左西孟旦联合托伐普坦治疗顽固性心力衰竭40例

苏喜乐, 赵光远, 樊亚格

河南省新密市中医院东院区内科,新密 452370

SU Xile, ZHAO Guangyuan, FAN Yage

Internal Medicine of East Area,Xinmi Chinese Medicine Hospital , Henan Province, Xinmi 452370,China

作者简介:苏喜乐(1981-),男,郑州新密人,主治医师,学士,主要从事心内科临床工作。电话:0371-56181799,E-mail:suxilexm@163.com。

中图分类号: R972.1;R541.61 文献标识码: A 文章编号: 1004-0781(2018)05-0563-05

摘要: 目的观察左西孟旦联合托伐普坦对伴有低钠血症的顽固性心力衰竭(RHF)患者心功能及心率变异性(HRV)的影响。方法伴有低钠血症的RHF患者 80 例,按随机数字表法分为两组,各40例,对照组在常规抗心力衰竭治疗基础上加用托伐普坦(15 mg,qd,po);治疗组在对照组治疗的基础上应用左西孟旦0.1 μg·kg^-1·min^-1,持续微泵注射24 h,检测两组患者治疗前及治疗7 d后心功能指标[左室射血分数(LVEF),每搏输出量(SV)],N末端B型利钠肽(NT-proBNP),电解质,HRV指标[心率(HR)、24 h正常RR间期的标准差(SDNN)、RR间期平均值的标准差(SDANN)、RR间期的标准差的平均值(SDNNI)、相邻RR间期差值均方根(RMSSD)、相邻RR间期差值>50 ms百分比(PNN50)、低频功率(LF)、高频功率(HF)]室性期前收缩的变化。结果治疗后两组患者LVEF、SV、血清钠、SDNN、SDANN、SDNNI、RMSSD、LF、HF均较治疗前升高(P<0.05或P<0.01),NT-proBNP及HR均较治疗前降低(均P=0.000),治疗组上述指标改善更显著(P<0.05或P<0.01)。治疗组室性期前收缩次数比对照组明显降低(P<0.05或P<0.01)。两组不良反应的发生率差异无统计学意义(P>0.05)。结论左西孟旦联合托伐普坦能够改善伴有低钠血症的RHF患者心功能,其作用机制可能是减少室性期前收缩,改善心率变异性。

关键词: 左西孟旦 ; 托伐普坦 ; 低钠血症 ; 心力衰竭 ; 心功能 ; 心率变异性

Abstract:

Objective To study the effect of levosimendan combined with tolvaptan on cardiac function and heart rate variability (HRV) in patients with refractory heart failure(RHF). Methods 80 cases of RHF patients with hyponatremia were randomly divided into two groups: the control group (40 cases) was given tolvaptan (15 mg, qd, po) on the basis of conventional anti heart failure therapy, the treatment group(40 cases) was given levosimendan 0.1 μg ·kg^-1·min^-1 by continuous micropump injection on the basis of the treatment of the control group. The cardiac function [left ventricular ejection fraction(LVEF), stroke volume(SV)], N terminal B type natriuretic peptide (NT-proBNP), electrolyte, HRV index[ heart rate (HR), standard deviation of 24 hours normal RR interval (SDNN), standard deviation of average normal RR interval (SDANN), SDNN index (SDNNI), root mean square of successive RR interval differences (RMSSD), percent of NN50 in the total number of N-N intervals (PNN50), low-frequency (LF), high-frequency power (HF)], ventricular premature beat of two groups before and after 7 days treatment were detected. Results LVEF, SV, serum sodium, SDNN, DANN, SDNNI, RMSSD, LF, HF of two groups after treatment were higher than before (P<0.05 or P<0.01). NT-proBNP and HR after treatment were lower than before (P=0.000). The above indicators of the treatment group were improved significantly(P<0.05 or P<0.01). The ventricular premature contractions in the treatment group was significantly decreased than those in the control group (P<0.05 or P<0.01). There was no significant difference in the incidence of adverse reactions between the two groups (P>0.05). Conclusion Levosimendan combined with tolvaptan can improve heart function in patients with RHF with the possible mechanism of reduceing premature ventricular contraction and improving heart rate variability.

Key words: Levosimendan ; Tolvaptan ; Hyponatremia ; Heart failure ; Cardiac function ; Heart rate variability

顽固性心力衰竭(refractory heart failure,RHF)又称之为难治性终末期心衰,是各种心脏病终末期心功能失去代偿能力所表现出来的一种临床症候群^[1],病死率高,预后极差。在RHF的发生发展过程中,神经激素活性过度代偿一直被认为是心脏结构功能恶化和自主神经调节失衡的主要决定因素。近年来研究发现左西孟旦具有正性肌力作用^[2],可改善心功能不全患者体内异常的神经激素^[3,4]。但左西孟旦与托伐普坦联合应用对伴有低钠血症的RHF患者心率变异性(heart rate variability,HRV)的影响目前临床报道较少。2015年2月—2016年12月,笔者观察了左西孟旦联合托伐普坦对RHF患者HRV的影响,分析其降低心血管事件发生率的可能机制。

