Scholarly article on topic 'Comparison of B-type natriuretic peptide and left ventricular dysfunction in patients with constrictive pericarditis undergoing pericardiectomy'

Comparison of B-type natriuretic peptide and left ventricular dysfunction in patients with constrictive pericarditis undergoing pericardiectomy Academic research paper on "Clinical medicine"

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Academic research paper on topic "Comparison of B-type natriuretic peptide and left ventricular dysfunction in patients with constrictive pericarditis undergoing pericardiectomy"

Original Article

Comparison of B-type natriuretic peptide and left ventricular dysfunction in patients with constrictive pericarditis undergoing pericardiectomy

Poonam Malhotra Kapoor, Vikram Aggarwal, Ujjwal Chowdhury1, Minati Choudhury, Sarvesh Pal Singh, Usha Kiran

Department of Cardiothoracic Vascular Anesthesia and 1CTVS, CN Center, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029, India

ABSTRACT

Received: 24-12-09 Accepted: 22-04-10

Chronic constrictive pericarditis (CCP) due to tuberculosis has high morbidity and mortality in the periopeartive period following pericardiectomy because of left ventricular (LV) dysfunction. Brain-type natriuretic peptide (BNP) is considered a marker for both LV systolic and diastolic dysfunction. We undertook this prospective study in 24 patients, to measure the BNP levels and to compare it with transmural Doppler flow velocities, that is, the E/A ratio (E = initial peak velocity during early diastolic filling and A = late peak flow velocity during atrial systole), as a marker of diastolic function and systolic parameters, pre- and post-pericardiectomy, at the time of discharge. The latter parameters have been taken as a flow velocity across the mitral valve on a transthoracic echo. There was a significant decrease in the mean values of log BNP (6.19 ± 0.33 to 4.65 ± 0.14) (P = 0.001) and E/A ratio (1.81 ± 0.21 to 1.01 ± 0.14) (P = 0.001) post pericardiectomy, with a positive correlation, r = 0.896 and 0.837, respectively, between the two values at both the time periods. There was significant improvement in the systolic parameters of the LV function, that is, stroke volume index, cardiac index, systemic vascular resistance index, and delivered oxygen index. However, no correlation was observed between these values and the BNP levels. We believe that BNP can be used as a marker for LV diastolic dysfunction in place of the E/A ratio in patients with CCP, undergoing pericardiectomy. However, more studies have to be performed for validation of the same.

Key words: Brain-type natriuretic peptide, constrictive pericarditis, left ventricular dysfunction, pericardiectomy

DOI: 10.4103/0971-9784.62942

INTRODUCTION

Chronic constrictive pericarditis (CCP) due to various pathologies, especially tuberculosis, is quite prevalent in tropical countries.[1-3] The patients are often young, and present with congestive heart failure with severe left ventricular (LV) dysfunction and renal and hepatic dysfunction late in the disease process, leading not only to increased medical costs not only decreased productivity of the hospitals resources. Diagnosis of CCP is made

by physical examination and radiological techniques, such as, two-dimensional and Doppler Echo, computerized tomography (CT) scan, and magnetic resonance imaging (MRI).[4]

However, the resultant left ventricular (LV) dysfunction measurement requires either invasive monitoring or echocardiography. Cardiac Catheterization performed to document the hemodynamics of constrictive physiology, LV function, and differentiation from restrictive cardiomyopathy is not only

Address for correspondence: Dr. Poonam Malhotra Kapoor, Department of Cardiac Anesthesia, Room No. 8, 7th Floor, CN Center, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029, India. E-mail: drpoonamaiims@gmail.com

time- and labor-intensive, but also expensive, and exposes the patient to intravenous contrast media, with side-effects such as allergic reactions and renal failure.11,51 Although M-mode, two-dimensional (2D), and Doppler echocardiography are noninvasive tests to assess cardiac function, they are not without pitfalls.[6] Doppler echocardiography is yet the standard method used to quantify LV diastolic dysfunction.

Brain-type natriuretic peptide (BNP) is synthesized in the cardiac ventricles in response to LV dysfunction and wall stress in patients with congestive heart failure, ventricular hypertrophy, and acute myocardial infarction.17,81 It has also been seen to be higher in conditions with higher LV filling pressures.19,101 Thus, it is gaining the potential of being termed as the 'white count' for heart failure.1111

The present study was undertaken to measure BNP levels in patients with CCP before and after pericardiectomy, at the time of discharge from the hospital, as well as, to evaluate its association with LV systolic and diastolic function indices.

