The organ protective effects of penehyclidine hydrochloride (PHC) in patients undergoing cardiac surgery: a systematic review and meta-analysis

Abstract

Background

As a novel selective anticholinergic drug, penehyclidine hydrochloride (PHC) provided the potential to protect organs by inhibiting the inflammatory response, attenuating oxidative stress, and alleviating ischemia / reperfusion injury. This study aimed to evaluate the organ protective effects of PHC in patients undergoing cardiac surgery.

Methods

Six electronic databases were searched systematically for randomized-controlled trials (RCTs) published April 30th 2025 that explored the application of PHC on cardiac surgical patients. Primary outcomes of interest included the biomarkers and variables of major organs (e.g. heart, lung, gastrointestinal tract and immune system) injury. Secondary outcomes of interest included the mechanical ventilation duration and hospital length of stay (LOS). Mean difference (MD) with 95% confidence interval (CI) or odds ratios (OR) with 95% CI were employed to analyze the data.

Results

A total of 37 RCTs with 1929 cardiac surgical patients (PHC group, 1043 patients; Control group, 886 patients) were included. The current study demonstrated that the adult patients in PHC group had lower cardiac troponin I (cTnI) [MD: -1.70, 95%CI: -2.63 to -0.77, P = 0.0003, with heterogeneity (P < 0.00001)] and creatine kinase (CK)-MB levels on post-operative day (POD)-1 after cardiac surgery, while the pediatric patients had lower cardiac troponin T (cTnT) (MD: -0.10, 95%CI: -0.12 to -0.09, P < 0.00001, without heterogeneity) in PHC group on POD-1. The levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α were significantly lower in both adult and pediatric patients of PHC group on POD-1. The incidence of postoperative pulmonary infection was significantly reduced in the PHC group, and the duration of mechanical ventilation and hospital LOS were shortened in adult patients.

Conclusions

This meta-analysis demonstrated that PHC could provide myocardial protection and suppress the inflammatory response in patients undergoing cardiac surgery, thereby potentially facilitating rapid recovery.

Clinical trial number

PROSPERO registration number CRD42020183260.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12871-025-03396-1.

Introduction

Approximately 40% of patients undergoing cardiac surgery experience organ damage that affects vital organs such as the heart, lungs, brain, or kidneys, which can significantly increase the risk of mortality [1–4]. Surgical trauma and cardiopulmonary bypass during cardiac surgery initiates significant systemic inflammatory response due to tissue damage, hemodynamic disorders, coagulation dysfunction, and so on [5]. It is characterized by massive proinflammatory cytokines release, and subsequent vital organ dysfunction, such as myocardial dysfunction, respiratory failure, acute kidney injury, neurocognitive disorders, coagulopathy, hepatic dysfunction, even multiple organ failure [6]. Acute and persistent organ dysfunction commonly followed cardiovascular surgery, impairing patient prognosis and substantially increasing healthcare-related economic burden.

Anticholinergic drugs (e.g., scopolamine, atropine) have been used as preoperative medications due to antisialogogue, vagolytic, antiemetic, sedative and amnesic effects [7, 8]. In contrast to scopolamine and atropine, penehyclidine hydrochloride (PHC) selectively blocks M1, and M3 receptors distributed in the airway smooth muscle, submucosal glands and alveolar walls, and has no M2 receptor-associated cardiovascular side effects [9]. In recent years, with the exploration of organ-protective effects in ischemia/reperfusion injury, PHC has attracted much attention. Accumulative experimental evidences have demonstrated that, PHC could also provide vital organ protection [10–12]. Most of them have reported that administration of PHC could inhibit inflammation and provide myocardial and pulmonary protection [12, 13]. It has been shown that both pre- and post-conditioning with PHC attenuated myocardial injury by decreasing the release of inflammatory cytokines and mediators, lowering nuclear factor-κB (NF-κB) signaling and reducing Ca²⁺ overload [11]. Shen and his colleagues have reported that PHC pre-conditioning significantly alleviated lipopolysaccharide-induced inflammatory cell infiltration and alveolar hemorrhage in rat lung pathological changes [14].

Currently, only few relevant meta-analyses have been published showing that PHC has multiple organ protection in the perioperative treatment. Therefore, this study was designed to systemically evaluate the organ protective effects of PHC in cardiac surgical patients.

Methods

Ethics

The ethics approval was not required for meta-analysis.

Search strategy

This systematic review followed the methodology outlined in the Preferred Instrument for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [15]. The protocol of current meta-analysis has been registered on the International Prospective Systematic Reviews Registry database (CRD42020183260). Relevant randomized controlled trials (RCTs) were identified by computerized searches of PubMed, Ovid, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), China National Knowledge Infrastructure (CNKI) database, and Wanfang Data till April 30th 2025, using different combination of search words as follows: (penehyclidine) AND (cardiopulmonary bypass OR heart OR cardiac surgery OR coronary artery bypass surgery OR valve surgery OR congenital heart surgery) AND (randomized controlled trial OR controlled clinical trial OR randomly OR clinical trial) (in Supplemental Table 1). No language restriction was used. To ensure the comprehensiveness of the literature review, two authors (LJT and YTY) conducted a non-blind standardized method to independently evaluate all retrieved records by examining the titles, abstracts, and keywords.

