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Ann Thorac Surg 1998;65:761-764
© 1998 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Hemodynamic Effects of Human Atrial Natriuretic Peptide After Modified Fontan Procedure

Department of Pediatric Cardiac Surgery, Heart Institute of Japan, Tokyo Women’s Medical College, Tokyo, Japan
Department of Pediatric Cardiology, Heart Institute of Japan, Tokyo Women’s Medical College, Tokyo, Japan

Accepted for publication August 24, 1997.

Dr Hiramatsu, Department of Pediatric Cardiac Surgery, Heart Institute of Japan, Tokyo Women’s Medical College, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162 Japan.

	Abstract

Top Abstract Introduction Patients and Methods Results Comment References

 
Background. Reduction of pulmonary vascular resistance and maintenance of urine output are important after the modified Fontan procedure. Atrial natriuretic peptide (ANP) has the effects of a vasodilator (including the pulmonary arteries) and a physiologic diuretic, and newly synthesized human ANP is available. We measured plasma ANP levels before and after the Fontan procedure and examined the effects of human ANP on hemodynamic parameters after the Fontan procedure.

Methods. Eight patients, aged 2 to 15 years, underwent the Fontan procedure (atriopulmonary connection). Blood samples were taken before and 3 hours after operation, and plasma ANP levels were measured by radioimmunoassay. The correlation between central venous pressure and ANP was examined. Human ANP was infused intravenously at a dosage of 0.1 µg · kg^-1 · min^-1 for 1 hour after the Fontan procedure under controlled ventilation and another blood sample was obtained. Urine volume and central venous pressure were measured, and pulmonary vascular resistance and the cardiac index were calculated by the thermodilution catheter method before and after human ANP infusion. One hour after human ANP infusion was discontinued, the evaluation was repeated. No other diuretics were given and the infusion rates of catecholamine were kept constant during these measurements.

Results. Plasma ANP levels before and after the Fontan procedure were 29.1 and 54.9 pg/mL, respectively, and a positive correlation was obtained between central venous pressure and plasma ANP levels (r = 0.661, p < 0.05). Human ANP infusion significantly decreased central venous pressure and pulmonary vascular resistance, and increased urine volume and the cardiac index, whereas the plasma ANP level was elevated to 617.5 pg/mL. Systemic blood pressure did not change significantly.

Conclusions. Atrial natriuretic peptide is secreted in response to elevated central venous pressure after the Fontan procedure, but its concentration might not be sufficient. Human ANP can be a therapeutic choice after the Fontan procedure as a physiologic diuretic and a pulmonary vasodilator.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment References

 
The use of the modified Fontan procedure recently was extended to patients with more complex congenital heart defects who have poor indications and marginal criteria for operation [1]. Pulmonary vascular resistance (PVR) is one of the most important criteria in deciding whether to perform the Fontan procedure [1] and postoperative manipulation of the typically high PVR is mandatory to maintain stable hemodynamics. Another typical postoperative hemodynamic characteristic of the Fontan procedure is high central venous pressure (CVP), which causes systemic venous congestion and often leads to massive pleural effusion, ascites, and peripheral edema. Maintaining sufficient urine output is more important for hemodynamic stability after the Fontan procedure than after conventional congenital cardiac operations with normal postoperative CVP.

Natriuretic peptide is a peptide with cyclically formed amino acid residues that has multiple biologic actions. Of the natriuretic peptide family, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are derived from the heart. Atrial natriuretic peptide is secreted mainly from the atrial muscles, with the major stimulus being atrial stretch [2], and BNP is secreted from the ventricular muscles [3]. Increases in plasma ANP levels have been documented in states of severe congestive heart failure, and ANP has been used as a marker for diagnosing the degree of congestive heart failure [4]. Atrial natriuretic peptide has two major effects: (1) as a vasodilator that acts directly on both the pulmonary and systemic arteries, and (2) as a physiologic diuretic that acts on the renal tubule. Human ANP (HANP) is produced commercially by a genetic recombinant technique by a Japanese pharmaceutical company (Suntory; Osaka & Zeria, Tokyo, Japan) and its administration is expected to be one of the most suitable interventions after the Fontan procedure because of its hemodynamic effects as a pulmonary vasodilator and a physiologic diuretic.

