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Synthetic Human α-Atrial Natriuretic Peptide Improves the Management of Postoperative Hypertension and Renal Dysfunction after the Repair of Abdominal Aortic Aneurysm

Hayashi, Yoshitaka MD, PhD; Ohtani, Masakatsu MD; Sawa, Yoshiki MD, PhD; Hiraishi, Taizo MD; Akedo, Hiroshi MD; Kobayashi, Yasuhiko MD; Matsuda, Hikaru MD, PhD

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Journal of Cardiovascular Pharmacology: November 2003 - Volume 42 - Issue 5 - p 636-641
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Abstract

After aortic operations accompanied by infra-renal aortic cross-clamping (AXC), delayed hypertension (HT) and acute renal dysfunction (RD) are observed in association with the perioperative mortality. 1–5 Especially for the high-risk patients with cardiovascular insufficiency, cerebrovascular disorders, or preexistent renal impairment, the incidence may be a crucial factor of attendant myocardial ischemia, congestive heart failure, cerebral infarction, or multiple organ failure. An intensive care for blood pressure (BP) control and renal protection during the early postoperative period are essential to avoid these critical complications. For adequate and sufficient management, however, the mechanism of AXC-induced HT and RD should be considered.

Both clinically and experimentally, various effects of infra-renal AXC on systemic and renal hemodynamics have been suggested. 6–13 Previous studies demonstrated that renal blood flow decreased during and after infra-renal AXC. 6,10–13 Berkowitz and Shetty 9 demonstrated that infra-renal AXC induced a substantial shift in the ratio of cortical to medullary flow in mongrel dogs. In the clinical study, Welch et al 13 indicated that renal impairment after infra-renal aortic operation may be a result of renal ischemia secondary to reduced renal artery blood flow. This renal hemodynamic deterioration, shown as the renal ischemia accompanied by the imbalance of blood flow ratio between cortex and medulla, is thought to induce a sustained renal vasoconstriction mediated by the activation of renin-angiotensin system (RAS), which enhances cortex ischemia and subsequent RD. 9,11,14–16 Therefore, the regulation of AXC-induced RAS activation seems to be a pathophysiologically reliable and effective management for postoperative HT and RD.

Atrial natriuretic peptide (ANP), one of the natriuretic peptide family, has various pharmacologic effects such as natriuresis, diuresis, vasodilation, the RAS inhibition, and renal protection. 17,18 Regarding the mechanism of postoperative HT and RD after infra-renal AXC, ANP is expected to simplify the early postoperative management and provide sufficient effects on BP control and renal protection. 19,20 Synthetic human α-ANP (hANP) is currently available in the various clinical circumstances of surgical fields 21–23 and the present study was designed to examine the hypothesis that hANP infusion improves the management of postoperative HT and RD after the repair of infra-renal abdominal aortic aneurysm (AAA).

PATIENTS AND METHODS

Study Patients and Group Classification

Fifty patients who underwent elective aneurysmectomy for infra-renal AAA between 1998 and 2001 were enrolled in the present study. Forty-three were males and 7 were females, and their ages at operation ranged from 51 to 88 years with a mean of 70.5 ± 7.7 years. Preoperatively, all study patients received calcium antagonist, β-blocker, or both. Exclusion criteria are as follows: an emergency operation due to ruptured aneurysm, serious cardiovascular or cerebrovascular disease to be treated before aneurysmectomy, severe pre-existent renal impairment dependent on diuretics or hemodialysis, or deteriorated left-ventricular function shown as ejection fraction below 50%. All patients gave their informed consent for the present study, and we followed the guidelines of our internal review board. The investigation conformed to the principles outlined in the Declaration of Helsinki.

These patients were randomly allocated to one of 2 groups according to the postoperative hANP infusion. For patients in Group H (n = 24), intravenous infusion of hANP (HANP; Suntory Inc., Zeria Pharmaceutical, Co., Ltd., Daiichi Pharmaceutical, Co., Ltd., Tokyo, Japan) was started immediately after entering the intensive care unit. The hANP has mainly been used for congestive heart failure, and the recommended dose for initial use is 0.05 to 0.10 μg/kg/min. Therefore, the initial dose was set at 0.025 μg/kg/min to prevent abrupt hypotension possibly induced by hANP infusion. The hANP dose was changed only to control systemic BP. Group C (n = 26) served as the control group and received no hANP infusion. To control systemic BP for patients in Group C, only intravenous infusion of nicardipine hydrochloride was applied.

