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Ann Thorac Surg 2000;70:1319-1326
© 2000 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Effects of intraoperative administration of atrial natriuretic peptide

^a Department of Surgery, Kurume University, Kurume, Japan

Address reprint requests to Dr Hayashida, Department of Surgery, Kurume University, 67 Asahi-machi, Kurume Fukuoka, 830–0011, Japan;
e-mail: nobuhiko{at}med.kurume-u.ac.jp

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Biological activity of endogenous atrial natriuretic peptide (ANP) may decrease during cardiopulmonary bypass. To evaluate the effects of intraoperative administration of exogenous ANP in patients undergoing cardiopulmonary bypass, we conducted a prospective randomized study.

Methods. Eighteen patients undergoing mitral valve surgery were randomized to receive either ANP treatment (ANP group; n = 9) or no ANP treatment (control group; n = 9). Atrial natriuretic peptide was given immediately after initiation of cardiopulmonary bypass for 6 hours (0.05 µg · kg^-1 · min^-1). Plasma ANP, brain natriuretic peptide and cyclic guanosine monophosphate (cGMP) levels, hemodynamic variables and renal function were assessed perioperatively.

Results. Administration of ANP increased plasma cyclic guanosine monophosphate levels, urine output and fractional sodium excretion, and decreased preload, afterload and plasma brain natriuretic peptide levels significantly (p < 0.05). Plasma cyclic guanosine monophosphate levels correlated with plasma ANP levels (r = 0.95, p = 0.0001), correlated with fractional sodium excretion (r = 0.53, p = 0.02), and correlated inversely with systemic vascular resistance (r = -0.54, p = 0.02).

Conclusions. Intraoperative administration of ANP had potent effects on natriuresis and systemic vasodilation by elevating cyclic guanosine monophosphate levels. The results suggest that the technique is useful for the management of hemodynamics and water-sodium retention after cardiopulmonary bypass.

	Introduction

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Many reports have proven that heart serves not only the function of muscular pump for the circulatory system, but also that of an endocrine organ [1, 2]. Atrial natriuretic peptide (ANP) has been demonstrated to be produced and secreted mainly from the atrium and to be implicated in the homeostasis of body fluids and blood pressure through the potent biological effects including natriuresis, vasodilation, and inhibition of renin and aldosterone secretion [1, 2]. The cardiac secretion of ANP is stimulated by an increase in atrial pressure, and the plasma concentration increases as the severity of heart failure progresses [3]. Despite the chronically elevated plasma levels and down-regulation of ANP receptor in patients with congestive heart failure, administration of exogenous ANP has been demonstrated to have beneficial effects on hemodynamics, renal function, and neurohormonal values [4]. In patients with acute myocardial infarction, the plasma ANP level was reported to decrease after an excessive release of the peptide to the point of depleting the atrial storage granules, so-called hypoANPism [5]. Administration of ANP for such patients has been reported to induce significant diuresis and natriuresis, as wells as to reduce plasma aldosterone concentration, which may prevent the development of circulatory volume overload and further deterioration in cardiac function [6]. The mechanism of action appears to be mediated by activation of guanylate cyclase, resulting in the production of cyclic guanosine monophosphate (cGMP) [2, 7]. The increase in cGMP level was associated with the dilatation of intramural coronary arteries during ischemic stimulation, causing redistribution of blood flow to the ischemic subendocardium [7]. In a recent report, administration of exogenous ANP has been shown to have cardioprotective effects preventing reperfusion arrhythmias and preserving high-energy phosphates through an increase in cGMP in an ischemia and reperfusion model [8].

In cardiac operations, hypothermia, atrial manipulations and hemodynamic changes during cardiopulmonary bypass (CPB) may blunt the production and secretion of ANP [9–11]. Moreover, hemodilution during CPB may decrease its plasma level considerably. In a recent report, CPB has been shown to decrease ANP biological activity during early postoperative period [12]. Thus, it is expected that administration of exogenous ANP during and early after CPB may have beneficial effects on hemodynamics and management of water-sodium retention after surgery. Currently, however, it is unknown whether supplementation of ANP has such effects in patients undergoing CPB. In the present study, thus, we evaluated the effects of exogenous ANP administered during and early after CPB in patients undergoing cardiac operations.

