Effect of perioperative glutamine-enriched nutritional support on patients with colorectal cancer: A systematic review and meta-analysis

Table 1 Data sources and search strategy

Data sources	Search strategy
PubMed, EMBASE, Web of Science, Cochrane Library, Chinese Biomedical Database, CNKI, VIP, and Wanfang Electronic Database	"Rectal Neoplasms," "Colorectal Neoplasms,” "Colonic Neoplasms,” "Glutamine," and "randomized controlled trial" as subject terms combined with their corresponding free words for all possible combinations. Search terms were combined using the Boolean operators "AND" and "OR"
Others	Additional articles were manually searched in the reference lists of articles selected for the full-text search. For overlapping authors, institutions, or patients, the most recent or highest-quality articles were selected

Table 2 Classification of complications

Infectious complications	Non-infectious complications
Incision infection	Poor wound healing
Urinary infection	Anastomotic leak
Pulmonary infection	Haemorrhage
Abdominal infection	Stress ulcer
Peritonitis	Pulmonary embolism
Systemic inflammatory response syndrome

Table 3 Summary of the basic characteristics of the included studies

Ref.	Years	Types	Sample size (n)		Ages (year)		Gender (male/female)		Dose of Ala-Gln	Route	Time of duration
			Control	Experimental	Control	Experimental	Control	Experimental
Zhao et al[30]	2022	CC	44	44	54.31 ± 5.62	55.26 ± 5.86	25/19	23/21	20 g/d	PN	Preop. 3 days-postop
Zhao et al[31]	2019	CRC	28	32	54.42 ± 5.21	56.75 ± 5.60	19/9	22/10	50 mL	PN	Preop. 24 hours and postop. 1 hour
Zhang et al[32]	2008	CRC	47	47	57.35 ± 16.4		NR		100 mL/d	PN	POD1-7
Yuan et al[33]	2011	CRC	30	30	61.83 ± 6.23	62.57 ± 7.38	15/15	15/15	0.4 g /kg/d	PN	Preop. 4 days-postop
Xu et al[34]	2006	CRC	30	30	NR		NR		NR	PN	POD1-7
Wang et al[35]	2005	CRC	20	19	NR		NR		0.4 g /kg/d	PN	Postop.
Wang et al[36]	2008	RC	30	30	60.3 ± 4.5	58.7 ± 3.6	11/19	17/13	0.3 g /kg/d	PN	POD1-7
Song et al[37]	2002	CRC	20	20	56.6 ± 12.1	55.4 ± 17.1	12/8	13/7	0.3-0.4 g /kg/d	PN	POD1-7
Li et al[38]	2002	CRC	20	20	58.02 ± 4.63	57.81 ± 3.75	10/10	11/9	NR	PN	POD1-7
Huang et al[39]	2006	CRC	15	15	56.8 ± 3.5	57.0 ± 4.7	9/6	7/8	0.4 g /kg/d	PN	POD1-5
Cui et al[40]	2011	CC	20	20	56 ± 11	55 ± 11	11/9	12/8	0.5 g/kg	PN	Preop. 24 hours and postop.1 hour
Chen et al[41]	2019	CC	42	42	62.7 ± 11.3	62.1 ± 10.6	24/18	22/20	0.5 g/(kg/d)	PN	Preop-POD 7
Chen et al[42]	2004	CC	24	24	68.12 ± 4.46	66.84 ± 5.52	17/7	15/9	0.4 g /kg/d	PN	Preop. 5 days-POD 7
Cao et al[43]	2007	CRC	20	20	NR		NR		NR	PN	POD1-7
Cao et al[44]	2006	CRC	15	15	NR		NR		NR	PN	Preop. 5 days-POD 5
Oguz et al[45]	2007	CRC	52	57	57 ± 17	52 ± 12	31/21	40/17	1 g /(kg/d)	PN	Preop.: 6 ± 2, POD: 5 ± 1
Morlion et al[46]	1998	CRC	13	15	68.2 ± 12.5	67.1 ± 10.7	6/7	6/9	0.3 g /(kg/d)	PN	POD1-5
Aosasa et al[47]	1999	CRC	5	6	54.8 ± 10.7	63.8 ± 6.2	4/1	3/3	30 g /d	PN	Preop.: > 5 days
Zhang et al[48]	2012	CRC	20	20	42-74		NR		30 g/d	EN	POD1-7
Liu et al[49]	2018	CC	40	40	59.1 ± 7.5	61.4 ± 7.0	25/15	21/19	20 g/d	EN	POD1-7
Liu et al[50]	2017	CC	44	44	59.1 ± 8.5	60.4 ± 7.3	28/16	26/18	20 g /d	EN	POD1-7
Li et al[51]	2016	RC	30	30	50.5 ± 4.9	50.1 ± 4.6	18/12	18/12	0.4 g /kg/d	EN	Postop.
Li et al[52]	2019	CRC	32	32	65.5 ± 9.0	62.6 ± 9 .6	19/13	19/13	0.5 g/ (kg/d)	EN	POD0.5-7
De et al[53]	2020	CC	52	52	53.24 ± 11.38	53.54 ± 11.57	29/23	27/25	100 mL/d	EN	Preop. 1 day- POD 7
Chen et al[54]	2022	CRC	45	45	67.9 ± 7.2	68.5 ± 7.8	25/20	27/18	30 g /d	EN	POD 1-7
Chen et al[55]	2014	CRC	22	22	58.7 ± 6.7		NR		30 g/d	EN	POD1-10
Cai et al[56]	2021	RC	56	56	68.3 ± 3.6	67.2 ± 3.5	34/22	31/25	POD2-3: 5 g, POD4-7: 10 g	EN	POD2-7

