Background
Methods
Search strategy and study identification
Eligibility criteria
Data synthesis
Clinical outcomes
Subgroup analysis
Results
Study identification and selection
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) |
Study | Mortality | Infections | Length of stay | Diarrhea | |||||
---|---|---|---|---|---|---|---|---|---|
Intervention | Control | Intervention | Control | Intervention | Control | Intervention | Control | ||
1 | Tempe 1983 [30] | 3/20 (15) | 3/20 (15) | NR | NR | NR | NR | Diarrhea days 34/389 (9) | Diarrhea days 63/373 (17) |
2 | Schlotterer 1987 [31] | NR | NR | NR | NR | NR | NR | Diarrhea days 3/150 (2) | Diarrhea days 19/143 (13) |
3 | Heimburger 1994 [32] | NR | NR | NR | NR | NR | NR | Diarrhea 5/16 (31) | Diarrhea 2/18 (11) |
4 | Bleichner 1997 [33] | NR | NR | NR | NR | NR | NR | Diarrhea 18/64 (28) Days w/diarrhea 91/648 (14) | Diarrhea 24/64 (38) Days w/diarrhea 134/683 (20) |
5 | Kecskes 2003 [34] | Hospital 1/22 (5) | Hospital 2/23 (9) | Septic compl 1/22 (5) | Septic compl 7/23 (30) | Hospital 13.7 ± 8.7 | Hospital 21.4 ± 17.9 | NR | NR |
6 | Jain 2004 [36] | Hospital 22/45 (49) | Hospital 20/45 (45) | Septic compl 33/45 (73) | Septic compl 26/45 (58) | Hospital 24.0 ± 31.5 ICU 11.9 ± 13.1 | Hospital 18.7 ± 13.5 ICU 9.0 ± 8.9 | NR | NR |
7 | Lu 2004 [35] | Hospital 2/20 (10) | Hospital 1/20 (5) | Infectious compl 8/20 (40) | Infectious compl 11/20 (55) | NR | NR | NR | NR |
8 | Klarin 2005 [37] | Hospital 2/8 (25) ICU 1/8 (12) | Hospital 2/7 (29) ICU 2/7 (29) | NR | NR | Hospital 48.3 ± 30.4 ICU 14.2 ± 10.6 | Hospital 34.3 ± 15.4 ICU 16.3 ± 15.7 | NR | NR |
9 | McNaught 2005 [38] | 18/52 (35) | 18/51 (35) | Septic morbidity 21/52 (40) | Septic morbidity 22/51 (43) | ICU 5 (2–9) | ICU 4 (2–7) | NR | NR |
10 | Kotzampassi 2006 [39] | ICU 5/35 (14) | ICU 9/30 (30) | Infections 22/35 (63) VAP 19/35 (54) Septic compl 17/35 (49) Central venous line infections 13/35 (37) Wound infections 6/35 (17) UTI 6/35 (17) | Infections 27/30 (90) VAP 24/30 (80) Septic compl 23/30 (77) Central venous line infections 20/30 (66) Wound infections 8/30 (26) UTI 13/30 (43) | ICU 27.7 ± 15.2 | ICU 41.3 ± 20.5 | Diarrhea 5/35 (14) | Diarrhea 10/30 (30) |
11 | Alberda 2007 [40] | ICU 1/10 (10) | ICU 1/9 (11) | NR | NR | NR | NR | Diarrhea 1/10 (14) | Diarrhea 2/9 (23) |
12 | Li 2007 [41] | NR | NR | Infections 8/14 (58) | Infections 10/11 (91) | Hospital 42 ± 5.0 | Hospital 49 ± 6.8 | NR | NR |
13 | Olah 2007 [42] | Hospital 2/33 (6) | Hospital 6/29 (21) | Infections 9/33 (27) Septic compl 7/33 (12) Pancreatic abscess 2/33 (6) Infected pancreatic necrosis 2/33 (6) UTI 3/33 (9) | Infections 15/29 (52) Septic compl 17/29 (28) Pancreatic abscess 2/29 (7) Infected pancreatic necrosis 6/29 (21) UTI 3/33 (9) | Hospital 14.9 ± 3.3 | Hospital 19.7 ± 4.5 | NR | NR |
14 | Forestier 2008 [44] | NR | NR | VAP 19/102 (19) | VAP 21/106 (20) | ICU 22.5 ± 20.6 | ICU 19.7 ± 16.7 | NR | NR |