In this study, we attempted to evaluate the hemodynamic effects of HANP after the Fontan procedure for complex congenital heart disease.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment References

 
Patients
Eight children underwent the Fontan procedure (connection of the right atrial appendage to the pulmonary artery), 1 for pulmonary atresia with an intact ventricular septum, 1 for pure pulmonary stenosis, 1 for a criss-crossed heart, 2 for a common atrioventricular canal, 1 for a single right ventricle, and 1 for a single left ventricle. The children ranged in age from 2 to 15 years (mean, 7.6 ± 1.1 years). Permission to conduct the study was granted by the Ethical Committee of the Tokyo Women’s Medical College and informed consent was obtained from all the parents.

Surgical Technique
Anesthesia was induced by the intravenous infusion of diazepam (0.2 mg/kg) and maintained with muscle relaxants and morphine. No inhalational agents were used. Immediately before the institution of cardiopulmonary bypass (CPB), 5 mL of venous blood was drawn to measure the plasma ANP level before operation and CVP was measured simultaneously. The inspired oxygen concentration was kept at 40% during the measurements. Conventional CPB was initiated with one episode of aortic cross-clamping and multiple-dose cardioplegia (glucose-insulin-potassium solution). The perfusion flow rate was 2.2 to 2.4 L · m^-2 · min^-1, with moderate hypothermia (25° to 28°C rectal temperature). The hematocrit was kept between 18% and 28% during CPB. The duration of CPB ranged from 57 to 181 minutes (mean, 114 ± 38 minutes) and the aortic cross-clamp time ranged from 0 to 128 minutes (mean, 52 ± 38 minutes). Dopamine, 4 to 8 µg · kg^-1 · min^-1, was infused continuously after CPB.

Three hours after the patients were weaned from CPB, urine volume, systemic blood pressure, and CVP were measured, the cardiac index was determined by the thermodilution catheter method, and PVR was calculated in the intensive care unit. At the same time, 5 mL of venous blood was taken to measure the plasma ANP level after the operation (the inspired oxygen concentration was kept at 40%). Human ANP then was infused intravenously at 0.1 µg · kg^-1 · min^-1 for 1 hour under controlled ventilation. At the end of the infusion, 5 mL of venous blood was taken again for analysis of the plasma ANP level, and the same parameters were measured to evaluate the hemodynamic effects of HANP. One hour after the HANP infusion was discontinued, the evaluation was repeated to confirm that the effects of HANP had disappeared. No other diuretics were given and the infusion rates of catecholamine were kept constant during these measurements.

Blood samples were refrigerated immediately. Blood collected in tubes containing 7.5 mM of ethylenediaminetetraacetic acid was centrifuged at 2,000 x g for 10 minutes at 4°C and the plasma immediately was separated and stored at -70°C to minimize degradation.

Bioassay of Plasma Atrial Natriuretic Peptide Concentrations
Concentrations of plasma ANP were measured by a commercially available specific radioimmunoassay system (SRL, Tokyo, Japan). Briefly, two kinds of iodine-128–labeled monoclonal antibodies that react with ANP or BNP specifically (Shionogi Inc, Tokyo, Japan) were added to plasma samples and the mixture was incubated. Radioimmunoactivity was measured by a gamma counter (ARC-950; Aroka, Tokyo, Japan). The concentrations of ANP and BNP were expressed in picograms per milliliter.

Statistics
All values are expressed as the mean plus or minus the standard deviation. Data were compared using the Student-Newman-Keuls test. A p value of less than 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Patients and Methods Results Comment References

 
Plasma Atrial Natriuretic Peptide
The plasma ANP level was 29.1 ± 15.6 pg/mL before operation and increased significantly to 54.9 ± 16.3 pg/mL after operation (Fig 1). The plasma BNP level increased slightly after operation, but the difference did not reach statistical significance. After the administration of HANP for 1 hour, the plasma ANP level increased to 617.5 ± 132.4 pg/mL.

View larger version (12K): [in this window] [in a new window]   Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels before and after operation (Op.). The asterisk indicates p < 0.05 versus before operation.

View larger version (12K): [in this window] [in a new window]   Correlation between central venous pressure (CVP) and plasma atrial natriuretic peptide (ANP) levels.