Inclusion and exclusion criteria

The inclusion criteria were as follows: (1) the target population comprised patients undergoing cardiovascular surgery; (2) intravenous PHC administration versus Control (saline); (3) RCTs; (4) at least one of the predetermined outcomes listed in the following reported. Primary outcomes of interest included the biomarkers and variables of major organs (e.g. heart, lung, gastrointestinal tract and immune system) injury. Secondary outcomes of interest included the mechanical ventilation duration, intensive care unit (ICU) stay and hospital length of stay (LOS). The following exclusion criteria were applied: (1) studies published in the form of review articles, case reports, or abstracts; (2) retrospective or observational studies; (3) animal studies; (4) studies lacking information about outcomes of interest; (5) Duplicate publications.

Study quality assessment

The risk of bias in the studies which were included was assessed independently via the revised Cochrane risk-of-bias tool (RoB 2.0) [16] by two investigators (LJT and YTY). Using RoB 2.0, two investigators independently assessed each study for bias arising from (1) the randomization process, (2) deviations from the intended intervention, (3) missing outcome data, (4) outcome measurement, and (5) selective reporting of results. LJT and JFG independently assessed the methodological quality of each included trial using the modified Jadad score (ranging from 0 to 5) [17]. This scale evaluated the generation of random sequences, randomized concealment, blinding, and reporting of withdrawals. Each item was evaluated based on associated criteria and scores, with ≤ 3 points indicating low-quality research and 4–7 points indicating high-quality research.

Data abstraction

Data were extracted independently by investigators LJT and YTY, and compared to ensure accuracy. Data consisted of research title, first author, year of publication, journal, country, number of patients, gender, age, type of surgical procedure and data regarding outcomes of interest. Disagreements were resolved by discussion among all authors at the end of assessment.

Statistical analysis

All data were analyzed by utilizing RevMan 5.4 (Cochrane Collaboration, Oxford, UK). Pooled odds ratio (OR) and 95% confidence interval (CI) were estimated for dichotomous data, and mean difference (MD) and 95% CI for continuous data, respectively. To account for methodological and clinical heterogeneity, the random-effect model was employed when substantial heterogeneity was detected (I² >50% or P < 0.05). Conversely, the fixed-effect model was utilized for analysis that there was no significant heterogeneity. In accordance with the Cochrane Handbook, I² values ranging from 0% to 25%, 25% to 50%, and 75% to 100% indicated low, medium, and high heterogeneity, respectively. The results showed significant heterogeneity when I² ≥ 50%, in which case a sensitivity analysis and subgroup analyses would be conducted to identify the source of heterogeneity. Subgroup analysis in adult patients was employed to investigate the associations among CPB time (< 120 min vs. ≥ 120 min) [18], surgical technique, and clinical outcomes (myocardial injury and inflammatory biomarkers). Sensitivity analyses were performed to evaluate the influence of individual study on the overall effects. Publication bias was explored through visual inspection of funnel plots of the outcomes. All P-values were two-sided and statistical significance was defined as P < 0.05.

Results

Literature search and study characteristics

As depicted in the flow chart (Fig. 1), database search identified 58 RCTs for complete evaluation. Finally, 37 eligible RCTs were included in the meta-analysis. The baseline characteristics and perioperative data of the patients were presented in Table 1 and Supplemental Table 2. Among the 37 included RCTs, 29 included only adult cardiac surgical patients, the other 8 enrolled only pediatric cardiac surgical patients.

Fig. 1.

Flowchart of the study search and selection process

Table 1.