MATERIALS AND METHODS

After obtaining approval from the ethics committee and a written informed consent, 28 patients undergoing total pericardiectomy via midline sternotomy (by a single surgeon) for CCP, in the year 2009, were included in this prospective study. The diagnosis of CCP was based on physical examination, echocardiography, and detection of > 4 mm pericardial thickness on magnetic resonance imaging (MRI).[1] Patients excluded were those having atrial fibrillation and those who died before discharge from the hospital.

After adequate premedication, the patients were shifted to the Operating Room. Electrocardiography (ECG), pulse oximetry (SpO2), right internal jugular vein (RIJV) catheterization, for central venous pressure (CVP), and radial artery invasive blood pressure monitoring were applied under mild sedation. The Flotrac Vigileo system (Edwards Lifesciences, Irvine, CA, USA) connected to the radial artery catheter was used to measure the stroke volume index (SVI), cardiac index (CI), delivered O2 index (DO2I), systemic vascular resistance index (SVRI), and stroke volume variation (SVV).

BNP measurements

Blood samples (5 ml) were collected from RIJV in

ethylenediaminetetraacetic acid (EDTA) vacuettes. The plasma was separated, labeled, and frozen. The analysis was performed using Triage BNP (Triage Cardiac; Biosite Diagnostics, San Diego, CA, USA), which was a point-of-care fluorescence immunoassay test.

Echocardiography

Mitral inflow velocities were assessed from the apical four-chamber view, in the left lateral position, using a pulsed wave (PW) Doppler (2.5 to 4 mHz transducer, Sonos, Agilent 5500, USA), with the volume sample placed on valvular leaflet tips, with adequate gain reduction, and a filter for better definition of the flow.[6] Three values of the maximum E/A ratio were calculated and the mean value was taken for study purposes. [Figure 1]

All the measurements were taken before the induction of anesthesia when the patient was breathing spontaneously (TJ. The patient was brought back to the Operating Room on the day of discharge (Postoperative day - 6 / 7) and all the measurements were repeated (T2).

Statistics

The statistical analysis was done using SPSS 15.0 version (Chicago. Ill, USA). Categorical variables were expressed as the number of subjects and percentages and continuous variables as mean ± SD. The paired Student's t-test was used for univariate comparison. The values of BNP were outside the Gaussian distribution and log transformed. The Spearman's coefficient was used for correlation between log BNP values and other variables. Statistical significance was assumed at P < 0.05.

RESULTS

Four patients were excluded — two with atrial fibrillation and two who died due to low cardiac output state before discharge from the hospital. The data of the remaining 24 patients is presented in [Table 1], which shows the demographic data and preoperative signs and symptoms. All the patients had tuberculosis. The patients were in the young age group (median age 32 years) with 75% in New York Heart Association (NYHA) III and 25% in NYHA IV cardiac status, with varying features of congestive heart failure. Hepatic and renal derangement was seen in 58 and 46% of the patients, respectively.

Hemodynamic changes

There was significant (P = 0.001) improvement in LV systolic function [Table 2] with significant increase in

stroke volume index (SVI) (28.35 ± 13.52 to 42.05 ± 15.31, P < 0.001) ml, cardiac index (CI) (2.9 ± 0.95 to 4.5 ± 1.2 l/min/m2, P < 0.001), and delivered oxygen index (DO2I) (537 ± 126 to 806 ± 172 ml/min/m2, P < 0.001). There was a significant decrease in CVP (20 ± 3.1 to 12 ± 2.9 mmHg, P < 0.001), systemic vascular resistance index (SVRI) (1762 ± 752 to 1225 ± 608 dynes/s/ cm5/ m2, P = 0.001), and stroke volume variation (SVV) (20.3 ± 6.2 to 10.2 ± 5.8%, P < 0.001). However, there were no significant changes in heart rate and blood pressure.

Changes in E/A ratio and BNP

There was a significant decrease in E/A ratio (1.81 ± 0.21 to 1.01 ± 0.14, P < 0.001) between T1 and T2. [Table 3, Figure 1]

The BNP levels significantly decreased from 513.71 ± 147.21 to 107.12 ± 14.83 pg/ml (P < 0.001) as also the log BNP value from 6.19 ± 0.33 to 4.65 ± 0.14 pg/ml (P < 0.001) at discharge from the hospital.

