超短效β阻滞剂治疗严重冠脉病变患者心肌缺血疗效的观察

　　作者：钱海燕1，黄　觊2，杨跃进1，李志忠2，张京梅2 作者单位：1.中国医学科学院北京协和医学院阜外心血管病医院冠心病诊治中心，北京，100037;2.首都医科大学附属北京安贞医院　北京市心肺血管疾病研究所

　　【摘要】 目的：探讨超短效β受体阻滞剂艾司洛尔缓解严重冠状动脉病变所致心肌缺血的效果。方法：连续入选冠状动脉病变严重的冠心病患者57例，男34例，女23例，年龄55～87，平均(69±19) 岁。所有入选患者均具有与心肌缺血相关的典型症状，心电图有缺血性ST-T改变，不具备条件或不愿意行血运重建，常规使用硝酸酯、吗啡等药物后症状未能完全缓解;给予盐酸艾司洛尔注射液， 以用药前及之后4h为疗效评价时间点;其指标包括症状评分、血常规及心肌标记物，心电图和超声心动图等指标。结果：41例显效，9例有效，7例无效，有效率达87.7%。41例显效患者在用药后(66±23) min症状完全缓解(P<0.0001)，心率和血压均显著下降(P<0.0001)，心电图ST段恢复至基线(P<0.0001)。9例有效患者在用药后4h症状获得部分缓解，与缺血相关症状减轻(59.1±13.9)%(P<0.0001)，心率和血压均显著下降(P<0.0001)，心电图ST段较用药前恢复60.1%(P<0.0001)。所有患者用药期间均无严重不良反应。结论：艾司洛尔可迅速、安全、有效缓解因严重冠脉病变导致的心肌缺血症状和心电图ST-T变化。

　　【关键词】 艾司洛尔,冠状动脉疾病,心绞痛;心肌梗塞

　　Abstract：Objective：To explore the efficacy of Esmolol on cardiac ischemia in patients with serious coronary lesions who are not candidates for coronary revascularizations.Methods：Fifty seven aged patients (34 male) with serious coronary artery disease not candidates for coronary revascularizations were included. All patients had classical angina involved in cardiac ischemia， and definitely ischemic ST-segment depressions in surface electrocardiogram， however which were not relieved by routine treatment including intravenous nitrate or even morphine. All patients received loading dose injection and continuously intravenous infusion of Esmolol， and the baseline characteristics before treatment and the effects at 4 hours after infusion of Esmolol were carefully recorded. Results：After infusion of Esmolol， the ischemia-related symptoms of 41 patients completely relieved， and their ST depressions recovered to the baseline accompanied with significant reduction in blood pressure and heart rate (P<0.0001 all) within (66±23) min. Moreover， nine patients were observed that their ischemia-related symptoms relieved and ST alteration recovered partially (P<0.0001 both) at 4 h after continuous infusion of Esmolol.Conclusion：Esmolol is effective to relieve the serious cardiac ischemia-related symptoms and ST-T alteration of ECG in patients with serious coronary lesions.

　　Key words：Esmolol; Coronary Artery Disease; Angina; Myocardial Infarction

　　With the progress in people′s lives， the prevalence of coronary heart disease (CHD) increases. Although percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) can be used to revascularize for stenotic or occluded coronary arteries， there are still numerous patients who are not candidates for coronary revascularization because of the extremely severe or extensive lesions of coronary arteries or associated other clinical diseases， such as liver dysfunction， renal failure， etc. However， ischemia-related symptoms are difficult to be relieved by routine therapies， such as intravenous nitrate and morphine etc. in these patients. As a kind of ultra-short-acting β-blocker， Esmolol is highly selective to block β1 adrenergic receptors， and can be used to alleviate cardiac ischemia via inhibiting cardiac constriction， decreasing heart rate (HR) and reducing cardiac oxygen requirements. However， there were not reports about treatment with Esmolol in CHD patients with severe coronary lesions up to date. Based on this， the present study is aimed to explore the effectiveness of Esmolol on seriously cardiac ischemia in CHD patients who are not candidates for coronary revascularization.

　　1　Data and methods

　　1.1　Clinical data

　　There were 57 patients [34 male (59.6%)， 23 female (40.4%)] aged 55-78 years old [mean age (69±19) years old] enrolled in the study， who were admitted in Fuwai Hospital from January 2008 to December 2010. All included patients at least have one kind of concomitant diseases and risk factors for CHD， such as hypertension， diabetes， hyperlipidemia， dysfunction of liver or kidney， serious anemia， thrombocytopenia， cerebral infarction or hemorrhage， malignant tumor， etc. In addition， most of these patients received at least one time of coronary revascularization， including PCI or CABG.

