Introduction
Study | Population | Exclusions for renal/liver failure | Methods (score) | Intervention dose of glutamine gm/kg/day | Mortality # (%)† | Infections # (%)‡ | Length of stay (days) | |||
---|---|---|---|---|---|---|---|---|---|---|
Experimental | Control | Experimental | Control | Experimental | Control | |||||
Single-center, mixed ICU, patients, N = 84 | Not defined | C.Random: yes, ITT: yes, Blinding: yes (11) | PN, 0.26 IV glutamine + PN vs. PN, isocaloric, isonitrogenous | Hospital 18/42(43) | Hospital 25/42(60) | 28/42 (67) | 26/42 (62) | ICU 10.5 (6-19)* | ICU 10.5 (6-24)* | |
2) Powell-Tuck 1999 [36] | Single-center, mixed ICU/hospital, patients N = 168 | Renal: creatinine >200 μmol/l Liver: if failure resulted in a PTR >1.8 or hepatic encephalopathy | C.Random: yes ITT: yes Blinding: yes (8) | PN, 0.26 IV glutamine + PN vs. PN, isocaloric, isonitrogenous. | Hospital 14/83(17) | Hospital 20/85(24) | NR | NR | Hospital 43.4 ± 34.1 (83) | Hospital 48.9 ± 38.4 (85) |
3) Wischmeyer 2001 [40] | Single-center, critically ill burns N = 31 | Renal: severe failure, Liver: severe failure | Random: not sure ITT: no Blinding yes (8) | PN, 0.57 IV glutamine + EN or EN + PN vs. AAcids + PN or EN or EN + PN, isocaloric, Isonitrogenous | Hospital 1/12 (8) | Hospital 4/14 (29) | 7/12 (58) | 9/14 (64) | Hospital 40 ± 10 (12) | Hospital 40 ± 9 (14) |
4) Fuentes-Orozco 2004 [25] | Single-center, secondary peritonitis requiring TPN N = 33 | Renal: creatinine >180 μmol/l. Liver: bilirubin >40 μmol/l, alanine aminotransferase >100 U/l and aspartate aminotransferase >100 U/l | C.Random: yes, ITT: yes. Blinding: double (11) | PN, 0.27 IV glutamine + PN vs. PN, isocaloric, isonitrogenous | Hospital 2/17 (12) | Hospital 3/16 (19) | 4/17 (23) | 12/16 (75) | ICU 7.2 ± 9.2 (17), Hospital, 16.5 ± 8.9 (17) | ICU 7.3 ± 4.5 (16) Hospital 16.7 ± 7 (16) |
5) Zhou 2004 [42] | Severe burns N = 30 | Renal: chronic disease. Liver: chronic disease | C.Random: yes. ITT: yes. Blinding: double (11) | PN, 0.35 IV glutamine + PN vs. PN, isocaloric, isonitrogenous. | NR | NR | 3/15 (20) | 4/15 (26) | Hospital 42 ± 7.0 (15) | Hospital 46 ± 6.6 (15) |
6) Xian-Li 2004 [30] | Single-center, severe acute pancreatitis, N = 69 | Renal: renal dysfunction. Liver: liver dysfunction | C.Random: yes. ITT: no Blinding: no (5) | PN, 0.4 IV glutamine + PN vs. PN | Hospital 0/20 (0) | Hospital 3/21 (14) | # Compl 4 | # Compl 11 | Hospital 25.3 ± 7.6 (20) | Hospital 28.6 ± 6.9 (21) |
7) Dechelotte 2006 [9] | Multiple trauma, surgery, sepsis, pancreatitis from 16 ICUs N = 114 | |||||||||
Renal: creatinine >250 μmol/L. Liver: Prothrombin time >23.7 sec | C. Random: NR. ITT: yes. Blinding: double (NA) | PN, 0.35 IV glutamine + PN vs. PN, isocaloric, isonitrogenous. | Hospital 2/58 (3), 6-month 16/58 (28) | Hospital 2/56 (3) 6-month 9/56 (16) | All 23/58 (40) Pneumonia 10/58 (17) | All 32/56 (58), Pneumonia 19/56 (34) | ICU 12.5 (1–430), Hospital 30 (1-560) | ICU 11.5 (3–121),* Hospital 26 (4-407)* | ||
8) Palmese 2006 [33] | Single-center, mixed ICU N = 84 | Renal: severe renal disease. Liver: severe hepatic disease | C.Random: yes, ITT: yes, Blinding: single (10) | PN, 0.14 IV glutamine + EN with FOS vs. EN without FOS | ICU 6/42 (14) | ICU 8/42 (19) | All 13/42 (31), Pneumonia 2/42 (5) | All 21/42 (50), Pneumonia 6/42 (14) | ICU 12 ± 4.6 (42) | ICU 13 ± 3.4 (42) |
9) Tian 2006 [38] | Single-center, MODS N = 40 | Not defined | C.Random: not sure, ITT: yes, Blinding: none (6) | PN, 0.27 IV glutamine vs. PN | Unspecified 2/20 (10) | Unspecified 5/20 (25) | NR | NR | NR | NR |
