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Ann Thorac Surg 2000;69:732-738
© 2000 The Society of Thoracic Surgeons

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Original Articles

Low-dose continuous infusion of human atrial natriuretic peptide during and after cardiac surgery

^a Second Department of Surgery, Nihon University School of Medicine, Tokyo, Japan

Address reprint requests to Dr Akira Sezai, Second Department of Surgery, Nihon University School of Medicine, 30-1 Oyaguchi-kamimachi, Itabashi-ku, Tokyo, 173-8610, Japan

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. We evaluated the effects of human atrial natriuretic peptide (hANP) during cardiopulmonary bypass (CPB).

Methods. Forty patients undergoing coronary artery bypass grafting were investigated. A group of patients given hANP for 24 hours from the start of CPB (hANP group) was compared with a non-hANP group. Parameters examined were hemodynamics, urine volume, dosage of furosemide, respiratory index, pleural effusion, ANP, cyclic guanosine monophosphate, renin activity (renin), angiotensin-II, aldosterone, and glomerular filtration rate.

Results. Central venous pressure, systemic vascular resistance index, and pulmonary vascular resistance index were significantly lower in the hANP group than in the non-hANP group. The hANP group showed significantly higher levels of ANP, cyclic guanosine monophosphate, glomerular filtration rate, and respiratory index, and significantly lower levels of renin, angiotensin-II, aldosterone, and pleural effusion, as compared with the non-hANP group. The dosage of furosemide was significantly lower and the urine volume was significantly larger in the hANP group.

Conclusions. hANP can satisfactorily compensate for the shortcomings of CPB by decreasing the peripheral vascular resistance, suppressing the renin-angiotensin-aldosterone system, and exerting a strong diuretic effect.

	Introduction

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Human atrial natriuretic peptide (hANP) is a hormone secreted by extension of the atrial wall. It relaxes arterial and venous smooth muscles and exercises a strong diuretic effect by directly affecting the entire glomeruli and renal tubules. Its advantages are: (1) it has vasodilative and strong diuretic effects; (2) it inhibits hormone secretion, including the renin-angiotensin system and catecholamine; (3) it has a strong natriuretic effect that helps avoid aggravation of impaired electrolyte balance because of the administration of a large amount of diuretics; and (4) it reduces myocardial oxygen demand [1–5]. As for shortcomings: (1) hANP may induce hypotension, and (2) there are no oral substitutive drugs.

During cardiac surgery, abnormal increases in hormones such as the renin-angiotensin system and catecholamine occur because of the influence of cardiopulmonary bypass (CPB), leading to a decrease in urine volume and water retention in the third space [6]. Thus, we carried out the present study to evaluate the effects of hANP on the assumption that its administration might be effective for such pathology.

	Material and methods

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Patients
We studied 40 patients with normal renal function undergoing elective coronary artery bypass grafting (CABG). The patients were randomly allocated to two groups receiving blind infusions of hANP (Suntory Inc, Osaka, Japan; and Zeria Inc, Tokyo, Japan) from the start of CPB (hANP group) or placebo (vehicle alone, non-hANP group), respectively. Before inclusion in this study, we explained the details of the study to patients and obtained their consent. The protocol of this study was approved by the Institutional Review Board of Nihon University Itabashi Hospital. The preoperative systolic blood pressure was measured in the operating room before anesthesia, and the initial dose of hANP was set at 0.05 µg/kg/min when the preoperative systolic blood pressure exceeded 120 mm Hg, and at 0.03 µg/kg/min when it was 120 mm Hg or less. The initial dose was maintained for 20 hours and then reduced to 0.02 µg/kg/min. Infusion of hANP was discontinued after 24 hours. Dopamine (DOA) and dobutamine (DOB) were started at 3 µg/kg/min at the end of CPB.

Operative patient management
Pethidine hydrochloride was intramuscularly given to all patients as a premedication for the anesthesia at 30 minutes before entrance to the operating room. Anesthe-sia was induced and maintained with midazolam and fentanyl, and isoflurane was also used when necessary. The extracorporeal circuit was primed with 1,500 mL of Ringer’s solution, 300 mL of mannitol, and 1 mL/kg of sodium bicarbonate. CPB was performed under mild hypothermia (rectal temperature 32°C to 34°C) with a centrifugal pump (BP-80; BioMedicus Inc, Minneapolis, MN) and a membrane oxygenator (Spiral OXY; Baxter Inc, Irvine, CA), and the perfusion flow was maintained at 2.3 to 2.4 L/min/m². For cardioplegia, St. Thomas solution cooled to 4°C was used in an initial dose of 30 mL/kg and then progressively administered at 10 mL/kg at 30-minute intervals.

