Table 1 Randomized studies evaluating glutamine (PN) in critically ill patients

1) Griffiths 1997 & 2002 [28, 29]

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)