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Interact CardioVasc Thorac Surg 2005;4:242-247. doi:10.1510/icvts.2004.101576
© 2005 European Association of Cardio-Thoracic Surgery
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ESCVS article - Experimental

NT-proBNP in cardiac surgery: a new tool for the management of our patients?{star}

Guillermo Reyesa,*, Gloria Forésb, R. Hugo Rodríguez-Abellaa, Gregorio Cuerpoa, José Luis Vallejoa, Carlos Romeroc and Ángel Pintoa

a Department of Cardiovascular Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
b Department of Anesthesia, Hospital General Universitario Gregorio Marañón, Madrid, Spain
c Department of Chemistry, Hospital General Universitario Gregorio Marañón, Madrid, Spain

Received 28 October 2004; received in revised form 28 February 2005; accepted 1 March 2005

{star} Presented at the 53rd International Congress of the European Society for Cardiovascular Surgery, Ljubljana, Slovenia, June 2–5, 2004.

*Corresponding author. Tel.:+34 915868370/34 915411254; fax: +34 915868369.

E-mail address: guillermo_reyes_copa{at}yahoo.es (G. Reyes).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Objectives: Our aim was to determine NT-proBNP levels in patients undergoing cardiac surgery and if those levels are related to any of the baseline clinical characteristics of patients before surgery or any of the outcomes or events after surgery. Methods: Prospective, analytic study including 83 consecutive patients undergoing cardiac surgery. Preoperatory and postoperatory data were collected. NT-proBNP levels were measured before surgery, the day of surgery, twice the following day and every 24 h until a total of nine determinations. Venous blood was obtained by direct venipuncture and collected into serum separator tubes. Samples were centrifuged within 20 min from sampling and stored for a maximum of 12 h at 2–8 °C before the separation of serum. Serum was stored frozen at –40 °C and thawed only once at the time of analysis. Results: Mean age was 65±11.8 years. An Euroscore 6 was found in 30% of patients. NYHA classification was as follows: I:27.7%; II:47%; III:25.3%. Preoperative atrial fibrilation occurred in 20.5% of patients. After surgery 18.1% of patients required inotropes. Only one death was recorded. A great variability was found in preoperative NT-proBNP levels; 759.9 (S.D.:1371.1); CI 95%: 464.9 to 1054.9 pg/ml, with a wide range (6.39–8854). Median was 366.5 pg/ml. Preoperative NT-proBNP levels were unrelated to the type of surgery (CABG vs. others), sex, age and any of the cardiovascular risk factors. NT-proBNP levels were higher in high risk patients (Euroscore 6); (P=0.021), worse NYHA class (P=0.020) and patients with preoperative atrial fibrilation (m 1767 (2205) vs m 621 (1017); P=0.001). After surgery NT-proBNP levels started increasing the following day until the fourth day (P=0.03), decreasing afterwards (P=0.019). These levels were significantly higher in patients requiring inotropes after surgery (P<0.001). We did not find any relationship between NT-proBNP levels and complications rate (P=0.59). Conclusions: Preoperative NT-proBNP levels depend on preoperative patient status (Euroscore, NYHA class and cardiac rhythm) and they increase significantly after cardiac surgery. This increase is higher when postoperative inotropes are needed. We found no relation between NT-proBNP levels and complications rate. An association have been shown between NT-proBNP levels and the use of inotropes after cardiac surgery.

Key Words: NT-proBNP; Cardiac surgery; Biomarker; Inotropes


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Neurohormones like atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), are natriuretic cardiac peptides whose function are to regulate sodium and water homeostasis, and to control intravascular volume and blood pressure. High filling pressures of cardiac chambers and ventricle dysfunction are the main mechanisms that increase the synthesis and release of these peptides. In the same manner, BNP levels increase with diastolic ventricle dysfunction and in patients with hypertension or aortic stenosis. Although originally isolated from pig brain samples, the primary site of synthesis is ventricular myocardium [1,2]. Therefore, these peptides can be used in the diagnosis, prognosis and efficacy of cardiac diseases [3,4]. ProBNP is the peptide from BNP and NT-proBNP originates. It is known that NT-proBNP can be found in higher concentration in plasma than BNP, is more stable, and some authors have suggested that it could be a better biomarker, regarding prognosis, than BNP [5,6].

