Article, Cardiology

The effects of continuous positive airway pressure on plasma brain natriuretic peptide concentrations in patients presenting with acute cardiogenic pulmonary edema with preserved left ventricular systolic function

Brief Report

The effects of continuous positive airway pressure on plasma brain natriuretic peptide concentrations in patients presenting with acute cardiogenic pulmonary edema with preserved left ventricular systolic function?

Andrea Bellone MDa,?, Massimiliano Etteri MDa, Marco Vettorello MDc,

Vittorio Berruti MDa, Carlo Maino MDa, Massimo Mariani MDa, Dante Clerici MDa, Italo Nessi MDa, Giancarlo Gini MDa, Anna Natalizi MDa, Pietro Brunati MDb

aemergency unit, Ospedale Valduce, 22100 Como, Italy bLaboratory, Ospedale Valduce, 22100 Como, Italy cICU University-Hospital L.Sacco, 20100 Milano, Italy

Received 9 October 2008; revised 29 October 2008; accepted 1 November 2008

Abstract

Background: It has been established that plasma Brain natriuretic peptide concentrations in patients with Acute cardiogenic pulmonary edema increase in proportion to heart failure. Objectives: The aim of this study is to assess the effects of Continuous positive airway pressure treatment on plasma BNP concentrations in patients presenting with ACPE with preserved left ventricular (LV) systolic function.

Methods: This was a prospective, observational single-center study in the emergency unit of Valduce Hospital. Twelve patients (group A) presenting with ACPE and preserved LV ejection fraction and 14 patients (group B) with systolic heart dysfunction (LV ejection fraction b45%) underwent CPAP (10 cm H2O) through a face mask and standard medical therapy. Plasma BNP concentrations were collected immediately before CPAP and 3, 6, and 24 hours after treatment. All patients underwent a morphological echocardiographic investigation shortly before CPAP.

Results: Three hours after admission, BNP significantly decreased in patients with ACPE and preserved LVEF (from 998 +- 467 pg/mL to 858 +- 420 pg/mL; P b .05), whereas in those with systolic dysfunction, BNP was higher than during baseline (from 1352 +- 473 pg/mL to 1570 +- 595 pg/mL; P b .05).

? Author contributions: Andrea Bellone carried out the study, analyzed and interpreted the data, and drafted the manuscript. Marco Vettorello analyzed and interpreted the data. Massimiliano Etteri, Giancarlo Gini, Massimo Mariani, Dante Clerici, Vittorio Berruti, Anna Natalizi, Italo Nessi, and Carlo Maino recruited patients and interpreted the data. Pietro Brunati analyzed the data. All authors read and approved the study.

* Corresponding author. 20146 Milano, Italy. Tel.: +39 031324375; fax: +39 031324372.

E-mail address: [email protected] (A. Bellone).

0735-6757/$ – see front matter (C) 2010 doi:10.1016/j.ajem.2008.11.002

Conclusions: The preliminary results of the present study show that CPAP, after 3 hours, lowers BNP levels in patients with ACPE and preserved LV systolic function compared with patients affected by systolic ACPE dysfunction where BNP levels do not change significantly.

(C) 2010

Introduction

Continuous positive airway pressure (CPAP) has a definite role in the management of acute cardiogenic pulmonary edema (ACPE), and recently, 5 meta-analyses have shown that CPAP decreases the rate of intubation and improves survival in patients with ACPE [1-5].

A large number of patients presenting with ACPE have preserved left ventricular systolic function (LVSF), and they are assumed to be affected by diastolic dysfunction. In these patients, survival is similar to that of patients with reduced ejection fraction [6,7].

Plasma brain natriuretic peptide (BNP) concentrations increase in proportion to heart failure severity, and their plasma levels are being incorporated into the clinical assessment and management of systolic and diastolic HF [8]. Two recent studies have shown that Myocardial stiffness is the most important determinant of plasma BNP production in clinically stable patients with both diastolic and systolic HF [9,10].