	Material and methods

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Patients and grouping
A prospective randomized study was performed on 18 patients undergoing primary mitral valve surgery. All patients signed a consent form approved by the Human Experimental Committee of Kurume University. The patients were randomized into two groups by means of a computer-generated randomization table. The control group received no ANP treatment (n = 9); the ANP group (n = 9) received continuous infusion of a genetic recombinant -human ANP [3, 6] (carperitide, Suntory Co, Tokyo, Japan) immediately after initiation of CPB at a rate of 0.05 µg · kg^-1 · min^-1 for 6 hours. The demographic data are shown in Table 1.

Plasma ANP, brain natriuretic peptide, and cGMP measurements
Blood was collected from the patient’s peripheral arterial lines or the arterial side of the CPB circuit immediately after induction of anesthesia, before aortic cross-clamping, 5 minutes, 1, 3, and 18 hours after aortic declamping. All blood samples were drawn in chilled vacuum tubes containing ethylenediaminetetraacetic acid (1.5 mg/mL) and aprotinin (500 kallikrein inactivator units/mL) for determination of ANP and brain natriuretic peptide (BNP) and in chilled vacuum tubes containing disodium ethylenediaminetetraacetic acid (1.5 mg/mL) for determination of cGMP. The samples were centrifuged (1500 g for 10 minutes) at -4° and plasma was stored at -80°C until assayed. Plasma ANP levels were determined by an immunoreactive radiometric assay kit (Shiono RIA ANP, Shionogi Pharmaceutical Co, Osaka, Japan) that recognizes a carboxyterminal sequence of ANP. The minimal detectable quantity of -human ANP is 1 pg per tube and the cross-reactivity with human BNP was less than 0.01% on a molar basis. The intraassay and interassay coefficients of variation were 7.2% and 7.8%, respectively. Plasma BNP levels were determined by an immunoreactive radiometric assay kit (Shiono RIA BNP, Shionogi Pharmaceutical Co, Osaka, Japan.) that recognizes the ring structure of human BNP. Cross-reaction for -human ANP was less than 0.005% on a molar basis. The intraassay and interassay coefficients of variation were 8.4% and 6.4%, respectively. Plasma cGMP level was measured by radioimmunoassay (Cyclic GMP Assay Kit, Yamasa Shoyu, Choshi, Japan). Reference range of plasma ANP, BNP, and cGMP were less than 40 pg/mL, less than 20 pg/mL, and 1.1 to 5.1 pmol/L, respectively. No adjustment was made for hemodilution.

Hemodynamic measurements
Heart rate (HR), mean arterial blood pressure (MAP), mean pulmonary artery pressure (MPA), mean right atrial pressure (RAP), and pulmonary capillary wedge pressure (PCWP) were measured. Cardiac output (CO) was measured in triplicate by the thermodilution technique using a Swan-Ganz catheter (Edwards Swan-Ganz Model 744H-7.5F, Baxter Healthcare Corp, Irvine, CA). Derived hemodynamic indices were calculated as follows: cardiac index (CI) = CO/body surface area (L · min^-1 · m^-2); stroke index (SI) = CI/HR (mL · min^-1 · m^-2); left ventricular stroke work index (LVSWI) = SI x (MAP -PCWP) x 0.0136 (g · m · m^-2); right ventricular stroke work index (RVSWI) = SI x (MPA - AP) x 0.0136 (g · m · m^-2); pulmonary vascular resistance (PVR) = (MPA - PCWP)/CI x 80 (dyne · s^-1 · cm^-5); and systemic vascular resistance (SVR) = (MAP - RAP)/CI x 80 (dyne · s^-1 · cm^-5). These hemodynamic variables were measured after induction of anesthesia and 1, 3, 6, and 18 hours after aortic declamping.