PA: Prealbumin; CRC: Colorectal cancer; PN: Parenteral nutrition; EN: Enteral nutrition; POD: Postoperative day; Preop.: Preoperative; Postop.: Postoperative.

Table 4 Subgroup analysis

Outcomes	Category	Study characteristic (number of studies)	Overall MD/SMD (95%CI)	P value
ALB	Type of tumor	CC (5)	4.69 (3.51, 5.87)	aP < 0.00001
		RC (3)	2.61 (1.40, 3.83)	aP < 0.00001
		CRC (13)	1.94 (0.77, 3.11)	aP = 0.001
	Routes	EN (9)	3.02 (2.06, 3.98)	aP < 0.00001
		PN (12)	2.32 (1.06, 3.58)	aP = 0.0003
	Timing of infusion	POD (15)	1.91 (1.02, 2.81)	aP < 0.0001
		Pre-op, POD (6)	4.46 (3.09, 5.82)	aP < 0.00001
	Sample size	> 30 (8)	4.29 (3.48, 5.09)	aP < 0.00001
		≤ 30 (13)	1.71 (0.77, 2.65)	aP = 0.0004
PA	Type of tumor	RC (3)	29.67 (14.44, 44.90)	aP = 0.0001
		CC (5)	16.49 (1.91, 31.08)	aP = 0.03
		CRC (2)	35.53 (-10.36, 81.41)	P = 0.13
	Routes	EN (5)	39.97 (21.45, 58.50)	aP < 0.0001
		PN (5)	13.81 (7.74, 19.88)	aP < 0.00001
	Timing of infusion	POD (5)	32.22 (14.63, 49.80)	aP = 0.0003
		Pre-op, POD (5)	19.47 (8.97, 29.97)	aP = 0.0003
	Sample size	> 30 (6)	35.53 (20.40, 50.66)	aP < 0.00001
		≤ 30 (4)	12.15 (7.38, 16.92)	aP < 0.00001
CD8+	Type of tumor	CC (3)	-4.77 (-10.76, 1.22)	P = 0.12
		RC (1)	-2.40 (-3.16, -1.64)	aP < 0.00001
		CRC (7)	-0.01 (-2.83, 2.82)	P = 1.00
	Routes	EN (5)	-2.07 (-4.40, 0.25)	P = 0.08
		PN (6)	-1.54 (-6.38, 3.31)	P = 0.53
	Time of duration	> 7 days (5)	-1.16 (-4.82, 2.50)	P = 0.53
		≤ 7 days (6)	-2.13 (-5.13, 0.87)	P = 0.16
	Timing of infusion	POD (7)	-0.49 (-3.15, 2.18)	P = 0.72
		Pre-op, POD (4)	-3.74 (-8.82, 1.34)	P = 0.15
	Sample size	> 30 (4)	-2.06 (-5.36, 1.24)	P = 0.22
		≤ 30 (7)	-1.64 (-5.20, 1.91)	P = 0.37
CD4+/CD8+	Type of tumor	CC (2)	0.26 (-0.11, 0.63)	P = 0.17
		CRC (4)	0.04 (-0.54, 0.61)	P = 0.90
	Routes	EN (3)	-0.06 (-0.67, 0.55)	P = 0.86
		PN (3)	0.30 (0.02, 0.58)	P = 0.04
	Time of duration	> 7 days (4)	0.03 (-0.46, 0.53)	P = 0.90
		≤ 7 days (2)	0.26 (-0.14, 0.65)	P = 0.20
	Timing of infusion	POD (3)	-0.12 (-0.74, 0.50)	P = 0.70