15 | Besselink 2008 [43] | 24/152 (16) | 9/144 (6) | Infections 46/152 (30) VAP 24/152 (16) Bacteremia 33/152 (22) Infected necrosis 21/152 (14) Urosepsis 1/52 (2) | Infections 41/144 (28) VAP 16/144 (11) Bacteremia 22/144 (15) Infected necrosis 14/144 (10) Urosepsis 2/144 (1) | Hospital 28.9 ± 41.5 ICU 6.6 ± 17 | Hospital 23.5 ± 25.9 ICU 3.0 ± 9.3 | Diarrhea 25/152 (16) | Diarrhea 28/144 (19) |
16 | Klarin 2008 [45] | Hospital 3/22 (5) ICU 2/22 (9) | Hospital 2/22 (0) ICU 2/22 (9) |
C. difficile + fecal samples 0/71 |
C. difficile + fecal samples 4/80 | Hospital 25.8 ± 19.4 ICU 8.0 ± 5.4 | Hospital 50.3 ± 75.2 ICU 11.6 ± 14 | NR | NR |
17 | Knight 2009 [46] | Hospital 35/130 (27) ICU 28/130 (22) | Hospital 42/129 (33) ICU 34/129 (26) | VAP 12/130 (9) | VAP 17/129 (13) | ICU 6 (3–11) | ICU 7 (3–14) | Diarrhea 7/130 (5) | Diarrhea 9/129 (7) |
18 | Barraud 2010 [47] | ICU 21/87 (24) 28 days 22/87 (25) 90 days 27/87 (31) | ICU 21/80 (26) 28 days 19/80 (24) 90 days 24/80 (30) | All infections 30/87 (34) Infection > 96 h 26/87 (30) VAP 23/87 (26) Catheter-related BSI 3/87 (4) UTI 4/87 (5) | All infections 30/80 (38) Infection > 96 h 29/80 (36) VAP 15/80 (19) Catheter-related BSI 11/80 (14) UTI 4/89 (5) | Hospital 26.6 ± 22.3 ICU 18.7 ± 12.4 | Hospital 28.9 ± 26.4 ICU 20.2 ± 20.8 | Diarrhea 48/87 (55) | Diarrhea 42/80 (53) |
19 | Morrow 2010 [10] | 12/68 (18) | 15/70 (21) | VAP 13/73 (18) | VAP 28/73 (38) | Hospital 21.4 ± 14.9 ICU 14.8 ± 11.8 | Hospital 21.7 ± 17.4 ICU 14.6 ± 11.6 | Non C. difficile diarrhea 42/68 (62)
C. difficile diarrhea 4/68 (6) | Non C. difficile diarrhea 44/70 (63)
C. difficile diarrhea 13/70 (19) |
20 | Frohmader 2010 [48] | 5/20 (25) | 3/25 (12) | NR | NR | ICU 7.3 ± 5.7 | ICU 8.1 ± 4 | Diarrhea episodes/pt/day 0.53 ± 0.54 | Diarrhea episodes/pt/day 1.05 ± 1.08 |
21 | Ferrie 2011 [49] | Hospital 2/18 (11) 6 months 7/18 (39) | Hospital 2/18 (11) 6 months 5/18 (28) | Infections 14/18 (78) | Infections 16/18 (89) | Hospital 54.50 ± 31.26 ICU 32.04 ± 24.46 | Hospital 59.04 ± 33.92 ICU 29.75 ± 18.81 | Duration of diarrhea 3.83 ± 2.39 Loose stools/day 1.58 ± 0.88 | Duration of diarrhea 2.56 ± 1.85 Loose stools/day 1.10 ± 0.79 |
22 | Sharma 2011 [50] | Hospital 2/24 (8) | Hospital 2/26 (8) | NR | NR | Hospital 13.23 ± 18.19 ICU 4.94 ± 9.54 | Hospital 9.69 ± 9.69 ICU 4.0 ± 5.86 | NR | NR |
23 | Tan 2011 [51] | 28 days 3/26 (12) | 28 days 5/26 (19) | Infections 9/26 (35) VAP 7/26 (27) | Infections 15/26 (58) VAP 13/26 (50) | ICU 6.8 ± 3.8 | ICU 10.7 ± 7.3 | NR | NR |
24 | Cui 2013 [20] | Hospital 1/23 (4) | Hospital 1/25 (4) | N/A | N/A | Hospital 10.4 ± 3.9 (23) | Hospital 13.4 ± 5.2 (25) | NR | NR |
25 | Tan 2013 [21] | 28 days 23/26 (12) | 28 days 5/26 (19) | NR | NR | ICU 6.8 ± 3.8 (26) | ICU 10.7 ± 7.3 (26) | NR | NR |
26 | Wang 2013 [22] | Unspecified 1/62 (8.1) | Unspecified 3/61 (9.8) | Pancreatic sepsis 8/62 (13) MODS 7/62 (11.3) | Pancreatic sepsis 13/61 (21) MODS 15/61 (25) | NR | NR | NR | NR |