The aim of our study was to evaluate the effects of CPAP treatment on plasma BNP concentrations in patients presenting with ACPE with preserved LVSF.

Methods

Study design

A prospective, preliminary, observational single-center study was conducted over a 6-month period on all adult patients affected by ACPE in the emergency department of Valduce Hospital.

Study setting and population

The study was conducted in the emergency department, with the approval of our institutional ethics committee. Written, informed consent was obtained from patients’ next- of-kin.

In the last 6 months (from December 2007 to May 2008),

62 consecutive patients were initially admitted to our emergency department because of acute dyspnea.

For the purpose of our study, we used the inclusion/ exclusion criteria when the patients met all the following in order to confirm the diagnosis of ACPE: older than 18 years, acute onset of severe respiratory distress (breathing rate N30 breaths/min), peripheral Arterial oxygen saturation

(SpO2) less than 88% while breathing air or less than 90% with inhaled oxygen, and finding of pulmonary congestion on physical examination. A chest radiograph was obtained within 10 to 15 minutes after admission to the emergency department. All patients underwent a morphological echo- cardiographic investigation shortly before CPAP. Two- dimensional echocardiogram (SONOS 2000; Hewlett-Pack- ard, Andover, MA) was performed to qualitatively estimate LVSF. Patients were considered as having LVSF if the ejection fraction was estimated to be less than 45%. In the absence of this condition and significant valvular abnorm- alities, patients were considered to have a preserved LVSF. Thirty patients initially screened in the study were not included because they did not meet the entry criteria (21 patients had chronic obstructive pulmonary disease exacer- bation, 7 had pneumonia, and 2 had acute pulmonary embolism). Two patients were immediately intubated and submitted to invasive mechanical ventilation. Four patients were excluded because they presented an electrocardiogram suggesting acute myocardial infarction with ST elevation. Twenty-six patients, found to have respiratory distress suggestive of acute pulmonary edema, were enrolled and included in the analysis. According to the LVEF value, they were divided into 2 groups: 12 patients with preserved LVEF comprised group A and 14 patients with systolic dysfunction comprised group B.

Patients were excluded if they had systolic arterial blood

pressure lower than 90 mm Hg, impaired level of consciousness at presentation, intractable vomiting, acute myocardial infarction with persistent ST-segment elevation at presentation, or another decompensated pulmonary disease, such as pulmonary embolism, chronic obstructive pulmonary disease exacerbation, pneumonia, and pneu- mothorax. In addition, patients were excluded if they required dialysis for renal insufficiency.

Blood samples were taken for the estimation of plasma BNP on study entry (Abbott Laboratories Abbott Park, IL). Collection of BNP concentrations was repeated at 3, 6, and 24 hours after CPAP.

The method for BNP measurement is a 2-step chemilu- minescent immunoassay based on chemiluminescent micro- particle immunoassay (CMIA) technology. Total imprecision values for BNP were ~10% pg/mL at 100 pg/mL, with a reference change value of 87% (CV1, 30%), and analytical

sensitivity was less than 10%. The analytical measurement range was 10 to 5000 pg/mL. All measurements were performed within 2 hours of specimen collection.

Electrocardiogram tracing and peripheral oximetry were monitored continuously. Respiratory rate and arterial blood

pressure were monitored every 5 minutes, and an arterial blood sample was collected before CPAP and after 30 and 60 minutes.

Table 1 Baseline characteristics of the patients and history and causes of acute pulmonary edema

All emergency physician ultrasonographers underwent a training course on fast echography in an emergency setting (1 year before the study), and they performed at least 75 cardiac ultrasounds with a credentialed supervision. The cardiologists’ supervision showed good reliability among interemergency physicians with regard to echomorphologic evaluation of LVEF.

