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ISSN (On-line): 1678-9741 Impact Factor: 0.809
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Volume 28 Number 4, October - December, 2013

ORIGINAL ARTICLE

DOI: http://dx.doi.org/10.5935/1678-9741.20130074

Myocardial protection with prophylactic oral metoprolol during coronary artery bypass grafting surgery: evaluation by troponin I

Proteção cardíaca com uso profilático de betabloqueador oral em cirurgia de revascularização miocárdica: avaliação pela troponina I

João Manoel Rossi Neto; Carlos Gun; Rui Fernando Ramos; Antonio Flávio Sanchez Almeida; Mario Issa; Vivian Lener Amato; Jarbas J. Dinkhuysen; Leopoldo Soares Piegas

MD, PhD. Instituto Dante Pazzanese de Cardiologia (IDPC), São Paulo, SP, Brazil

Work carried out at Instituto Dante Pazzanese de Cardiologia (IDPC), São Paulo, SP, Brazil.

Correspondence To:
João Manoel Rossi Neto
Instituto Dante Pazzanese de Cardiologia
Ambulatório novo - Setor de Disfunção Ventricular
Av. Dante Pazzanese, 500 - Vila Mariana
São Paulo, SP, Brazil - Zip code: 04012-180
E-mail: jmrossi@sti.com.br

ABSTRACT

INTRODUCTION: Biochemical markers of myocardial injury are frequently altered after cardiac surgery. So far there is no evidence whether oral beta-blockers may reduce myocardial injury after coronary artery bypass grafting.
OBJECTIVE: To determine if oral administration of prophylactic metoprolol reduces the release of cardiac troponin I in isolated coronary artery bypass grafting, not complicated by new Q waves.
METHODS: A prospective randomized study, including 68 patients, divided in 2 groups: Group A (n=33, control) and B (n=35, beta-blockers). In group B, metoprolol tartrate was administered 200 mg/day. The myocardial injury was assessed by troponin I with 1 hour and 12 hours after coronary artery bypass grafting.
RESULTS: No significant difference between groups regarding pre-surgical, surgical, complication in intensive care (15% versus 14%, P=0.92) and the total number of hospital events (21% versus 14%, P=0.45) was observed. The median value of troponin I with 12 hours in the study population was 3.3 ng/ml and was lower in group B than in group A (2.5 ng/ml versus 3.7 ng/ml, P<0,05). In the multivariate analysis, the variables that have shown to be independent predictors of troponin I release after 12 hours were: no beta-blockers administration and number of vessels treated.
CONCLUSION: The results of this study in uncomplicated coronary artery bypass grafting, comparing the postoperative release of troponin I at 12 hours between the control group and who used oral prophylactic metoprolol for at least 72 hours, allow to conclude that there was less myocardial injury in the betablocker group, giving some degree of myocardial protection.

Keywords Troponin I. Postoperative care. Adrenergic beta-antagonists.


RESUMO

INTRODUÇÃO: Os marcadores bioquímicos de lesão miocárdica estão frequentemente alterados após cirurgia cardíaca. Até o momento não existem evidências de que o betabloqueador oral possa reduzir a lesão miocárdica após cirurgia de revascularização miocárdica.
OBJETIVO: Determinar se a administração oral profilática de metoprolol reduz a liberação de troponina cardíaca I na cirurgia de revascularização miocárdica isolada não complicada por novas ondas Q.
MÉTODOS: Estudo prospectivo, randomizado, incluindo 68 pacientes divididos em 2 grupos: Grupo A (n=33, controle) e B (n=35, betabloqueador). No grupo B, o tartarato de metoprolol foi administrado na dose de 200 mg/dia. A lesão miocárdica foi avaliada pela troponina I com 1 hora e 12 horas após a cirurgia de revascularização miocárdica.
RESULTADOS: Não foi observada diferença significativa entre os grupos quanto às variáveis pré-cirúrgicas, cirúrgicas, incidência de complicações na terapia intensiva (15% versus 14%; P=0,92) e o número total de eventos hospitalares (21% versus 14%; P=0,45). O valor da mediana da troponina I com 12 horas na população estudada foi de 3,3 ng/ml e foi menor no grupo B do que no grupo A (2,5 ng/ml versus 3,7 ng/ml; P<0,05). Na análise multivariada, as variáveis que demonstraram serem preditoras independentes da liberação de troponina cardíaca I com 12 horas foram: não uso de betabloqueadores e número de vasos tratados.
CONCLUSÃO: Os resultados desta investigação na cirurgia de revascularização miocárdica isolada, não complicada, comparando a liberação pós-operatória de troponina cardíaca I com 12 horas entre os grupos controle e o que usou metoprolol oral profilático por pelo menos 72 horas, permitem concluir que houve menor lesão miocárdica no grupo betabloqueador, conferindo algum grau de proteção miocárdica.