1 资料与方法

1.1 临床资料

选取在新密市中医院内科住院的伴有低钠血症的RHF患者80例,按照数字表法随机分为两组:治疗组和对照组各40例。入选标准:①符合中华医学会心血管病学分会修订的《中国心力衰竭诊断和治疗指南2014》^[5]中关于慢性心力衰竭诊断标准,有明确的器质性心脏病和显著的呼吸困难和(或)颈静脉充盈、下肢水肿等心衰症状及体征,经过常规抗心衰[休息、限盐、利尿药、洋地黄、血管紧张素转换酶抑制药(ACEI)等]治疗≥3 d,疗效不佳;②美国纽约心脏病学会心功能分级(New York Heart Association,NYHA)Ⅲ或Ⅳ级,超声心动图检测左心室射血分数(left ventricular ejection fraction,LVEF)≤40%;③血清钠浓度<135 mmol·L^-1;④基础病因为冠心病、高血压性心脏病或扩张型心肌病。排除标准:①严重低血压(卧位收缩压<90 mmHg,1 mmHg=0.133 kPa)、血容量不足或心源性休克;②肥厚性或限制性心肌病、严重的心脏瓣膜病、缩窄性心包炎、心包积液、分流性先心病、室壁瘤、心脏肿瘤等显著影响心室射血的机械性结构障碍;③病窦综合征、Ⅱ或Ⅲ度房室传导阻滞或快速心律失常(心室率>120次·min^-1)、洋地黄中毒及电解质紊乱;④严重肝肾功能不全、自身免疫性疾病、甲状腺功能异常、感染性心内膜炎、严重感染、恶性肿瘤、未控制的糖尿病;⑤妊娠、哺乳期妇女;⑥对试验用药过敏或禁忌。本研究经过我院伦理委员会批准,所有患者均签署知情同意书。

两组患者的性别、年龄、体质量指数(BMI)、心衰病程、血压、NYHA分级、原发病及基础用药等基线资料比较均差异无统计学意义(均P>0.05),具有可比性。见表1。

表1

两组患者基线资料比较

Tab.1

Comparison of baseline data between two groups of patients $\begin{matrix} \bar{x} \end{matrix}$ ±s

组别	例数		男					女			年龄/ 岁		BMI/ [kg·(m²)^-1]				心衰病程/ 年		血压/mmHg						NYHA分级
			例			%													例		%	收缩压			舒张压		Ⅲ级			Ⅳ级
																									例	%	例	%
对照组	40		23		57.5				17					42.5	58.98±9.55	23.92±3.20				3.06±1.27			136.83±11.92			86.95±5.34			25	62.5	15	37.5
治疗组	40		26		65.0			14		35.0	61.21±10.42		24.01±3.47				3.25±1.38		136.48±9.86			87.90±5.07			27	67.5		13	32.5
χ² /t			0.474								0.999		0.124				0.631		-0.143			0.815			0.220			0.220
P			0.491								0.321		0.902				0.530		0.887			0.417			0.639			0.639
组别		原发病												基础用药
		高血压					冠心病					扩张型心肌病		地高辛		利尿药			ACEI			ARB			β受体阻断药			硝酸酯
		例				%	例		%		例		%	例		%	例	%	例		%	例	%	例	%	例	%
对照组		20		50.0		17			42.5		3	7.5		15	37.5	25		62.5	29	72.5		5	12.5		30	75.0		14	35.0
治疗组		17		42.5		19			47.5		4	10.0		13	32.5	28		70.0	26	65.0		3	7.5		33	82.5		16	40.0
χ²/t		0.453				0.202					0.000			0.220		0.503			0.524			0.139			0.672			0.213
P		0.501				0.653					1.000			0.639		0.478			0.469			0.709			0.412			0.644

BMI:body mass index;ACEI:angiotensin converting enzyme inhibitor;ARB:angiotensin receptor antagonist

BMI:体质量指数;ACEI:血管紧张素转换酶抑制药;ARB:血管紧张素受体拮抗药

1.2 治疗方法

两组患者均遵循《中国心力衰竭诊断和治疗指南2014》^[5]给予常规抗心衰治疗,包括限盐限水、吸氧、洋地黄、利尿药、ACEI等。对照组应用托伐普坦片(规格:30 mg,浙江大冢制药有限公司,批准文号:国药准字H20110115)口服,第1天剂量15 mg,服药24 h后测定血钠,根据血钠浓度变化调整药物剂量。若血钠浓度<135 mmol·L^-1,且增加量<5 mmol·L^-1,则增加剂量至30 mg·d^-1,有效性终点血钠浓度>150 mmol·L^-1停用。在托伐普坦治疗期间,密切监测电解质和血容积的变化。治疗组在对照组治疗的基础上加用左西孟旦注射液(规格:5 mL:12.5 mg,成都圣诺生物制药有限公司,批准文号:国药准字H20110104)12.5 mg,以0.9%氯化钠溶液45 mL稀释后,采用持续微泵注射,初始负荷剂量6~12 μg·kg^-1,时间>10 min,之后按照0.1 μg·kg^-1·min^-1微泵持续滴注。在负荷剂量给药时以及持续给药开始1 h内,密切观察患者的反应,如有低血压或心动过速,应减至0.05 μg·kg^-1·min^-1或停药。如耐受性良好且需要增强血液动力学效应,可增加至0.2 μg·kg^-1·min^-1静脉泵入并持续23 h。

1.3 检测指标及方法

两组患者于治疗前及治疗7 d后分别检测下列指标。

1.3.1 心功能指标 LVEF、每搏输出量(stroke volume,SV)采用东芝660A彩色多普勒超声诊断仪(日本TOSHIBA公司生产),嘱咐患者取左侧卧位,使用二维彩色,按照超声心动图左室壁16节段分法分别显示心尖四腔心切面与心尖左室长轴切面,测量左室舒张末期内径及左室收缩末期内径,应用Teichholtz公式法计算LVEF,应用Simpsom面积长度法测量SV。每组数据取连续3个心动周期测定值的平均值。N末端B型利钠肽原(N-terminal pro-B-type natriuretic peptide,NT-proBNP)采用BIORAD550型酶标仪检测,应用酶联免疫吸附测定法,试剂盒由上海越研生物科技有限公司提供。

