盐酸戊乙奎醚作为术前用药不增加术后认知功能障碍及术后谵妄发生率：一项系统综述和meta分析

doi:10.24920/003630

Abstract

Objective Post-operative cognitive dysfunction (POCD) and post-operative delirium (POD) are two common post-operative cerebral complications. The current meta-analysis was to systematically review the effects of penehyclidine hydrochloride (PHC) on POCD and POD in surgical patients.Methods Electronic databases were searched to identify all randomized controlled trials comparing PHC with atropine/scopolamine/placebo on POCD and POD in surgical patients. Primary outcomes of interest included the incidences of POCD and POD; the secondary outcomes of interest included peri-operative mini-mental state examination (MMSE) scores. Two authors independently extracted peri-operative data, including patients’ baseline characteristics, surgical variables, and outcome data. For dichotomous data (POCD and POD occurrence), treatment effects were calculated as odds ratio (OR) and 95% confidential interval (CI). Each outcome was tested for heterogeneity, and randomized-effects or fixed-effects model was used in the presence or absence of significant heterogeneity. For continuous variables (MMSE scores), treatment effects were calculated as weighted mean difference (WMD) and 95% CI. Statistical significance was defined as P<0.05.Results Our search yielded 33 studies including 4017 patients. Meta-analysis showed that, the incidence of POCD in PHC group was comparable to that in saline group (OR=0.97; 95% CI: 0.58-1.64; P=0.92), scopolamine group (OR=0.78; 95% CI: 0.48-1.27; P=0.32) and atropine group (OR=1.20; 95% CI: 0.86-1.67; P=0.29). The incidence of POD in PHC group was comparable to that in saline group (OR=1.53; 95% CI: 0.81-2.90; P=0.19) and scopolamine group (OR=0.53; 95% CI: 0.06-4.56; P=0.56), but higher than that in atropine group (OR=4.49; 95% CI: 1.34-15.01; P=0.01).Conclusions PHC premedication was not associated with increased incidences of POCD or POD as compared to either scopolamine or placebo.

Key words: penehyclidine hydrochloride, post-operative cognitive dysfunction, post-operative delirium, meta-analysis

Yao Yuntai,Ying Hua,Fang Nengxin,Zhang Yongbao,Yuan Xin. Penehyclidine Hydrochloride Premedication Is Not Associated with Increased Incidence of Post-Operative Cognitive Dysfunction or Delirium:A Systemic Review and Meta-Analysis[J].Chinese Medical Sciences Journal, 2020, 35(2): 121-134.

Figures/Tables 10

Figure 1.

Table 1

Patients and surgery data of the included studies (n=33)"