Study protocol

All studied patients were immediately submitted to echocardiographic evaluation while they were started on nitrates, furosemide, and morphine. Then, patients were fitted with an oronasal mask (Respironics, Murrysville, PA) and were connected to CPAP adjusted to 10 cm H2O (Vela, Viasys; Critical Care Division, California). Fraction of inspired oxygen (FIO2) was delivered to achieve an SpO2 of 96%. When the goal of SpO2 of 96% was reached, FIO2 was maintained constant. Standard medical treatment was started consisting of the following: con- tinuous infusion of glyceryl trinitrate (15 mg/250 mL of saline) titrated to the arterial blood pressure response, furosemide 60 mg IV, and morphine sulfate 2 mg IV if needed. Concentration of BNP was obtained on study entry and at 3, 6, and 24 hours after CPAP.

Data analysis

Data are expressed as mean +- SD. The primary end point was the comparison of plasma BNP levels before and after CPAP in patients with ACPE and different systolic function.

We compared physiologic measurements in both groups of patients using unpaired t tests for data obtained at study entry. Paired t tests were used for within-group compa- risons of variables at study entry and 3 hours later. Multiple comparisons were made using analysis of variance for repeated measures. Fisher’s exact test was used to compare the rates of intubation and in-hospital mortality in the 2 groups.

Results

The baseline characteristics of the patients, their history, and the causes of acute pulmonary edema are reported in Table 1. The course of BNP concentrations is showed in Fig. 1. Three hours after admission, BNP significantly decreased in group A (from 998 +- 467 pg/mL to 858 +- 420 pg/mL; P b .05), whereas in group B, it was higher than during baseline (from 1352 +- 473 pg/mL to 1570 +- 595 pg/mL; P b .05). After 24 hours, BNP level was significantly lower than during baseline in both groups of

Group A (n

=

12)

Group B (n = 14)

Age (y) 78 +- 5

Sex, M/F 5/7

APACHE II score 15.3 +- 1.6

History

Arterial hypertension 11 (92)

Diabetes 2 (17)

Atrial fibrillation 1 (8)

Chronic renal failure 1 (8) Chronic heart failure 0 Ischemic heart disease 3 (25) Causes of ACPE

Hypertension 10 (83)

Myocardial infarction 2 (17)

Lower airways 2 (17) infection

Atrial fibrillation 1 (8)

76 +- 6

8/6

16.3 +- 1.7

9 (64)

3 (21)

2 (14)

2 (14)

4 (28)

7 (50)

4 (28)

5 (36)

4 (28)

2 (14)

Data are expressed as absolute number or mean +- SD or number (%).

patients (from 998 +- 467 pg/mL to 847 +- 429 pg/mL, P b

.05, in group A and from 1352 +- 473 pg/mL to 1060 +- 568 pg/mL, P b .01, in group B). arterial blood gases and respiratory rate were similar in both groups of patients and were shown to be significantly improved after 1 hour of CPAP (Table 2). The time of CPAP treatment was about 60 minutes. Heart rate and arterial blood pressure showed a significant reduction after 90 minutes in both groups of patients (P b .05) compared with baseline values (Table 2). No patient required endotracheal intubation. No patient died during the hospital stay. The dose of nitrate, furosemide, and morphine did not significantly differ between the 2 groups of patients. (The dose of furosemide was similar in the 2 groups of patients because in patients with ACPE and preserved LVEF, the end diastolic volume is normal).

Discussion

Our results show that the level of plasma BNP was significantly lowered after 3 hours from starting CPAP in patients with ACPE and preserved LVEF, whereas in patients with systolic dysfunction and ACPE, it was unaffected by CPAP.

During systole, CPAP induces an increase in intrathoracic pressure and reduces the venous return, decreasing the right and left ventricular preload, thereby improving mechanics in an overloaded ventricle, whereas in diastole, CPAP increases pericardial pressure, reduces transmural pressure, and thus decreases afterload. Other mechanisms by which CPAP improves ACPE include unloading of respiratory muscles, preventing microatelectasis, decreasing dead space, and

Fig. 1 Plasma BNP concentrations before and after CPAP in both groups of patients.

improving alveolar ventilation. In our study, patients with preserved systolic function were assumed to be affected by left ventricular diastolic dysfunction, but the absence of a complete ultrasound examination of the mitral-valve annulus to assess diastolic dysfunction does not permit to definitively confirm our hypothesis.