1.3.2 HRV指标采用美国MORTARA动态心电图分析仪行动态心电图检查,用计算机软件处理自动检出24 h的窦性心律,进行HRV指标分析,包括时域分析指标:①心率(heart rate,HR);②24 h连续正常RR间期的标准差(standard deviation of 24 h normal RR interval,SDNN);③24 h内连续5 min节段的平均正常RR间期平均值的标准差(standard deviation of average normal RR interval,SDANN);④RR间期的标准差的平均值(SDNN index,SDNNI);⑤24 h内连续正常RR间期差值均方的平方根(root mean square of successive RR interval differences,RMSSD);⑥相邻RR间期差值>50 ms的心搏数占所有分析信息期内心搏数的百分比(percent of NN50 in the total number of N-N intervals,PNN50);频域分析指标:低频功率(low-frequency power,LF)、高频功率(high-frequency power,HF)。时域和频域的分析包括①时域分析指标:SDNN<50 ms 或 RMSSD<15 ms 为心率变异性明显降低;②频域分析指标:将患者心电信号通过傅立叶转换,可得到以功率谱密度为纵坐标,以频率为横坐标的功率谱图,LF(0.040~0.150 Hz),HF(0.150~0.401 Hz)。

1.3.3 室性心律失常两组患者行24 h动态心电图,统计24 h内室性期前收缩发生频次及室性心动过速发生的例数。

1.3.4 安全性指标监测两组患者血常规、尿常规、肝肾功能、心电图及药物不良反应。

1.4 统计学方法

采用SPSS 22.0版统计软件进行数据分析,计量资料以均数±标准差( $\begin{matrix} \bar{x} \end{matrix}$ ±s)表示,组内治疗前后比较采用配对样本均数t检验,两组之间的比较采用独立样本均数t检验;计数资料以率表示,采用χ²检验。以P<0.05为差异有统计学意义。

2 结果

2.1 临床指标

治疗前两组患者的心功能指标(LVEF、SV、NT-proBNP),电解质(血清钠、血清钾),HRV指标(HR、SDNN、SDANN、SDNNI、RMSSD、PNN50、LF、HF)及室性期前收缩比较,均差异无统计学意义(均P>0.05),具有可比性。治疗后两组患者LVEF、SV、血清钠、SDNN、SDANN、SDNNI、RMSSD、LF、HF均较治疗前升高(P<0.05或P<0.01),NT-proBNP及HR均较治疗前降低(均P=0.000),而治疗组的上述指标改善更显著(P<0.05或P<0.01)。治疗后治疗组室性期前收缩次数比对照组及治疗前均明显降低(P<0.05或P<0.01),而对照组室性期前收缩次数治疗前后差异无统计学意义(P>0.05)。在治疗7 d内两组室性心动过速的发生率比较(治疗组1例,对照组4例,χ²=0.853,P=0.356),差异无统计学意义。血清钾水平两组间治疗前后及组内治疗前后比较均差异无统计学意义(均P>0.05)。见表2。

表2

两组患者治疗前后临床指标的比较

Tab.2

Comparison of clinical indexes between two groups of patients before and after treatment $\begin{matrix} \bar{x} \end{matrix}$ ±s,n=40

组别与时间	心功能		电解质		HRV
	LVEF/ %		SV/ mL		NT-proBNP/ (μg·L^-1)	血清钠	血清钾	HR/ (次·min^-1)	SDNN	SDANN
	LVEF/ %	(mmol·L^-1)	SV/ mL			ms		HR/ (次·min^-1)
对照组
治疗前	25.1±2.8	45.1±9.5	1.50±0.38		129.73±1.73	4.15±0.26		106.1±15.5	79.6±6.8	55.5±6.2
治疗后	36.4±4.5	60.2±16.8	0.91±0.20		137.48±1.66	4.06±0.17		75.8±9.9	89.0±8.2	65.2±8.0
t	-12.276	-4.933	8.585		-21.744	1.643		11.208	-4.838	-5.561
P	0.000	0.000	0.000		0.000	0.108		0.000	0.000	0.000
治疗组
治疗前	24.0±2.7	45.9±12.0	1.39±0.32		129.38±2.03	4.10±0.24		109.5±12.8	78.7±6.1	56.1±8.2
治疗后	38.8±4.6	69.4±17.1	0.76±0.18		137.96±1.58	4.02±0.22		70.7±8.0	101.0±9.2	80.8±7.4
t	-17.273	-6.900	11.771		-20.426	1.413		15.341	-13.176	-13.136
P	0.000	0.000	0.000		0.000	0.165		0.000	0.000	0.000
治疗前两组比较
t	-1.810	0.328	-1.465		-0.825	-0.842		1.062	-0.620	0.379
P	0.074	0.744	0.147		0.412	0.403		0.291	0.537	0.705
治疗后两组比较
t	2.320	2.431	-3.595		1.333	-0.844		-2.552	6.178	9.058
P	0.023	0.017	0.001		0.186	0.401		0.013	0.000	0.000
组别与时间	HRV
	SDNNI	RMSSD		PNN50/ %	LF	HF		24 h室性期前收缩/次
	ms	(ms²)		PNN50/ %				24 h室性期前收缩/次
对照组
治疗前	32.0±5.7	26.2±4.6	4.90±1.97	165.0±10.0	68.2±5.6	1345±284
治疗后	35.1±6.1	29.3±7.5	4.93±2.61	181.8±10.7	80.0±5.4	1311±212
t	-2.282	-2.606	-0.054	-7.303	-9.993	0.595
P	0.028	0.013	0.957	0.000	0.000	0.555
治疗组
治疗前	32.8±4.4	26.1±5.6	4.28±2.12	163.3±10.5	69.2±4.8	1393±300
治疗后	43.4±5.9	37.4±8.4	5.09±2.30	199.6±13.6	90.2±7.5	1184±245
t	-8.350	-7.416	-1.869	-13.664	-15.174	3.515
P	0.000	0.000	0.069	0.000	0.000	0.001
治疗前两组比较
t	0.706	-0.129	-1.355	-0.774	0.786	0.731
P	0.482	0.897	0.179	0.442	0.434	0.467
治疗后两组比较
t	6.194	4.589	0.291	6.513	6.999	-2.477
P	0.000	0.000	0.722	0.000	0.000	0.015