Study	Surgery	Patient characteristics			Comparator drug(s)	Jadad assessment
Study	Surgery	Age (years)	Education	ASA	Comparator drug(s)	Randomization	Blindness	Withdrawals
Bi el al., 2012^[34]	Ortho, Uro	75-89	>High school	Ⅱ-Ⅲ	Scopolamine	1	0	1
Chen el al., 2011^[19]	Ex, Ab	>65	6-9 years	Ⅰ-Ⅲ	Saline	1	0	1
Guo el al., 2010^[20]	Ex, Ab	20-59	6-9 years	Ⅰ-Ⅱ	Atropine	1	0	1
Guo el al., 2014^[50]	Ab	61-73	NR	NR	Penehyclidine	1	0	1
Hu el al., 2015^[48]	Thorax	61-80	NR	Ⅱ-Ⅲ	Penehyclidine	2	0	1
Kong el al., 2010^[39]	Ab	≥60	>9 years	Ⅰ-Ⅱ	Atropine/Scopolamine/Saline	1	0	1
Li el al., 2008^[24]	NCS	>60	NR	Ⅰ-Ⅱ	Atropine	1	0	1
Li el al., 2009^[31]	LC	65-75	Illiteracy	Ⅰ-Ⅲ	Saline	1	1	1
Li el al., 2010^[22]	NCS	>60	NR	Ⅰ-Ⅳ	Atropine	1	0	1
Li el al., 2012^[21]	LC	60-80	NR	Ⅰ-Ⅲ	Penehyclidine	1	0	1
Liao el al., 2017^[44]	Ortho	≥60	NR	Ⅰ-Ⅱ	Atropine/Saline	1	0	1
Liu el al., 2009^[29]	NCS	>65	NR	Ⅰ-Ⅱ	Atropine	1	0	1
Liu el al., 2013^[26]	NCS	60-85	NR	Ⅰ-Ⅲ	Atropine	1	0	1
Liu el al., 2014^[46]	NR	52-79	NR	NR	Penehyclidine	1	0	1
Liu el al., 2015^[25]	Thyroid	18-85	NR	Ⅰ-Ⅱ	Atropine/Saline	1	0	1
Liu el al., 2016^[49]	NCS	34-67	NR	Ⅱ-Ⅲ	Penehyclidine	2	0	1
Lv el al., 2009^[35]	Maxillo-facial	61-79	Mixed	Ⅰ-Ⅲ	Atropine	1	1	1
Shu el al., 2009^[27]	NCS	65-78	NR	Ⅱ-Ⅲ	Atropine/Scopolamine	1	0	1
Shu el al., 2013^[47]	NCS	65-78	NR	Ⅱ-Ⅲ	Penehyclidine	1	0	1
Tang el al., 2010^[38]	CS	15-55	NR	Ⅱ-Ⅲ	Saline	1	0	1
Wang el al., 2013^[33]	Mixed	35-60	NR	Ⅱ-Ⅲ	Scopolamine	1	1	1
Wang el al., 2017^[32]	Thorax	43-65	NR	Ⅰ-Ⅱ	Saline/Ulinastatin	1	0	1
Wu el al., 2010^[18]	Ab	65-75	>9 years	Ⅱ-Ⅲ	Saline	1	0	1
Wu el al., 2014^[40]	Ab	60-83	NR	Ⅰ-Ⅲ	Scopolamine	1	0	1
Xia el al., 2017^[36]	NCS	60-78	NR	Ⅰ-Ⅲ	Atropine	2	0	1
Xiang el al., 2011^[42]	Thorax, Ab	60-80	NR	NR	Atropine	1	0	1
Xu el al., 2008^[28]	Ab	>65	>9 years	Ⅰ-Ⅲ	Saline	1	0	1
Yang el al., 2011^[43]	LC	64-70	NR	NR	Atropine	1	0	1
Ye el al., 2011^[41]	Ex	65-90	NR	Ⅰ-Ⅲ	Atropine/Saline	1	0	1
Ye el al., 2015^[45]	LC	65-80	>5 years	Ⅰ-Ⅱ	Saline	2	0	1
Yu el al., 2011^[23]	Vocal cord	31-70	NR	Ⅰ-Ⅱ	Atropine/Scopolamine	1	0	1
Zhang el al., 2012^[30]	NCS	>65	>9 years	Ⅰ-Ⅲ	Saline	1	0	1
Zou el al., 2017^[37]	NCS	65-76	NR	Ⅰ-Ⅲ	Atropine	2	0	1

Table 1

Table 2

PHC administration scheme and reported outcomes of the included trials (n=33)"

