The Cardiopulmonary Protective Effect Of Penehyclidine Hydrochloride On Patients Undergoing Cardiopulmonary Bypass

Background and ObjectiveCompletion of great majority of cardiac procedures requires cardiopulmonary bypass (CPB). However, CPB-induced systemic inflammatory response (SIR) can cause multi-organ dysfunction, including heart or lung.failure. Myocardial injury, which inevitablely happens during the CPB, can cause postoperative cardiac dysfunction, which manifested as complications such as arrhythmia and heart failure. Acute lung injury (ALI) is a mainstay of SIR at lungs, which is characterized by spread of pulmonary infiltration of inflammatory cells, increased pulmonary capillary vascular permeability succeeded by hypoxemia. The incidence of acute respiratory insufficiency after open-heart surgery is up to 15%-30%. The number of deaths caused by acute respiratory insufficiency accounted for 30% of the total number of deaths of postoperation. Therefore, recent clinical researches focus on exploring effective methods to protect hearts and lungs from CPB-induced systemic inflammatory response. At present, the more determined drugs consist of steroid drugs, Ulinastatin, heparin and other glucosamine glycan, phosphodiesterase inhibitors such as Milrinone and Amrinone, anti-oxidants, and Sodium Nitroprusside and so on. However, the clinical application of these drugs is not satisfying because of poor efficacy and/or adverse reaction. So far, there is no safe and effective treatment. Anticholine medicines have been used in the treatment of ALI for many years. In recent years, Anisodamine has also made remarkable achievements in the prevention and treatment of SIR. But the clinical application of traditional anticholine drugs such as Anisodamine is limited because of non-selective on cholinergic receptor subtypes as well as side effects. Penehyclidine Hydrochoride (PH) main selectively acts on the M1 and M3 acceptor which most exists in the visceral smooth muscle and the gland, and has no or less action on the M2 receptor which distributing presynaptic membrane and heart. Recent studies have shown that Penehyclidine Hydrochoride has the effect of improving microcirculation, reducing capillary wall permeability, cell protection, and reducing the release of lysosomal discharge, etc, which points that Penehyclidine Hydrochoride may have a therapeutic effect on ALI, and also on CPB-related SIR. Therefore, this study was to investigate the protective effect of Penehyclidine Hydrochloride on myocardium and lung injury induced by CPB and its protection mechanism, and provide dose basis for the clinical application. This study was divided into two parts.Materials and MethodsPart I Myocardial protective effect of penehyclidine hydrochloride on patients undergoing heart valve replacement under cardiopulmonary bypassSixty patients undergoing valve replacement under CPB were randomly divided into three groups(20 patients for each group):PH group 1 (P1), PH group 2 (P2) and control group (C) were received 0.05 mg/kg,0.1 mg/kg of PH (diluted to 10mL with saline) and equal volume saline, respectively at beginning of operation via central vein. Pieces of right auricle tissue were collected at before CPB (T1),30min after aortic clamping (T2) and 30 min after aortic unclamping (T3) to check the expression of nuclear transcription fator-k B (NF-кB) with immunohistochemistry. And artery blood was drawn at before intravenous injection of PH (T1),30min after aortic clamping (T2),30 min after aortic unclamping (T3),4h and 24h after aortic unclamping (T4 and T5) to measure concentrations of tumor necrosis factor-α(TNF-α) and cardiac troponin I (cTn-I). Recordings of heart rate (HR), mean arterial pressure (MAP) and central venous pressure(CVP) were measured at each measuring point.Part II Pulmonary protective effect of penehyclidine hydrochloride during heart valve replacement under cardiopulmonary bypassThe patients, groups and drug administration in the second part were the same as the first part. Radial artery blood 1ml collected from the first part of T1-T5 time points was used to do artery blood gas analysis. Recordings of PaCO2, PaO2, and FiO2 were measured at each measuring point to calculate respiratory index (RI) and oxygenation index (OI). VT, Pmax and PEEP were recorded at after intubation 10min,30min, the beginning of CPB, after CPB 30min and 60min to calculate pulmonary dynamic compliance (Cd).ResultsPart I Myocardial protective effect of penehyclidine hydrochloride on patients undergoing heart valve replacement under cardiopulmonary bypass1.Compare with T1, NF-кB in three groups significantly increased at T2 and <0.01), but NF-кB in group P1 and group P2 were much lower than those in group C (P<0.05). NF-кB of group P1 and group P2 were no significantly different(P>0.05). 2. Compare with T1, TNF-αin three groups significantly increased at T3-T5 (P< 0.01), but TNF-αin group P1 and group P2 were much lower than those in group C (P<0.05). TNF-αof group P1 and group P2 were no significantly different(P>0.05).3. Compare with T1, cTn-I in three groups significantly increased at T2-T5 (P< 0.01), but cTn-I in group P1 and group P2 were much lower than those in group C (P<0.05). cTn-I of group P1 and group P2 were no significantly different(P >0.05).PartⅡPulmonary protective effect of penehyclidine hydrochloride during heart valve replacement under cardiopulmonary bypass1. There were no significant differences in RI among three groups at T1(P>0.05). RI in group P1 and group P2 were much lower than those in group C at T2-T5(P <0.01), but RI of group P1 and group P2 were no significantly different(P> 0.05).2. There were no significant differences in OI among three groups at T1(P>0.05). OI in group P1 and group P2 were much higher than those in group C at T2-T5(P<0.01), but OI of group P1 and group P2 were no significantly different(P>0.05).3. There were no significant differences in Cd among three groups at after intubation 10min (P>0.05). Cd in group P1 and group P2 were much higher than those in group C at after intubation 30min, before and after CPB (P<0.01), but Cd of group P1 and group P2 were no significantly different(P>0.05).Conclusion1. PH, inhibiting the increase of NF-кB transcript activity in myocardium and TNF-α, cTn-I in plasma induced by CPB-related SIR in patients undergoing heart valve replacement under CPB, protects myocardium against injury. 2. Penehyclidine hydrochloride, significantly lowering RI and heightening OI and Cd, can improve pulmonary function and reduce acute lung injury.