Renal function
Blood and urine specimens for the measurements of serum and urinary levels of creatinine, osmolality, sodium, and potassium were obtained before the operation and 6 hours after initiation of CPB (which coincided with the end of ANP infusion in the ANP group), and 18 hours after initiation of CPB. Perioperative urinary output was also recorded hourly. Creatinine clearance (C_cr), osmolar clearance (C_osm), and free water clearance (C_H2O) were calculated by standard formulas. Fractional sodium excretion (%Na_Exc) and fractional potassium excretion (%K_Exc) were calculated as follows: %Na_Exc = ([Na_u/Na_s]/[Cr_u/Cr_s]) x 100; %K_Exc = ([K_u/K_s]/[Cr_u/Cr_s]) x 100; where Na_u is the concentration of urinary sodium, Na_s is the concentration of serum sodium, Cr_u is the concentration of urinary creatinine, Cr_s is the concentration of serum creatinine, K_u is the concentration of urinary potassium, and K_s is the concentration of serum potassium.

Statistical analysis
Statistical analysis was performed with StatView 5.0 software (SAS Institute, Cary, NC). All data were expressed as a mean ± standard error of the mean. One-way or two-way repeated measures analysis of variance (ANOVA) was used to test the effect of group and time on the levels of ANP, BNP, and cGMP, hemodynamic measurements, and renal function. When ANOVA indicated a significant effect of group or time (p < 0.05), the differences were specified with Sheffé’s test for within-group comparison and unpaired Student’s t test for between-groups comparison. The Pearson’s correlation coefficient test was used to explore the correlation between the two continuous variables measured in this study. The unpaired Student’s t test was used to compare other continuous variables. Categorical data were analyzed using the ² test or Fisher’s exact test where appropriate. Statistical significance was assumed at a probability level of less than 0.05.

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Clinical and operative data for the two patient groups are shown in Table 1. No significant differences were noted in the clinical and operative data. Mitral valve repair using a rigid annuloplasty ring was performed in 5 patients. Intraoperative evaluation by a transesophageal echocardiography revealed either no residual regurgitation or trivial residual regurgitation after the repair.

Plasma ANP, BNP and cGMP levels
Plasma levels of ANP, BNP and cGMP are shown in Figure 1. Plasma ANP levels in the ANP group were significantly (p < 0.05) greater than those in the control group before cross-clamping and 5 minutes, 1 hour, and 3 hours after aortic declamping. Plasma BNP levels in the ANP group were significantly (p < 0.05) lower than those in the control group 3 and 18 hours after aortic declamping. Plasma cGMP levels increased significantly (p < 0.05) during carperitide administration in the ANP group, whereas the levels decreased significantly (p < 0.05) 5 minutes after aortic declamping in the control group. The levels were significantly greater before aortic cross-clamping and 5 minutes and 1 and 3 hours after aortic declamping in the ANP group (p < 0.05) than in the control group. Plasma cGMP levels correlated with concurrent plasma ANP levels 5 minutes (r = 0.95, p = 0.0001), 1 hour (r= 0.72, p = 0.001) and 3 hours (r= 0.92, p = 0.0001) after aortic declamping (Figure 2).

View larger version (21K): [in this window] [in a new window]   Fig 1. Plasma levels of ANP, BNP, and cGMP. Plasma levels of ANP and cGMP in the ANP group were significantly greater than those in the control group. Plasma BNP levels in the ANP group were significantly lower than those in the control group 3 and 18 hours after aortic declamping. (ANP = atrial natriuretic peptide;BNP = brain natriuretic peptide; CPB = cardiopulmonary bypass; cGMP = cyclic guanosine monophosphate; ind = induction of anesthesia; pre= before aortic cross-clamping; XCL = aortic crossclamping; 5 min = 5 minutes after aortic declamping; 1 hr = 1 hour after aortic declamping; 3 hrs = 3 hours after aortic declamping; 18 hrs = 18 hours after aortic declamping.)

View larger version (21K): [in this window] [in a new window]   Fig 2. Relationship between the plasma ANP and cGMP levels. Plasma cGMP levels 5 minutes after aortic declamping correlated with concurrent plasma ANP levels (r = 0.95, p = 0.0001). (ANP = atrial natriuretic peptide;cGMP = cyclic guanosine monophosphate.)