Palavras-Chave Troponina I. Cuidados pós-operatórios. Antagonistas adrenérgicos beta.

ABBREVIATIONS AND ACRONYMS

CABG: Coronary artery bypass grafting

EKG: Electrocardiogram

ICU: Intensive Care Unit

MMN: Markers of myocardial necrosis

TnI: Troponin I

INTRODUCTION

An increase in troponin levels is observed following cardiac surgery, indicating myocardial injury [1,2]. The values considered normal or expected after coronary artery bypass grafting (CABG) suffer multifactorial influences such as type of surgery, duration of ischemia and myocardial protection, inflammatory response, reperfusion injury, excessive stretching and contraction of the heart, atheromatous embolism, inadequate coronary perfusion and excessive perioperative cardiac work.

Beta-blockers can be defined as pharmacologic agents that antagonize specifically, competitive and reversible the action of endogenous or exogenous catecholamine in beta-adrenergic receptors. Particularly in the heart, beta-adrenergic stimulation leads to increased heart rate and myocardial contractility. Depending upon the selective ability to antagonize the effects of catecholamines in certain tissues at doses lower than those required in others, beta-blockers may be classified as selective and non-selective. The beta-1 selective blockers are considered cardioselective because the heart contains predominantly beta-1 and less beta-2; since the bronchodilation is mediated by beta-2 receptors, and this characteristic is dose-dependent and decreases or disappears when employing high doses. Possible deleterious effects resulting from the use of beta-blockers that could cause myocardial depression and/or worsening of existing lung disease, however, are of concern for some cardiac surgeons.

The clinical benefits of beta-blocker therapy have been proven in the treatment of myocardial infarction, heart failure, protection of preoperative patients with ischemic heart disease and in the prevention of atrial fibrillation postoperatively [3,4].

From the clinical and research perspective, it is desirable to describe the plasma levels of markers of myocardial necrosis (MMN) as troponins, released in CABG that are not caused by infarction postoperatively and evaluate possible myocardial protection procedures that could reduce the MI. It is plausible to expect that the results of the protective effects of beta-blockers can be extrapolated to CABG. Therefore, the aim of this study is to test the hypothesis that the prophylactic use of oral metoprolol tartrate reduces MI, assessed by the release of troponin I (TnI) in the first 12 hours of post-CABG alone and not complicated by the presence of new Q waves on the electrocardiogram (EKG), conferring myocardial protection.

 

METHODS

This is a randomized, open-label and single center study. Inclusion criteria for the study were indication for CABG regardless of age or gender with signed informed consent term. Exclusion criteria for the study were: previous use of beta-blockers; contraindication to beta-blockers; clinical signs of systolic heart failure, global ejection fraction less than 50%; CABG associated with other procedures (valve replacement or aneurysmectomy or endoaneurysmorrhaphy), presence of new Q waves on EKG during the period of stay in the Intensive Care Unit (ICU) and presence of acute myocardial infarction less than 30 days of evolution.

All patients underwent CABG with the same surgical technique (intermittent aortic clamping) and a graft of the left internal thoracic artery had to be implanted.

The metoprolol tartrate (oral) was initiated at least 72 hours before surgery, in the target dose of 200 mg/day.

TnI concentrations were determined by immunometric method using the Immulite Analyser (DPC - Diagnostic Products Corporation - Los Angeles, USA). Three samples of blood were collected for the determination of TnI: in the preoperative period, with one hour and 12 hour arrival in the ICU. A program developed by the authors of the EuroSCORE was used for the score calculation of each patient [5].

The intercurrences and complications (inotropes >24 hours, intubation >24 hours, temporary pacemaker, the ICU stay for >24 hours, stroke, atrial fibrillation, and death) were registered in the medical record and transferred to the clinical form of the study.

Due to the difficulty of finding information on the variability of the difference between TnI between the two groups (with and without beta-blockers) initially several simulations were performed to estimate the sample size. After the completion of the study, the statistical difference (1.2) and standard deviation of the difference (1.7) were calculated, and it was observed a test power of 85%.

