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* From the Saint Vincent Catholic Medical Centers, New York, NY.
Correspondence to: Marc Klapholz, MD, Chief, Heart Failure Prevention & Treatment Program, Saint Vincent Catholic Medical Centers, 170 West 12th St, Spellman 690, New York, NY 10011; e-mail: mklapholz{at}svcmcny.org
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Abstract |
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Key Words: brain natriuretic peptide • nesiritide • pulmonary hypertension • renal
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Introduction |
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Case Report |
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The patient was born in 1944 in the United States (Georgia) and developed acute rheumatic fever at 6 years of age. She had episodic fever and arthritis during her childhood and teenage years. Symptoms of dyspnea first appeared at age 18 years during pregnancy, although she was able to complete three full-term pregnancies between the ages of 18 and 24 years.
At the age of 25 years (in 1969), she underwent her first MVR (Kay-Shiley tilting disk), followed by a second MVR in 1974 (Starr-Edwards caged ball), and a third in 1987 (mechanical of unknown type). Her last MVR (St. Jude bileaflet tilting disk) was performed in 1999 in conjunction with a bioprosthetic tricuspid valve replacement for severe tricuspid regurgitation (see corresponding hemodynamics in 1969, 1974, 1999, and 2003 [Table 1 ]).
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On presentation, the patient was in moderate respiratory distress and was significantly volume overloaded (ie, 3+ lower extremity edema and rales in more than two thirds of lung fields bilaterally). A laboratory examination was remarkable for severe microcytic anemia (hemoglobin concentration, 6.4 g/dL), a WBC count of 24.1 x 103 cells/µL with a leftward shift, an international normalized ratio of 2.77, a BUN concentration of 46 mg/dL, and a creatinine concentration of 1.5 mg/dL. Blood cultures were drawn and remained sterile. An ECG showed atrial fibrillation with controlled ventricular response (heart rate, 88 beats/min), right axis deviation, left posterior hemi-block, and nonspecific ST-T changes. Chest radiograph findings were consistent with pulmonary vascular congestion, without the presence of discrete infiltrates. The cardiac silhouette showed evidence of dilated pulmonary arteries. Echocardiography demonstrated a normal functioning mechanical mitral valve and a bioprosthetic tricuspid valve, with no paravalvular or intravalvular regurgitation. Left ventricular systolic function was normal. There was biatrial enlargement with mild right ventricular dilatation and dysfunction. Right ventricular systolic pressures could not be obtained secondary to the absence of tricuspid regurgitation. A bleeding gastric arteriovenous malformation was cauterized, and the anemia was corrected. Multiple attempts at diuresis were unsuccessful, as they were limited by worsening renal function.
On the 26th hospital day, the patient was transferred to the coronary care unit (CCU) for the placement of a pulmonary artery (PA) catheter to quantify filling pressures and cardiac output. Measured values revealed severe pulmonary hypertension and moderately elevated pulmonary vascular resistance (PVR) [Table 1]. Cardiac outputs were normal. Prior to PA catheterization, cardiovascular medications included furosemide, metolazone (Zaroxolyn), enalapril, verapamil, digitalis, and warfarin (Coumadin; Bristol-Myers Squibb; New York, NY). Due to elevated left-sided filling pressures and diuretic-induced renal dysfunction (creatinine concentration, 1.5 mg/dL) with standard diuresis, therapy with nesiritide (Natrecor; Scios Inc; Sunnyvale, CA) was initiated and was titrated to 0.03 µg/kg/min. Over the ensuing 24 h, the patient’s mean capillary wedge pressure decreased from 30 to 18 mm Hg, PA systolic pressures decreased from 70 to 48 mm Hg, and PVR decreased from 3.7 to 1.9 Wood units. Despite obtaining 2 L of fluid from diuresis, the patient’s renal function improved.
Nesiritide therapy was discontinued on CCU day 5, and during the following 48 h PA systolic pressures increased back to baseline level (70 mm Hg), urinary output decreased, and renal function worsened. On CCU day 7, a trial of therapy with IV calcium-channel blockade was started with minimal effect.
Therapy with prostacyclin (Flolan; GlaxoSmithKline; Research Triangle Park, NC) was initiated on CCU day 9 and was titrated to 8 ng/kg/min. Despite dose-limiting symptoms, the patient’s PA pressures improved only modestly (PA systolic pressure, 62 mm Hg), and renal function remained impaired (creatinine concentration, 1.4 g/dL), resulting in a positive fluid balance despite the continued use of IV diuretic agents.
A trial of subcutaneous nesiritide (10 µg/kg every 12h) was attempted but produced no significant hemodynamic response. On CCU day 17, therapy with IV nesiritide was reinstituted, and the patient again demonstrated a marked hemodynamic response (PA systolic pressure decrease, 72 to 52 mm Hg), renal response (decrease in creatinine concentration decrease, 1.4 to 0.7 g/dL), and diuretic response (4.2 L urine output over the next 72 h) [Fig 1 ].
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Discussion |
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BNP has been shown to have pulmonary vasodilatory effects in in vitro animal studies.3 In patients awaiting heart transplantation for severe left ventricular failure, log-term infusions of nesiritide were noted to significantly reduce mean PA pressures.4,5
BNP has been shown to have beneficial effects on renal function. Continuous infusions of BNP in humans increases urine volume and the urinary excretion of sodium in both healthy subjects6789 and in those with left ventricular dysfunction.10,11 BNP may increase the glomerular filtration rate,12 and in patients with heart failure BNP inhibits renal sympathetic activity.13
Our report makes several clinical observations. BNP was a safe and effective therapy for the treatment of patients with severe pulmonary hypertension secondary to rheumatic mitral valve disease. In our patient, BNP therapy simultaneously improved renal function. The improvement of renal function appears to be an independent effect of the drug that is not determined by the improvement in central hemodynamics. This is supported by the observation that with prostacyclin renal function remained compromised despite the ability of prostacyclin to improve filling pressures and to increase cardiac output to a similar degree as that with nesiritide. Fluid balance also was unable to be maintained with prostacyclin even with the concomitant use of IV diuretic agents. This suggests that nesiritide might be a superior alternative for the treatment of patients with severe pulmonary hypertension complicated by right ventricular failure and volume overload.
Our patient underwent insertion of a permanent IV port for continuous home infusions of nesiritide. The subcutaneous administration of BNP, previously described in one animal study,14 was attempted in our patient, but she did not demonstrate either an improvement in central hemodynamics or in renal function.
In summary, we have presented a patient with severe symptomatic pulmonary hypertension due to rheumatic mitral valve disease who was refractory to traditional therapies, including prostacyclin. Continuous nesiritide infusions resulted in optimal cardiorenal indexes with symptom relief, diuresis, and maintenance of fluid balance. The combined vascular and renal effects of nesiritide might offer a particular benefit in patients with refractory pulmonary hypertension and should be further explored.
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Footnotes |
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Received for publication November 3, 2003. Accepted for publication February 13, 2004.
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This article has been cited by other articles:
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  J. R. Klinger, S. Thaker, J. Houtchens, I. R. Preston, N. S. Hill, and H. W. Farber Pulmonary hemodynamic responses to brain natriuretic Peptide and sildenafil in patients with pulmonary arterial hypertension. Chest, February 1, 2006; 129(2): 417 - 425. [Abstract] [Full Text] [PDF]
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L. J. Rubin Epoprostenol and Nesiritide in Pulmonary Hypertension Chest, May 1, 2005; 127(5): 1870 - 1870. [Full Text] [PDF]
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