　　1.2　Inclusion criteria

　　All included patients had cardiac ischemic symptoms， ischemia-related ST segment depression in electrocardiogram (ECG)， and related data of coronary angiography (CAG). In addition， they met all of the following criteria： (1) They received CAG in the near 12 months; (2) According united consultation by PCI physicians and thoracic surgeons， they were not candidates for coronary revascularization， including PCI or CABG， due to the extremely risks such as poor coronary conditions or too many concomitant diseases; (3) When being included into the present study， these patients were suffering from an attack of cardiac ischemia， including chest pain or dyspnea that assessed as class IV of angina classification of Canadian Cardiology Society (CCS)， and had the ST segment depression >1mm in two or more neighboring ECG leads. The cardiac biomarkers (cardiac troponin I) increased or not increased in these patients; (4) At the time of attack of the cardiac ischemia， blood pressure (BP) and HR increased (more than 120/80mmHg and 80 beats/min); (5) After being treated with routinely intravenous infusion of nitrates and morphine， the ischemia-related symptoms were not obviously alleviated.

　　1.3　Treatment protocol

　　All subjects received loading dose injection of Esmolol with 0.5mg/kg during 1min， and then were given continuous intravenous drop infusion with 0.05mg/kg?min as the beginning dose. If the effects were not obvious， the Esmolol was repeated loading dose and the sustaining dose was increased by 0.05mg/kg?min every time until the maximal dose of 0.3mg/kg?min. During Esmolol administration， ECG， pulse， and BP were monitored bedsidely.

　　The criteria of stopping infusing Esmolol： (1) The effects were not significant yet until 4h after Esmolol administration; (2) The bradyarrhythmias were significant (HR<50 beats/min); (3) BP was lower than the normal level (<90/60mmHg).

　　1.4　Effects assessment

　　From the beginning of Esmolol treatment to 4h after Esmolol treatment (endpoint)， the symptom score of cardiac ischemia and changes of ST segment depression were continuously recorded. The symptom score of cardiac ischemia was recorded according to patient′s subjective assessment， in which the most severe indisposition was recorded as 100 scores. Furthermore， the changes of ST segment depression were recorded as the number of millimeter.

　　In general， the therapeutic efficacy at 4h after treatment was classified as three kinds： (1) remarkable effects (RE)： the ischemia-related symptoms completely alleviated and ST segment depressions recovered to the baseline level; (2) partial effects (PE)： the ischemia-related symptoms alleviated with less than 50% and ST segment depressions recovered with >50% but not to baseline level; (3) no effects (NE)： the ischemia-related symptoms not significantly alleviated and ST segment depressions not changed or recovered with less than 50%.

　　All subjects were examined with echocardiography， blood routine， blood glucose， blood lipid， blood clotting， blood gas and myocardium biomarkers， etc.

　　1.5　Statistical analysis

　　Measurement data were presented as means ± standard deviation(x-±s)， and numberation data were expressed as percentage. The paired t-test was used to analyze symptom scores and alteration of ST segment in ECG before and after Esmolol administration. P<0.05 was considered statistically significant， and all analyses were performed with SPSS version 13.0 (SPSS， Illinois， USA).

　　2　Results

　　2.1　The general clinical data

　　Most of these subjects complicated with， such as hypertension (82.5%)，hyperlipidemia (77.2%)，diabetes (75.4%)， and a few of them with valvular heart disease and cardiomyopathy. There were 9 subjects (15.8%) with NYHA class Ⅱ-Ⅲ. Moreover， it is important that most of the subjects complicated with dysfunction of liver or kidney. Echocardiography showed that the end-diastolic left ventricular diameter was (59±11)mm， and left ventricular ejection fraction was (48±10)%， suggesting that their heart function were injured. The detailed data were shown in Table 1.Table 1　Clinical Data

　　COPD： Chronic obstructive pulmonary disease; CABG： coronary artery bypass grafting; PCI： percutaneous coronary intervention; LVEDd： left ventricular end-diastolic dimension; LVEF： left ventricular ejection fraction.

　　Further analyses of CAG data showed that most subjects had double or triple coronary arterial lesions (45.6%)， and that 29.8% of subjects had serious lesions in left main coronary artery plus triple coronary arteries. In addition， complete occlusion existed in at least one major coronary artery in 78.9% of subjects. The detailed data were shown in Table 2.

　　2.2　Therapeutic effects

　　The total effective rate was 87.7%.

　　2.2.1　Remarkable effects(RE)： RE was observed in 41 patients (71.9%)， the effects were achieved at (66±23) min after Esmolol administration (P<0.0001)， accompanied with reduction in BP and HR (P<0.0001 both). In addition， ST segment recovered to the baseline level (P<0.0001).

　　2.2.2　Partial effects (PE)： PE was observed in 9 patients (15.8%)， the symptoms were partially alleviated with (59.1±13.9)% (P<0.0001) at 4h after Esmolol administration compared with the baseline values， accompanied with reduction in BP and HR (P<0.0001 both)， and with recovery of ST segment depression with (60.1±19.2)% (P<0.0001).Table 2　Coronary Angiography data*Lesion： stenosis of coronary arterial lumen ≥70%; LM： left main coronary artery; #major vessel：indicating left anterior descending coronary artery， left circumflex coronary artery， or right coronary artery;LIMA：left interhal mammary artery;SVG：saphenous vein.

