Brief Report

Decrease in NTproBNP plasma levels indicates clinical improvement of acute decompensated heart failure^B

Salvatore Di Somma MD^a,*, Laura Magrini MD^a, Marinella Mazzone MD^b, Raffaella De Leva MD^a, Fabio Tabacco MD^c, Rossella Marino MD^a,

Veronica Talucci MD^a, Enrico Ferri MD^a, Paola Forte MD^a, Patrizia Cardelli MD^c,

Nicola Gentiloni MD^b, Valerio Pittoni MD^a

^aEmergency Medicine Department, II Medical School University bLa Sapienza,Q Sant’Andrea Hospital, 00189 Rome, Italy

^bEmergency Department, bSacro CuoreQ Catholic University, Policlinico A. Gemelli, Rome, Italy

^cCellular Biotechnologies and Hematology Department, 28 Medical School University bLa Sapienza,Q Sant’Andrea Hospital, 00189 Rome, Italy

Received 19 May 2006; revised 27 June 2006; accepted 6 August 2006

Abstract Thirthy-seven consecutive patients with acute decompensated heart failure admitted to emergency departments for acute dyspnea were investigated. Ten patients with acute exacerbation of chronic obstructive pulmonary disease and 10 patients with hypertension crisis were also included as controls. For each patient, a plasma amino-terminal pro-B-type natriuretic peptide (NTproBNP) concentration measurement was performed at admission, 4, 12, and 24 hours later, and on the day of discharge. In patients with ADHF, the observation of a progressive reduction to a complete relief of symptoms of heart failure was accompanied by a reduction of 58% of NTproBNP plasma levels on the day of discharge. Amelioration of symptoms was accompanied by improvement of physiologic parameters and New York Heart Association functional class. In the Control population (chronic obstructive pulmonary disease and hypertension crisis patients), no significant variation of NTproBNP levels in comparison with those at admission was found at each time point. In conclusion, a plasma profile obtained with sequential measurements indicates that a significant decrease in NTproBNP levels is associated with the clinical improvement of patients with ADHF at the time of discharge.

D 2007

Introduction

Over the last 30 years, the prevalence of heart failure has progressively increased, affecting a variable

^B NTproBNP sequential measurement in the emergency department: insights into the achievement of clinical improvement of decompensated heart failure.

* Corresponding author. Tel.: +39 06 33775275; fax: +39 06

33775053.

E-mail address: [email protected] (S. Di Somma).

percentage of adult European population (from 0.4% to 2%) [1]. In industrialized countries, HF is considered one of the leading causes of adult hospitalization especially in patients older than 65 years. Moreover, patients with HF need to be hospitalized for acute decompensation of heart function at an average of 4 or 5 times/year [2,3].

The contribution of the measurement of brain Natriuretic peptides (BNP) and amino-terminal pro-B-type natriuretic peptide (NTproBNP) to HF diagnosis and prognosis has been well documented [4-9]. NTproBNP is the inactive

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prohormone of BNP, because it is cleaved to form active BNP. NTproBNP is cleared from the blood stream more slowly than BNP given that the former has a half-life of 60 to 120 minutes, the latter of 20 minutes [10]. Both BNP and NTproBNP levels have been shown to accurately mirror HF severity and correlate to New York Heart Association (NYHA) classification [4,11]. Recently, Maisel

[11] proposed an algorithm to use BNP plasma level determination in patients referred to the emergency depart- ment (ED) for dyspnea. Moreover, serial evaluations of BNP concentration have been demonstrated to be useful to guide therapy decisions for these patients [12-16]. However, no definitive data on the potential utility of repeated determinations of NTproBNP for acute decompensated HF (ADHF) management in the ED are available. Appropriate timing for NTproBNP plasma concentration evaluation could give insights into the need of carrying on with intensive pharmacologic treatment or as an alternative into the achievement of the goal of therapy. The aims of our study were (1) to define NTproBNP plasma concentration profile from admission to discharge to establish the more appropriate timing for these measurements, and (2) to assess the role of NTproBNP sequential measurement as a marker of clinical improvement of patients with ADHF in response to therapy.