		Pre-op, POD (3)	0.34 (0.07, 0.60)	aP = 0.01
	Sample size	> 30 (3)	0.21 (-0.04, 0.46)	P = 0.10
		≤ 30 (3)	0.03 (-0.86, 0.92)	P = 0.94
IgM	Type of tumor	RC (2)	0.20 (0.14, 0.25)	aP < 0.00001
		CRC (5)	0.45 (0.03, 0.88)	aP = 0.03
	Routes	EN (3)	0.65 (-0.05, 1.36)	P = 0.07
		PN (4)	0.19 (0.10, 0.29)	aP < 0.0001
	Time of duration	> 5 days (5)	0.44 (0.03, 0.85)	aP = 0.04
		≤ 5 days (2)	0.20 (0.15, 0.26)	aP < 0.00001
	Sample size	> 30 (2)	0.20 (0.14, 0.26)	aP < 0.00001
		≤ 30 (5)	0.45 (0.10, 0.80)	aP = 0.01
IgG	Type of tumor	RC (2)	2.09 (1.52, 2.66)	aP < 0.00001
		CRC (4)	1.04 (-0.23, 2.32)	P = 0.11
	Routes	EN (2)	1.04 (-0.81, 2.88)	P = 0.27
		PN (4)	1.71 (0.39, 3.03)	aP = 0.01
	Sample size	> 30 (2)	1.16 (-0.69, 3.01)	P = 0.22
		≤ 30 (4)	1.63 (0.10, 3.16)	aP = 0.04
TNF-α	Type of tumor	CC (3)	-17.77 (-33.20, -2.34)	aP = 0.02
		CRC (3)	-8.80 (-21.26, 3.66)	P = 0.17
	Routes	EN (3)	-16.85 (-29.89, -3.81)	aP = 0.01
		PN (3)	-9.52 (-21.34, 2.30)	P = 0.11
	Time of duration	≥ 7 days (3)	-16.85 (-29.89, -3.81)	aP = 0.01
		< 7 days (3)	-9.52 (-21.34, 2.30)	P = 0.11
	Timing of infusion	POD (1)	-4.65 (-5.82, -3.48)	aP < 0.00001
		Pre-op, POD (4)	-14.92 (-24.30, -5.55)	aP = 0.002
	Sample size	> 30 (3)	-16.85 (-29.89, -3.81)	aP = 0.01
		≤ 30 (3)	-9.52 (-21.34, 2.30)	P = 0.11
CRP	Time of duration	≥ 7 days (2)	-3.83 (-4.35, -3.30)	aP < 0.00001
		< 7 days (2)	-5.73 (-15.78, 4.31)	P = 0.26
LOS	Type of tumor	CC (2)	-3.16 (-4.13, -2.18)	aP < 0.00001
		CRC (8)	-2.07 (-3.20, -0.93)	aP = 0.0003
	Routes	EN (5)	-1.97 (-3.15, -0.79)	aP = 0.001
		PN (5)	-2.64 (-4.25, -1.03)	aP = 0.001
	Sample size	> 30 (4)	-2.23 (-3.29, -1.16)	aP < 0.0001
		≤ 30 (6)	-2.34 (-4.08, -0.59)	aP = 0.009

^aP < 0.05.

LOS: Length of hospital stay; ALB: Albumin; PA: Prealbumin; CRC: Colorectal cancer; PN: Parenteral nutrition; EN: Enteral nutrition; TNF-α: Tumor necrosis factor-α; CRP: C-reactive protein; MD: Mean differences; SMD: Standardized mean differences.