Studies	Sample size	Groups (n)	PHC group				Control group			Outcomes reported
Studies	Sample size	Groups (n)	n	Dose	Route	Timing	n	Comparator	Dose	POCD	POD	MMSE
Bi et al., 2012^[34]	90	3	30	0.002 mg/kg	iv	After iv access	30	Scopolamine	0.002 mg/kg	√	-	√
Bi et al., 2012^[34]	90	3	30	0.01 mg/kg	iv	After iv access	30	Scopolamine	0.002 mg/kg	√	-	√
Chen et al., 2011^[19]	124	3	42	0.5 mg	iv	10’ BA	42	Saline	Same volume	√	-	√
Chen et al., 2011^[19]	124	3	40	1.0 mg	iv	10’ BA	42	Saline	Same volume	√	-	√
Guo et al., 2010^[20]	300	6	50	0.008 mg/kg	im	10’ BA	50	Atropine	0.08 mg/kg	√	-	√
			50	0.01 mg/kg
			50	0.012 mg/kg
			50	0.014 mg/kg
			50	0.016 mg/kg
Kong et al., 2010^[39]	320	4	78	1.0 mg	im	30’ BA	80	Saline	Same volume	√	-	√
							80	Scopolamine	0.3 mg
							82	Atropine	0.5 mg
Li et al., 2008^[24]	80	2	40	0.01 mg/kg	iv	30’ BA	40	Atropine	0.01 mg/kg	-	√	-
Li et al., 2009^[31]	120	3	40	0.5 mg	iv	10’ BA	40	Saline	Same volume	-	√	√
Li et al., 2009^[31]	120	3	40	1.0 mg	iv	10’ BA	40	Saline	Same volume	-	√	√
Li et al., 2010^[22]	289	3	98	0.01 mg/kg	im	30’ pre-op	96	Atropine	0.01 mg/kg	-	√	-
Li et al., 2010^[22]	289	3	95	0.02 mg/kg	im	30’ pre-op	96	Atropine	0.01 mg/kg	-	√	-
Liao et al., 2017^[44]	144	3	48	1.0 mg	im	30’ pre-op	48	Blank	-	√	√	-
Liao et al., 2017^[44]	144	3	48	1.0 mg	im	30’ pre-op	48	Atropine	0.5 mg	√	√	-
Liu et al., 2009^[29]	60	2	30	0.5 mg	im	30’ pre-op	30	Atropine	0.5 mg	√	-	√
Liu et al., 2013^[26]	60	2	30	0.5 mg	iv	10’ BA	30	Atropine	0.5 mg	√	-	√
Liu et al., 2015^[25]	116	4	29	0.01 mg/kg	iv	30’ BA	29	Saline	Same volume	-	-	√
Liu et al., 2015^[25]	116	4	29	0.02 mg/kg	iv	30’ BA	29	Atropine	0.06 mg/kg	-	-	√
Lv et al., 2009^[35]	120	2	60	0.01 mg/kg	iv	30’ pre-op	60	Atropine	0.01 mg/kg	√	-	√
Shu et al., 2009^[27]	120	3	40	0.5 mg	im	30’ BA	40	Scopolamine	0.3 mg	√	-	√
Shu et al., 2009^[27]	120	3	40	0.5 mg	im	30’ BA	40	Atropine	0.5 mg	√	-	√
Tang et al., 2010^[38]	40	2	20	0.015 mg/kg	im	30’ BA	20	Saline	Same volume	√	-	√
Wang et al., 2013^[33]	60	2	30	1.0 mg	im	Pre-op	30	Scopolamine	0.3 mg	-	√	-
Wang et al., 2017^[32]	60	2	30	0.02 mg/kg	iv	15’ BA	30	Saline	Same volume	-	-	√
Wu et al., 2010^[18]	71	2	40	0.5 mg	iv	10’ BA	31	Saline	Same volume	√	√	√
Wu et al., 2014^[40]	120	4	30	0.005 mg/kg	im	40’ BA	30	Scopolamine	0.006 mg/kg	√	√	-
			30	0.01 mg/kg
			30	0.02 mg/kg
Xia et al., 2017^[36]	90	2	45	0.5 mg	iv	10’ BA	45	Atropine	0.5 mg	√	-	√
Xiang et al., 2011^[42]	80	2	40	1.0 mg	im	30’ pre-op	40	Atropine	0.5 mg	-	-	√
Xu et al., 2008^[28]	80	2	42	0.5 mg	iv	10’ BA	38	Saline	Same volume	√	√	√
Yang et al., 2011^[43]	64	2	32	0.01-0.02 mg/kg	im	40’ BA	32	Atropine	0.008-0.01 mg/kg	-	-	√
Ye et al., 2011^[41]	180	3	60	1.0 mg	im	30’ BA	60	Saline	Same volume	√	-	√
Ye et al., 2011^[41]	180	3	60	1.0 mg	im	30’ BA	60	Atropine	0.5 mg	√	-	√
Ye et al., 2015^[45]	60	3	20	0.01 mg/kg	iv	30’ BA	20	Saline	Same volume	√	-	√
Ye et al., 2015^[45]	60	3	20	0.02 mg/kg	iv	30’ BA	20	Saline	Same volume	√	-	√
Ye et al., 2015^[45]	241	4	80	0.5 mg	iv	40’ BA	50	Scopolamine	0.3 mg	-	√	-
Ye et al., 2015^[45]	241	4	61	1.0 mg	iv	40’ BA	50	Atropine	0.5 mg	-	√	-
Zhang et al., 2012^[30]	60	2	30	0.02 mg/kg	iv	10’ BA	30	Saline	Same volume	√	√	-
Zou et al., 2017^[37]	120	2	60	0.5 mg	iv	10’ BA	60	Atropine	0.5 mg	-	-	√
Guo et al., 2014^[50]	60	3	20	0.004 mg/kg	im	30’ BA	-			√	-	√
			20	0.008 mg/kg
			20	0.012 mg/kg
Hu et al., 2015^[48]	146	2	73	0.005 mg/kg	iv	30’ BA	-			√	-	√
Hu et al., 2015^[48]	146	2	73	0.015 mg/kg	iv	30’ BA	-			√	-	√
Li et al., 2012^[21]	120	4	30	0.25 mg	iv	5’ BA	-			√	√	√
			30	0.50 mg
			30	0.75 mg
			30	1.00 mg
Liu et al., 2014^[46]	200	5	40	0.008 mg/kg	iv	30’ BA	-			√	√	-
			40	0.011 mg/kg
			40	0.014 mg/kg
			40	0.017 mg/kg
			40	0.020 mg/kg
Liu et al., 2016^[49]	102	3	34	0.50 mg	in	20’ BA	-			-	-	√
			34	1.00 mg
			34	1.50 mg
Shu et al., 2013^[47]	120	3	40	0.005 mg/kg	iv	30’ BA	-			√	-	√
			40	0.010 mg/kg
			40	0.015 mg/kg