Patients and methods

This study was performed in accordance to the principles of Declaration of Helsinki (1964). The approval of the ethics committee was obtained, and all subjects gave written informed consent.

A total of 57 subjects (37 patients and 20 controls) (27 males, 30 females; mean age F SE, 73.2 F 9.3 years; age range, 51-95 years) admitted to 2 ED (Emergency Medicine II Medical School, S. Andrea Hospital University of Rome bLa SapienzaQ and ED UCSC Policlinico A. Gemelli, Rome, Italy) for acute onset of dyspnea were enrolled from December 2003 to September 2004. Patients’ and controls’ characteristics are summarized in Table 1: 37

patients (16 males, 21 females; mean age F SE, 75.4 F 9.1 years) with dyspnea due to ADHF (the diagnosis was made in accordance to guidelines [17] and supported by clinical history, examination, and echocardiographic and radiologic data); 10 controls (4 males, 6 females; mean age F SE, 71.6 F 6.4 years) with dyspnea due to exacerbation of chronic obstructive pulmonary disease (COPD) diagnosed according to guidelines and on the basis of clinical history and examination, abnormal arterial blood gas analysis, abnormal chest x-ray, and normal heart function at echocardiogram [18]; and 10 controls (4 males, 6 females; mean age F SE, 73.2 F 11.3 years) with hypertension crisis (HC) (blood pressure measured, N200/100 mm Hg) diagnosed in accordance to guidelines [19]. The Modified Medical Research Council (MMRC) dyspnea scale was used to estimate the severity of dyspnea in patients with ADHF [20].

In all patients and controls, 12-lead electrocardiogram, chest x-ray, echocardiogram, arterial blood gas analysis, a routine blood test including electrolytes, renal function test, hemocromocytometric, and Myocardial necrosis enzyme tests were performed. In patients with ADHF, a concomitant pulmonary disease was excluded on the basis of chest x-ray, arterial blood gas analysis, and clinical history. Acute coronary syndromes, cerebrovascular ischemia, neoplasms, chronic kidney failure (serum Creatinine levels N2.5 mg/dL), Paroxysmal atrial fibrillation, and traumatic chest events were exclusion criteria for both patients and controls.

A continuous monitoring of life parameters (12-lead electrocardiogram, blood pressure, respiratory rate, arterial blood gas analysis, and diuresis) was performed in all patients. Patients with ADHF were treated with a standard dosage of nitrates, b-blockers, angiotensin-converting en- zyme inhibitors, and diuretics. Controls with HC were treated with Antihypertensive drugs intravenously, and controls with COPD were treated with steroids intravenous- ly and Inhaled bronchodilators. Drug administration was accurately recorded all over the period of hospitalization.

To evaluate the changes of NTproBNP plasma concen- tration, the peptide was measured in the plasma of each

Table 1 Patients’ and control’s clinical features
Characteristics of patients and controls	ADHF	COPD	HC
No.	37	10	10
Age (y)*	75.4 F 9.1	71.6 F 6	73.2 F 11.3
Sex, M/F	16/21	4/6	4/6
SBP/DBP (mm Hg)*	131 F 23/75 F 11	142 F 28/79 F 12	205 F 45/103 F 26
HR (beats/min)	106.2 F 21.4	102.6 F 26.3	74.8 F 10.6
Respiratory rate*	23.4 F 11.5	23.1 F 12.6	15.4 F 3.2
Temperature (8C)*	36.4 F 0.6	37 F 0.5	36.5
SatO2 %*	94 F 3	84 F 6	98 F 2
M indicates male; F, female; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate. * Mean F SE.

patient and control at different time points (admission, 4, 12, and 24 hours later and at discharge).