2.2 不良反应

治疗过程中,治疗组出现口干、口渴2例,眩晕、恶心1例,不良反应发生率7.50%;对照组出现口干、口渴3例,头痛和失眠各1例,不良反应发生率12.50%。两组患者不良反应均较轻微,经对症处理后缓解,未影响继续用药。两组不良反应发生率差异无统计学意义(χ²=0.139,P=0.709)。

3 讨论

HRV是目前公认的判断心血管自主神经活动的常用定量指标^[6]。HRV降低是预测恶性心律失常和心脏性猝死最有价值的独立指标^[7],对于评估心衰患者预后和危险性有重要的临床价值。在HRV的各项指标中,SDNN 能够反映交感神经和迷走神经的整体功能,SDANN、SDNNI主要反映交感神经张力,RMSSD、PNN50主要反映迷走神经张力,LF 反映交感和迷走神经的双重调节,而HF只反映迷走神经的调节。SDNN、SDANN、SDNNI等时域指标<50 ms,为HRV显著减低,病死率显著增高。而且HRV异常程度与心功能损伤程度相一致^[8],可能是因为它含有神经体液因素对窦房结调节的信息。在心衰的发生进展中,神经内分泌激素活性过度代偿被认为是自主神经调节失衡、心室重构和心功能恶化的重要因素。NT-proBNP由心室心肌细胞分泌,随心室容量负荷或压力负荷增加而合成释放增加,其血中浓度与心衰严重程度有高度相关性,目前已作为心功能不全最敏感和特异的指标之一^[9,10]。

左西孟旦具有下列优势:①可直接与肌钙蛋白相结合,不依赖 Ca²⁺内流,不引起心肌钙超载,对缺血再灌注损伤的心肌具有保护作用^[11],可降低因钙超负荷而引起的心律失常^[12];②促进K⁺内流、细胞膜发生超极化,扩张冠状动脉阻力血管和外周静脉容量血管,在不增加心率和心肌氧耗的前提下,降低了心脏前后负荷^[13];③抑制心脏磷酸二酯酶3(phosphodiesterases3,PDE3)活性,增加了细胞内环磷腺苷酸浓度,发挥额外的正性肌力作用^[14];④它与肌钙蛋白的亲和力依赖心肌细胞内的Ca²⁺浓度,避免或减轻舒张功能受损^[15,16];⑤具有抗炎、抗氧化、抗心肌细胞凋亡作用^[17],可抑制上述炎症细胞因子的表达而减少NT-proBNP的分泌。左西孟旦改善心室收缩同步性,可改善心率变异性的时域及频域^[18],其可能机制是降低体内异常的神经内分泌激素(如NT-proBNP),增加了迷走神经张力,同时也降低了交感神经的张力,重新建立起交感-副交感神经平衡,从而减少室性期前收缩的发生,改善RHF患者预后。托伐普坦是一种新型保钠利尿药,可作用于血管加压素V2受体,增加尿液排泄量及自由水清除率,降低尿液渗透压,在提升血清钠离子浓度的同时使多余水分从尿液中排出,同时不会对血钾浓度产生不利影响^[19]。

本研究结果表明,在常规抗心衰药物+托伐普坦基础上加用左西孟旦治疗RHF,与采用常规抗心衰药物+托伐普坦比较,能更显著改善心功能指标,降低室性期前收缩发生次数,不增加药物不良反应。说明应用左西孟旦改善心功能安全有效,并能改善HRV。左西孟旦与托伐普坦联合应用能够改善低钠血症,并未增加不良反应,说明两者联用具有安全性与协同作用。左西孟旦耐受性良好,常见的不良反应为头痛和低血压,偶见心动过速和心悸,多因剂量偏大、滴速偏快导致血管扩张引起,及时调整剂量及滴速,并尽可能停用米力农及其他血管扩张药物,即可避免低血压风险。

综上所述,左西孟旦联合托伐普坦治疗RHF,能改善心功能及低钠血症,还可提高心率变异性,减少室性期前收缩的发生,安全有效。但本研究亦存在不足:①样本量较小;②心衰是一种慢性病,需要长期治疗,而本研究只对左西孟旦进行了短期(7 d)的观察,缺乏对远期疗效和预后的评价,更科学的结论需要更大样本更长时间的临床随机对照试验来证实。

The authors have declared that no competing interests exist.