View larger version (20K): [in this window] [in a new window]   Hemodynamic effects of human atrial natriuretic peptide (HANP). The asterisk indicates p < 0.05 before HANP. (BP = blood pressure; CI = cardiac index; CVP = central venous pressure; PVR = pulmonary vascular resistance; UV = urine volume.)

Human ANP did not significantly affect the systemic blood pressure or the heart rate (data not shown). Systemic vascular resistance decreased after the administration of HANP, although the difference did not reach statistical significance. It returned to baseline levels thereafter (data not shown).

	Comment

Top Abstract Introduction Patients and Methods Results Comment References

 
In the natriuretic peptide family, ANP and BNP are derived from the heart and are strongly associated with the pathophysiology of heart failure [4]. Atrial natriuretic peptide, with 28 amino acid residues, has multiple biologic actions. It is a diuretic, a natriuretic, a vasodilator of the systemic and pulmonary arteries, and an inhibitor of the secretion of aldosterone [2]. Brain natriuretic peptide, with 32 amino acid residues, plays an important role in regulating somatic fluid and blood pressure [3]. There have been some clinical experiences with ANP infusion in adults. Saito and colleagues [5] reported the clinical application of ANP in patients with congestive heart failure and demonstrated its beneficial effects on left ventricular function. We previously evaluated the effects of HANP administration in adult patients after cardiac operations such as coronary artery bypass grafting and valve operations [6]. Human ANP significantly increased urine output and cardiac output, decreased pulmonary wedge pressure and systemic vascular resistance, and did not change blood pressure [6]. However, there have been few clinical reports of ANP infusion in children. Experimental data suggest that ANP has pulmonary vasodilator activity [7] and that its administration is beneficial to children with pulmonary hypertension. Modi and Midgley [8] examined the effect of ANP infusion up to a dosage of 100 ng · kg^-1 · min^-1 in patients with severe, persistent pulmonary hypertension of the newborn and showed an appreciable rise in arterial oxygen tension. They concluded that ANP should be added to the list of therapeutic options in the management of persistent pulmonary hypertension of the newborn [8].

Elevated PVR has been known to increase the risks associated with the Fontan procedure, particularly when it is higher than 2 to 4 U/m² [1]. Pulmonary vascular resistance is one of the most important factors in making the decision to perform the Fontan procedure and reduction of PVR is mandatory for hemodynamic stability after the operation. The administration of HANP might become one of the most suitable interventions after the Fontan procedure because of its hemodynamic effects as a pulmonary vasodilator and a physiologic diuretic.

In this study, plasma ANP levels were increased significantly after the Fontan procedure. Atrial natriuretic peptide is released by the distention of either of the atria. An abrupt increase in right atrial pressure after the Fontan procedure was associated with extreme elevations in plasma levels of ANP, with a positive, statistically significant correlation between CVP and plasma ANP levels (r = 0.661, p < 0.05). Increased levels of plasma ANP, with its natriuretic, diuretic, and vasorelaxant properties, should promote diuresis rather than fluid retention, in part by direct effects on the kidney and in part by interactions with other humoral systems. However, the plasma levels of ANP seemed to be insufficient because they were increased more than 10-fold after the administration of HANP. The administration of HANP significantly decreased CVP and PVR, increased urine volume and the cardiac index, and did not change systemic blood pressure in our patients. These results suggest that HANP can be a valid therapeutic choice after the Fontan procedure as a physiologic diuretic and a pulmonary vasodilator. The cardiac index was not increased significantly after the administration of HANP, but HANP itself has no direct positive inotropic action and concomitant infusion of a positive inotrope such as dopamine might be advisable during the infusion of HANP.

When HANP is used clinically, the plasma sodium level must be monitored carefully. However, ANP induces a physiologic diuresis that is different from that of diuretics such as furosemide, which inevitably cause hypokalemia and arrhythmias when the plasma potassium level is not adjusted. We have never adjusted the plasma potassium level during the infusion of HANP in our patients. Further, because this peptide is endogenous, its half-life is relatively short (30 minutes), and it is excreted from the kidney [5], it may be safe even if it does induce systemic hypotension, because it will be metabolized easily and the systemic pressure will reverse smoothly to the preinfusion level. The administration of HANP seems to be advantageous in infants and children because they have relatively lower systemic pressure and are accustomed to vasodilation compared with adults. Consequently, the administration of HANP might cause less systemic hypotension in this patient population.