NTproBNP determination

A venipuncture of 10 mL of blood was collected in blood-collection tubes made of transparent polypropylene containing separating gel plus Li-heparin. Plasma were prepared by centrifugation (2000g for 10 minutes) and immediately frozen below -208C until determination. Samples were stabilized at Room temperature (20-258C) and analyzed within 2 hours. Aliquots of 500 AL of plasma were analyzed with a commercial Kit (Elecsys NTproBNP Kit, Roche Diagnostics, Germany-ElectroChemiLumines- cence ImmunoAssay bECLIAQ) following the manufactur- er’s instructions and using the Elecsys-2010 bench top analyzer [21-23]. A pool of normal human plasma was included in the assay as control samples.

Statistical analysis

Mann-Whitney (M-W) test was used to find differences in NTproBNP levels in ADHF plasma at different time points and to evaluate difference between patients and controls at each time point. A Wilcoxon signed ranks (W) test was also used to compare NTproBNP plasma levels in patients with ADHF at different time points.

A multiple Linear regression analysis was conducted to study the influence on NTproBNP plasma level at discharge of the following variables: age, sex, diagnosis

at admission, and NTproBNP plasma levels at admission (backward procedure).

Results

There were no significant differences in age and sex distribution, and the respiratory rate at admission resulted comparable in patients with ADHF and controls with COPD (Table 1). The mean respiratory rate at admission was significantly higher in patients with ADHF and controls with COPD than in controls with HC ( P b .01). SatO₂ % was significantly lower in controls with COPD than in ADHF ( P b .001) and controls with HC ( P b .001).

The average hospitalization period for patients and controls was (mean F SE) 5.1 F 3.5 days. At the time of discharge, a satisfactory improvement of the overall clinical conditions and the disappearance of dyspnea were reported in all patients and controls. Thoracic rales and Lower extremity edema were totally cleared in patients with ADHF. In all patients with ADHF, an improvement of dyspnea was obtained: none of the patients with ADHF were free of dyspnea at admission (MMRC dyspnea scale 4-5), whereas at discharge, the MMRC dyspnea scale was 0. With reference to the severity of HF, at admission, 17 patients were in NYHA class IV, 13 were in NYHA class III, and 7 were in NYHA class II. At discharge, no patients were in class IV, 2 patients were in NYHA class III, 28 patients were in NYHA class II, and 7 patients were in NYHA class I.

In all patients, an improvement of chest x-ray at discharge compared with admission was demonstrated.

Fig. 1 NTproBNP plasma levels in patients with ADHF as against controls with HC and COPD at admission, 4, 12, and 24 hours, and at discharge. In ADHF patients a significant decrease in NTproBNP plasma levels as against those at the admission was reported at the time of discharge (-58.0%, P b .01).

The respiratory rate was significantly ( P b .05) reduced in all patients at discharge (at admission, [mean F SE] 23.4 F 11.5/min; at discharge, 14.3 F 4.4/min) ( P b .01). Moreover, the heart rate was reduced from (mean F SE)

106.2 F 21.4 to 72.8 F 18.3 beats/min ( P b .05).

At discharge time, blood pressure was significantly reduced to (mean F SE) 132 F 12/89 F 14 mm Hg ( P b

.001) in controls with HC. A reduction of respiratory rales, arterial blood gas analysis, and chest x-ray improvements were observed in controls with COPD.

At each considered time point (admission, 4, 12, 24 hours, discharge), NTproBNP plasma levels were measured in patients and controls.

In patients with ADHF, NTproBNP plasma concen- trations measured were as follows (mean F SE): admis- sion, 5709.8 F 1639 pg/mL; after 4 hours, 5915.2 F

1619.4 pg/mL; after 12 hours, 6437.9 F 1763.6 pg/mL;

after 24 hours, 4631.5 F 1270.2 pg/mL; at discharge, 3676.1 F 882.5 pg/mL (W vs admission, P b .05).

A slight decrease in percentage NTproBNP levels in patients with ADHF was found at 24 hours (-18.8% M-W, P N .05), but a significant reduction was only reported at the time of discharge (-58.0% M-W, P b .01) (Fig. 1).