参考文献

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[1]	郭圣敏,任建明.不同剂量心脉隆注射液对老年慢性心力衰竭患者心功能及血浆B型钠尿肽水平的影响[J].医药导报,2016,35(1):54-57. 目的观察不同剂量心脉隆注射液对老年慢性心力衰竭(CHF)患者心功能及血浆B型钠尿肽(BNP)水平的影响.方法选取＞65岁CHF住院患者156例,采用完全随机数字表法分为治疗组1、治疗组2和对照组,每组52例.3组均给予常规治疗,治疗组1在常规治疗的基础上加用心脉隆注射液4 mL+0.9％氯化钠注射液200 mL静脉滴注;治疗组2在常规治疗的基础上加用心脉隆注射液6 mL+0.9％氯化钠注射液200 mL静脉滴注.两组用法均为每天2次,2次之间间隔＞6 h,疗程10 d.比较3组治疗前后左心室射血分数(LVEF)、6 min步行距离(6-WMD)、左心室舒张末期内径(LVDd)及血浆BNP水平.结果对照组、治疗组1和治疗组2治疗后LVDd分别为(46.06±8.73),(42.88±4.73)和(41.42±5.00) mm;LVEF分别为(43.94±2.67)％,(47.23±2.48)％和(50.71±1.68)％;BNP分别为(654.08±139.15),(436.56±53.21)和(161.44±28.58) ng·L-1;6-WMD分别为(350.69±56.33),(423.77±34.62)和(442.88±22.40)m.3组心功能指标治疗前均差异无统计学意义(P＞0.05),治疗后均明显改善(均P＜0.05).治疗组2心功能指标及血浆BNP均较治疗组1、对照组改善更加明显(均P＜0.05).结论在常规治疗基础上加用心脉隆注射液治疗老年CHF,可明显提高疗效,降低血浆BNP水平,改善心功能,且在相同治疗周期下,按说明书标准剂量治疗效果更明显. DOI:10.3870/j.issn.1004-0781.2016.01.014 URL [本文引用:1]
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[8]	IMAMURA T,NITTA D,KINUGAWA K.Optimization of pressure settings during adaptive servo-ventilation support using real-time heart rate variability assessment:initial case report[J].BMC Cardiovasc Disord,2017,17(1):11. Adaptive servo-ventilation (ASV) therapy is a recent non-invasive positive pressure ventilation therapy that was developed for patients with heart failure (HF) refractory to optimal medical therapy. However, it is likely that ASV therapy at relatively higher pressure setting worsens some of the patients prognosis compared with optimal medical therapy. Therefore, identification of optimal pressure settings of ASV therapy is warranted. We present the case of a 42-year-old male with HF, which was caused by dilated cardiomyopathy, who was admitted to our institution for evaluating his eligibility for heart transplantation. To identify the optimal pressure setting [peak end-expiratory pressure (PEEP) ramp test], we performed an ASV support test, during which the PEEP settings were set at levels ranging from 4 to 8 mmHg, and a heart rate variability (HRV) analysis using the MemCalc power spectral density method. Clinical parameters varied dramatically during the PEEP ramp test. Over incremental PEEP levels, pulmonary capillary wedge pressure, cardiac index and high-frequency level (reflecting parasympathetic activity) decreased; however, the low-frequency level increased along with increase in plasma noradrenaline concentrations. An inappropriately high PEEP setting may stimulate sympathetic nerve activity accompanied by decreased cardiac output. This was the first report on the PEEP ramp test during ASV therapy. Further research is warranted to determine whether use of optimal pressure settings using HRV analyses may improve the long-term prognosis of such patients. DOI:10.1186/s12872-016-0455-4 PMID:5217667 URL [本文引用:1]
[9]	侯维娜,金凤表,孙宏超,等.血清Syndecan-4、PTX-3、BNP水平检测在诊断慢性心力衰竭的临床价值[J].实用医学杂志,2016,32(22):3709-3712. 目的:研究血清(Syndecan-4)、正五聚体蛋白-3(PTX-3)及脑钠肽(BNP)水平检测在诊断慢性心力衰竭(CHF)的临床价值.方法:慢性心衰患者105例(心衰组),按纽约心脏病学会心功能分级分为NY-HAⅡ级24例、Ⅲ级35例、Ⅳ级46例,以同期正常人45例作为对照组.采用超声心动图检测心功能,ELISA法检测Syndecan-4、PTX-3,BNP检测仪测定BNP.结果:心衰组Syndecan-4、PTX-3、BNP基线水平均明显高于对照组(P＜0.01).与NYHAⅡ级比较,NYHAⅢ、Ⅳ级心衰患者血清Syndecan-4、PTX-3、BNP水平高(P＜0.01).Spearman相关性分析显示Syndecan-4、PTX-3、BNP与NYHA心功能分级、左室舒张末期前后径(LVEDV)均呈正相关;与射血分数(LVEF)呈负相关;Syndecan-4、PTX-3与BNP呈显著正相关(均P＜0.01).ROC曲线分析显示,Syndecan-4+BNP、PTX-3 +BNP的曲线下面积分别是0.907,0.918(均P＜0.01).结论:血清Syndecan-4、PTX-3、BNP水平均与慢性心衰患者心功能状态密切相关,且均能反映患者病情严重程度;但联合BNP在诊断慢性心衰患者有较高的灵敏度和特异度. DOI:10.3969/j.issn.1006-5725.2016.22.022 URL [本文引用:1]
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[11]	SUNNY,YUNUS M,KARIM H M,et al.Comparison of levosimendan,milrinone and dobutamine in treating low cardiac output syndrome following valve replacement surgeries with cardiopulmonary bypass[J].J Clin Diagn Res,2016,10(12):UC05-UC08. [本文引用:1]
[12]	SUOMINEN P,MATTILA N,NYBLOM O,et al.The hemodynamic effects and safety of repetitive levosimendan infusions on children with dilated cardiomyopathy[J].World J Pediatr Congenit Heart Surg,2017,8(1):25-31. Abstract Limited treatment options are available for children with decompensated dilated cardiomyopathy (DCM), while they wait for either functional recovery or heart transplantation. We evaluated the safety of repetitive levosimendan infusions and short-term and long-term impacts of the therapy in this patient population. DOI:10.1177/2150135116674466 PMID:28033083 URL [本文引用:1]
[13]	YAMAN M,ARSLAN U,KAYA A,et al.Levosimendan accelerates recovery in patients with takotsubo cardiomyopathy[J].Cardiol J,2016,23(6):610-615. The aim of this study was to determine the efficacy and safety of levosimendan in takotsubo cardiomyopathy (TC). The study was conducted in a retrospective design and 42 consecutive patients were enrolled in 6 cardiovascular centers in Turkey. The records of TC patients having left ventricular ejection fraction (LVEF) 35% were examined at admission, discharge and recovery period including their clinical and echocardiographic data. Of these 42 TC patients, 17 were treated with loading dose and i.v. infusion of levosimendan (group 1) and 25 were treated without levosimendan (group 2). Echocardiographic findings at admission and at discharge were similar and no serious complications were observed in either group. However recovery period including the interval of 50% increase in LVEF, time to achieve the baseline troponin values and hospitalization were significantly lower in patients taking levosimendan. This is the first study using loading dose and subsequent continuous intravenous administration of levosimendan demonstrating accelerated recovery in patients with TC. DOI:10.5603/CJ.a2016.0100 PMID:27910084 URL [本文引用:1]
[14]	FRUHWALD S,POLLESELLO P,FRUHWALD F.Advanced heart failure:an appraisal of the potential of levosimendan in this end-stage scenario and some related ethical considerations[J].Expert Rev Cardiovasc Ther,2016,14(12):1335-1347. The later stages of heart failure are characterized by a steady decline in quality of life. Clinical priorities should be to maintain functional capacity and quality of life. In the absence of sufficient organs for transplantation, options include left ventricular assist devices and inotropic support. Areas covered: We examined data published in the last two decades on the use of inotropes and inodilators in advanced heart failure. Expert commentary: In the literature, use of conventional inotropes, including adrenergic agonists and phosphodiesterase inhibitors, appears to be suboptimal for achieving the clinical priorities of late-stage heart failure. Evidence suggests instead that the calcium-sensitizing inodilator levosimendan, administered intermittently, delivers improvements in functional capacity and quality of life and does so with no adverse impact on life expectancy. At a terminal or near-terminal stage of heart failure, the therapeutic philosophy should shift towards meeting patients' existential priorities rather than traditional heart failure-centric targets. DOI:10.1080/14779072.2016.1247694 PMID:27778514 URL [本文引用:1]