Measurements
Hemodynamic parameters, measured to 72 hours after CPB, included systolic arterial pressure (sAoP), mean arterial pressure (mAoP), central venous pressure (CVP), systolic pulmonary arterial pressure (sPAP), mean pulmonary arterial pressure (mPAP), pulmonary capillary wedge pressure (PCWP), cardiac index (CI), systemic vascular resistance index (SVRI), and pulmonary vascular resistance index (PVRI).

Chemical parameters, measured to 72 hours after CPB, included ANP concentration (ANP), cyclic guanosine monophosphate (cGMP), renin activity (renin), angiotensin-II, aldosterone, blood urea nitrogen (BUN), creatinine (Cr), glomerular filtration rate (GFR), and urinary sodium (U-Na). ANP, BUN, and Cr were also measured 7 days after surgery. The respiratory index was measured at the time of return to the intensive care unit (ICU) under 70% FiO₂, 10 mL/kg of tidal volume, and 12 times/minute of respiratory rate. It is generally regarded as a good index of oxygen transport in the lung. It was defined as follows: A-aDO₂/PaO₂ [7] (A-aDO₂ = [FiO₂ x 713 - (PaCO₂/0.8)] - PaO₂). Further, we also determined the intubation time, urine volume, presence of pleural effusion, and dosages of furosemide, KCl, and catecholamines.

Statistical analysis
Measurements were expressed as means ± standard deviations. Patients’ background factors, total dosages of furosemide, KCl, and the presence of pleural effusion were statistically compared using unpaired t tests. The other data were analyzed using Scheffe’s method for repeated-measure analysis of variance. The level of significance was set at p less than 0.05.

	Results

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Patient age, gender, body surface area, numbers of bypasses, aortic cross-clamping time, CPB time, and dosages of DOA and DOB administered did not significantly differ between the two groups. In the hANP group, none of the patients required discontinuation of hANP because of hypotension, and none developed the rebound phenomenon after the hANP was discontinued (Tables 1, 2).

View larger version (27K): [in this window] [in a new window]   Fig 1. Changes in ANP concentration (ANP) (top) and cyclic GMP concentration (cGMP) (bottom).

View larger version (29K): [in this window] [in a new window]   Fig 2. Changes in renin activity (renin) (top) and angiotensin-II (bottom).

View larger version (31K): [in this window] [in a new window]   Fig 3. Changes in aldosterone (top) and urinary sodium (U-Na) (bottom).

GFR, urine volume, and U-Na
GFR remained at the preoperative level in the hANP group but began to decrease to significantly lower levels in the non-hANP group compared with the hANP group after the start of CPB (Figs 3, 4). The urine volume was significantly higher in the hANP group during CPB until 6 hours after CPB. It was noted that the urine volume in the hANP group was twofold more than that in the non-hANP group without the use of furosemide during CPB. U-Na decreased during CPB and improved thereafter in the non-hANP group, and it was significantly different from that in the hANP group during CPB, at the end of CPB, and at 3, 6, and 72 hours after CPB.

View larger version (33K): [in this window] [in a new window]   Fig 4. Changes in glomerular filtration rate (GFR) (top) and urine volume (bottom).

View larger version (33K): [in this window] [in a new window]   Fig 5. Dosages of furosemide (top) and KCl (bottom).

	Comment

Top Abstract Introduction Material and methods Results Comment References

 
De Bold and associates discovered unique granules in the atrium of the rat, and these granules were found to have a marked natriuretic effect [8]. Kangawa and Matsuo successfully extracted and purified a substance with a strong natriuretic effect from these granules and designated it as human atrial natriuretic peptide (hANP) [9]. Subsequently, hANP was found to have not only a natriuretic effect, but various other effects as well, such as vasodilatation and inhibition of the renin-angiotensin system [1–4]. Although the effectiveness of hANP in cardiac surgery has also been reported in recent years, the usage of this medication is practically limited to the postoperative treatment of severe valvular diseases and heart failure complicated with diuretic resistance or pulmonary hypertension [10, 11]. Cardiac surgery usually induces abnormal increases in hormones such as the renin-angiotensin system and catecholamine because of the effects of CPB in decreasing the urine volume and creating water retention in the third space. It is also reported that resection or ligation of the right atrial appendage on surgery reduces postoperative ANP secretion [12]. Therefore, on the assumption that the administration of hANP might be effective for this pathology, the present study was carried out to evaluate the effects of hANP on hemodynamics, hormone secretion, renal function, and pulmonary function.