Results were expressed as mean and standard error or median and quartiles for quantitative variables, while qualitative variables were expressed as relative frequencies. Possible associations between qualitative variables were evaluated using the chi-square or Fisher exact test. For comparison of quantitative variables between the control and beta-blocker groups was used t-test for variables with normal distribution and for those without normal distribution (with an hour I TnI, TnI 12 hours and number of vessels treated) the Mann-Whitney test was applied. The Spearman correlation was used to examine the association between quantitative variables and Tn I of 12 hours.

For the choice of the independent variables on the model of multivariate analysis, variables that had significant correlation were selected and by clinical judgment the ones that could also influence the release of TnI 12 hours. For the selection of best model, which had a reduced number of variables the Akaike method was applied, that uses a generalized linear model of gamma distribution (link function log). The gamma model was selected by presenting a better fit in the residual analysis.

Results were considered statistically significant when P-values were less than 0.05.

This study was approved by the Ethics Research Committee of our Institution (protocol number: 2089).

 

RESULTS

Initially 70 patients were selected and after recruitment, two cases were not considered from the analysis because they had new Q waves on EKG 12 hours after surgery.

Patients were allocated for two groups, 33 (48.5%) patients in the control group, and the other 35 (51.5%) in the beta-blocker group. The dose in one patient was reduced to 100 mg/day due to asymptomatic heart rate less than 50 bpm.

The clinical and surgical characteristics of the groups are described in Tables 1, 2 and 3.

 

 

 

Table 4 presents the results of the values of Tn I with 1 hour and 12 hours of arrival in the ICU between the control and beta-blockers. TnI values were lower in the beta-blocker group than in the control group.

 

However, this difference was only statistically significant in the 12 hours postoperatively data (2.50 versus 3.70, P=0.048).

The changes of TnI were analyzed 12 hours post-operative and their association with some clinical and surgical variables. In addition to the variable group, univariate analysis showed that the factors to be correlated with the release of TnI 12 hours were perfusion time, cross clamp time and the number of grafts performed (Table 5). Although statistically significant, this relationship was considered weak by analyzing the values of correlation (R).

 

There was no significant difference in relation to postoperative complications in the ICU and in-hospital events between groups (21% in the control group versus 14% in patients with beta-blocker, P=0.454) (Table 6).

 

In the final model of the multivariate analysis, the variables that have shown to be independent predictors of TnI release after 12 hours were: no beta-blockers administration and number of grafts required. Table 7 shows the percentage increase and the results expected. No beta-blockers administration increases in 22% the expected value of troponin 12 hours and for each graft required adds a 33% increase.

 

 

DISCUSSION

The results of this study prospectively evaluated 68 patients undergoing isolated CABG revealed for the first time in literature, a myocardial injury reduction in the group using oral beta-blocker at a dose of 200 mg/day for at least 72 hours preoperatively.

Some demographic characteristics in the general population of the study should be highlighted as the presence of women in one third of patients, average age below 60 years, more than a third with previous myocardial infarction, diabetes mellitus with a third, more than 70% with hypertension, more than 50% with dyslipidemia and all with ventricular function regarded as good. This population was considered low risk (mean EuroSCORE 2.0). Clinical characteristics were distributed equally in both groups, except for preoperative heart rate, which was lower in the beta-blocker group (73.8 versus 68.2, P=0.035).

The myocardial injury is associated with cardiac surgery and can be caused by different mechanisms, including: direct trauma by suturing and manipulation of the heart; regional or global ischemia by inadequate cardiac protection, coronary dissection, microvascular events related to reperfusion or failure to perform the grafts [6]. Moreover, no biological marker is able to distinguish the injury caused by infarction that occurs in small quantities in myocardial cells, which usually are associated with the procedure itself [6]. However, the higher the value for a cardiac biochemical marker after the procedure, the greater the myocardial injury, regardless of the mechanism of injury. Despite the difficulties in interpreting the troponin level after a CABG, it is known that the higher this value, the worse the prognosis [7,8].

In this study, patients who used beta-blockers had a significant reduction in the levels of cTnI (2.50 ng/ml versus 3.70 ng/ml, P=0.048), with a trend in the reduction of hospital events, despite not achieving statistical significance (14% versus 21%, P=0.454). It was also shown that the longer the perfusion time, the anoxic time, and the number of grafts required, the higher levels of TnI at 12 hours postoperatively. However, in multivariate analysis, independent predictors of troponin release were the number of grafts required and the fact of not using beta-blockers (control group).