PHC administration scheme and reported outcomes

Trials	Patients	Surgery	Group PHC				Group Control			Outcomes
			Timing	Dose	Route	n	Comparator	Dose	n	①	②	③	④	⑤	⑥	⑦	⑧
Sun 2013[19]	Adults	VR	10 min pre-CPB	0.05 mg/kg	iv	20	Saline	Same volume	20		√	√	√
Shi 2019[20]	Adults	VR VR	AI	0.05 mg/kg	iv	20	Saline	Same volume	20	√			√	√	√
			AI	0.10 mg/kg	iv	20
Zhou 2010[21]	Adults	VR	CPB	3 mg	CPB prime	12	Saline	Same volume	12			√		√
Wei 2007[22]	Adults	VR	10 min pre-CPB	3 mg	iv	10	Saline	Same volume	10			√			√	√	√
Li 2017[23]	Adults	OPCAB	AI	0.05 mg/kg	iv	20	Saline	Same volume	20	√			√	√	√
Shu 2012(1)[24]	Adults	VR	AI and CPB	0.01 mg/kg 0.015 mg/kg	iv CPB prime	92	Saline	Same volume	92			√			√	√	√
Duan 2009[25]	Adults	CABG	10 min pre-CPB	3 mg	iv	20	Saline	Same volume	20			√			√	√	√
Wu 2014[26]	Adults	VR	AI	0.02 mg/kg	iv	42	Saline	Same volume	42				√	√	√		√
Li 2009[27]	Adults	CPB-CS	BA pre-CPB	0.02 mg/kg 0.02 mg/kg	iv iv	12	Saline	Same volume	12			√		√
Shu 2012(2)[28]	Adults	VR	BA and CPB	0.01 mg/kg 0.015 mg/kg	iv CPB prime	20	Saline	Same volume	20			√			√	√	√
Zhang 2015[29]	Adults	VR	During induction and CPB	0.02 mg/kg 0.04 mg/kg	iv CPB prime	50	Saline	Same volume	50			√		√		√	√
Yu 2010[30]	Adults	VR CABG	30 min pre-CPB	0.02 mg/kg	iv	12	Saline	5 ml	12			√		√
Li 2016[31]	Adults	CPB-CS	BA	0.03 mg/kg	iv	20	Saline	Same volume	19					√	√	√
Zhang 2013[32]	Adults	VR	AI	0.02 mg/kg	iv	20	Saline	Same volume	20				√		√
Peng 2012[33]	Adults	VR	10 min pre-CPB	0.06 mg/kg	iv	25	Saline	Same volume	25		√	√
Liu 2010[34]	Adults	VR	CPB	0.03 mg/kg	CPB prime	20	Saline	Same volume	20				√
Sun 2011[35]	Adults	VR	10 min pre-CPB	0.05 mg/kg	iv	20	Saline	Same volume	20		√				√		√
Ai 2009[36]	Adults	VR	AI	0.05 mg/kg	iv	10	Saline	Same volume	10			√
				0.10 mg/kg	iv	10
Sun 2012[37]	Adults	VR	10 min pre-CPB	0.05 mg/kg	iv	20	Saline	Same volume	20			√	√				√
Zheng 2014[38]	Adults	VR	AI	0.05 mg/kg	iv	20	Saline	Same volume	20			√		√
Li 2010[39]	Adults	VR	CPB	0.05 mg/kg	iv	15	Saline	Same volume	15			√		√		√
He 2007[40]	Adults	VR	CPB	2 mg	CPB prime	30	Saline	Same volume	30	√
Gao 2018[41]	Adults	OPCAB	AI	0.01 mg/kg	iv	30	Saline	Same volume	30	√					√	√	√
			AI	0.03 mg/kg	iv	30
			AI	0.05 mg/kg	iv	30
Ai 2010[42]	Adults	VR	10 min pre-CPB	0.04 mg/kg	iv	15	Saline	Same volume	15	√
			10 min pre-CPB	0.08 mg/kg	iv	15
Dai 2012[43]	Adults	VR	10 min pre-CPB	0.04 mg/kg	iv	15	Saline	Same volume	15			√
Wang 2010[44]	Adults	VR and CABG	CPB	0.05 mg/kg	CPB prime	20	Saline	Same volume	20				√	√	√
Hu 2008[45]	Adults	VR	10 min pre-CPB	3 mg	iv	20	Saline	Same volume	20	√
Wei 2018[46]	Adults	AD	BA	0.05 mg/kg	iv	30	Saline	Same volume	30			√		√		√
He 2023[47]	Adults	VR	BA and CPB	0.02 mg/kg of PHC before anesthesia and with a total dose of 0.04 mg/kg during CPB	iv and CPB prime	45	Saline	Same volume	43			√		√	√	√
Zhang 2014[48]	Pediatrics	ASD-R VSD-R	BA	0.02 mg/kg	iv	20	Saline	Same volume	20			√					√
			AI	0.04 mg/kg	iv	20
Lang 2017[49]	Pediatrics	TOF-R	AI	0.04 mg/kg	iv	50	Saline	Same volume	50	√		√
Qin 2013[50]	Pediatrics	ASD-R VSD-R	CPB	0.05 mg/kg	CPB prime	20	Saline	Same volume	20				√	√	√
Fang 2010[51]	Pediatrics	ASD-R VSD-R	AI	0.02 mg/kg	iv	18	Saline	Same volume	12			√		√
			AI	0.04 mg/kg	iv	20
Lu 2011[52]	Pediatrics	ASD-R VSD-R	AI	0.02 mg/kg	iv	15	Saline	Same volume	12			√		√		√
Li 2012[53]	Pediatrics	ASD-R VSD-R	During induction	0.05 mg/kg	iv	10	Saline	Same volume	10	√
Wu 2017[54]	Pediatrics	TOF-R	AI	0.04 mg/kg	iv	50	Saline	Same volume	50	√		√				√	√
Wei 2023[55]	Pediatrics	CPB-CS	CPB	0.02 mg/kg	CPB prime	10	Saline	Same volume	10			√				√	√

Outcomes: ①=Myocardial biomarkers, ②=Gastrointestinal variables, ③=Inflammatory biomarkers/endotoxin/catecholamine, ④=Blood glucose/L-lactate/coagulation variables, ⑤=Respiratory/oxygenation variables, ⑥=Intraoperative surgical variables/fluid balance, ⑦=Postoperative recovery profiles, ⑧ =Postoperative mortality

CPB-CS  Cardiopulmonary bypass-cardiac surgery, AD  Aortic Dissection, VR  Valve replacement, OPCAB  Off-pump coronary artery bypass graft, CABG  Coronary artery bypass grafting, ASD-R  Repair of atrial septal defect, VSD-R  Repair of ventricular septal defect, TOF-R  Radical correction of tetralogy of Fallot, CPB  Cardiopulmonary bypass, BA  Before anesthesia, AI  After induction, PHC  Penehyclidine hydrochloride, iv  Intravenously

As shown in Table 1, the 37 eligible RCTs involved totally 1929 patients, 1043 of whom were allocated into PHC group, and the other 886 into Control group. PHC administration regimens (dosage, timing of administration and route) was not uniform due to differences in the design endpoints of the included trials. The dosages of PHC ranged from 0.01 mg/kg to 0.10 mg/kg, or from 2 mg to 3 mg. PHC was administered before or after anesthesia induction intravenously, or added to the cardiopulmonary bypass (CPB) prime.