To evaluate whether preoperative renal impairment influences the effects of hANP infusion or not, each group was subdivided into 2 groups according to preoperative plasma creatinine level (Crn). Crn was under 1.4 mg/dL (Crn < 1.5 mg/dL) in Group Ha (0.92 ± 0.16 mg/dL, n=17) and Ca (0.95 ± 0.24 mg/dL, n = 18). Crn was over 1.5 mg/dL (Crn ≥ 1.5 mg/dL) in Group Hb (1.87 ± 0.42 mg/dL, n = 7) and Cb (1.93 ± 0.49 mg/dL, n = 8). The preoperative demographic and operative data of the patients are shown in Table 1.

TABLE 1
TABLE 1:
Preoperative Demographic and Operative Patient Data

Operative Procedures Related to Abdominal Aortic Aneurysmectomy

General anesthesia was introduced and maintained with diazepam (0.4 mg/kg), fentanyl (20–30 μg/kg), and inhaled isoflurane via endotracheal intubation. Arterial and central venous lines were employed to monitor hemodynamics during intraoperative and postoperative period. Retroperitoneal approach was applied to all patients in the present study for aneurysmectomy. A skin incision was put at the level of the umbilicus just lateral to the lateral border of the rectus umbilicus, and was extended superiorly and posteriorly in a curvilinear fashion toward the eleventh intercostal space. After the exposure of the infra-renal aorta and its branches, 1 mg/kg body weight of heparin sulfate was infused and abdominal aorta was clamped. Graft replacement operation was performed using a collagen-coated knitted polyester vascular graft (InterGard; InterVascular, La Ciotat, France). Intraoperative BP just before and during AXC was controlled by bolus infusion of chlorpromazine hydrochloride. After aortic unclamping, BP was maintained by intravenous infusion of crystalloid or plasma solution if necessary.

Protocol of Management for Postoperative Hypertension and Renal Dysfunction

Until the third postoperative-day, BP was kept between 100 and 140 mm Hg systolic by the use of either nicardipine hydrochloride (Group C) or hANP (Group H). The dose of nicardipine or hANP was gradually tapered after the initial 24 postoperative hours. The infusion was discontinued by the third postoperative-day, and then oral medication of β-blocker was started.

Biochemical examinations concerning renal function were performed every 12 hours after operation. Urine volume was properly controlled by the venous injection of furosemide, not by the change in hANP dose. When plasma Crn showed a tendency to increase, aggressive diuretic therapy was performed using additional crystalloid infusion and bolus furosemide injection.

Measurements and Evaluations

The incidence of postoperative BP over 160 mm Hg systolic was considered delayed HT. The number of patients showing delayed HT was counted and compared between the groups to evaluate the effect of hANP infusion on the prevention of delayed HT. Just for reference, the maximum dose of nicardipine (Group C) or hANP (Group H) was recorded. On the first postoperative day, plasma levels of ANP, brain natriuretic peptide (BNP), renin-activity, and aldosterone were measured by radioimmunoassay to evaluate the effect on the change in plasma natriuretic peptides and the degree of RAS activation. Total amount of furosemide infused during the initial three days after operation was calculated to indicate the simplicity of diuretic management. Peak plasma Crn level during postoperative period was used for a marker of postoperative RD.

STATISTICAL ANALYSIS

All data are expressed as mean ± standard deviation (SD). χ2 test for independence and unpaired Student t test were used to compare values between the groups. Analyses were performed with the StatView ver-5.0 statistical package (Abacus Concepts Inc., Berkeley, CA). A P value of less than 0.05 was considered statistically significant.

RESULTS

All patients in the present study tolerated the surgical procedures and were discharged. No critical complications, such as myocardial ischemia, congestive heart failure, cerebral infarction, or acute peripheral arterial occlusion, were observed in either group. No patients underwent hemodialysis during the postoperative period because of renal dysfunction. In addition, an abrupt hypotension related to hANP infusion did not occur.