Brain natriuretic peptide activity has been extensively studied in chronic HF, but little is known in the context of ACPE. In a previous study [11] where the authors evaluated the effect of CPAP and plasma BNP concentrations in patients with ACPE and reduced systolic function, BNP level continued to rise, peaking at 6 hours before falling below baseline values by 24 hours. This finding is consistent with patients in our study presenting with a depressed LVEF. In fact, despite CPAP treatment being effective in improving the clinical data of these patients, the Plasma BNP levels rose at 3 and 6 hours.

On the other hand, we showed that in patients with ACPE and preserved LVSF, the BNP concentrations fell rapidly within the first 3 hours after CPAP treatment.

Previous studies [9,10] showed that myocardial stiffness and diastolic wall stress may be the most important

determinant in plasma BNP production in patients with both diastolic and systolic HF. Therefore, the fall of BPN level at 3 hours in patients with preserved LVEF and ACPE might reflect the effect of positive airway pressure on lowering transmural pressure and consequently improving left ventricle compliance where myocardial stiffness is more prominent compared with systolic heart dysfunction. Finally, the acute significant fall of BNP production after CPAP in these patients might be related to a reduced left ventricle end- diastolic wall stress.

Limitations

There are limitations to our study. The small number of patients may not have been sufficient to detect a definitive conclusion, but it is very difficult to collect at the same time BNP, noninvasive ventilation, and morphological echo evaluation in an acute setting. However, further studies are needed to verify our results. The second limitation is the lack of a control group of patients with only medical

Table 2 Physiological data at study entry and progression

Group A (n = 12)

Group B (n = 14)

Study entry

After 1 h

Study entry

After 1 h

pH

7.27 +- 0.14

7.35 +- 0.08 ?

7.27 +- 0.11

7.36 +- 0.08 ?

PaCO2 (mm Hg)

53 +- 12.5

43 +- 7.8 ?

51 +- 10.2

41 +- 4.2 ?

PaO2/Fio2 (ratio)

181 +- 37.6

237 +- 62 ?

188 +- 41.1

243 +- 72 ?

SpO2 (%)

78 +- 12.5

93.4 +- 4.1 ?

80 +- 10.4

93.1 +- 6.4 ?

HCO3 (mEq)

22 +- 3.8

22 +- 3.4

22 +- 3.4

23.1 +- 2.2

Heart rate (beats/min)

114 +- 18

90 +- 13 ?

108 +- 16

91 +- 18 ?

Respiratory frequency (breaths/min)

46 +- 6

25 +- 6 ?

43 +- 8

26 +- 6 ?

Systolic pressure (mm Hg)

193 +- 22

138 +- 29 ?

144 +- 38 +

121 +- 22 ?

Diastolic pressure (mm Hg)

108 +- 16

76 +- 9 ?

81 +- 18 +

71 +- 10

Data are expressed as mean +- SD.

* P b .05 (Student’s t test) in group between study entry and after 1 hour.

+ P b .05 (Student’s t test) between groups at study entry.

treatment, and this might influence the results. The third limitation is the absence of a complete ultrasound examination such as Tissue Doppler imaging of the mitral- valve annulus to assess diastolic dysfunction, but in the acute setting of emergency department, there is not enough time to perform quantitative echocardiographic measure- ments in acute dyspnea. The fourth limit is the absence of a clinical assessment of symptoms. However, a recent study

[12] suggests that eyeballing ejection fraction may be the most accurate echocardiographic method for the assessment of LVSF and could be used for routine echocardiography instead of formal methods.

Conclusion

The preliminary results of the present study show that CPAP, after 3 hours, lowers BNP levels in patients with ACPE and preserved LVSF compared with patients affected by systolic ACPE dysfunction where BNP levels do not change significantly.

Acknowledgments

The authors thank the entire emergency unit nursing team of Valduce Hospital.

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