Table 2

Figure 2.

Figure 3.

Table 3

Table 4

Table 5

Table 6

Figure 4.

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Incidence of the outcomes (%)	Trials (n)	Group PHC (n)	Group Control (n)	Heterogeneity		Analysis model	OR	95% CI	Overall effect P
Incidence of the outcomes (%)	Trials (n)	Group PHC (n)	Group Control (n)	I² (%)	P	Analysis model	OR	95% CI	Overall effect P
POCD
Penehyclidine vs. Saline	8	385	339	50	0.05	M-H, random	0.97	0.58,1.64	0.92
Penehyclidine vs. Scopolamine	4	270	180	22	0.28	M-H, fixed	0.78	0.48,1.27	0.32
Penehyclidine vs. Atropine	8	389	392	48	0.06	M-H, fixed	1.20	0.86,1.67	0.29
POD
Penehyclidine vs. Saline	3	162	109	0	0.62	M-H, fixed	1.53	0.81,2.90	0.19
Penehyclidine vs. Scopolamine	2	171	80	82	0.02	M-H, random	0.53	0.06,4.56	0.56
Penehyclidine vs. Atropine	3	374	186	0	0.90	M-H, fixed	4.49	1.34,15.01	0.01

Outcomes	Trials (n)	Group PHC (n)	Group Control (n)	Heterogeneity		Analysis model	WMD	95% CI	Overall effect P
Outcomes	Trials (n)	Group PHC (n)	Group Control (n)	I² (%)	P	Analysis model	WMD	95% CI	Overall effect P
Penehyclidine vs. Saline
Pre-op	9	493	390	0	0.97	IV, fixed	0.10	-0.11,0.31	0.34
POD1	5	214	197	95	<0.00001	IV, random	-0.22	-1.82,1.38	0.79
POD2	4	187	151	95	<0.00001	IV, random	0.14	-1.62,1.90	0.88
POD3	5	178	139	89	<0.00001	IV, random	-0.68	-1.87,0.51	0.26
POD5	1	60	60	NA	NA	IV, random	-2.30	-2.87,-1.73	<0.00001
POD7	2	118	111	0	0.55	IV, fixed	0.07	-0.37,0.52	0.75
Penehyclidine vs. Scopolamine
Pre-op	3	208	148	57	0.05	IV, random	0.11	-0.17,0.39	0.44
POD1	3	208	148	97	<0.00001	IV, random	0.88	-0.36,2.13	0.17
POD2	3	208	148	95	<0.00001	IV, random	0.87	-0.04,1.78	0.06
POD3	2	130	70	71	0.02	IV, random	-0.12	-0.51,0.27	0.54
POD5	0	NA	NA	NA	NA	NA	NA	NA	NA
POD7	1	78	78	NA	NA	IV, random	0.20	-0.30,0.70	0.44
Penehyclidine vs. Atropine
Pre-op	12	771	546	40	0.04	IV, fixed	-0.02	-0.18,0.13	0.78
POD1	8	399	374	81	<0.00001	IV, random	-0.38	-1.09,0.32	0.29
POD2	3	178	182	4	0.35	IV, fixed	-0.16	-0.55,0.22	0.41
POD3	4	193	193	81	0.001	IV, random	-0.23	-1.20,0.74	0.64
POD5	2	310	110	79	0.0002	IV, random	0.95	-1.09,3.00	0.36
POD7	5	210	214	96	<0.00001	IV, Random	-0.74	-2.57,1.08	0.42

