Efficacy and Safety of Ketamine Compared with Placebo and Other Medications for Preventing Propofol Injection Pain in Adults: A Systematic Review and Meta-Analysis

Figures & data

Figure 1 The flow diagram of the selection process.

Table 1 Characteristics of Included RCTs

Study Year	Country	Grouping and Intervention	N	Age in Years (mean ± SD)	F/M	Pre-Sedation	Venous Occlusion	Propofol Type	Manner	Interval Time	Injection Site	Pain Scale
Ayatollahi^Citation25 2012	Iran	0.1 mg/kg ketamine	35	28.22 ± 7.32	57/83	NR	No	NR	SI	30 s	NR	VRS
		0.1 mg/kg ephedrine	35
		40 mg lidocaine	35
		2 mL saline	35
Tan^Citation33 1998	China	10 mg ketamine	50	41 ± 7.7	100/0	No	No	1%	SI	30 s	DVH	3PS
		1mL saline	50	40 ± 9.1
Jayaprakash^Citation29 2020	India	0.1 mg/kg ketamine	32	41.14	108/52	Yes	No	1%	SI	0 s	DVH	VRS
		0.3 mg/kg ketamine	32
		0.5 mg/kg ketamine	32
		1.5 mg/kg lignocaine	32
		3 mL saline	32
Iwata^Citation28 2010	Japan	0.5 mg/kg ketamine	15	69 ± 5	7/8	No	No	1%	SI	30 s	DVH	VRS
		1.0 mg/kg ketamine	15	68 ± 10	7/8
		0.1 mL/kg saline	15	66 ± 10	5/10
Batra^Citation26 2005	Kuwait	10 mg ketamine	50	NR	NR	Yes	Yes	NR	SI	60 s	DVH	VRS
		20 mg lignocaine	50
		2 mL saline	50
Saadawy^Citation32 2007	Egypt	0.4 mg/kg ketamine	25	39.9 ± 13.6	11/14	No	Yes	1%	SI	60 s	DVH	VRS
		0.5 mg/kg thiopental	25	40.1 ± 14.1	12/13
		0.5 mg/kg meperidine	25	47.7 ± 20.1	12/13
		1.0 mg/kg lignocaine	25	46.2 ± 26.7	11/14
		3 mL saline	25	39.9 ± 13.6	13/12
Zahedi^Citation36 2009	Iran	0.05 mg/kg ketamine	100	29.4 ± 7.8	52/48	No	No	1%	SI	0 s	DVHW	VRS
		0.075 mg/kg ketamine	100	29.7 ± 8.8	44/56
		0.1 mg/kg ketamine	100	30.7 ± 6.6	51/49
		1.0 mg/kg lidocaine	100	29.7 ± 6.8	49/51
		5 mL saline	100	28.9 ± 7.4	45/55
Koo^Citation30 2006	Korea	0.01 mg/kg ketamine	30	40.3 ± 11.3	17/13	No	No	1%	SI	0 s	DVHW	VRS
		0.05 mg/kg ketamine	30	45.0 ± 10.5	20/10
		0.10 mg/kg ketamine	30	39.5 ± 11.7	18/12
		40 mg lidocaine	30	41.3 ± 9.9	25/5
		2 mL saline	30	40.8 ± 11.2	19/11
		0.10 mg/kg ketamine	30	43.4 ± 11.8	17/13				MI	—
		0.10 mg/kg ketamine	30	37.3 ± 11.8	12/18				SI	3 min
		0.10 mg/kg ketamine	30	40.4 ± 11.4	8/22	Yes			SI	0 s
Akbari^Citation24 2018	Iran	0.5 mg/kg ketamine	25	31.32 ± 13.41	14/11	NR	No	2%	SI	60 s	DVH	VRS
		30 mg/kg MgSO4	25	34.00 ± 10.74	12/13
		0.5 mg/kg thiopental	25	35.80 ± 12.91	11/14
Wani^Citation35 2018	India	0.25 mg/kg ketamine	50	39.16 ± 10.20	31/19	No	No	NR	SI	0 s	DVH	VRS
		0.5 µg/kg DEXM	50	37.82 ± 11.42	23/27
Thukral^Citation34 2015	India	0.5 mg/kg ketamine	54	31.96 ± 8.71	40/14	No	No	1%	SI	0 s	DVH	VRS
		0.5 µg/kg DEXM	54	34.04 ± 8.30	45/9
Naz^Citation31 2020	Pakistan	0.5 mg/kg ketamine	87	34.56 ± 9.81	38/49	NR	Yes	NR	SI	0 s	DVH	VAS
		0.5 mg/kg lignocaine	87	32.36 ± 8.63	39/48
Hwang^Citation27 2009	Korea	10 mg ketamine	94	49 ± 15	50/44	NR	Yes	1%	SI	30 S	DVH	VRS
		10 mg ketamine	94	45 ± 16	47/47				MI	—

Abbreviations: N, number of samples; SD, standard deviation; F/M, female/male; NR, not reported; SI, separate injection; MI, mixed injection; VRS, Verbal Rating Scale; 3PS, 3-point scale; VAS, Visual Analogue Scale; DVH, dorsal vein of hand; DVHW, dorsal vein of hand or wrist; MgSO₄, magnesium sulfate; DEXM, dexmedetomidine.

Figure 2 The risk of bias of the included studies; (a) risk of bias for each study; (b) risk of bias summary.

Figure 3 The incidence of propofol injection pain in the ketamine group compared with the saline group.

Figure 4 The incidence of propofol injection pain in the ketamine group compared with the lidocaine group.

Figure 5 The incidence of propofol injection pain in the ketamine group compared with the dexmedetomidine group.

Figure 6 The incidence of propofol injection pain in the ketamine group compared with the thiopental group.

Figure 7 The incidence of propofol injection pain in the separate injection group compared with the mixed injection group.

Figure 8 The incidence of severe propofol injection pain in the ketamine group compared with the saline group.

Figure 9 The incidence of severe propofol injection pain in the ketamine group compared with the lidocaine group.

Figure 10 The incidence of severe propofol injection pain in the ketamine group compared with the dexmedetomidine group.

Figure 11 The incidence of severe propofol injection pain in the ketamine group compared with the thiopental group.

Figure 12 The incidence of severe propofol injection pain in the separate injection group compared with the mixed injection group.

Figure 13 Sensitivity analysis for meta-analysis comparing the incidence of PIP in the ketamine group and the saline group.

Figure 14 Sensitivity analysis for meta-analysis comparing the incidence of PIP in the ketamine group and the lidocaine group.

Table 2 Results of Egger Tests and Trim-and-Fill Procedure

Meta-Analysis	Egger Test	Trim-and-Fill Procedure
		Observed (RR, 95% CI)	Observed + imputed (RR, 95% CI)
1.1	P < 0.0001	0.43, [0.34, 0.55]	0.55, [0.43, 0.69]
2.1	P = 0.0145	0.12, [0.08, 0.19]	0.26, [0.16, 0.41]

Abbreviations: RR, risk ratio; CI, confidence interval; 1.1, the incidence of propofol injection pain of the ketamine group compared with the saline group; 2.1, the incidence of severe propofol injection pain of the ketamine group compared with the saline group.

Figure 15 The funnel plot for the meta-analysis 1.1 processed by the trim-and-fill method.

Figure 16 The funnel plot for the meta-analysis 2.1 processed by the trim-and-fill method.

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