Because there has been no report on the administration of hANP from the start of CPB, we should first establish the dose of hANP, timing for the initiation of administration, and infusion time. hANP is usually administered for heart failure through continuous infusion at a starting dose of 0.1 µg/kg/min or through single intravenous injection [5, 11]. In the present study, hANP was administered at doses as low as 0.03 to 0.05 µg/kg/min because it was used for patients undergoing elective operations rather than for heart failure, and also because we were concerned about its safe use for patients in a dehydrated condition at the start of the operation, because it has been reported that hANP may lower blood pressure in dehydrated patients. Although no comparison between the two doses (0.03 and 0.05 µg/kg/min) was made in the present study, sufficient efficacy was obtained even at 0.03 µg/kg/min, suggesting that hANP can exert its pharmacologic effect at very low doses. With regard to the timing for the start of administration, we decided to administer hANP from the start of CPB because earlier administration from the induction of anesthesia would facilitate hypotension, while later administration after the induction of CPB would more likely enable control of hypotension. We elected the 24-hour duration after the start of CPB as the period of hANP administration for determination of the drug’s effect because the hormonal environment is known to be most unstable during the early postoperative period. Because it has been reported that resistance may arise against the diuretic effect of hANP, we also intended to limit the administration of this drug to a period under strict control in the ICU. Also, the diuretic medication was shifted to an oral diuretic from 1 postoperative day to avoid an excessive diuretic effect, again restricting the use of hANP to a short 24-hour period. As a result, continuous low-dose infusion of hANP from the start of CPB caused neither withdrawal because of hypotension nor rebound phenomenon, and a very satisfactory physiologic condition was provided from the standpoint of hemodynamics and biochemistry. Although 24-hour continuous administration provided sufficient efficacy, further consideration seems to be necessary to establish an optimal infusion time.

As for hemodynamics, sAoP and mAoP were significantly lower in the hANP group than in the non-hANP group. However, none of the patients in the hANP group required discontinuation of hANP administration because of hypotension. CVP, sPAP, mPAP, SVRI, and PVRI were significantly lower in the hANP group than in the non-hANP group, whereas CI was significantly higher in the hANP group. These results clearly indicated that administration of hANP reduces both preload and afterload. In the present study, DOA or DOB at doses exceeding 3 µg/kg/min was used in all patients after weaning from CPB, so it is very likely that these medications influenced the hemodynamics and other aspects of the in vivo environment. However, there was no difference in the amounts of DOA and DOB administered, and in both cases the doses were low. Thus, it was concluded that hANP can be safely used to dilate the peripheral blood vessel without reduction of the aortic pressure in combination with low-dose DOA or DOB.

Many reports concerning the effects of hANP on the kidney have also been published. This medication is reported to increase creatinine clearance, leading to increases in urine volume and urinary sodium excretion [13]. Valsson and associates observed increases in urine volume, GFR, and renal blood flow when they administered hANP to patients developing acute renal failure after cardiac surgery [14]. Many investigators have reported the inhibitory effect of hANP on the renin-angiotensin system. Although some reported that renin was not lowered by administration of high-dose hANP, many have observed a strong inhibitory effect [15, 16]. In this study, renin, angiotensin-II, and aldosterone were all decreased, probably because of the use of hANP at a low dose. The incidence of acute renal failure after cardiac surgery has been reported to range from 5% to 30% [14]. In this study, the Cr level exceeded 1.3 mg/dL in 5 patients (25%) in the non-hANP group. Compared with the non-hANP group, effective outcomes including increases in urine volume and GFR, inhibition of renin and aldosterone, and decreases in the amounts of diuretic and potassium were observed in the hANP group. Because furosemide exercises its diuretic effect forcedly, this drug may pose postsurgical problems, such as the onset of arrhythmia due to electrolyte abnormality and resistance. The dosages of diuretic and potassium were markedly decreased by administration of hANP in this study, and there was no aggravation of impaired electrolyte balance during the unstable postoperative period. Because a more physiologic hormonal condition could be maintained through the use of this drug, its use might offer a means of decreasing the incidence of postoperative acute renal failure. Downregulation on the hANP receptor, one of the shortcomings of this drug, should be considered as a possible reason for the lack of any difference in urine volume between the hANP and control groups from 9 hours after weaning from CPB, but because hANP was used only for a short period of time at a low dose in the present study, we think a more likely cause was the significantly higher dose of furosemide used in the control group from 9 hours after weaning from CPB.