Quality assessment

Out of 37 RCTs, 4 (10.8%) had a high risk of bias in the randomization process [25, 35, 43, 45] and 1 (2.3%) had a high risk of bias in measurement of the outcome [27]. Most RCTs were assessed as low risk of bias due to deviations from intended intervention [19, 22, 24–35, 37] and missing outcome data. Overall, a total of 13 trials (35.1%) had an overall low risk of bias [22, 24, 30, 33, 37, 38, 41, 44, 47, 48, 52, 54, 55] 19 trials (51.4%) had some concerns [19, 23, 26, 28, 29, 31, 32, 34, 36, 39, 40, 42, 46, 49–51, 53] and 5 trials (13.5%) had a high risk of bias [25, 27, 35, 43, 45] (Fig. 2). Of the 37 included trials, 16 trials had Jadad scores ≥ 4 and were considered as high-quality RCTs, shown in Supplemental Table 3.

Fig. 2.

Risk of bias traffic light plot for RCT articles

Outcomes

Cardiac function

Due to heterogeneity in outcome definition, measurement, and reporting, we were not able to perform meta-analysis on all endpoints. The summary of all outcomes is shown in Table 1.

As shown in Tables 1 and 2 , 9 RCTs reported perioperative levels of myocardial injury biomarkers [cardiac troponin (cTn), creatine kinase (CK), CK-MB, myoglobin (MYO) and aspartate transaminase(AST)]. As shown in Table 2, meta-analysis demonstrated that, cTnI levels were significantly lower in adult patients of PHC group on post-operative day(POD)−1 [MD: −1.70, 95%CI: −2.63 to −0.77, P = 0.0003, with heterogeneity (I² = 90%, P < 0.00001)], as compared to those of Control group. CK-MB levels were significantly lower in adult patients of PHC group on POD-1 [MD: −11.32, 95%CI: −20.34 to −2.30, P = 0.0003, with heterogeneity (I² = 79%, P = 0.0002)], as compared to those of Control group. Similarly, meta-analysis demonstrated that cTnT levels were significantly lower in pediatric patients of PHC group on POD-1 (MD: −0.10, 95%CI: −0.12 to −0.09, P < 0.00001, without heterogeneity), as compared to those of Control group. One study [41] including 120 patients reported on the occurrence of post-operative myocardial infarction (MI) with an overall incidence was 2.5% (PHC, 2.2%; Saline, 3.3%). There was no significant difference with respect to the incidence of post-operative MI in PHC group relative to Control Group (Fig. 3). One trial reported that there was no difference between the PHC group and the Control group in terms of heart failure [1/92 (1.1%) vs. 4/92 (4.3%), P = 0.21].

Table 2.

Myocardial injury biomarkers.

Variables	Patients	Comparisons (N)	PHC (n)	Control (n)	Heterogeneity		Analysis model	MD	95%CI	Overall effect P
					I2	P
cTnI	Adults
Baseline		10	230	135	0%	0.88	Fixed	−0.00	−0.01 to 0.01	0.91
POD-1		10	230	135	85%	< 0.0001	Random	−1.70	−2.63 to −0.77	0.0003
CK	Adults
Baseline		3	90	30	0%	0.40	Fixed	1.01	−11.56 to 13.58	0.88
POD-1		3	90	30	0%	0.67	Fixed	−106.38	−211.33 to −1.42	0.05
CK-MB	Adults
Baseline		5	120	45	0%	0.98	Fixed	0.14	−0.13 to 0.42	0.29
POD-1		6	150	75	79%	0.0002	Random	−11.32	−20.34 to −2.30	0.01
MYO	Adults
Baseline		3	90	30	0%	0.43	Fixed	0.03	−2.86 to 2.92	0.98
POD-1		3	90	30	38%	0.20	Fixed	−38.51	−92.34 to 15.33	0.16
cTnT	Pediatrics
Baseline		2	100	100	0%	1.00	Fixed	−0.00	−0.00 to 0.00	0.16
POD-1		2	100	100	0%	0.95	Fixed	−0.10	−0.12 to −0.09	< 0.00001
CK	Pediatrics
Baseline		1	10	10	NA	NA	Random	−149.00	−276.53 to −21.47	0.02
POD-1		1	10	10	NA	NA	Random	−621.00	−1151.11 to −90.89	0.02
CK-MB	Pediatrics
Baseline		1	10	10	NA	NA	Random	−5.00	−16.64 to 6.64	0.40
POD-1		1	10	10	NA	NA	Random	−43.00	−59.00 to −27.00	< 0.0001
AST	Pediatrics
Baseline		1	10	10	NA	NA	Random	−3.00	−15.40 to 9.40	0.64
POD-1		1	10	10	NA	NA	Random	−40.00	−66.48 to −13.52	0.003

PHC  Penehyclidine hydrochloride, MD Mean difference, CI  Confidence interval, cTn  Cardiac troponin, CK  Creatine kinase, MYO  Myoglobin, AST  Aspartate transaminase, POD-1 Postoperative day-1, NA  Not applicable

Fig. 3.