Several authors have studied BNP levels after extracorporeal circulation and how these levels increase after surgery requiring even weeks to return to preoperative levels [7–11]. In some cases, a relationship has been proved between BNP levels and the appearance of complications after surgery [7,10]. However, only a few studies have been reported using NT-proBNP as a tool in cardiac surgery [12].

The present study aims at determining several objectives: (1) the relationship between NT-proBNP levels and baseline clinical characteristics of patients undergoing cardiac surgery, (2) how NT-proBNP behaves after cardiac surgery and (3) its possible usefulness as a predictor of complications and prognosis in patients following cardiac surgery.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Acknowledgments
 References
 
2.1. Patients

A prospective and analytical study was performed during a six month period (from June 2003 to November 2003) analyzing NT-proBNP levels in 83 consecutive patients undergoing elective major cardiac surgery in our hospital.

Exclusion criteria were: patients with severe hepatic failure or established cirrhosis, patients with severe renal failure (creatinine 3.5 mg/dl or patients with dialysis), off-pump surgery and emergency surgery. Informed consent was obtained from all patients before inclusion.

Conventional median sternotomy was performed in all patients. Anesthesia was induced with midazolam, propofol and fentanyl. Anesthesia was maintained with sevoflurane before cardiopulmonary bypass (CBP) and with propofol and remifentanyl on CBP, according the anaesthetist criteria. Anticoagulation was achieved with heparin 3–4 mg/kg to maintain an activated clotting time over 450 s. Reversal of heparin was achieved with protamine.

Cardiopulmonary bypass was achieved with a roller pump and a membrane oxigenator. After the aortic clamp was applied, a solution of 1000–1500 cc of hematic cardioplegia was administered. Then another 400–550 cc. of solution was administered every 20–30 min until the end of the procedure. Patients were cooled to a core temperature of 28 °C. Mean arterial pressure was maintained above 60 mmHg for the duration of CBP.

Preoperatory and postoperatory data were collected. A perioperative myocardial infarction was considered when two out of the following three conditions were found: (1) New Q waves in the postoperative electrocardiogram; (2) Increase of CPKMB levels above 10% of CPK; (3) Myocardial contractility alterations objectified by an echocardiogram that did not exist previously. Respiratory failure was considered when mechanical ventilation was required for more than 72 h.

2.2. Blood samples and laboratory test

A total of 9 samples of NT-proBNP were taken in every patient. The first one was taken at the same time as the rest of preoperatory analysis. The next eight samples were obtained after surgery. Once on the afternoon of surgery (20:00 h), twice the following day (08:00 and 20:00) and then at 08:00 h during the next five days.

Venous blood was obtained by direct venipuncture and collected into serum separator tubes. Samples were centrifuged within 20 min from sampling and stored for a maximum of 12 h at 2–8 °C before the separation of serum. Serum was stored frozen at –40 °C and thawed only once at the time of analysis. NT-proBNP serum concentrations were determined using an automated method (Elecsys 2010; Roche Diagnostics).

Elecsys ProBNP assay is an electrochemiluminescence sandwich immunoassay, which uses two polyclonal antibodies directed against the epitopes NT-proBNP [1–21] and NT-proBNP [39–59] as described previously [5]. The analytical range extends from 5–35.000 pg/ml. At our laboratory the intra- and interassay variation coefficient was 3% and 1.8%, respectively.