Correlation between BNP and E/A and systolic parameters [Tables 3 and 4]

BNP values were comparable to the E/A ratio at both T1 and T2, with a Positive correlation coefficient ratio of 0.896 and 0.837, respectively. Although the BNP values showed an inverse relationship with LV systolic variables, Correlation between the two was poor with correlation ratio r<-0.25 in all the cases (Table 4)

DISCUSSION

The present study demonstrates that the patients diagnosed with CCP had high levels of BNP preoperatively, which decreased significantly post pericardiectomy, on the day of discharge from the hospital (postoperative day - 6 / 7). These

Table 1: Patient demographics and preoperative conditions

Total no. of patients

n = 24

Figure 1: Levels of log BNP & E/A ratio, Pre operative & at discharge

Male 18 (75%)

Female 6 (25%)

Age (years) Median 32 (range 15 to 55)

Wt (kg) 51.9 ± 9.3

Duration of illness (months) 16.3 ± 11.9

Preoperative cardiac status

NYHA III 18 (75%)

NYHA IV 6 (25%)

Tuberculosis 24 (100%)

Orthopnea 8 (33%)

Peripheral edema 12 (50%)

Pleural effusion 14(58%)

Ascitis 16 (67%)

Renal derangement 11 (46%)

Hepatic derangement 14 (58%)

ECG changes 20 (83%)

Pericardial calcification on chest X-Ray 8 (33%)

Table 2: Hemodynamic parameters

Hemodynamic T, T2 P value

parameter

Pulse rate (/min) 106 ± 16.24 107.08 ± 15.87 0.81

MAP (mmHg) 85 ± 12.9 86.5 ± 11.23 0.72

CVP (mmHg) 20 ± 3.1 12 ± 2.9 0.001

SVI (ml/beat/m2) 28.35 ± 13.52 42.05 ± 15.31 0.001

CI (l/min/m2) 2.9 ± 0.95 4.5 ± 1.2 0.001

SVRI Dynes/s/cm5/m2 1762 ± 752 1225 ± 608 0.001

DO2I (ml/min) 537 ± 126 806 ± 172 0.001

SVV (%) 20.3 ± 6.2 10.2 ± 5.8 0.001

BNP (pg/ml) 513.71 ± 147.21 107.12 ± 14.83 0.001

Log BNP 6.19 ± 0.33 4.65 ± 0.14 0.001

E/A ratio 1.81 ± 0.21 1.01 ± 0.14 0.001

T. - Preoperative, T2 - At discharge, MAP - Mean Arterial Pressure,

CVP - Central Venous Pressure, SVI - Stroke Volume Index,

CI - Cardiac Index, SVRI - Systemic Vascular Resistance Index,

DO2I - Delivered Oxygen Index, SVV - Stroke Volume Variation,

Table 3: Scatter diagram provided as Figure 5 and 6.

Parameter Spearmen coefficient P value

E/A ratio

T1 0.896 0.001

T2 0.837 0.001

Table 4: Correlation of BNP with LV Systolic Function

Parameters

Parameter Spearmen coefficient P value

T1 - 0.18 0.58

T2 - 0.21 0.63

T, - 0.16 0.72

T2 - 0.12 0.78

T2 - 0.16 0.43

T2 - 0.19 0.38

findings Showed a Positive correlation with the Doppler echocardiography measurement of diastolic dysfunction, that is, the E/A ratio at both time periods.

Any comparison of semi-invasive hemodynamic monitoring with the validated 1.10 version of the Flo Trac Vigileo monitor along with BNP monitoring has still not been quoted in literature.

The thickened, dense pericardium in CCP limits the diastolic filling of the ventricles, with equalization of the end diastolic pressure in all the four chambers, and presentation of congestive heart failure and hepatic and renal dysfunction, finally leading to a low cardiac output state with fatigue, muscle wasting, and cachexia. [1] The primary measurements include the peak early filling velocity [Figure 2]. Deceleration time is defined as the time interval from the early peak inflow velocity (the E wave) to the cessation of the rapid early filling phase. It is inversely proportional to the chamber stiffness and is obtained by tracing the deceleration curve from the maximal E-wave velocity to the baseline, which represents the time of pressure equalization between the two chambers (when inflow ends and velocity is zero). Post pericardiectomy also, we face a big challenge because of the massive fluid shifts, auto transfusion, electrolyte imbalances, and recovering LV dysfunction, with a high 5 to 15% mortality.112,131 This makes it very important to intensively monitor the hemodynamics, not only intraoperatively, but till the patient is discharged. We used the Flo Trac sensor Vigileo monitor, which is a semi-invasive technique, to measure SV, CI, SVRI, DO2I, and SVV in the patients, throughout the periopeartive period.[14,15] It needs no calibration and has been validated with values comparable to the pulmonary artery catheter.

