Elevation of B-type natriuretic peptide levels in acute respiratory distress syndrome

B-type natriuretic peptide (BNP) is a 32amino acid polypeptide secreted by the cardiac ventricles in response to volume and pressure overload. BNP exhibits vasodilatory and natriuretic effects and counterbalances the deleterious effects of the renin-angiotensin-system in heart failure [1]. BNP as marker of left ventricular (LV) wall stretch and consecutive neurohumoral activation has emerged as a widely used tool in the diagnosis and exclusion of congestive heart failure (CHF) [1, 2]. Less is known about natriuretic peptides in sepsis and acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Elevated A-type natriuretic peptide (formerly atrial natriuretic peptide, ANP) levels have been found in patients with sepsis [3] and ALI/ARDS [4, 5] and have been associated with sepsis-induced myocardial depression [3] and severity of ARDS [4], whereas only one study demonstrated elevated BNP levels in patients with ARDS [5]. These BNP values were moderately high and have been shown to correlate with pulmonary and systemic vascular resistance, but not with the partial pressure of arterial oxygen (paO2) or the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (paO2/FiO2) [5]. We report very high BNP levels in a young patient with ARDS. Background: B-type natriuretic peptide (BNP) has been proven to be a biochemical marker of severity of congestive heart failure. We are aware of only few papers reporting the association of BNP elevation and pulmonary hypertension (primary, thromboembolic, or as a consequence of chronic obstructive pulmonary disease). Less is known about BNP in patients with acute respiratory distress syndrome (ARDS). Case description and results: We present the case of a previously healthy 27-year-old man with parapneumonic ARDS and an extraordinarily increased BNP level. The ventricular systolic ejection fraction assessed echocardiographically was normal with no evidence of left ventricular diastolic dysfunction. However, a peak BNP level of >1300 pg/mL (normal <100 pg/mL) was recorded. Repeated BNP values were obtained on nine separate days over a period of 3 weeks of mechanical ventilation. With the respiratory improvement following the inhalation of nitric oxide BNP levels decreased to 113 pg/mL. The possible pathophysiological mechanisms of BNP release are discussed. Conclusion: There is evidence for BNP elevation in the absence left ventricular dysfunction. This case is an example of impressively high BNP levels associated with ARDS, probably attributable to right ventricular overload due to increased pulmonary vascular resistance.

B-type natriuretic peptide (BNP) is a 32amino acid polypeptide secreted by the cardiac ventricles in response to volume and pressure overload.BNP exhibits vasodilatory and natriuretic effects and counterbalances the deleterious effects of the renin-angiotensin-system in heart failure [1].BNP as marker of left ventricular (LV) wall stretch and consecutive neurohumoral activation has emerged as a widely used tool in the diagnosis and exclusion of congestive heart failure (CHF) [1,2].Less is known about natriuretic peptides in sepsis and acute lung injury (ALI) or acute respiratory distress syndrome (ARDS).Elevated A-type natriuretic peptide (formerly atrial natri-uretic peptide, ANP) levels have been found in patients with sepsis [3] and ALI/ARDS [4,5] and have been associated with sepsis-induced myocardial depression [3] and severity of ARDS [4], whereas only one study demonstrated elevated BNP levels in patients with ARDS [5].These BNP values were moderately high and have been shown to correlate with pulmonary and systemic vascular resistance, but not with the partial pressure of arterial oxygen (paO 2) or the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (paO2/FiO2) [5].We report very high BNP levels in a young patient with ARDS.
Background: B-type natriuretic peptide (BNP) has been proven to be a biochemical marker of severity of congestive heart failure.We are aware of only few papers reporting the association of BNP elevation and pulmonary hypertension (primary, thromboembolic, or as a consequence of chronic obstructive pulmonary disease).Less is known about BNP in patients with acute respiratory distress syndrome (ARDS).
Case description and results: We present the case of a previously healthy 27-year-old man with parapneumonic ARDS and an extraordinarily increased BNP level.The ventricular systolic ejection fraction assessed echocardiographically was normal with no evidence of left ventricular diastolic dysfunction.However, a peak BNP level of >1300 pg/mL (normal <100 pg/mL) was recorded.
Repeated BNP values were obtained on nine separate days over a period of 3 weeks of mechanical ventilation.With the respiratory improvement following the inhalation of nitric oxide BNP levels decreased to 113 pg/mL.The possible pathophysiological mechanisms of BNP release are discussed.
Conclusion: There is evidence for BNP elevation in the absence left ventricular dysfunction.This case is an example of impressively high BNP levels associated with ARDS, probably attributable to right ventricular overload due to increased pulmonary vascular resistance.