[15]	BOZHINOVSKA M,TELESKA G,FABIAN A,et al.The role of levosimendan in patients with decreased left ventricular function undergoing cardiac surgery[J].Open Access Maced J Med Sci,2016,4(3):510-516. The postoperative low cardiac output is one of the most important complications following cardiac surgery and is associated with increased morbidity and mortality. The condition requires inotropic support to achieve adequate hemodynamic status and tissue perfusion. While catecholamines are utilised as a standard therapy in cardiac surgery, their use is limited due to increased oxygen consumption. Levosimendan is calcium sensitising inodilatator expressing positive inotropic effect by binding with cardiac troponin C without increasing oxygen demand. Furthermore, the drug opens potassium ATP (KATP) channels in cardiac mitochondria and in the vascular muscle cells, showing cardioprotective and vasodilator properties, respectively. In the past decade, levosimendan demonstrated promising results in treating patients with reduced left ventricular function when administered in peri- or post- operative settings. In addition, pre-operative use of levosimendan in patients with severely reduced left ventricular ejection fraction may reduce the requirements for postoperative inotropic support, mechanical support, duration of intensive care unit stay as well as hospital stay and a decrease in post-operative mortality. However, larger studies are needed to clarify clinical advantages of levosimendan versus conventional inotropes. DOI:10.3889/oamjms.2016.071 PMID:5042644 URL [本文引用:1]
[16]	MANSIROGLU A K,ONER E,ERTURK M,et al.Assess-ment of sustained effects of levosimendan on right ventricular systolic functions in patients with advanced heart failure[J].Acta Cardiol,2016,71(4):411-415. Abstract Background Poor right ventricular function is an independent prognostic marker for mortality in heart failure patients. Echocardiographic studies concerning effects of levosimendan on right ventricular function performed second measurements just after or 24 hours after levosimendan infusion. We aimed to detect sustained effects of levosimendan infusion on right ventricular systolic function. Method The study consisted of 47 patients with acutely decompensated heart failure with NYHA class III or IV symptoms. Levosimendan was infused for 24 hours. Before and 5 days after the initiation of infusions, functional class was assessed, NT-proBNP levels and LVEF, RVEF, using tissue Doppler imaging, RV isovolumic myocardial acceleraton (IVA), peak myocardial velocity during isovolumic contraction (IVV), peak systolic velocity during ejection period (Sa), early (E’) and late (A’) diastolic velocities, and E’/A’ ratio were measured. Results NYHA class improved and NT-proBNP levels were significantly reduced. LVEF and RVEF also improved significantly. Tissue Doppler-derived systolic indices of IVV and IVA increased and RV diastolic indices improved. Conclusion Improvements in RV systolic and diastolic functions continue after levosimendan infusion as expressed by conventional echocardiographic and TDI-derived parameters in patients with acute decompensated HF. DOI:10.2143/AC.71.4.3159693 PMID:27594356 URL [本文引用:1]
[17]	GORDON A C,PERKINS G D,SINGER M,et al.Levosimen-dan for the prevention of acute organ dysfunction in sepsis[J].N Engl J Med,2016,375(17):1638-1648. Abstract Background Levosimendan is a calcium-sensitizing drug with inotropic and other properties that may improve outcomes in patients with sepsis. Methods We conducted a double-blind, randomized clinical trial to investigate whether levosimendan reduces the severity of organ dysfunction in adults with sepsis. Patients were randomly assigned to receive a blinded infusion of levosimendan (at a dose of 0.05 to 0.2/g per kilogram of body weight per minute) for 24 hours or placebo in addition to standard care. The primary outcome was the mean daily Sequential Organ Failure Assessment (SOFA) score in the intensive care unit up to day 28 (scores for each of five systems range from 0 to 4, with higher scores indicating more severe dysfunction; maximum score, 20). Secondary outcomes included 28-day mortality, time to weaning from mechanical ventilation, and adverse events. Results The trial recruited 516 patients; 259 were assigned to receive levosimendan and 257 to receive placebo. There was no significant difference in the mean (卤SD) SOFA score between the levosimendan group and the placebo group (6.68卤3.96 vs. 6.06卤3.89; mean difference, 0.61; 95% confidence interval [CI], -0.07 to 1.29; P=0.053). Mortality at 28 days was 34.5% in the levosimendan group and 30.9% in the placebo group (absolute difference, 3.6 percentage points; 95% CI, -4.5 to 11.7; P=0.43). Among patients requiring ventilation at baseline, those in the levosimendan group were less likely than those in the placebo group to be successfully weaned from mechanical ventilation over the period of 28 days (hazard ratio, 0.77; 95% CI, 0.60 to 0.97; P=0.03). More patients in the levosimendan group than in the placebo group had supraventricular tachyarrhythmia (3.1% vs. 0.4%; absolute difference, 2.7 percentage points; 95% CI, 0.1 to 5.3; P=0.04). Conclusions The addition of levosimendan to standard treatment in adults with sepsis was not associated with less severe organ dysfunction or lower mortality. Levosimendan was associated with a lower likelihood of successful weaning from mechanical ventilation and a higher risk of supraventricular tachyarrhythmia. (Funded by the NIHR Efficacy and Mechanism Evaluation Programme and others; LeoPARDS Current Controlled Trials number, ISRCTN12776039 .). DOI:10.1056/NEJMoa1609409 PMID:27705084 URL [本文引用:1]
[18]	黄宏艳. 左西孟旦在小儿心脏手术中的应用进展[J].医药导报,2016,35(5):475-477. 小儿心脏手术后早期易发生低心排血量综合征,其治疗首选能优化心功能的正性肌力药。左西孟旦是一种新的正性肌力药物,能改善成人体外循环后的心功能和血流动力学,但在小儿心脏外科中的应用尚有争议,目前主要用于围手术期严重低心排血量综合征的治疗及高风险患儿手术。 DOI:10.3870/j.issn.1004-0781.2016.05.011 URL [本文引用:1]
[19]	DE VECCHIS R,NOUTSIAS M,ARIANO C,et al.Does accidental overcorrection of symptomatic hyponatremia in chronic heart failure require specific therapeutic adjustments for preventing central pontine myelinolysis?[J].J Clin Med Res,2017,9(4):266-272. This review aims at summarizing essential aspects of epidemiology and pathophysiology of hyponatremia in chronic heart failure (CHF), to set the ground for a practical as well as evidence-based approach to treatment. As a guide through the discussion of the available evidence, a clinical case of hyponatremia associated with CHF is presented. For this case, the severe neurological signs at presentation justified an emergency treatment with hypertonic saline plus furosemide, as indicated. Subsequently, as the neurological emergency began to subside, the reversion of the trend toward hyponatremia overcorrection was realized by continuous infusion of hypotonic solutions, and administration of desmopressin, so as to prevent the very feared risk of an osmotic demyelination syndrome. This very disabling complication of the hyponatremia correction is then briefly outlined. Moreover, the possible advantages related to systematic correction of the hyponatremia that occurs in the course of CHF are mentioned. Additionally, the case of tolvaptan, a vasopressin receptor antagonist, is concisely presented in order to underline the different views that have led to different norms in Europe with respect to the USA or Japan as regards the use of this drug as a therapeutic resource against the hyponatremia. DOI:10.14740/jocmr2933w PMID:5330768 URL [本文引用:1]