10) Sahin 2007 [37] | Single-center, acute pancreatitis N = 40 | Not defined | C.Random: not sure, ITT: yes, Blinding: single (9) | PN, 0.3 IV glutamine + PN vs. PN, isocaloric, isonitorgenous. | Hospital 2/20 (10) | Hospital 6/20 (30) | NR | NR | Hospital 14.2 ± 4.4 (20) | Hospital 16.4 ± 3.9 (20) |
11) Zhang 2007 [43] | Emergency and neurosurgical ICU, pts requiring PN for >7 days, N = 44 | Not defined | C.Random: not sure, ITT: yes, Blinding: no (6) | EN and PN, IV glutamine 0.4 g/kg/day vs. EN and PN alone | NR | NR | NR | NR | ICU 11.73 ± 6.57 (22) | ICU 13.39 ± 5.08 (22) |
12) Cai 2008 [21] | Single-center, elderly, severe sepsis N = 110 | Renal: creatinine >220 μmol/L and/or dialysis. Liver: bilirubin >43 μmol/L and/or history of chronic liver disease | C.Random: not sure, ITT: yes, Blinding: no (10) | PN, 0.19 IV glutamine Patients received PN or EN + PN isocaloric, isonitrogenous | 28-day 17/55 (31) | 28-day 20/55 (36) | NR | NR | ICU 22.1 ± 4.9 (55) | ICU 23.8 ± 5.1 (55) |
13) Duska 2008 [15]∂ | Single-center, trauma N = 30 | None | C.Random: not sure, ITT: yes, Blinding: single (8) | PN, 0.3 IV glutamine + PN vs. normal saline + supplemental PN, isocaloric, isonitrogenous | ICU 2/10 (20) | ICU 0/10 (0) | NR | NR | ICU 23 (median) | ICU 24 (median) |
14) Estivariz 2008 [24] | Single-center, pancreatic and non pancreatic surgery N = 63 | Renal: evolving acute renal failure or dialysis. Liver: total bili >4 mg/dL or >5 fold elevation in serum transaminase concentrations | C.Random: not sure, ITT: no**, Blinding: double (9) | PN, 0.5 IV glutamine + PN vs. PN isocaloric, isonitrogenous | Hospital 1/32 (3) | Hospital 6/31 (19) | Pneumonia 13/30 (43) | Pneumonia 16/29 (55) | ICU 12 ± 2 (32), Hospital 20 ± 2 (32) | ICU 23 ± 6 (31) Hospital 30 ± 6 (31) |
17) Perez-Barcena 2008 [35] | Single-center, mixed ICU N = 30 | Not defined | C.Random: not sure, ITT: yes, Blinding: single (10) | PN, 0.35 IV glutamine + PN vs. PN isocaloric, isonitrogenous | Hospital 3/15 (20) | Hospital 0/15 (0) | 11/15 (73) | 13/15 (87) | ICU 22.9 ± 20.6 (15), Hospital, 35.5 ± 33.6 (15) | ICU 20.5 ± 16.0 (15) Hospital 42.9 ± 28.8 (15) |
18) Ozgultekin 2008 [32] | Single-center, CHI & GCS pts, ventilated, sedated, mean APACHE II 18-19 N = 60 | Not defined | C.Random: not sure ITT: no, Blinding: none (4) | EN, 0.2-0.4 g/kg/d IV glutamine vs. EN | 30-day 12/20 (60) | 30-day 12/20 (60) | NR | NR | ICU 11.8 ± 5.9 (20) | ICU 17.3 ± 16.4 (20) |
19) Yang 2008 [41] | Single-center, severe pancreatitis N = 61 | Not defined | C.Random: not sure, ITT: no Blinding: single (4) | PN, IV glutamine (dose unknown) vs. PN, saline | Hospital 1/25 (4) | Hospital 3/25 (12) | NR | NR | Hospital 13.48 ± 1.42 (25) | Hospital 15.18 ± 1.14 (25) |
20) Eroglu 2009 [23] | Single-center, severe trauma, ISS >20 N = 40 | Renal: on renal replacement therapy, Liver: none | C.Random: yes, ITT: yes, Blinding: double (12) | EN, 0.5 g/kg/d IV glutamine vs. EN, saline | ICU 1/20 (5) | ICU 1/20 (5) | Overall 8/20 (40) VAP 1/20 (5) | Overall 10/20 (50), VAP 1/20 (5) | ICU 14 ± 2 (20) | ICU 15 ± 2 (20) |
21) Perez-Barcena 2010 [34] | Single-center, trauma pt ISS >12, requires PN based on ASPEN N = 43 | Not defined | C.Random: not sure, ITT: yes, Blinding: single (6) | PN, 0.35 g/kg/d IV glutamine vs. PN | ICU 4/23 (17), Hospital 0/23 (0) | ICU 2/20 (10), Hospital 1/20 (5) | Pneumonia 11/23 (48) | Pneumonia 8/20 (40) | ICU 21 (17–25),* Hospital 31 (19-42)* | ICU 21 (14-47)* Hospital 40 (24-80)* |