View larger version (21K): [in this window] [in a new window]   Fig 3. Relationship between the plasma cGMP levels and hemodynamic variables. Plasma cGMP levels 1 hour after aortic declamping correlated inversely with SVR (r = -0.54, p = 0.02) 3 hours after aortic declamping and correlated with LVSWI (r = 0.53, p = 0.02) 3 hours after aortic declamping. (cGMP = cyclic guanosine monophosphate; LVSWI = left ventricular stroke work index; SVR = systemic vascular resistance.)

View larger version (24K): [in this window] [in a new window]   Fig 4. Perioperative urine flow. The mean urine flow were significantly greater in ANP group than those in the control group during CPB, during the first 3 hours after CPB, and during 3 and 6 hours after CPB. (ANP = atrial natriuretic peptide;CPB = cardiopulmonary bypass; Preop = before operation; 0–3 = during the first 3 hours after CPB;3–6 = during 3 and 6 hours after CPB; 6–9 = during 6 and 9 hours after CPB; 9–12 = during 9 and 12 hours after CPB; 12–18 = during 12 and 18 hours after CPB.)

View larger version (20K): [in this window] [in a new window]   Fig 5. Relationship between the plasma cGMP levels and fractional sodium excretion and between the plasma cGMP levels and urine flow. Plasma cGMP levels 5 minutes after aortic declamping correlated with the mean urine flow (r = 0.65, p = 0.003) during the first 3 hours after CPB. The levels also correlated with %NaExc (r = 0.53, p = 0.02) during the first 6 hours after initiation of CPB. (cGMP = cyclic guanosine monophosphate; %NaExc= fractional sodium excretion.)

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
In cardiac operations, CPB triggers the production and release of numerous vasoactive substances, such as hormones, autacoids, and cytokines, with resulting vasoconstriction, increase in vascular permeability, and fluid and sodium retention [9]. Of these vasoactive substances, secretion of ANP and the plasma level have been shown to be decreased by hypothermia during CPB or atrial manipulations [10, 11]. In contrast, the level was shown to increase with rewarming or after discontinuation of CPB [10, 14]. Recently, however, Seghaye and colleagues [12] have demonstrated that ANP biological activity decreased significantly despite a significant increase in ANP level during and after CPB in infants undergoing cardiac surgery. Because the decrease in ANP biological activity correlated with the duration of CPB [12], it was suggested that the impairment of ANP biological activity may relate to the nonpulsatile flow or hypothermia during CPB and may contribute to fluid retention after surgery [11, 12]. Therefore, it is expected that the supplementation of ANP by an infusion of carperitide, a genetic recombinant -human ANP, during and early after CPB may offset this condition. The present study has clearly demonstrated that infusion of ANP resulted in significant increases in the urine output and sodium excretion, whereas similar changes in other renal function values were observed in both groups. The results were consistent with a previous report that investigated the diuretic and natriuretic effects of exogenous ANP in humans [6]. Thus, the present results confirm the potent diuretic and natriuretic effects of ANP administered during and early after CPB, which may contribute to the prevention of water-sodium retention after surgery. A significant effect of the regimen on afterload (SVR) reduction was also observed in hemodynamic variables in this study. The reduction in SVR accompanied by the increase in CI and LVSWI after CPB in the ANP group suggests an improvement of cardiac performance associated with systemic vasodilation. Despite its systemic vasodilator activity, no significant effects of ANP on MPA and PVR were found in the present study. It has been documented that lung is rich in ANP receptors coupled to guanylate cyclase and that exogenous ANP dilates isolated pulmonary vascular preparation in humans [15, 16]. Thus, would be expected that administration of exogenous ANP improves pulmonary circulation. The discrepancy between the previous results [15, 16] and our results is probably due to the fact that pulmonary vascular bed may not have been perfused with ANP supplemented blood during CPB because the use of dual vena cava cannula excluded pulmonary circulation. Moreover, down-regulation of ANP receptors has been shown to occur in the pulmonary vascular beds in patients in New York Heart Association functional class III or IV [15]. Because one third of our patients were assessed as being in class III, the possibility exists that down-regulation ANP receptors in pulmonary vascular beds may have already occurred in these patients.