Stewart and associates [9] reported increased plasma levels of vasopressin and ANP in patients undergoing the Fontan procedure and concluded that these agents could act synergistically to result in the development of postoperative effusions when ANP-induced capillary transduction is combined with vasopressin-induced antidiuresis. In our patients, however, the infusion of HANP after the Fontan procedure did not cause increased fluid retention, although we did not measure plasma vasopressin levels in this study.

The inhalation of nitric oxide or the infusion of prostaglandin E₁ recently has become accepted widely as a method of pulmonary vasodilation in patients with postoperative pulmonary hypertension or high PVR [10][11], and has been shown to be effective after the Fontan procedure. Nitric oxide and prostaglandin E₁ have no diuretic effects, whereas HANP does, making it a potentially more advantageous drug for use after the Fontan procedure.

Our conclusions are limited by the possibilities that measured plasma ANP levels might be dependent on the site of blood sampling [12]. However, it is unlikely that our results have been altered qualitatively by this factor because all our patients who underwent the Fontan procedure had plasma ANP levels measured at similar venous sites and similar surgical stages. The effects of a longer infusion of HANP must be examined.

In conclusion, ANP is secreted in response to elevated CVP after the Fontan procedure, but its concentration might not be sufficient. Human ANP can be a therapeutic choice after the Fontan procedure as a physiologic diuretic and a pulmonary vasodilator.

	References

Top Abstract Introduction Patients and Methods Results Comment References

 

1. Mayer JE, Jr, Helgason H, Jonas RA, et al. Extending the limits for modified Fontan procedures. J Thorac Cardiovasc Surg 1986;92:1021-1028.[Abstract]
2. De Bold AJ Atrial natriuretic factor: a hormone produced by the heart. Science 1985;230:767-770.[Abstract/Free Full Text]
3. Sudoh T, Kanagawa K, Minamino N, et al. A new natriuretic peptide in porcine brain. Nature 1988;332:78-81.[Medline]
4. Yoshimura M, Yasue H, Tanaka H, et al. Different secretion patterns of atrial natriuretic peptide and brain natriuretic peptide in patients with congestive heart failure. Circulation 1993;87:464-469.[Abstract/Free Full Text]
5. Saito Y, Nakao K, Nishimura K, et al. Clinical application of atrial natriuretic polypeptide in patients with congestive heart failure. Beneficial effects on left ventricular function. Circulation 1987;76:115-124.[Abstract/Free Full Text]
6. Taniyasu N, Koh E, Hiramatsu T Experiences of Carperitide (synthetic human atrial natriuretic peptide) after cardiovascular surgery. Jpn J Thorac Surg 1996;49:359-363.
7. Adnot S, Andrivet P, Chabrier PE, et al. Atrial natriuretic factor in chronic obstructive lung disease with pulmonary hypertension. J Clin Invest 1989;83:986-993.
8. Modi N, Midgley JP Atrial natriuretic peptide. Arch Dis Child 1992;67:1410-1411.
9. Stewart JM, Gewitz MH, Clark BJ, et al. The role of vasopressin and atrial natriuretic factor in postoperative fluid retention after the Fontan procedure. J Thorac Cardiovasc Surg 1991;102:821-829.[Abstract]
10. Jonas RA Advances in surgical care of infants and children with congenital heart disease [Review]. Curr Opin Pediatr 1995;7:572-579.[Medline]
11. Kieler-Jensen N, Lundin S, Ricksten SE Vasodilator therapy after heart transplantation: effects of inhaled nitric oxide and intravenous prostacyclin, prostaglandin E1, and sodium nitroprusside. J Heart Lung Transplant 1995;14:436-443.[Medline]
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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Yasuharu Imai Yoshinori Takanashi Makoto Nakazawa Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hiramatsu, T. Articles by Nakazawa, M. Search for Related Content PubMed PubMed Citation Articles by Hiramatsu, T. Articles by Nakazawa, M.