The clinical significance of this minimum or expected TnI amount has not yet been elucidated. In this study, despite the lower release in the beta-blocker group, there was no significant difference in relation to in-hospital events, probably because the study was not designed with this objective and the sample size was insufficient.

On the other hand, the main interest of this study was to observe the behavior changes of TnI with a single prophylactic pharmacological intervention. Therefore, we excluded those who had a specific diagnostic criteria for perioperative myocardial infarction (presence of new Q waves on postoperative) known to elevate a lot the level of TnI. The use of a simple method of myocardial protection, as the use of prophylactic oral metoprolol, combined with new advances in surgical techniques and postoperative care, can further reduce the minimum expected release of markers of myocardial necrosis and thus possibly improve prognosis in CABG.

The mechanisms of myocardial protection of beta-blockers in CABG are not yet fully understood. Animal experiments suggest that beta-blockade is cardioprotective during reperfusion, either by reduction in infarct size, improvement of ventricular function, reduction in apoptosis or decrease of myocardial edema [9,10]. The possible mechanisms involved in this protection include reducing the release of oxygen free radicals and adhesion to endothelium nuclear polymorphs (major source of inflammatory response) [11]. During cardiac surgery with extracorporeal circulation there is a significant increase in the levels of catecholamines, resulting in an acute desensitization of beta-adrenergic receptors induced by these agonists. It is a cause of myocardial depression that occurs after surgery [12]. Probably the mechanisms of myocardial protection with the use of metoprolol are related, in part, with reductions of some ischemic process or metabolic changes that occur after surgery. There are no data in the literature to confirm whether reduced levels of TnI are the result of minor trauma straight from the heart with the use of beta-blockers, and what role of this mechanism in myocardial injury and its clinical relevance.

Limitations of this study include being a single center, there is no standardization of the available tests for troponin, using intermittent clamping as surgical technique (and not be applied to other techniques) and cases of infarction without Q-wave in post-CABG are not identified, since there is no definition for diagnosis in clinical studies. This study used a low-risk population, and therefore with lower prevalence of hospital events, which may have contributed to no statistical differences between the groups. Finally, a larger sample of patients could extend the results obtained, but as the hospital morbidity and mortality are considered low in low-risk patients undergoing CABG surgery, multicenter clinical trials would be needed with a very large population to assess reduction of infarction postoperatively and hospital events with the use of prophylactic beta-blockers in addition to the impact of the minimum TnI changes in the possible risk factors and prognosis. There is a need to clarify whether changes of TnI in non-complicated patients with new Q waves on EKG have any clinical consequences after discharge, because this study was limited to in hospital follow up.

The clinical implications of this study allow us to assure that there is some degree of myocardial injury even in uncomplicated patients and it becomes mandatory, therefore to define which the minimum reference value of cTnI is after CABG and correlate the values with prognosis. The reduction of TnI in the beta-blocker group in this study may help to understand the benefits of this medication, since it is known that the higher the levels of troponin, the worse the prognosis of patients, regardless of the pathophysiological mechanisms involved [8,13].

 

CONCLUSION

The results of this research in isolated CABG, not complicated by the presence of new Q waves on EKG, comparing the release of TnI with 12 hours postoperative between the control group and who used oral prophylactic metoprolol for at least 72 hours, allow us to conclude that there was less myocardial injury in the beta-blocker group, conferring myocardial protection.


REFERENCES

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13. Taniguchi FP, Pego-Fernandes PM, Jatene FB, Kwasnicka KL, Strumz CMC, Oliveira SA. Implicação prognóstica da creatino-quinase miocárdica e troponina na revascularização do miocárdio. Rev Bras Cir Cardiovasc. 2003;18(3):210-6. [See article]

Article received on march 4, 2013.

Article accepted on july 10, 2013.

No financial support.

Author's roles & responsibilities

JMRN: Protocol design, data collection, discussion of results and manuscript writing

CG: Discussion of results

RFR: Discussion of results

AFSA: Surgical procedures and discussion of results

MI: Surgical procedures and discussion of results

VLA: Data collection and discussion of results

JJD: Discussion of results

LSP: Protocol design, discussion of results and manuscript writing

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