It is believed that the action of ANP is mediated by the activation of particulate guanylate cyclase, resulting in the production of its second messenger, cGMP [2, 17]. Intracellular cGMP leaks out from the target cells to extracellular space, and thus the plasma cGMP concentration is considered to be substantially relevant to its physiologic effects [17]. It has therefore been hypothesized that plasma cGMP levels serve as biological markers for the action of ANP, such as natriuresis and vasodilation [2, 12, 17]. The present study also has demonstrated a marked increase in plasma cGMP level during exogenous ANP infusion, resulting in significant natriuresis and vasodilation, a result in keeping with previous reports. Thus the present study is the first to confirm the theoretical action of ANP supplemented exogenously in patients undergoing CPB.

In a recent report it has been shown that CPB may decrease the biological activity of endogenous ANP [12]. Although the mechanisms remain to be clarified, hypothermia, exclusion of pulmonary circulation, or nonpulsatile flow during CPB may be associated with the phenomenon. In fact, ANP biological activity, determined by the molar ratio of cGMP to ANP, decreased during CPB (at anesthesia induction, 434 ± 106; 5 minutes after aortic declamping, 173 ± 33, p = 0.04) in the control group. Therefore, it is suggested that administration of exogenous ANP may overcome the decrease in ANP biological activity during CPB, resulting in an increase in cGMP levels over a physiologic range.

A recent study that investigated the release of natriuretic peptides after cardioplegic arrest has demonstrated a significantly enhanced myocardial BNP release during early reperfusion despite the unloaded ventricle under CPB support [18]. Although the mechanisms of BNP release during myocardial ischemia remains unclear, it seems likely that the production and secretion of BNP are induced not only by ventricular overload but also by myocardial ischemia per se. In a previous report, ANP has been shown to have beneficial effects on ischemic myocardium by improving myocardial perfusion to areas of ischemia through dilation of coronary vessels with restricted inflow [7]. Because the patients in this study received blood cardioplegia prepared by mixing four parts of oxygenated blood from the CPB circuit with each part of crystalloid, it is probable that myocardium was protected by administration of ANP during cardioplegia. Therefore, the possibility exists that the lesser BNP levels after aortic declamping in patients receiving ANP treatment were attributable not only to the reduction of ventricular overload after CPB through its natriuretic and vasodilator activities but also to its cardioprotective effect during ischemia. In recent reports, ANP has also been demonstrated to serve such physiologic functions as preserving contractility and metabolism of myocardium exposed to hypoxic conditions [19, 20]. Moreover, infusion of ANP has cardioprotective effects during myocardial ischemia and reperfusion, preventing reperfusion arrhythmias and preserving high-energy phosphates through an increase in cGMP [8]. Therefore, the better left ventricular function, or LVSWI, after CPB in the ANP group can potentially be explained by its myocardial protective effect during cardioplegic arrest. However, its protective effect against ischemia was not investigated in detail in this study; moreover, ANP was administered not only during aortic cross-clamping but also during and after CPB. Thus, further studies are required to assert whether ANP has myocardial protective effect during cardioplegic arrest.

Because of its potent diuretic, natriuretic, and vasodilator effects, we believe that patients with congestive heart failure secondary to the valvular disease or impaired left ventricular function after myocardial infarction may benefit most from the ANP treatment during cardiac operations. However, because the number of patients involved in the present study was small and little is known regarding the effects of ANP during cardiac surgery, further investigations involving more patients are required for its routine use. Another important consideration regarding the universal application of the therapy is the direct costs incurred. A genetic recombinant -human ANP (carperitide), as used in the present study, costs approximately $30. Therefore, we believe that the cost is universally relevant and that it would be offset by the shortened patient recovery time.

In conclusion, administration of ANP during and early after CPB increased plasma cGMP levels, with resulting significant diuresis, natriuresis, and systemic vasodilation in patients undergoing mitral valve surgery. It also decreased BNP levels postoperatively. The results suggest that the technique is useful for the management of hemodynamics and water-sodium retention in patients undergoing CPB.[21]

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
This work was supported in part by the Grant-in-Aid for Encouragement of Young Scientists, Japan Society for the Promotion of Science, Japan (grant A-11770753).

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) 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 Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hayashida, N. Articles by Aoyagi, S. Search for Related Content PubMed PubMed Citation Articles by Hayashida, N. Articles by Aoyagi, S.