Incidence of postoperative myocardial infarction, heart failure, pulmonary infection/pneumonia, and systemic inflammatory response syndrome

Gastrointestinal function

As shown in Tables 1 and 3 , 3 RCTs [19, 35] reported perioperative gastrointestinal variables and biomarkers [pH value of gastric mucosa (pHi), intestinal fatty acid-binding protein (I-FABP), D-lactate and diamine oxidase (DAO)] in adult patients. As shown in Table 3, meta-analysis demonstrated that, D-lactate levels were significantly lower in adult patients of PHC group at end of surgery (EOS) (MD: −1.11, 95%CI: −1.29 to −0.94, P < 0.00001, without heterogeneity). The study by Peng et al. [33] suggested that, pHi values in adult patients of PHC group were significantly higher than those of Control group at EOS (MD: 0.07, 95%CI: 0.06 to 0.08, P < 0.00001). The study by Sun et al. [19] suggested that, I-FABP values were significantly lower in adult patients of PHC group at EOS (MD: −234.40, 95%CI: −382.25 to −86.55, P = 0.002). The study by Peng et al. [33] suggested that, DAO values were significantly lower in adult patients of PHC group at EOS (MD: −0.58, 95%CI: −0.69 to −0.47, P < 0.00001).

Table 3.

Gastrointestinal variables.

Variables	Patients	Comparisons (N)	PHC (n)	Control (n)	Heterogeneity		Analysis model	MD	95%CI	Overall effect P
					I2	P
PHi
Baseline	Adults	1	25	25	NA	NA	Random	−0.01	−0.02 to 0.00	0.19
EOS		1	25	25	NA	NA	Random	0.07	0.06 to 0.08	< 0.00001
I-FABP
Baseline	Adults	1	20	20	NA	NA	Random	2.90	−73.24 to 79.04	0.94
EOS		1	20	20	NA	NA	Random	−234.40	−382.25 to −86.55	0.002
D-Lactate
Baseline	Adults	2	45	45	0%	0.86	Fixed	0.04	−0.13 to 0.21	0.67
EOS		2	45	45	0%	0.76	Fixed	−1.11	−1.29 to −0.94	< 0.00001
DAO
Baseline	Adults	1	25	25	NA	NA	Random	−0.02	−0.15 to 0.11	0.76
EOS		1	25	25	NA	NA	Random	−0.58	−0.69 to −0.47	< 0.00001

PHC  Penehyclidine hydrochloride, MD  Mean difference, CI  Confidence interval, PHi pH value of gastric mucosa, I-FABP  Intestinal fatty acid-binding protein, DAO  Diamine oxidase, EOS  End of surgery, NA  Not applicable

Pulmonary function

As shown in Tables 1 and 4 , 13 RCTs reported perioperative respiratory and oxygenation parameters [compliance, respiratory index (RI), oxygenation index (OI) and mixed venous oxygen saturation (SmVO₂)] in adult patients. As shown in Table 2, meta-analysis demonstrated that the compliance and OI variables were significantly higher in adult patients of PHC group at EOS [MD: 8.35, 95%CI: 2.47 to 14.23, P = 0.005, with heterogeneity (I² = 88%, P = 0.0003); MD: 64.88, 95%CI: 53.50 to 76.26, P < 0.00001, without heterogeneity]. RI was significantly lower in adult patients of PHC group at EOS [MD: −0.28, 95%CI: −0.52 to −0.03, P = 0.03, with heterogeneity (I² = 95%, P < 0.00001)], as compared to those of Control group. SmVO₂ was significantly higher in adult patients of PHC group at POD-1 (MD: 7.93, 95%CI: 7 0.06 to 8.80, P < 0.00001, without heterogeneity). The occurrence of pulmonary infection/pneumonia was reported in three trials including 372 adult patients with an overall incidence of 13.2% (PHC: 8.0%; Control: 18.4%), there was a significant reduction in pulmonary infection after cardiac surgery in the PHC group (Fig. 3; OR: 0.40; 95% CI: 0.21 to 0.78; P = 0.007; I² = 0%).

Table 4.

Respiratory and oxygenation parameters

Variables	Patients	Comparisons (N)	PHC (n)	Control (n)	Heterogeneity		Analysis model	MD	95%CI	Overall effect P
					I2	P
Compliance	Adults
Baseline		2	47	47	0%	0.73	Fixed	0.04	−2.29 to 2.36	0.97
EOS		2	47	47	88%	0.0003	Random	8.35	2.47 to 14.23	0.005
Respiratory index	Adults
Baseline		5	139	137	0%	0.97	Fixed	0.02	−0.01 to 0.04	0.17
EOS		5	139	137	95%	< 0.00001	Random	−0.28	−0.52 to −0.03	0.03
Oxygenation index	Adults
Baseline		5	122	120	0%	0.95	Fixed	3.97	−10.53 to18.48	0.59
EOS		5	122	120	21%	0.28	Fixed	64.88	53.50 to 76.26	< 0.00001
S m VO 2	Adults
Baseline		3	60	40	85%	0.001	Random	−1.13	−2.92 to 0.66	0.22
POD-1		3	60	40	0%	0.76	Fixed	7.93	7.06 to 8.80	< 0.00001
L-Lactate	Adults
Baseline		5	100	80	0%	0.68	Fixed	0.01	−0.03 to 0.05	0.66
POD-1		4	80	60	77%	0.005	Random	−0.81	−0.98 to −0.65	< 0.00001