22) Andrews 2011 [20] | Multi-center, critically ill adults, 25% medical pts, from 10 centres. N = 502 | Renal: estimated GFR <10 ml/min and not receiving renal replacement therapy. Liver: none | C.Random: yes, ITT: yes, Blinding: double (13) | PN, 0.2-0.4 g/kg/day (20.2 g/day x 7 days) IV glutamine vs.PN isocaloric, isonitrogenous | ICU 88/250 (35), 6-month 115/250 (46) | ICU 80/252 (32), 6-month 106/252 (42) | 134/250 (54) | 131/252 (52) | ICU 15 (7.9-28.4)*, Hospital 32.5 (14.7-55.6)* | ICU 13.4 (8.2-23.9)*, Hospital 28.2 (15.1-52.4)* |
23) Cekmen 2011 [22] | Single-center, mixed surgical ICU, ISS >10, APACHE II >10 N = 30 | Renal: significant renal dysfunction (evolving acute renal failure or on dialysis). Liver: significant hepatic dysfunction (total bilirubin >4.0 mg/dL or more than fivefold elevation in serum transaminase concentrations) | C.Random: yes, ITT: yes, Blinding: double (10) | PN, 0.5 g/kg IV glutamine vs. PN | ICU (presumed) 3/15 (20) | ICU (presumed) 6/15 (40) | NR | NR | ICU 19.2 ± 12 (15) | ICU 27.4 ± 12 (15) |
24) Grau 2011 [27] | Multi-center, mechanically ventilated, APACHE II >12, need TPN N = 127 | Renal: chronic renal failure requiring dialysis, acute renal failure not treated with hemofiltration or hemodialysis [plasmatic creatinine >2.5 mg/dL]. Liver: hepatic failure with hepatic encephalopathy or portal hypertension | C.Random: not sure, ITT: yes Blinding: double (11) | PN, 0.5 g/kg IV glutamine vs. PN | ICU 9/59 (15), 6-month 16/59 (27) | ICU 13/68 (19), 6-month 23/68 (34) | All 24/59 (41), Surgical, 13/59 (22), Pneu (#/1000 vent days), 13.5, # infect/pt 1.5 | All 31/68 (46), Surgical, 17/68 (25), Pneu (#/1000 vent days), 27.2, # infect/pt 2.4 | ICU 12 (7-22)*, Hospital 35 (23-56)* | ICU 12 (7-24)*, Hospital, 31 (20-58)* |
25) Wernerman 2011 [39] | Multi-center, mixed ICU, APACHE II >10 N = 413 | Not defined | C.Random: yes, ITT: yes Blinding: double (11) | EN or PN, 0.28 g/kg/day IV glutamine vs. EN or PN, normal saline IV | ICU 8/205 (4) 28-day 14/205 (7) | ICU 11/208 (5) 28-day 20/208 (10) | NR | NR | NR | NR |
26) Ziegler 2012 [44] | Multi-center, N = 150 | Renal: history of chronic renal failure requiring dialysis, or significant renal dysfunction (creatinine >2.5 mg/dL and is not receiving continuous renal replacement therapy) or requiring acute hemodialysis postoperatively. Liver: current encephalopathy or known history of cirrhosis or total bilirubin ≥10.0 mg/dL | C.Random: yes ITT: yes, Blinding: double (12) | PN, 0.5 gm/kg/day IV vs. PN, isocaloric. Isonitrogenous. | Hospital, 11/75 (15) | Hospital 13/75 (17) | Any 33/75 (44). Pneumonia, 10/75 (13) | |||
Any, 24/75 (32) Pneumonia, 12/75 (16) | ICU 17.5 ± 14.6 (75). Hospital 33.6 ± 28 (75) | ICU 13.6 ± 10 (75). Hospital 29.7 ± 20.7 (75) |
Methods
Study identification
Study selection criteria
Data abstraction
Score | |||
---|---|---|---|
0 | 1 | 2 | |
Randomization
| … | Not concealed or not sure | Concealed randomization |
Analysis
| Other | … | Intention-to-treat |
Blinding
| Not blinded | Single-blind | Double-blinded |
Patient selection
| Selected patients or unable to tell | Consecutive eligible patients | ….. |
Comparability of groups at baseline
| No or not sure | Yes | …. |
Extent of follow-up
| <100% | 100% | …. |
Treatment protocol
| Poorly described | Reproducibly described | …. |
Co-interventions
| Not described | Described but not equal or not sure | Well described and all equal |
Outcomes
| Not described | Partially described | Objectively defined |
Data synthesis
Subgroup analyses
Results
Study identification and selection
Meta-analyses of primary and secondary outcomes
Effect of GLN supplementation on mortality
Effect of GLN supplementation on infectious complications, ICU length of stay and hospital length of stay
Subgroup analysis