　　2.2.3　No effects(NE)： There were 7 patients (12.3%) although BP and HR significantly decreased (P<0.0001 both) compared with before Esmolol treatment， but the ischemia-related symptoms not significantly alleviated (P=0.059)， and ST segment recovered with (24.4±13.3)% which was not statistically significant (P=0.061). The detailed analyses were shown in Table 3.

　　2.2.4　Side effects： There were 13 subjects (22.8%) including 6， 4 and 3 subjects whose HR decreased to less than 50 beats/min and 9 subjects (15.8%) including 5， 2 and 2 patients whose BP decreased to less than 90/60 mmHg respectively in RE， PE and NE patients. Those patients with reduction in BP or HR felt sweating， dizziness， palpitation， which could recover in 30min after decreasing the dose or stop the application of Esmolol. Besides， other side effects related to Esmolol were not observed， such as heart failure， hypoglycemia， damage to liver or kidney， and bronchus spasm， etc.Table 3　Clinical Indices Pre-and Post-treatment with Esmolol

　　3　Discussion

　　As a kind of highly selective blocker to β1 adrenergic receptor in heart， Esmolol exerts efficacy very quickly and maintains its effects for a short time. It has not an intrinsic sympathomimetic acitivity or membrane-stabilizing action at the dose of treatment. However， if being given large dose， the β2 adrenergic receptors are also blocked in smooth muscles of bronchus and vessels. After intravenous injection， the distribution half life (T1/2) of Esmolol is about 2 min， and the elimination half life is 9 min. Esmolol is metabolized rapidly in vivo by esterase in erythrocytes cytoplasm. The characteristic of Esmolol is that its total elimination rate is about 20L/kg h， which is more than cardiac output， therefore， its metabolism is not affected by the tissue blood flow (such as liver and kidney) [1].

　　Esmolol can reduce the HR of healthy people both at rest and exercise， and block the response of increasing HR derived from isoprenaline. Electrophysiology study indicates that Esmolol has a typical efficacy of the blockers to β adrenergic receptors， such as reducing HR， decreasing the automaticity of sinus node， and extending the recovery time of sinus node， the AH interval and the prorsad Wenckebach conduction cycle， etc. The radionuclide angiocardiography showed that Esmolol (0.2mg/kg?min) can reduce the HR at rest， systolic blood pressure (SBP)， biventricular ejection fraction， and cardiac index [2-5]. Its action lowering BP is correlated with the extent of blocking β adrenergic receptors. The blocking effects on β adrenergic receptors will disappear in 10-20min after stopping injection of Esmolol.

　　After an appropriate loading dose of Esmolol followed with continuous intravenous infusion of 0.05～0.3mg/kg?min， the plateau concentration in blood will be quickly achieved in 5 min. If being not given loading dose of Esmolol， then the plateau concentration in blood will be achieved in 30 min. The plateau concentration in blood can be maintained during the continuous infusion of Esmolol， and be rapidly decreased after stopping administration. Because of the short half life， the concentration of Esmolol in blood can be changed by increasing or decreasing the infusion speed [1， 3].

　　The patients included into the present study have extremely severe coronary lesions， including extensive， diffuse and multi-vessel stenosis or occlusion (78.9%)， therefore， it is very limited in both the reserve and the expansion ability of their coronary arteries. Based on this， it is not surprise that even large-dose nitrate or morphine is not effective in these patients. However， the ischemia-related symptoms alleviated and ST segment depression recovered within 4 h after being given intravenous infusion of Esmolol in 87.7% of subjects. All subjects experienced the reduction in BP and HR， suggesting that the alleviation mechanisms by Esmolol are involved in the decrease in the cardiac oxygen requirements， to achieve a balance between oxygen consumption and supply at a new level [2-6].

　　As regards the 12.3% of patients with NE， the ischemia-related symptoms not significantly alleviated in spite of the reduction in BP and HR. The CAG data showed that these patients had more severe coronary lesions such as more occlusion and more LM plus triple-vessel lesions. Therefore， the coronary reserve was extremely low and it was very difficult to achieve a balance between oxygen consumption and supply. However， it is unclear whether the continuous infusion of Esmolol with larger dose and for longer time can alleviate the symptoms? Moreover， the sample size is not large enough to achieve the statistical difference.

　　Furthermore， safety about Esmolol administration is primarily focused on impacts of BP， HR and cardiac function. Studies showed that Esmolol resulted in low BP in 20%-25% subjects (SBP<90mmHg， DBP<60mmHg)， sweating and dizziness in 12% subjects. Therefore it is recommended that dose not exceed 200 μg/kg?min， and close monitoring for BP and HR during infusion of Esmolol. This sudy showed that 15.8% of them with NYHA class II-III， and 22.8% subjects had slower HR (less than 50 beats/min)， and 15.8% subjects had lower BP under normal level， but the cardiac dysfunction was not provoked or aggravated， moreover， these side effects disappeared in 30 min after decreasing dose or stopping infusion; in addition， there were reports[7， 8]， even though cardiac dysfunction was aggravated by Esmolol administration， the recovery was very quick because of the ultra-short half life of Esmolol; so those suggest it is safe.

　　In conclusion， Esmolol is effective to relieve the serious cardiac ischemia-related symptoms in patients with serious coronary lesions.

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