Case report
A 27-year-old previously healthy man without cardiovascular risk factors was admitted to our intensive care unit because of acute respiratory decompensation.Chest x-ray showed bilateral pulmonary infiltrates and left-sided pleural effusion.Intravenous antibiotic treatment with clarithromycin 500 mg q12h, amoxicillin-clavulanate 2.2 g q8h and doxycycline 100 mg q12h was instituted.A bronchial secretion specimen revealed b-haemolytic group B streptococci, susceptible to all the currently used antibiotics.Pleurocentesis was consistent with parapneumonic effusion.Within hours the chest x-ray showed extensive bilateral alveolar opacities, and the patient had to be intubated and mechanically ventilated (figure 1).After 48 hours of intubation (in the subsequent text "day" refers to the "day of intubation") the maximal fraction of inspired oxygen (FiO2 1.0) was necessary and respiratory acidosis occurred.The antibiotic regimen was replaced by clarithromycin 500 mg q12h and piperacillin-tazobactam 4.5 g q8h.Transthoracic echocardiography revealed a normal sized, non-hypertrophic left ventricle (left ventricular muscle mass index 64 g/m2 ) the ejection fraction being 70%.The transmitral inflow pattern was normal (ratio of early peak flow velocity to atrial peak flow velocity (E/A ratio) 1.5, deceleration time 200 ms).The right ventricle was not dilated, and right ventricular (RV) ejection frac-tion was normal.No tricuspid regurgitation could be detected.There was a small pericardial effusion (day 2).The following criteria for ARDS were fulfilled: 1) acute onset, 2) bilateral infiltrates on chest radiography, 3) absence of clinical or echocardiographic evidence of left atrial hypertension, and 4) paO2/FiO2 of 200 or less [6].Laboratory analyses showed normal cardiac troponin I levels, but a markedly elevated BNP level (1110 pg/mL, Biosite Diagnostics, San Diego, California), which was even higher (>1300 pg/mL) the following day.
On the fifth day treatment with inhaled nitric oxide (iNO) was instituted (5 to 25 ppm).From the 4 th to the 19 th day respiratory tidal volumes were between 4.8 and 6.4 mL/kg body weight with a respiratory rate between 28 to 31 cycles/min, and PEEP was between 5 and 12 cm H2O.Methylprednisolone in a dosage of 125 mg (2 mg/kg body weight) q24h was given from day 8 to day 16 and was then reduced to 80 mg q 24h.Minimal paO2/FiO2 was 57 mm Hg (day 7), maximal pCO2 was 88 mm Hg (day 8), minimal pH was 7.21 (day 8), and maximal lactate was 1.7 mmol/L.
Table 1 demonstrates BNP levels during mechanical ventilation.Figure 2 summarises important clinical and laboratory variables (values assessed and blood samples taken between 6 and 8 a.m. of each day).Pulmonary recovery went parallel with a massive reduction of BNP levels from >1300 pg/mL to 113 pg/mL (days 3 to 14).Apart from norepinephrine up to a maximal dosage of 20 mcg/ min from day 1 to 4 for sustained hypotension despite adequate administration of fluids, no additional therapy with inotropic agents, systemic vasodilators or diuretics was required to stabilise haemodynamics and to maintain diuresis.Mean arterial pressure was not higher than 70 mm Hg during the first week.Creatinine did not exceed a level of 100 mcmol/L during hospitalisation.After 21 days of mechanical ventilation our patient could be extubated.Five days later BNP was 23 pg/mL.Pressure or volume overload of both ventricles due to different underlying conditions induces BNP release.Left ventricular systolic dysfunction [1,2] as well as LV diastolic dysfunction [7] are well known conditions associated with BNP secretion.Patients with LV systolic dysfunction have higher BNP levels than those with isolated LV diastolic dysfunction in most cases.However, there is a considerable overlap between the two groups [8].Levels higher than 1000 pg/ml usually are observed in patients with systolic left ventricular pump failure [1,2].Beyond LV dysfunction, there are reports of volume and pressure overload of the right ventricle leading to slightly to moderately elevated BNP levels [9].BNP levels secreted by the right ventricular (RV) myocardium are said not to exceed 300-600 pg/mL [2] and not to be as high as in cases of elevated LV end-diastolic pressure [1,2].Acute cor pulmonale as a consequence of increased pulmonary vascular resistance (PVR) is known to occur in 60% of patients with ARDS submitted to conventional mechanical ventilation without airway pressure limitation [10] and still in 25% of patients with ARDS submitted to protective ventilatory support [10], which might cause BNP elevation as it does chronic RV pressure overload [9].
In patients with sepsis, biventricular dilatation and depression of ventricular ejection fraction as a consequence of not precisely known mediators can occur [11].Decreased peripheral resistance results in reduced LV afterload and therefore sometimes allows maintaining or even elevating cardiac output despite the presence of depressed LV contractility.In contrast, PVR in sepsis and ARDS increases and may lead to RV overload and decreased RV output in the presence of impaired RV contractility [11].This reversible phenomenon of sepsis-induced cardiac depression usually lasts for about 7 to 10 days and is detectable by echocardiography [11].Despite the absence of common risk factors for the development of LV diastolic dysfunction including hypertension, older age and female gender [12] isolated diastolic dysfunction may occur even in young patients with septic shock [13].However, regarding the high normal LV ejection fraction and the normal mitral inflow pattern neither systolic nor diastolic left ventricular dysfunction may have caused the massive BNP release in the case presented here.Recently, elevated BNP levels in patients with septic shock were shown to be inversely correlated with the cardiac index [14].Preserved diuresis and haemodynamic stability without positive inotropic drugs or diuretics as well as the echocardiographic finding of a high normal LV ejection fraction let us assume that our patient was not suffering from low cardiac output.Additionally, our patient had repeatedly normal levels of cardiac troponin I, which is an argument against myocardial damage during hospitalisation even during the time of BNP elevation.Troponin I is known as a marker of depressed LV ejection fraction and a poor prognosis in critically ill patients without acute coronary syndromes [15].Norepinephrine is a predominantly a-receptor agonist with systemic and pulmonary vasoconstrictor properties [16].Its use during the first four days might have caused an increase in LV afterload causing BNP release.But the fact that mean arterial pressure did not exceed 70 mm Hg in response to norepinephrine administration with an absence of signs of impaired cardiac output, speaks against a massive increase in systemic vascular resistance leading to maximal BNP release.On the other hand, we suggest that acute cor pulmonale due to hypoxic vasoconstriction in ARDS [10,16] and a further increase in PVR due to norepinephrine infusion [16] might have caused BNP elevation.Echocardiographic signs of RV overload, eg, RV dilatation, may be absent, particularly if PEEP is used and causes relative hypovolaemia by reducing of venous return [17].Treatment with iNO can improve oxygenation and reduce PVR in a subgroup of patient with ARDS (responders) by its local vasodilatatory effects on preconstricted vessels in ventilated regions of the lung thereby reducing intrapulmonary shunting [16].We assume that the  [19], but also enhances concentrations of neutral endopeptidase 24.11 in human vascular smooth muscle cells [20], which in turn favours degradation of natriuretic peptides.The effect of methylprednisolone administration on BNP levels in our patient therefore remains speculative.