For cardiac surgeons, the most interesting aspect of hANP is what effect it exercises on water contents postoperatively retained in the tissue space. If hANP has the effect of transporting water into vessels from the tissue space, then it can be considered extremely useful for the management of patients during and after cardiac surgery. An experimental study demonstrated that hANP transported water from vessels to tissues, thereby leading to a decrease in the circulatory blood flow [17]. However, by measuring circulatory blood flow in terms of clearance of indocyanine green, Haruna and associates found that administration of hANP led to a decrease in edema in clinical cases by facilitating water transport from the tissue space into vessels [18]. Our study also suggested the possibility that hANP can transport water from the tissue space into blood vessels because postoperative retention of pleural effusion was markedly decreased by administration of hANP. Moreover, we also demonstrated that hANP may decrease alveolar edema because the respiratory index was significantly higher in the hANP group than in the non-hANP group. Given the increase in tissue fluid after cardiac surgery, hANP can be considered an extremely useful drug for the intraoperative and postoperative management in cardiac surgery if it indeed has the effect of transporting water from the tissue space into blood vessels.

It is reported that resection or ligation of the right arterial appendage in surgery is a cause of the postoperative decrease in ANP secretion [12]. It is also reported that ANP secretion is decreased in the presence of valvular disease because the atrium extends and dilates [10]. In the present study, ANP levels in the non-hANP group were 27.3 ± 20.7 pg/mL before surgery, 25.9 ± 14.6 pg/mL during CPB, 75.2 ± 39.8 pg/mL at the end of CPB, 49.8 ± 23.0 pg/mL at 3 hours after CPB, 48.8 ± 22.5 pg/mL at 6 hours, 47.3 ± 21.9 pg/mL at 24 hours, and 56.5 ± 35.3 pg/mL at 72 hours, so the absence of any postoperative decrease in ANP secretion was confirmed. These results are thought to result from favorable influences on the extension of atrium, probably because ligation of the right atrial appendage could be minimized because of the use of two-stage venous cannula, because the patients had no valvular disease, and because there were no serious cases.

Although there remain many uncertain aspects such as the duration of administration, and the timing for discontinuation, hANP was determined to suppress water retention in the third space, decrease peripheral vascular resistance, inhibit the renin-angiotensin system, and exert a strong diuretic effect. Moreover, because this substance decreased the dosage of furosemide, aggravation of impaired electrolyte balance could be avoided during the unstable postoperative period. Furthermore, sufficient effects of hANP could be observed even at low doses of 0.03 to 0.05 µg/kg/min, suggesting that the risk of hypotension and rebound phenomenon can be eliminated by clarifying the pathology and selecting an optimal dose of hANP. In the future, we will study the effects and shortcomings of hANP in greater detail, including its optimal dose, optimal duration of administration, and downregulation of hANP receptor. In the present study, it was clarified that administration of hANP from the start of CPB is extremely useful in compensating for the shortcomings of the CPB. In the future, hANP is expected to be newly introduced as a drug for the postoperative management of cardiac surgery.

Conclusion
In the present study, the applicability of continuous low-dose administration of hANP from the start of CPB was examined. The results revealed that hANP can compensate for the shortcomings of CPB by inhibiting water retention in the third space, decreasing peripheral vascular resistance, suppressing the renin-angiotensin system, and exerting a strong diuretic effect without causing hypotension or rebound phenomenon. Moreover, because hANP decreased the dosages of furosemide and potassium, worsening of the impaired electrolyte balance and the onset of arrhythmia could be avoided during the unstable postoperative period.

	References

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