Effects of neutrophil elastase inhibitor in patients undergoing esophagectomy: A systematic review and meta-analysis

Table 1 Basic characteristics of the included studies

Ref.	Year	Arm	Case (n)	Sex (M/F)	Age (yr)	Usage of sivelestat
Sato et al[19]	2001	SSH	8	-	63.9 ± 6.9	150000 U diluted in 20 mL normal saline every 12 h from operation to POD 5
		Saline	8	-	64.6 ± 8.7
Akamoto et al[20]	2007	SSH	6	5/1	70.8 ± 5.5	4.8 mg/kg per day of sivelestat + 240 mL saline from operation to POD 3
		Saline	7	5/2	65.7 ± 2.9
Kawahara et al[22]	2010	SSH	10	7/3	64 (50-78)1	300 mg/d of sivelestat + 200 mL saline from operation to POD 3
		Saline	10	10/0	63 (65-69)
Makino et al[24]	2011	SSH	16	12/4	65 (61-68)2	4.8 mg/kg per day of sivelestat + 240 mL saline from operation to POD 7
		Saline	15	13/2	66 (63-69)
Yamaguchi et al[29]	2011	SSH	12	9/3	59 ± 5	0.2 mg/kg per hour sivelestat from operation to POD 1
		Saline	12	9/3	60 ± 8
Iwahashi et al[21]	2011	Arm1	15	13/2	65 ± 8	Arm1: 0.2 mg/kg per hour sivelestat from operation to POD 1;
		Arm2	15	9/6	64 ± 7	Arm 2: 0.2 mg/kg per hour sivelestat from operation to POD 5
		Control	15	10/5	67 ± 8	0.2 mg/kg per hour sivelestat
Yamaki et al[30]	2005	SSH	9	-	62 ± 9
		Control	6	-	69 ± 8	0.2 mg/kg per hour sivelestat after operation till POD 5
Ono et al[28]	2007	SSH	7	4/3	61 ± 12
		Control	10	7/3	70 ± 7	0.2 mg/kg per hour sivelestat diluted with saline after operation till POD 6
Suda et al[14]	2007	SSH	18	15/3	60 (55-65)3
		Control	25	20/5	56 (52-66)	0.2 mg/kg per hour from operation and during mechanical ventilation support
Kobayashi et al[23]	2010	SSH	60	56/4	66 ± 7
		Control	28	24/4	60 ± 10	0.2 mg/kg per hour sivelestat diluted with saline after operation till POD 5
Mimatsu et al[25]	2011	SSH	22	21/1	59 ± 11
		Control	20	19/1	63 ± 9	0.2 mg/kg per hour sivelestat after operation till POD 3
Nishiyama et al[27]	2012	SSH	26	23/3	67 ± 8
		Control	27	23/4	63 ± 8	0.2 mg/kg per hour sivelestat with 5% dextrose in water from operation till POD 3
Nagai et al[26]	2013	SSH	42	39/3	66 ± 9
		Control	35	31/4	63 ± 8

¹Range;

²95%CI;

³Inter-quartile range. SSH: Sivelestat sodium hydrate; POD: Postoperative day; Age is shown as mean ± SD.