Outcomes	Trials (n)	Dosage 1 Events/Patients	Dosage 2 Events/Patients	Heterogeneity		Analysis model	OR	95% CI	Overall effect P
Outcomes	Trials (n)	Dosage 1 Events/Patients	Dosage 2 Events/Patients	I² (%)	P	Analysis model	OR	95% CI	Overall effect P
		1.0 mg	0.5 mg
POCD	2	22/69	6/70	56	0.13	M-H, random	6.00	0.67,53.51	0.11
POD	3	28/131	15/150	0	0.78	M-H, fixed	2.36	1.19,4.69	0.01
POCD+POD	4	50/200	21/220	0	0.52	M-H, fixed	3.05	1.75,5.29	<0.0001
		0.01 mg/kg	0.02 mg/kg
POCD	3	9/90	29/90	0	0.82	M-H, fixed	0.23	0.10,0.53	0.0005
POD	2	5/138	21/135	0	0.96	M-H, fixed	0.20	0.07,0.56	0.002
POCD+POD	4	14/228	50/225	0	0.98	M-H, fixed	0.22	0.12,0.41	<0.00001
		0.01 mg/kg	0.015 mg/kg
POCD	2	13/80	18/80	0	0.56	M-H, fixed	0.66	0.29,1.48	0.31
POD	1	2/40	2/40	NA	NA	NA	1.00	0.13,7.47	1.00
POCD+PD	2	15/120	20/120	0	0.79	M-H, fixed	0.70	0.33,1.47	0.34
		0.01 mg/kg	0.008 mg/kg
POCD	2	10/60	4/60	0	0.98	M-H, fixed	3.09	0.86,11.08	0.08
POD	1	2/40	2/40	NA	NA	NA	5.26	0.24,113.11	0.29
POCD+POD	2	4/100	12/100	0	0.95	M-H, fixed	3.39	1.05,10.98	0.04
		0.01 mg/kg	0.005 mg/kg
POCD	3	22/90	13/90	31	0.23	M-H, fixed	1.95	0.90,4.22	0.09
POD	0	0	0	NA	NA	NA	NA	NA	NA
POCD+POD	3	22/90	13/90	31	0.23	M-H, fixed	1.95	0.90,4.22	0.09

Statistical model	OR (95% CI) of POCD			OR (95% CI) of POD
Statistical model	PHC vs. SAL	PHC vs. SCO	PHC vs. ATR	PHC vs. SAL	PHC vs. SCO	PHC vs. ATR
Fixed effects	0.98 (0.69,1.38)	0.78 (0.48,1.27)	1.20 (0.86,1.67)	1.56 (0.83,2.93)	0.53 (0.24,1.16)	4.51 (1.35,15.08)
Random effects	0.97 (0.58,1.64)	0.73(0.40,1.32)	1.13 (0.70,1.83)	1.53 (0.81,2.90)	0.53 (0.06,4.56)	4.49 (1.34,15.01)

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Penehyclidine Hydrochloride Premedication Is Not Associated with Increased Incidence of Post-Operative Cognitive Dysfunction or Delirium:A Systemic Review and Meta-Analysis

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