2.3. Statistical analysis

We summarised categorical variables with frequency and percentages and continuous variables with mean (m), standard deviation (S.D.), median and interquartile range (IQR). We used Pearson chi-square or Fisher's exact test for univariate comparisons of categorical data and Mann–Whitney U test for comparisons of continuous data between groups and used Pearson's correlation coefficient or Spearman's rho for the bivariate correlations analysis. Finally we applied the General Lineal Model (GLM) Repeated Measures procedure that provides analysis of variance between-subjects factors and within-subjects (NT-proBNP before surgery, day of surgery, twice the following day and once every day until sixth day). The statistical model included a full factorial model that contained main effects and interaction effects. P values for all hypothesis tests were two sided and statistical significance was considered when P was <0.05. Data were analysed using a statistical software program (SPSS for Windows11.5, SPSS Inc., Chicago, IL, USA).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Acknowledgments
 References
 
3.1. Preoperative data

A total of 83 patients were included, 50 males and 33 females (ratio M/F 1.51), aged between 25 and 83 years (mean 64.6 [S.D.:11.9]; CI 95%: 62 to 67.2 years). NYHA classification was as follows: NYHA class I in 23 patients (27.7%), NYHA class II in 39 patients (47%) and NYHA class III in 21 (25.3%). According to the Euroscore classification 20 patients (24.1%) classified into the low risk group (Euroscore 0–2), 39 patients (47%) into the moderate risk group (Euroscore 3–5) and 24 patient (28.9%) into the high risk group (Euroscore≥6). Table 1 shows preoperative baseline characteristics of patients.


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  		Table 1 Baseline clinical characteristics of patients undergoing cardiac surgery

 
In Table 2 can be seen the need of inotropes and surgery complications. Twenty-eight patients underwent exclusively CABG surgery. Bypass time was 101.8 (S.D.:35.3); CI 95%: 94.2 to 109.4 min. Crossclamp time was 66.4 (S.D.:27.8); CI 95%: 60.3 to 72.5 min. Length of stay was 11.3 (S.D.:8.8); CI 95%: 9.4 to 13.2 days. Only one death was registered during the follow-up.


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  		Table 2 Need of inotropes and surgery complications

 
3.2. NT-proBNP preoperative levels

Preoperative NT-proBNP levels were 759.9 [S.D.:1371.1]; CI 95%: 464.9 to 1054.9 pg/ml, with a wide range (6.39–8854) which shows a great variability. Median was 366.5 pg/ml.

Preoperative NT-proBNP levels were unrelated to the type of surgery (CABG vs. others), sex, age and cardiovascular risk factors. Patients who previously were in atrial fibrilation had NT-proBNP higher levels than those patients in sinus rhythm (621;S.D.:1017 vs. 1767;S.D.:2205.2 pg/ml; P=0.001) There was no relation between NT-proBNP levels and comorbility. NT-proBNP levels were not higher in patients with previous history of myocardial infarction, however, there was a trend towards higher levels of NT-proBNP in those patients with previous history of heart failure (841;S.D.:1557.3 vs. 896;S.D.:947.2 pg/ml; P=0.09) (Table 1).

In Fig. 1, it may be observed how NT-proBNP levels increased in patients with worse NYHA class (median: class I: 248.8; class II: 430.1; class III: 700.9; Statistical significance in all three groups, P=0.02).



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  		Fig. 1. Relationship between preoperative NYHA class and NTproBNP levels. Data are expressed as box and whiskers plots. NT-proBNP levels increase significantly as the NYHA functional class gets worse; P=0.02.

 
In the same way a higher score in the Euroscore classification was accompanied by higher NT-proBNP levels (Fig. 2) (Median: low risk: 118.2; moderate risk: 365.9; high risk 562.8 pg/ml; Statistical significance in all three groups, P=0.02).



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  		Fig. 2. EUROSCORE stratification and NTproBNP levels. Euroscore classification was accompanied by higher NT-proBNP levels; P=0.02.

 
However, we did not find a relation between preoperative ejection fraction and NT-proBNP levels (851.7;S.D.: 193.7 vs. 872;S.D.: 206.5 pg/ml) (Table 1).