A high gradient across the mitral valve due to high left atrial pressure and the suctioning effect of an empty LV encased in a fibrosed pericardial sac results in early, rapid diastolic filling, but it stops abruptly once the pericardial constraining volume is reached.[1] There is no transmission of intrathoracic pressure to the left side of the heart during respiration. Thus, during spontaneous ventilation on inspiration, due to the small pulmonary vein to the left atrial gradient, increased RV filling, and the interventricular septal shift, less blood flows across the mitral valve to the LV and vice versa, during expiration.

Transthoracic echocardiography (TTE) is usually the initial investigation when pericardial disease is suspected. In recent years, cardiac MRI has become a routine imaging procedure to demonstrate anatomy, function, and even myocardial perfusion and coronary arteries. Pericardial thickening of greater than 4 mm indicates abnormal thickening, along with signs and symptoms of heart failure; and other signs, such as, abnormal motion of the interventricular septum, dilated inferior vena cava or dilated atria on MRI or TTE, are useful in differentiating constrictive pericarditis from restrictive cardiomyopathy in symptomatic patients.[16]

The Septal Bounce (Sb), a brief rapid motion of the ventricular septum toward the right ventricle in early diastole, is considered a reliable echocardiopraphic sign of pericardial constriction, but its genesis remains uncertain. Our hypothesis that the Sb is due to the unique pathophysiology of pericardial constriction is based on two postulates: (1) the ventricles are completely enclosed by the thick constricting pericardium, (2) in early diastole the left ventricular free wall, after very early initial expansion, can expand no further, whereas, the ventricular septum is not constricted and is the

Figure 2: Trans-mitral spectral doppler flow pattern

only part of the left ventricle that can yield to the filling forces. This septal yielding motion manifests on the 2-D echo as a typical SB, and on M-mode echo as an early diastolic brief anterior rightward motion or 'notch'.

On TTE, septal bounce, vena cava plethora, and pericardial adhesions are three 2-D echocardiographic signs that are useful in differentiating pericardial constriction from hemodynamically insignificant pericardial thickening or restrictive cardiopmyopathy.[17]

Two-dimensional and M-mode echocardiographies with findings of pericardial thickening, septal bounce, and systemic venous congestion, are routinely used for the diagnosis of CCP.[1,4] However, Doppler flow velocity measurements across the mitral valve have excellent sensitivity and specificity for diagnosing and distinguishing CCP from other cardiomyopathies.151 Typically the patients are in a pseudonormal stage of diastolic dysfunction with an E/A ratio 1 to 1.5 and DT > 240 ms, or in a restrictive-like stage with an E/A ratio of > 1.5 and DT < 160 ms.[9] They show an increase in mitral E velocity greater than or equal to a 25% during expiration, as explained earlier.[1] Tissue Doppler with mitral annulus velocity (E') has also been used for the measurement of diastolic dysfunction with good effects.1181 We observed two patients to be in pseudonormal stage with E/A ratios of 1.20 and 1.4, respectively, and 22 patients were in a restrictive stage with a mean E/A ratio of 1.85 [Figure 3]. Post pericardiectomy, this value came down significantly (P = 0.001) to 1.01 ± 0.14, with the patients in either impaired relaxation or in a pseudonormal stage of diastolic dysfunction.

BNP is a 32-amino acid peptide released by ventricular myocytes with elevated levels, seen in both LV systolic and diastolic dysfunction.[19] It acts via a c-GMP

pathway producing natriuresis, vasodilation, renin inhibition, antimitogenesis, and positive lusiotrophy.[20] A cut-off value of 100 pg/ml has a sensitivity of 82.4% and a specificity of 93% for diagnosis of congestive heart failure.[19] In our study, corresponding to the severe LV dysfunction imposed by CCP, the BNP levels at preoperative time were high at 513.71 ± 147.21 (pg/ ml) with log values of 6.19 ± 0.33.

Change in the BNP levels have been shown to obviate the need for invasive hemodynamic monitoring in the form of pulmonary artery catheter, with significant correlation (r = 0.73), with a change in pulmonary capillary wedge pressures.[11] The change in BNP is both rapid and finite during effective treatment.[11,21] In our study post pericardiectomy, the BNP levels fell significantly (P = 0.001) to 107.12 ± 14.83 (pg/ml) [Figure 4] with log values of 4.65 ± 0.14. This may be explained by the improvement in diastolic dysfunction due to the removal of any pericardial restriction on the LV. BNP can be measured by a simple, point-of-care immunofluorescence test, which does not require much skill or experience, and can be performed in 15 minutes, which is helpful in emergency settings. There is no inter-observer variation or chances of error, as are likely to be seen with Doppler echocardiography.16