In HC and controls with COPD, NTproBNP plasma concentrations measured were as follows (mean F SE): at admission, 347.6 F 162.7 and 1194.4 F 882.6 pg/mL,

respectively; after 4 hours, 427.6 F 168.3 and 285 F 67.7

pg/mL, respectively; after 12 hours, 520.5 F 265.3 and

392.7 F 152.8 pg/mL, respectively; after 24 hours, 452 F

260 and 488.4 F 153 pg/mL respectively; at discharge,

369.4 F 64.3 and 602.2 F 125.5 pg/mL, respectively.

NTproBNP plasma concentrations were significantly higher in patients with ADHF as against HC and controls with COPD at admission and each time point considered (M-W, P b .001). There were no statistically significant differences in NTproBNP levels between HC and controls with COPD at each time point considered (M-W, P = .4 at admission; P = .6 after 4 hours; P = .7 after 12 hours; P = .4 after 24 hours; P = .6 at discharge).

NTproBNP plasma levels measured at discharge in the 3 groups considered (patients with ADHF, HC, and controls with COPD) as a whole were significantly correlated to increasing age ( P b .01) and to NTproBNP levels at admission ( P b .028, t = 2.273, b coefficients = .075), whereas no correlation with these parameters was found at the other time points. NTproBNP plasma levels in a pool of normal human plasma included in the study as further controls were (mean F SE) 97.0 F 27.1 pg/mL.

Discussion

The aim of the present study was to evaluate NTproBNP plasma level sequential measurement of patients with ADHF in the ED with reference to the variation of their clinical conditions. Because several previous studies confirmed the

role of this hormone in ADHF diagnosis [7-11], the current use of NTproBNP determination in the ED is limited, in case of normal value of this peptide, to the exclusion of dyspnea of Cardiac origin [16]. Although not specifically designed for this purpose, the present study is in accordance with these previous observations, because NTproBNP concentrations found in patients with ADHF were higher than in controls all over the observation period.

As a result of our investigation, patients with ADHF had a significant reduction in NTproBNP plasma levels from admission to discharge, which was accompanied by a satisfactory clinical improvement as suggested by the amelioration of physiologic parameters an NYHA function- al class variation. Plasma concentration values that we measured in patients with ADHF were considerably higher than those currently accepted in the literature as a cutoff value from a bnon-HFQ population (NTproBNPb406 pg/mL) [12]. This finding can be attributed to a referral bias because the population studied included patients referring to ED for severe ADHF and part of them were elderly patients (older than 75 years).

Although the role of repeated assessments of BNP plasma levels has been stressed by other authors to optimize the use of cardiovascular drugs such as b-blockers or angiotensin-converting enzyme inhibitors in the treatment of HF [24-27], fewer definitive data on the use of NTproBNP plasma levels are available for this purpose [28,29]. Because of its long half-life, NTproBNP plasma levels require almost

24 hours before they are influenced by treatment. Our preliminary study seems to indicate that when NTproBNP levels tend to decrease, the clinical stabilization begins.

The objective of this study was to investigate the potential role of sequential measurement of NTproBNP in ADHF management, but no comparison between NTproBNP and BNP concentration profiles was made. Conflicting data emerging from the literature on the 2 hormones gave no definitive answer to this issue [30,31]. Our results only suggest that monitoring NTproBNP levels in ADHF can be used to indicate a trend of stabilization of clinical conditions. No decrease in this hormone concentration was observed in the first 12 hours, whereas a trend to decline was not observed before 24 hours and a significant reduction was reported only at the time of discharge. This finding, which is in keeping with the fact that NTproBNP has a longer plasma half-life than BNP [10], suggests that measuring the former could give more insights into the achievement of a more stable clinical condition, whereas the latter could be an earlier and more sensitive marker of response to therapy as suggested by a recent report [12]. In any case, our study indicates that if the physician decides to measure NTproBNP levels, there is no need of repeated measure- ments of this hormone before the time of discharge to obtain indication of a clinical improvement.

Further larger studies addressing a more numerous multicentric population are probably needed to confirm the potential role of NTproBNP plasma level measurement to

ameliorate the clinical management of patients with ADHF referring to the ED.

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