不同剂量心脉隆注射液对老年慢性心力衰竭患者心功能及血浆B型钠尿肽水平的影响

2016

... 顽固性心力衰竭(refractory heart failure,RHF)又称之为难治性终末期心衰,是各种心脏病终末期心功能失去代偿能力所表现出来的一种临床症候群^[1],病死率高,预后极差.在RHF的发生发展过程中,神经激素活性过度代偿一直被认为是心脏结构功能恶化和自主神经调节失衡的主要决定因素.近年来研究发现左西孟旦具有正性肌力作用^[2],可改善心功能不全患者体内异常的神经激素^[3,4].但左西孟旦与托伐普坦联合应用对伴有低钠血症的RHF患者心率变异性(heart rate variability,HRV)的影响目前临床报道较少.2015年2月—2016年12月,笔者观察了左西孟旦联合托伐普坦对RHF患者HRV的影响,分析其降低心血管事件发生率的可能机制. ...

左西孟旦治疗老年顽固性充血性心力衰竭并肾功能不全的疗效评价

2016

Intermittent levosi-mendan infusions in advanced heart failure:a real world experience

2017

Levosi-mendan as a treatment for acute renal failure associated with cardiogenic shock after hip fracture

2017

中国心力衰竭诊断和治疗指南2014

2014

... 选取在新密市中医院内科住院的伴有低钠血症的RHF患者80例,按照数字表法随机分为两组:治疗组和对照组各40例.入选标准:①符合中华医学会心血管病学分会修订的《中国心力衰竭诊断和治疗指南2014》^[5]中关于慢性心力衰竭诊断标准,有明确的器质性心脏病和显著的呼吸困难和(或)颈静脉充盈、下肢水肿等心衰症状及体征,经过常规抗心衰[休息、限盐、利尿药、洋地黄、血管紧张素转换酶抑制药(ACEI)等]治疗≥3 d,疗效不佳;②美国纽约心脏病学会心功能分级(New York Heart Association,NYHA)Ⅲ或Ⅳ级,超声心动图检测左心室射血分数(left ventricular ejection fraction,LVEF)≤40%;③血清钠浓度<135 mmol·L^-1;④基础病因为冠心病、高血压性心脏病或扩张型心肌病.排除标准:①严重低血压(卧位收缩压<90 mmHg,1 mmHg=0.133 kPa)、血容量不足或心源性休克;②肥厚性或限制性心肌病、严重的心脏瓣膜病、缩窄性心包炎、心包积液、分流性先心病、室壁瘤、心脏肿瘤等显著影响心室射血的机械性结构障碍;③病窦综合征、Ⅱ或Ⅲ度房室传导阻滞或快速心律失常(心室率>120次·min^-1)、洋地黄中毒及电解质紊乱;④严重肝肾功能不全、自身免疫性疾病、甲状腺功能异常、感染性心内膜炎、严重感染、恶性肿瘤、未控制的糖尿病;⑤妊娠、哺乳期妇女;⑥对试验用药过敏或禁忌.本研究经过我院伦理委员会批准,所有患者均签署知情同意书. ...