3.3. NT-proBNP after cardiac surgery

In the first determination after surgery NT-proBNP levels were similar to preoperative levels (P=0.76). However, NT-proBNP levels started increasing the next day after surgery (2083.9±2090.5; P<0.001). NT-proBNP levels continued to increase until the fourth day when they started to decrease. Fig. 3 shows NT-proBNP levels after cardiac surgery.



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  		Fig. 3. NTproBNP levels after cardiac surgery. Nine samples were taken. One before surgery (1), one the day of surgery (2), twice the following day (3–4) and then once every day until the sixth day (5–9). NTproBNP levels started to increase the day after surgery up to the fourth day (sample 7) when they start to decrease.

 
NT-proBNP levels were much higher in those patients that required inotropes in theatre or during their stay in the intensive unit care (Fig. 4). These two groups of patients presented a slope of NT-proBNP levels much higher than those patients that did not need inotropes, starting this increase the following day after surgery (P<0.001). NT-proBNP levels started to decrease 2–4 days after the use of inotropes. The number of days that inotropes were needed was 2.3 (S.D.:2.4); CI 95%: 1.08 to 3.52; median 1 (range 1 to 10).



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  		Fig. 4. NTproBNP levels in patients with and without inotropic therapy. Comparison between patients needing inotropic drugs and patients that did not need them (P<0.001). These differences were noted regardless the inotropic therapy was started in the theater room or in the Intensive Care Unit.

 
NT-proBNP levels were unrelated to both bypass and crossclamp time (r=0.12; P=0.31; r=0.15: P=0.18, respectively). There was no relation between NT-proBNP levels and the appearance of complications after surgery (P=0.59). Likewise, NT-proBNP levels did not predict the length of stay.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Acknowledgments
 References
 
In the present study we found a great variability in preoperative NT-proBNP levels. These levels were higher in those patients with atrial fibrilation and previous history of heart failure. Also, we found a correlation between NT-proBNP levels and NYHA class classification. In the same manner, those patients with higher punctuation in the Euroscore system presented higher levels of NT-proBNP. NT-proBNP levels started to increase the day after surgery until the fourth day when they started to decrease. This increase was much higher when inotropes were needed.

Since it was originally described, BNP has been used mainly in the field of cardiology. BNP can be found in brain and atrial tissue, and its production comes mainly from the ventricle myocardium [2]. BNP produces different effects on the organism. BNP stimulates glomerular filtration and decreases sodium reabsorption, thereby increasing natriuresis [13]. Natriuretic peptides relax vascular smooth muscle and have important central and peripheral sympathoinhibitory effects, leading to reduced blood pressure and ventricle preload. In the same manner, BNP inhibits renin and aldosterone production system. Also, BNP has a positive lusotropic effect in the myocardium.

The usefulness of natriuretic peptides as biomarker has been already proved in the management of patients in heart failure, regarding diagnosis, prognosis and as a control in the effectiveness of medical treatment [3,4]. Similarly, NT-proBNP and BNP levels have been related to coronary disease, diastolic dysfunction, ventricle hypertrophy and age of patients [14].

Renal excretion is currently regarded as BNP main clearance mechanism, but some authors assert that this topic awaits further study [18]. To avoid confusion, we decided to exclude from our sample population those patients with severe liver or renal dysfunction.

Some studies have reported some differences between NT-proBNP and BNP [12,15]. NT-proBNP half-life is longer and its concentration in serum is higher than BNP. Also NT-proBNP is easier to handle in the laboratory [16,17]. This is why we decided to use NT-proBNP in our study.

We found a great variability in preoperative NT-proBNP levels. Some authors have reported similar results regarding NT-proBNP levels and NYHA class [19]. In a group of patients undergoing coronary surgery, Chello et al. obtained a positive relation between ANP and BNP levels and NYHA class [20].

The relationship between the Euroscore system and NT-proBNP levels is very promising. Euroscore system has been proved to be a very good prognosis scoring system in the majority of European countries [21]. Age, ejection fraction and previous myocardial infarction are components of the Euroscore system. All these factors have been related to NT-proBNP levels previously, and this may explain our findings. Whether or not NT-proBNP levels could improve the accuracy of the Euroscore system, needs further study.