27 | Lopez de Toro 2014 [23] | Hospital 19/46 (41) ICU 15/46 (33) | Hospital 18/43 (42) ICU 14/43 (33) | Hospital acquired infections 9/46 (20) | Hospital acquired infections 13/43 (30) | Hospital 18.5 (10–36) ICU 9 (3–19) | Hospital 24.5 (10–38) ICU 8 (2.5–16.5) | NR | NR |
28 | Sanaie 2014 [24] | 28 days 2/20 (10) | 28 days 5/20 (25) | Bacteremia 2/20(10) | Bacteremia 5/20(25) | ICU 13.85 ± 6.96 | ICU 14.16 ± 5.97 | NR | NR |
29 | Rongrungruang 2015 [25] | 28 days 18/75 (24) 90 day 25/75 (33) | 28 days 17/75 (22.7) 90 day 26/75 (34.7) | VAP 18/75 (24) | VAP 22/75 (29.3) | Hospital 20 (2–106) ICU 30.5 (4–98) | Hospital 19 (3–171) ICU 19 (5–30) | Diarrhea 19/75 (25.3) | Diarrhea 14/75 (18.7) |
30 | Zeng 2016 [26] | Hospital 26/118 (22) ICU 15/118 (12.7) | Hospital 25/117 (21.4) ICU 9/117 (7.7) | VAP 43/118 (36.4) | VAP 59/117 (50.4) | Hospital 13.5 ± 12.4 ICU 18 (14–32) | Hospital 10.6 ± 10.2 ICU 22 (11–56) | NR | NR |
Primary outcome: infections
Overall effect on new infections
Secondary outcomes
Ventilator associated pneumonia
Overall effect on mortality
Overall effect on ICU length of stay
Overall effect on hospital length of stay
Diarrhea
Antibiotic days
Subgroup analysis
Probiotics daily dose
L. plantarum vs. non L. plantarum
L. rhamnosus GG vs. other probiotics
Synbiotics vs. other strategies
Higher vs. lower mortality
Higher vs. lower methodological score
Publication bias
Discussion
Conclusion
Key messages
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Critical illness is characterized by a loss of commensal flora and an overgrowth of potentially pathogenic bacteria, leading to a high susceptibility of nosocomial infections
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Probiotics are living non-pathogenic microorganisms, which may protect the gut barrier, attenuate pathogen overgrowth, decrease bacterial translocation and prevent infection in ICU patients
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Probiotic use in the ICU remains widespread and controversial, current guidelines are not conclusive, and a significant number of new trials of probiotics have been published recently, which requires a current and comprehensive systematic analysis of probiotic and synbiotic therapy in critically ill patients
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Probiotics were associated with a significant reduction in infections and a significant reduction in the incidence of ventilator-associated pneumonia (VAP) was found in critically ill patients receiving probiotics alone versus synbiotic mixtures, demonstrating the greatest improvement in infectious outcome, limited synbiotic trial data are currently available
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Currently, clinical heterogeneity and potential publication bias reduce strong clinical recommendations and indicate further high-quality clinical trials are needed to conclusively prove these benefits
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Probiotics shows promise for the reduction of infections, including VAP in critical illness, and should be considered in critically ill patients