Table 2 Basic surgical characteristics of patients in the included studies

Ref.	Arm	Operative time (min)	Blood loss (mL)	Surgical procedure
Sato et al[19]	SSH	357 ± 58	615 ± 268	Extensive resection including lymph node dissection
	Saline	326 ± 23	712 ± 184
Akamoto et al[20]	SSH	496 ± 140	1 672 ± 426	Esophagectomy and esophagogastric anastomosis
	Saline	569 ± 46	1 339 ± 316
Kawahara et al[22]	SSH	517 (range 443-733)	305 (range 180-1050)	Video-assisted thoracoscopic oesophagectomy
	Saline	549 (range 453-785)	32 (range 150-1910)
Makino et al[24]	SSH	433 (95%CI: 399-467)	468 (95%CI: 380-556)	Video-assisted thoracoscopic oesophagectomy
	Saline	431 (95%CI: 407-455)	514 (95%CI: 386-643)
Yamaguchi et al[29]	SSH	387 ± 57	488 ± 229	Right-sided transthoracic esophagectomy with cervical esophagogastrostomy and lymph node dissection
	Saline	363 ± 85	376 ± 166
Iwahashi et al[21]	SSH	491 ± 62	422 ± 210	Radical esophagectomy with a two- or three-field lymph node dissection via a cervicothoracoabdominal approach
	SSH	466 ± 72	405 ± 262
	Control	482 ± 69	430 ± 173
Yamaki et al[30]	SSH	538 ± 121	969 ± 505	Radical esophagectomy
	Control	552 ± 157	1134 ± 682
Ono et al[28]	SSH	573.4 ± 72.6	1685.1 ± 1255.3	Esophagectomy and reconstruction with gastric mobilization by right posterolateral thoracotomy and laparotomy
	Control	568.7 ± 164.1	1032.4 ± 347.7
Suda et al[14]	SSH	458 (95%CI: 373-545)	361 (95%CI: 218-682)	Transthoracic esophagectomy
	Control	626 (95%CI: 541-700)	520 (95%CI: 216-700)
Kobayashi et al[23]	SSH	311 ± 66	359 ± 253	Thoracoscopy-assisted subtotal esophagectomy
	Control	412 ± 71	402 ± 161
Mimatsu et al[25]	SSH	407.3 ± 74.6	346.7 ± 122.2	Transthoracic esophagectomy with reconstruction of the stomach role via the posterior sternum
	Control	396.7 ± 96.3	354.4 ± 134.5
Nishiyama et al[27]	SSH	450.2 ± 64.1	813.6 ± 548.4	Thoracolaparotomic total thoracic esophagectomy, chest wall-antral stomach reconstruction, and 3-regional lymph node dissection
	Control	445.8 ± 87.9	735.2 ± 479.0
Nagai et al[26]	SSH	576.4 ± 126.7	630.1 ± 392.0	Subtotal esophagectomy and reconstruction through a right posterolateral thoracotomy and upper midline laparotomy
	Control	537.3 ± 120.2	494.2 ± 312.7

SSH: Sivelestat sodium hydrate.

Table 3 Quality assessment of the included trials

Ref.	Type	Randomization	Blinding	Allocation concealment	Eligibility criteria	Baseline comparability	> 85% participants followed up	ITT analysis	Selective reporting	Incomplete outcome	Other bias
Sato et al[19]	RCT	M	U	U	Y	Y	Y	Y	U	N	U
Akamoto et al[20]	RCT	Y	Y, single blinding	U	Y	Y	Y	Y	U	N	U
Kawahara et al[22]	RCT	M	M, double blinding	U	Y	Y	Y	Y	U	N	U
Makino et al[24]	RCT	Y	Y, triple blinding	Y	Y	Y	Y	Y	U	N	U
Yamaguchi et al[29]	RCT	M	U	U	Y	Y	Y	Y	U	U	U
Iwahashi et al[21]	non-RCT	N	U	U	Y	Y	Y	N	U	N	U
Yamaki et al[30]	non-RCT	N	N	N	M	Y	Y	U	U	N	U
Ono et al[28]	non-RCT	N	N	N	Y	Y	Y	Y	U	N	U
Suda et al[14]	non-RCT	N	N	N	Y	Y	Y	Y	U	N	U
Kobayashi et al[23]	non-RCT	N	N	N	Y	Y	Y	Y	N	N	U
Mimatsu et al[25]	non-RCT	N	N	N	Y	Y	Y	Y	N	N	U
Nishiyama et al[27]	non-RCT	N	N	N	Y	Y	Y	Y	N	N	U
Nagai et al[26]	non-RCT	N	N	N	M	Y	Y	Y	U	N	U

M: Mentioned (the study just mentioned the item but without detailed description); Y: Yes (the study mentioned and detailed the item); N: No (the study did not report the item); U: Unclear.

Table 4 Summary of qualitative pooled data

Study	Kawah et al1		Makino et al2		Suda et al3
	SSHvscontrol	P value	SSHvscontrol	P value	SSHvscontrol	P value
Mechanical ventilation	24.5 (24.3-28.7) vs 24.5 (23.9-49.1)	0.796	89.5 (57.3, 121.7) vs 204 (77.4, 330.6)	0.046	1 (1-1.5) vs 1.5 (1-2)	0.008
ICU stay	64.0 (39-109) vs 74.5 (39.0-109)	0.481	5.7 (4.1, 7.4) vs 8.8 (5.5, 12.1)	0.048	1.5 (1.5-1.9) vs 2.5 (1.5-3.5)	0.018
SIRS	17 (9-36) vs 49 (15-60)	0.009	2.8 (2.1, 3.6) vs 5.6 (4.2,7.0	0.001	3.5 (2-5.8) vs 5 (3.8-10.8)	0.026
Postoperative hospital stay	32 (19-46) vs 31 (18-81)	0.853	31.4 (23.8, 38.9) vs 37.1 (31.1, 43.1)	0.077

¹Data is shown as the mean (range); ²Data is shown as the mean (95%CI); ³Data is shown as the median (inter-quartile range). SSH: Sivelestat sodium hydrate.