Contrary to previous reports [19,20], in our study NT-proBNP levels were unrelated to preoperative ejection fraction. One reason for this finding could be the optimal treatment of our patients before surgery, as it is well known that NT-proBNP levels may vary depending on the quality of medical treatment [22].

It was not until the day after surgery that NT-proBNP levels began to increase significantly. Similar results have been reported by other authors [10–12,23,24]. Avidan et al. analyzed BNP levels before and after cardiac surgery [8]. In their study they reported that BNP levels decreased after aortic crossclamp. These levels did not become higher than preoperative levels until two hours after the end of extracorporeal circulation. Mair P. et al. reported that maximum peak of BNP was related to myocardial reperfution after cardioplegia arrest. The hemodilution caused by the extracorporeal circulation is probably the main reason for this. In our study all patients were cooled to 28 °C so we cannot predict the effect of severe hypothermia in cardiac surgery considering NT-proBNP levels.

Some studies with a long follow-up of patients report a complete recovery of NT-proBNP levels after surgery[22,25]. We presume that in our patients this would happen in the same manner after a long period.

We observed that NT-proBNP levels were significantly higher in those patients requiring inotropes. It is well known that some degree of myocardial dysfunction is caused after cardiac surgery. The measure of this dysfunction can be made by clinical features, haemodynamic parameters or by an echocardiogram test. The high association between NT-proBNP levels and the need of inotropic therapy is very promising. Our study suggests that NT-proBNP levels are useful for the use of inotropic drugs as a complementary tool for the management of patients undergoing cardiac surgery. Therefore NTproBNP levels may be an option when an ecocardiogram is not feasible and inotropes may be needed, especially if these levels can be measured in the patient's bed. Collison et al. [12] reported a similar study with 15 patients finding similar results, and they related NTproBNP levels to severe heart failure.

Besides the need of inotropes, we found no relation between NT-proBNP levels and the appearance of complications after surgery. The group of Collison described that 5 out of their 15 patients (33%) reached peaks of NT-proBNP over 25.000 pg/ml. This subgroup of patients suffered a higher rate of complications. In our population only 3 patients (3.6%) reached those levels. One died from multiorgan dysfunction. The second one needed inotropes in the postoperative care unit, suffered arrythmias and a septic shock. The third patient had a normal outcome. It seems that very high NTproBNP levels may reproduce very bad outcomes.

We found that NT-proBNP levels were unrelated to both crossclamp and bypass time. These findings are similar to what other authors have reported [8,11], although some others do find a relation between BNP levels and crossclamp time [9]. It would be interesting to see if NT-proBNP levels at discharge can predict the possibility of new cardiovascular events and the need of a new hospitalization.

Limitations of our study are that we did not find a NT-proBNP level cut off to predict the need of inotropic drugs. Maybe the inclusion of more patients, including emergency patients, is necessary to resolve some of the questions that we could not answer. Due to our short follow-up period, we could not know how NT-proBNP levels correlate with patient outcomes after discharge. Also it can be argued that the longer half-life of NT-proBNP can be a problem as it may not be very sensitive to acute changes. However, we found a clear relationship between NTproBNP levels and the use of inotropes. We determined BNP levels in the first 20 patients and we saw that BNP behaved in quite a similar way that NT-proBNP did. This made us think that both peptides may be appropriate in cardiac surgery.

In conclusion, we found a great variability in preoperative NT-proBNP levels. These levels were higher in those patients with AF, worse NYHA class and worse Euroscore punctuation. NT-proBNP levels started to increase the following day after surgery up to the fourth day. This increase was much higher in those patients requiring inotropes. All these data support that NT-proBNP levels may be a useful tool for the management of inotropes in patients undergoing cardiac surgery.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
References
 
This study has been made possible by the cooperation of Roche® diagnostic and their diagnostic kits, our Statistic Department and the nursery team which never seem to get tired of working.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 

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ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS