; Bac: Bacillus subtilis; Ent: Enterococcus (faecalis); PPMO: potentially pathogenic microorganism; CFU: colony-forming unit; GCS: Glasgow coma score; TBS: tracheobronchial secretions; CPIS: clinical pulmonary infection score; CRP: C-reactive protein; CDC: the US Centers for Disease Control and Prevention; NHSN: National Healthcare Safety Network; ISS: injury severity score. Ages are presented as median (range) or mean±sd.