PHC Penehyclidine hydrochloride, MD Weighted mean difference, CI  Confidence interval, S_mVO₂ Mixed venous oxygen saturation, EOS End of surgery, POD-1 Postoperative day-1

Inflammatory reaction

As shown in Tables 1, and 5 , 24 RCTs reported perioperative change of inflammatory biomarkers. Meta-analysis demonstrated that, the levels of interleukin (IL)−6 and tumor necrosis factor (TNF)-α were significantly lower in both adult [IL-6: MD: −4.75, 95%CI: −7.23 to −2.27, P = 0.0002, with heterogeneity (I² = 84%, P < 0.00001); TNF-α: MD: −2.52, 95%CI: −4.31 to −0.27, P = 0.006, with heterogeneity (I² = 74%, P = 0.0003)] and pediatric patients of PHC group on POD-1 [IL-6: MD: −5.44, 95%CI: −8.84 to −2.04, P = 0.002, with heterogeneity (I² = 92%, P < 0.00001); TNF-α: MD: −0.99, 95%CI: −1.63 to −0.35, P = 0.002, with heterogeneity (I² = 94%, P < 0.00001)]. The levels of IL-10 were significantly higher in adult patients of PHC group on POD-1 [MD: 11.50, 95%CI: 2.63 to 20.38, P = 0.01, with heterogeneity (I² = 76%, P = 0.006)]. The study by Wei et al. [46] suggested that, the levels of IL-1 in adult patients of PHC group were significantly lower than those of Control group on POD-1. The levels of IL-2 and IL-8 were significantly lower in pediatric patients of PHC group on POD-1. The occurrence of systemic inflammatory response syndrome (SIRS) was reported in two trials, including 204 adult patients, with an overall incidence of 17.2% (PHC: 12.7%; Control: 21.6%). There was a reduction in SIRS after cardiac surgery in the PHC group, but this reduction was not statistically significant (Fig. 3. OR: 0.52; 95% CI: 0.25 to 1.12; P = 0.09).

Table 5.

Inflammatory biomarkers and endotoxin

Variables	Patients	Comparisons (N)	PHC (n)	Control (n)	Heterogeneity		Analysis model	WMD	95%CI	Overall effect P
					I2	P
IL-1
Baseline	Adults	1	30	30	NA	NA	Random	−0.01	−0.09 to 0.07	0.81
POD-1		1	30	30	NA	NA	Random	−0.60	−0.82 to −0.38	< 0.00001
IL-6
Baseline	Adults	11	263	263	71%	0.0002	Random	−0.21	−0.53 to 0.11	0.21
POD-1		8	139	139	84%	< 0.00001	Random	−4.75	−7.23 to −2.27	0.0002
IL-8
Baseline	Adults	3	47	47	0%	0.97	Fixed	−0.60	−1.21 to 0.00	0.05
POD-1		2	35	35	85%	0.03	Random	−65.30	−207.45 to 76.85	0.37
IL-10
Baseline	Adults	4	65	65	0%	0.89	Fixed	1.39	−2.00 to 4.78	0.42
POD-1		4	65	65	76%	0.006	Random	11.50	2.63 to 20.38	0.01
TNF-α
Baseline	Adults	10	213	203	0%	0.95	Fixed	−0.01	−0.14 to 0.12	0.88
POD-1		8	109	99	74%	0.0003	Random	−2.52	−4.31 to −0.27	0.006
IL-2
Baseline	Pediatrics	2	40	20	0%	0.55	Fixed	−0.29	−0.85 to 0.27	0.31
POD-1		2	40	20	0%	0.74	Fixed	−1.03	−1.54 to −0.52	< 0.0001
IL-6
Baseline	Pediatrics	6	165	142	97%	< 0.00001	Random	−2.90	−6.10 to 0.30	0.08
POD-1		6	165	142	92%	< 0.00001	Random	−5.44	−8.84 to −2.04	0.002
IL-8	Pediatrics
Baseline		6	165	142	57%	0.04	Random	−0.29	−0.39 to −0.19	< 0.00001
POD-1		6	165	142	95%	< 0.00001	Random	−0.37	−0.72 to −0.03	0.04
TNF-α	Pediatrics
Baseline		8	203	154	0%	0.98	Fixed	−0.50	−0.56 to −0.43	< 0.00001
POD-1		8	203	154	94%	< 0.00001	Random	−0.99	−1.63 to −0.35	0.002
MMP-9
Baseline	Pediatrics	3	53	24	0%	0.99	Fixed	6.24	−10.23 to 22.72	0.46
POD-1		3	53	24	0%	0.81	Fixed	20.82	8.60 to 33.03	0.0008

PHC Penehyclidine hydrochloride, MD  Mean difference, CI  Confidence interval, IL  Interleukin, TNF  Tumor necrosis factor, MMP-9 Matrix metalloprotein-9, POD-1 Postoperative day-1, NA Not applicable