Elevated BNP levels have been previously reported both prior to and immediately after cardiac surgeries. Such findings have been associated with cardiac complications, prolonged hospital stay, and one-year mortality.[22-24] However, the reasons for BNP increase in these clinical settings have not been clarified yet, with BNP inconsistently associated with a variety of factors related to surgery, such as biomarkers of myocardial damage, anesthesia, and sternotomy. As a BNP increase reflects hemodynamic changes, we believe that the

(pg/ml)

600.00 -500.00 -400.00 -300.00 -200.00 -100.00 0.00

♦♦ ♦

♦♦♦ ♦ ♦

♦ T1 ■ T2

Frequency(n)

Figure 3: E/A ratios preoperative & at discharge of each patient Figure 4: BNP levels preoperative & at discharge

Figure 5: Preoperative correlation of BNP and E/A ratios

ultimate reason for BNP increase in these patients could be the immediate loading changes and ventricular stunning that occur during and after cardiac surgery. Also the use of a cardiac pulmonary bypass pump and aortic cross clamp in the above-mentioned studies (which were not needed in our study) could have caused an exaggerated systemic inflammatory response, with resultant myocardial injury.

A few studies have evaluated the relationship between BNP levels and the E/E' ratio in different clinical settings, with consistent results that demonstrate a relationship between BNP levels and echocardiographic indices of LV filling pressures.[25,26] Fernandez et al,[27] showed a positive correlation (r = 0.717, P = 0.003) between the log of BNP is taken as NT pro BNP in some studies as a marker for diastolic dysfunction.126, 17] The E/A ratio conducted on patients with pericardial effusion and constrictive pericarditis. However, no evidence in pericardiectomy patients exists in literature about relations between BNP and E/A ratios. The findings of the present study obtained in pericardiectomy patients shows, for the first time, a significant positive correlation between BNP levels and the E/A ratio of 0.896 and 0.837 (p = 0.001) in each (Figures 5 and 6) preoperatively and at discharge, respectively, indicating elevated filling pressures as the major determinant of BNP release over a period of time, postoperatively. The impairment of diastolic function leads to a significant change in the values of both the variables, respectively. With improvement in diastolic function, over a period of time postoperatively, there is an improvement in values of both the BNP and E/A ratios [Table 4].

Figure 6: Postoperative correlation of BNP and E/A ratios

significant improvement in LV systolic parameters, that is, SVI, CI, DO2I, SVRI, and SVV we did not find any significant correlation between these parameters and the BNP levels. One positive uptake of our study was the use of the Flo Trac Vigileo[15] system for monitoring. The trends of all the parameters helped in optimizing fluid therapy, especially the change in SVV value. The gradual normalization of SVV 20.3% to 10.2 % post pericardiectomy indicated the shift of patients from hypovolemic to normovolemic state.

STUDY LIMITATIONS

The first and foremost limitation of our study is the use of the E/A ratio as a marker of diastolic dysfunction. It is highly user-specific and a wrong interpretation can be obtained due to Doppler beam misalignment, misplaced sample volume, suboptimal machine settings, and failure to make the final small adjustments based on audio characteristics. The DT can also be misread because of the above-mentioned reasons, as also if a very high a Doppler gain is used. It also depends on the loading conditions and the heart rate. Therefore E/E' is considered better for evaluation of diastolic dysfunction. Second, we used the same set of patients as control in our study. In future a larger case controlled study may take care of this limitation. Another limitation is that though 46% of our patient population had renal impairment, we did not analyse the impact of creatinine of glomercular filtration rate to the BNP values, which according to Reddy et al.[27] are important variables upon which BNP values are dependent.

In patients with heart failure, the plasma BNP levels are inversely related to LV systolic function.[28] In contrast, in our study population, although there was

CONCLUSION

BNP released in response to LV wall stress and elevated

filling pressures is a very good comparable and substitutable marker for the E/A ratio, for measuring LV diastolic dysfunction. It is an economical, simple, reliable, reproducible, point-of-care laboratory test, which can be subsequently monitored to evaluate the effect of the therapy provided to the patients in congestive heart failure. However, more number of studies in a larger number of patients are needed for it to be validated as a 'gold standard' noninvasive marker for LV dysfunction.

ACKNOWLEDGMENT

The part of this study involving BNP testing was funded by the Indian Council of Medical Research (ICMR), New Delhi, India. The authors have no competing interests.

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Cite this article as: Kapoor P, Aggarwal V, Chowdhury U, Choudhury M, Singh SP, Kiran U. Comparison of B-type natriuretic peptide (BNP) and left ventricular dysfunction in patients with constrictive pericarditis undergoing pericardiectomy. Ann Card Anaesth 2010;13:123-9.

Source of Support: Nil, Conflict of Interest: None declared.

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