Overall mortality | Hospital mortality | Infectious complications | ICU LOS | VAP | ||||||||||||||||
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Subgroup analysis | Number of trials | Number of patients | Effect on overall mortality [RR (95% CI), p] | Test for subgroup differences | Number of trials | Number of patients | Effect on hospital mortality [RR (95% CI), p] | Test for subgroup differences | Number of trials | Number of patients | Effect on infectious complications [RR (95% CI), P] | Test for subgroup differences | Number of trials | Number of patients | Effect on ICU LOS [WMD (95% CI), P] | Test for subgroup differences | Number of trials | Number of patients | Effect on VAP [RR (95% CI), P] | Test for subgroup differences |
Study Quality
| ||||||||||||||||||||
Low quality (<8) | 5 | 214 | 0.81 (0.44, 1.48), P = 0.49 | P = 0.79 | 3 | 134 | 0.26 (0.06, 1.19), P = 0.08 | P = 0.21 | NA | NA | NA | |||||||||
High quality (≥8) | 19 | 2103 | 0.88 (0.74, 1.04) P = 0.12 | 10 | 733 | 0.70 (0.52, 0.94), P = 0.02 | ||||||||||||||
Number of sites
| ||||||||||||||||||||
Single center | 19 | 1011 | 0.75 (0.60, 0.93), P = 0.009 | P = 0.04 | 11 | 603 | 0.64 (0.47, 0.88), P = 0.006 | P = 0.45 | 8 | 371 | 0.77 (0.60, 0.98), P = 0.03 | P = 0.16 | NA | 4 | 226 | 0.86 (0.58, 1.28), P = 0.45 | P = 0.34 | |||
Multi-center | 5 | 1306 | 1.03 (0.83,1.28) P = 0.79 | 2 | 264 | 0.86 (0.43, 1.71), P = 0.67 | 4 | 893 | 0.97 (0.77, 1.23) P = 0.83 | 2 | 264 | 0.63 (0.38, 1.04) P = 0.07 | ||||||||
PN vs. EN
| ||||||||||||||||||||
Patients on PN | 20 | 2128 | 0.84 (0.71, 1.01) P = 0.07 | P = 0.66 | NA | 10 | 1140 | 0.89 (0.74, 1.06) P = 0.20 | P = 0.27 | 8 | 354 | -2.30 (-6.50, 1.90) P = 0.28 | P = 0.42 | 4 | 366 | 0.79 (0.57, 1.09) P = 0.16 | P = 0.40 | |||
Patients on EN | 4 | 184 | 0.94 (0.61, 1.47), P = 0.79 | 2 | 124 | 0.68 (0.45, 1.05), P = 0.08 | 3 | 184 | -0.47 (-1.84, 0.90) P = 0.50 | 2 | 124 | 0.44 (0.11, 1.67), P = 0.23 |
Effect of parenteral GLN supplementation of PN versus EN alone
Effect of study quality on outcomes
Role of multi-center versus single-center trials on outcomes
Risk of bias across studies
Discussion
Conclusions
Key messages
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Critical illness is characterized by severe metabolic stress and glutamine depletion has been associated with increased mortality in some recent studies. In this context, supplementation of parenteral glutamine, predominantly as a component of parenteral nutrition, may improve clinical outcomes when given to appropriate patients as part of complete nutrition support.
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Supplemental parenteral glutamine may significantly decrease hospital mortality and shorten hospital LOS in critically ill patients.
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Supplemental parenteral glutamine given as a component of nutrition support is associated with a trend towards a reduction in overall mortality, infectious morbidity, and ICU LOS in critically ill patients.
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We suggest supplemental glutamine should not be given in a high dose (>0.5 g/kg/day) or in patients early in the acute phase of critical illness in patients with multiple organ failure or unresuscitated shock requiring significant vasopressor support.
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When parenteral nutrition is prescribed to critically ill patients, parenteral supplementation with glutamine should continue to be considered safe and may potentially improve outcomes in the ICU in patients without specific contraindications.