Discussion
In conclusion, even very high BNP levels in critically ill patients do not exclusively implicate left-sided heart failure in all cases, but might reflect RV overload due to increased PVR in severe pulmonary disease or changes in BNP release and clearance not directly related to myocardial stretch.The widespread use of BNP testing and prospective clinical studies with the use of pulmonary artery catheters probably will further clarify the impact of BNP testing in critically ill patients.
Figure 1 Chest radiograph showing extensive bilateral alveolar opacities.

Figure 2
Figure 2 Time course of BNP, oxygenation, and haemodynamics.Note that the leftsided scale (until 1500) concerns BNP levels, whereas the right-sided scale (until 400) concerns the other three variables.Treatment with iNO and methylprednisolone are indicated.
Correspondence: Micha Maeder, MD Department of Internal Medicine Division of Intensive Care Hospital of St. Gallen Rorschacherstrasse CH-9007 St. Gallen E-Mail: micha.maeder@kssg.chSwiss Medical Weekly: Call for papers Swiss Medical Weekly The many reasons why you should choose SMW to publish your research Official journal of the Swiss Society of Infectious disease the Swiss Society of Internal Medicine the Swiss Respiratory Society Med Wochenschr (1871-2000) Swiss Med Wkly (continues Schweiz Med Wochenschr from 2001) Editores Medicorum Helveticorum