Post-operative recovery

The ICU stay was examined in five trials with 511 adult patients. The lengths of ICU stay were less in the PHC group with a marginal statistical significance (Fig. 4; MD: −0.34 days; 95% CI: −0.70 to 0.02; P = 0.07; I² = 89%). The pooled analysis found significant difference in hospital LOS between the groups (Fig. 4; MD: −1.78 days; 95% CI: −2.27 to −1.30; P < 0.00001; I² = 0%). The mechanical ventilation duration was explored in five trials with 412 adult patients and the effect of PHC was significant on reduction of ventilation time (Fig. 4; MD: −2.46 h; 95% CI: −4.80 to −0.19; P = 0.03; I² = 57%). The lengths of ICU and mechanical ventilation duration were recorded in 2 studies including 124 pediatric patients. The results showed that there was no significant difference between the two groups (Fig. 5). As shown in Tables 1 and 11 studies included 628 patients reported in-hospital mortality, but no deaths occurred.

Fig. 4.

Forest plot of mechanical ventilation duration, length of stay in the intensive care unit, and length of hospital stay in adult patients

Fig. 5.

Forest plot of mechanical ventilation duration, and length of stay in the intensive care unit in pediatric patients

Subgroup analyses for potential sources of heterogeneity

Subgroup analyses showed that PHC administration significantly reduced IL-6 levels in patients with CPB < 120 min [(MD: −3.10; 95% CI: −4.28 to −1.92) vs. (MD: −13.73; 95% CI: −38.76 to 11.30); P = 0.006 for the subgroup difference], whereas no significant reduction was observed in patients with CPB ≥ 120 min. Compared with patients undergoing off-pump surgery, PHC administration significantly reduced cTnI levels in patients undergoing on-pump surgery [(MD: −0.42; 95% CI: −0.63 to −0.21) vs. (MD: −2.60; 95% CI: −3.80 to −1.40); P = 0.0004 for subgroup difference] (in Table 6).

Table 6.

Subgroup analyses for the potential sources of heterogeneity

Variables	Patients	Outcomes	Comparisons (N)	WMD	95% CI	Heterogeneity P	I2	Overall effect P	P Difference
CPB duration	Adults	IL-6	8						0.006
CPB time < 120 min			6	−3.10	−4.28, −1.92	0.08	50%	< 0.00001
CPB time ≥ 120 min			2	−13.73	−38.76, 11.30	< 0.00001	96%	0.28
CPB duration	Adults	TNF-α	8						0.003
CPB time < 120 min			7	−1.60	−3.05, −0.15	0.009	65%	0.03
CPB time ≥ 120 min			1	−11.00	−17.09, −4.91	-	-	0.0004
CPB	Adults	cTnI	10						0.0004
Off-pump			4	−0.42	−0.63, −0.21	0.99	0	0.0001
On-pump			6	−2.60	−3.80, −1.40	0.0005	77%	< 0.0001
CPB	Adults	CK-MB	6						0.02
Off-pump			3	−1.67	−6.81, 3.47	0.99	0	0.52
On-pump			3	−27.69	−49.03, −6.36	0.006	80%	0.01

CPB Cardiopulmonary bypass, IL  Interleukin, TNF Tumor necrosis factor, cTn  Cardiac troponin, CK  Creatine kinase, WMD  Weighted mean difference, CI  Confidence interval

Publication bias assessment and sensitivity analysis

As for the publication bias, slight asymmetry can be found in the funnel plot for the incidence of postoperative complications. There was an insufficient number of trials providing data (less than 10 studies identified for each outcome), we concluded that there was possibility of publication bias. Sensitivity analysis was performed by excluding some studies to analyze the influence of the overall treatment effect on high heterogeneity outcomes (Supplemental Table 4) but no contradictory results were found.

Discussion

To our best knowledge, this is the first meta-analysis dedicated to evaluating the organ protective effects of PHC in patients undergoing cardiac surgery. The current study demonstrated that, PHC administration in cardiac surgical patients was associated with a significantly decreased incidence of postoperative pulmonary infection, as well as a reduction in the duration of mechanical ventilation and length of hospital stay in adult patients. The adult patients in PHC group had significantly lower cTnI and CK-MB levels on POD-1 after cardiac surgery, while the pediatric patients had lower cTnT levels on POD-1 in PHC group. The levels of IL-6 and TNF-α were significantly lower in both adult and pediatric patients of PHC group on POD-1. The levels of IL-10 were significantly higher in adult patients of PHC group on POD-1. PHC administration was associated with lower levels of MI biomarkers and inflammatory biomarkers, suggesting that PHC could attenuate myocardial injury and inflammatory response.