... 两组患者均遵循《中国心力衰竭诊断和治疗指南2014》^[5]给予常规抗心衰治疗,包括限盐限水、吸氧、洋地黄、利尿药、ACEI等.对照组应用托伐普坦片(规格:30 mg,浙江大冢制药有限公司,批准文号:国药准字H20110115)口服,第1天剂量15 mg,服药24 h后测定血钠,根据血钠浓度变化调整药物剂量.若血钠浓度<135 mmol·L^-1,且增加量<5 mmol·L^-1,则增加剂量至30 mg·d^-1,有效性终点血钠浓度>150 mmol·L^-1停用.在托伐普坦治疗期间,密切监测电解质和血容积的变化.治疗组在对照组治疗的基础上加用左西孟旦注射液(规格:5 mL:12.5 mg,成都圣诺生物制药有限公司,批准文号:国药准字H20110104)12.5 mg,以0.9%氯化钠溶液45 mL稀释后,采用持续微泵注射,初始负荷剂量6~12 μg·kg^-1,时间>10 min,之后按照0.1 μg·kg^-1·min^-1微泵持续滴注.在负荷剂量给药时以及持续给药开始1 h内,密切观察患者的反应,如有低血压或心动过速,应减至0.05 μg·kg^-1·min^-1或停药.如耐受性良好且需要增强血液动力学效应,可增加至0.2 μg·kg^-1·min^-1静脉泵入并持续23 h. ...

血压控制良好的原发性高血压患者夜间收缩压下降率与心率及心率变异性的关系

2015

... HRV是目前公认的判断心血管自主神经活动的常用定量指标^[6].HRV降低是预测恶性心律失常和心脏性猝死最有价值的独立指标^[7],对于评估心衰患者预后和危险性有重要的临床价值.在HRV的各项指标中,SDNN 能够反映交感神经和迷走神经的整体功能,SDANN、SDNNI主要反映交感神经张力,RMSSD、PNN50主要反映迷走神经张力,LF 反映交感和迷走神经的双重调节,而HF只反映迷走神经的调节.SDNN、SDANN、SDNNI等时域指标<50 ms,为HRV显著减低,病死率显著增高.而且HRV异常程度与心功能损伤程度相一致^[8],可能是因为它含有神经体液因素对窦房结调节的信息.在心衰的发生进展中,神经内分泌激素活性过度代偿被认为是自主神经调节失衡、心室重构和心功能恶化的重要因素.NT-proBNP由心室心肌细胞分泌,随心室容量负荷或压力负荷增加而合成释放增加,其血中浓度与心衰严重程度有高度相关性,目前已作为心功能不全最敏感和特异的指标之一^[9,10]. ...

Does heart rate variability correlate with long-term prognosis in myocardial infarction patients treated by early revascularization?

2017

Optimization of pressure settings during adaptive servo-ventilation support using real-time heart rate variability assessment:initial case report

2017

血清Syndecan-4、PTX-3、BNP水平检测在诊断慢性心力衰竭的临床价值

2016

BNP and NT-proBNP elevation after running—a systematic review

2015

10(12):UC05-UC08

2016

... 左西孟旦具有下列优势:①可直接与肌钙蛋白相结合,不依赖 Ca²⁺内流,不引起心肌钙超载,对缺血再灌注损伤的心肌具有保护作用^[11],可降低因钙超负荷而引起的心律失常^[12];②促进K⁺内流、细胞膜发生超极化,扩张冠状动脉阻力血管和外周静脉容量血管,在不增加心率和心肌氧耗的前提下,降低了心脏前后负荷^[13];③抑制心脏磷酸二酯酶3(phosphodiesterases3,PDE3)活性,增加了细胞内环磷腺苷酸浓度,发挥额外的正性肌力作用^[14];④它与肌钙蛋白的亲和力依赖心肌细胞内的Ca²⁺浓度,避免或减轻舒张功能受损^[15,16];⑤具有抗炎、抗氧化、抗心肌细胞凋亡作用^[17],可抑制上述炎症细胞因子的表达而减少NT-proBNP的分泌.左西孟旦改善心室收缩同步性,可改善心率变异性的时域及频域^[18],其可能机制是降低体内异常的神经内分泌激素(如NT-proBNP),增加了迷走神经张力,同时也降低了交感神经的张力,重新建立起交感-副交感神经平衡,从而减少室性期前收缩的发生,改善RHF患者预后.托伐普坦是一种新型保钠利尿药,可作用于血管加压素V2受体,增加尿液排泄量及自由水清除率,降低尿液渗透压,在提升血清钠离子浓度的同时使多余水分从尿液中排出,同时不会对血钾浓度产生不利影响^[19]. ...

The hemodynamic effects and safety of repetitive levosimendan infusions on children with dilated cardiomyopathy

2017

Levosimendan accelerates recovery in patients with takotsubo cardiomyopathy

2016

Advanced heart failure:an appraisal of the potential of levosimendan in this end-stage scenario and some related ethical considerations

2016

The role of levosimendan in patients with decreased left ventricular function undergoing cardiac surgery

2016

Assess-ment of sustained effects of levosimendan on right ventricular systolic functions in patients with advanced heart failure

2016

Levosimen-dan for the prevention of acute organ dysfunction in sepsis

2016

左西孟旦在小儿心脏手术中的应用进展

2016

Does accidental overcorrection of symptomatic hyponatremia in chronic heart failure require specific therapeutic adjustments for preventing central pontine myelinolysis?

2017