PHC is a novel anticholinergic drug derived from scopolamine that has anti-muscarinic and anti-nicotinic properties while retaining potent central and peripheral anticholinergic effects [7, 8, 10]. Based on clinical data, PHC has been shown to improve microcirculation, reduce microvascular permeability, inhibit the release of lysomes, prevent lipid peroxidation, and avoid organ injury [7, 14]. The result of this meta-analysis showed that PHC administration could signifcantly reduce the levels of CK-MB and cTn-I within 24 h after cardiac surgery, suggesting a pronounced early myocardial protective effect. Subgroup analyses showed that compared with patients undergoing off-pump surgery, PHC administration significantly reduced cTnI levels in patients undergoing on-pump surgery. The level of CK-MB and cTn-I were recommended for assessing myocardial injury, and its dynamic variations offer a more appropriate reference [56, 57]. Reversible postoperative cardiac dysfunction is predominantly attributable to ischemia–reperfusion injury, an inherent sequela of cardiac surgery performed with cardiopulmonary bypass [4]. Lin et al. demonstrated that preconditioning PHC conferred sustained cardioprotection, manifesting as preserved ventricular performance, smaller infarct size, attenuated oxidative stress, diminished cardiomyocyte apoptosis, and reduced release of inflammatory cytokines. Administration of PHC significantly decreased serum TNF-a, IL-1b, IL-6 and prostaglandin E2 levels [58]. Except for its influence on biomarkers associated with myocardial injury, PHC also reduces the severity of inflammation. Several studies have demonstrated that PHC may reduce ischemia/reperfusion injury, suppress inflammatory responses, and decrease cytokine release, all of which contribute to protect organs [8, 10]. The results showed that PHC decreased the levels of IL-6 and TNF-α within 24 h after cardiac surgery in adult and pediatric patients. In addition, the anti-inflammatory cytokine IL-10 was significantly increased in PHC group. The overall incidence of postoperative SIRS was 17.2%, which was numerically lower in the PHC group than in the control group; however, the difference was not statistically significant. Adequately powered, randomized trials focusing on high-risk cohorts are warranted to clarify the clinical relevance of PHC in attenuating SIRS after cardiac surgery.

PHC has been shown to improve pulmonary function by reducing airway resistance, relaxing airway smooth muscle, dilating bronchioles, and increasing lung compliance [7].Cardiac surgery with cardiopulmonary bypass can cause related atelectasis and pulmonary edema, which aggravates the related hazards of perioperative mechanical ventilation [59]. He et al. reported that the administration of PHC during anesthesia reduced the occurrence of postoperative pulmonary dysfunction, and improved the prognosis of patients undergoing cardiac surgery with CPB [47]. Li Baiqiang and his colleagues have shown that PHC significantly prevents the progression of acute lung injury (ALI) by down regulating the expression of Toll like receptor (TLR) 4 and inhibiting inflammatory cytokines, improving arterial oxygen pressure in patients with ALI [60]. OI and RI values were often used as indicators to evaluate lung function and gas exchange, and were associated with ICU mechanical ventilation time, ICU stay, and hospital stay. Postoperative OI can predict changes in pulmonary function and extubation time following heart valve surgery [61]. The results of this meta-analysis showed that adult patients in the PHC group had significantly lower RI, higher OI and SmVO₂ after cardiac surgery, along with a reduced incidence of postoperative pulmonary infection. Evidence indicated that postoperative IL-6 levels serve as an independent prognostic marker and that patients exhibiting IL-6 elevation after CPB might benefit from intensified anti-inflammatory therapy to preserve pulmonary function [62]. In the present study, PHC significantly reduced both IL-6 and TNF-a in both adult and pediatric cohorts. Subgroup analyses showed that PHC administration significantly reduced IL-6 levels in patients with CPB < 120 min, whereas no significant reduction was observed in patients with CPB ≥ 120 min. These findings were consistent with previous reports of PHC-mediated pulmonary protection during cardiac surgery. Moreover, PHC shortened both ICU and hospital length of stay, suggesting that it might facilitate rapid recovery in cardiac surgical patients.

This study has the weakness inherent in meta-analysis. First, there were concerns with quality and heterogeneity of included studies, as well as heterogeneity in the various PHC administration regimens (dosage, route, and timing), surgical procedures, outcome definitions, and patient comorbidities. Second, the meta-analysis included 37 RCTs with comparatively small sample sizes, particularly for several key parameters, which may increase the risk of publication bias. Various postoperative complication events were reported, but heterogeneity limited the pooling of data. The incidence of several complications was low, and most reports were limited to alternative parameters of a single organ system. We contacted the corresponding authors for missing data, but not much reply was received. Although the present meta-analysis confirmed the safety of PHC in adult cardiac surgical patients, the included trials were not powered to detect uncommon or delayed adverse effects. Consequently, the incidence of anticholinergic-related events (e.g., dry mouth, delirium) remained uncertain, and standardized adverse event monitoring in future investigations was warranted.

Conclusions

In conclusion, the available evidence indicated that PHC administration could provide myocardial protection, attenuate inflammatory responses, and decrease the incidence of postoperative pulmonary infection, which may be beneficial to the rapid recovery in cardiac surgical patients. However, further RCTs should focus on the more vulnerable cardiac patients to explore PHC on the protection of single- or multiorgan function.

Authors’ contributions

LJT, YTY: Substantial contribution to the conception and design of the work, and manuscript drafting.LJT, YTY: Acquisition, analysis, and interpretation of the data.JFG: Formal analysis and manuscript drafting.Evidence in Cardiovascular Anesthesia (EICA) Group: Providing resources and software.All authors were involved in drafting and revision of the manuscript for important intellectual content and approved the final version to be published.

Funding

None.

Data availability

The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

Ethical approval was not needed because this is a meta-analysis.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.