In Group C, 22 patients showed postoperative BP over 160 mm Hg systolic and all 26 patients required the infusion of nicardipine hydrochloride (4.41 ± 1.68 mg/h). Only 6 patients in Group H showed systolic BP greater than 160 mm Hg (P < 0.0001); these patients needed the increase in hANP dose. Maximum hANP dose in Group H was 0.035 ± 0.019 μg/kg/min. On the first postoperative day, Group H showed significantly higher plasma ANP (1095.3 ± 238.4 vs. 27.9 ± 10.1 pg/mL, P < 0.0001) and BNP (73.6 ± 18.1 vs. 42.3 ± 13.9 pg/mL, P < 0.0001) (Fig. 1), and showed significantly lower renin-activity (7.09 ± 2.38 vs. 11.52 ± 4.87 ng/mL/h, P = 0.0002) and plasma aldosterone (51.6 ± 12.7 vs. 81.2 ± 34.2 pg/mL, P = 0.0002) (Fig. 2). The total dosage of furosemide during the initial three days (H vs. C; 9.2 ± 11.0 vs. 58.8 ± 41.5 mg, P < 0.0001) and the peak Crn (H vs. C; 1.16 ± 0.53 vs. 2.58 ± 1.42 mg/dL, P < 0.0001) were significantly smaller in Group H (Fig. 3).

FIGURE 1.
FIGURE 1.:
Plasma levels of (a) atrial natriuretic peptide (ANP) and (b) brain natriuretic peptide (BNP) on the first postoperative day.
FIGURE 2.
FIGURE 2.:
Plasma levels of (a) renin-activity and (b) aldosterone on the first postoperative day.
FIGURE 3.
FIGURE 3.:
(a) The total dosage of furosemide during the initial 3 days, and (b) the peak plasma creatinine level during the postoperative period.

These statistically significant differences were also observed between Group Ha and Ca (renin-activity: 6.52 ± 2.19 vs. 8.93 ± 1.85 ng/mL/h, P = 0.0012; aldosterone: 46.9 ± 9.0 vs. 63.6 ± 17.3 pg/mL, P = 0.0011; furosemide: 6.5 ± 8.6 vs. 38.9 ± 22.5 mg, P < 0.0001; Crn: 0.99 ± 0.24 vs. 1.77 ± 0.47 mg/dL, P < 0.0001), and between Group Hb and Cb (renin-activity: 8.49 ± 2.41 vs. 17.34 ± 4.52 ng/mL/h, P = 0.0005; aldosterone: 63.2 ± 13.5 vs. 120.8 ± 29.3 pg/mL, P = 0.0004; furosemide: 15.7 ± 14.0 vs. 103.8 ± 40.0 mg, P < 0.0001; Crn: 1.56 ± 0.81 vs. 4.40 ± 1.09 mg/dL, P < 0.0001) (Fig. 4).

FIGURE 4.
FIGURE 4.:
Comparisons between the subgroups according to preoperative plasma creatinine (Crn) level; (a) plasma renin-activity on the first postoperative day; (b) plasma aldosterone level on the first postoperative day; (c) total dosage of furosemide during the initial 3 days; and (d) the peak plasma Crn during the postoperative period.

DISCUSSION

The hANP has mainly been used to improve hemodynamic condition under congestive heart failure, 24,25 and it has not actively been applied to the management of vascular diseases. Plasma levels of natriuretic-peptide increase to compensate hemodynamic deterioration under heart failure, 26–28 and hANP infusion is considered to support this adaptive compensation. In the present study, no patients have serious cardiac disease and only mild increase in plasma BNP was observed preoperatively. However, hANP has various types of beneficial pharmacological effects such as vasodilation, renal protection, and diuresis. 17–21 Therefore, hANP enables us to simplify the management for prevention of HT and RD after AAA operation, as shown in the present study.

A sudden change in systemic BP should be avoided after operations for cardiovascular disease because it often induces critical complications associated with perioperative morbidity and mortality. 1,5,29 Regarding this viewpoint, it is possible that the strong vasodilating effect provided by hANP infusion may induce abrupt and severe hypotension. However, the initial hANP dose in the present study (0.025 μg/kg/min) is small enough not to aggressively reduce systemic BP. In addition, h-ANP does not provide its pharmacological effects so quickly. 30 These pharmacological characteristics are also convenient for the management after vascular operations.

Although the present study demonstrated the efficacy of hANP infusion in the management after AAA operation, there seem to be 2 optional methods for hANP infusion to be evaluated. One is an intraoperative infusion in expectation of superior renal protection, which is not considered to be practically applied. AXC induces a sudden increase in afterload. 31 Furthermore, subsequent aortic unclamping may enhance renal hypoperfusion. 8,12 The slow exertion of hANP-mediated pharmacological effects seems inadequate to the treatment of hemodynamics during and just after AXC. Another is concerning the optimal duration of hANP infusion. Previous studies indicated that AXC-mediated effects on renal flow distribution and RAS activation last about 1 to 6 hours after aortic unclamping, 8,32 and thus, hANP infusion may be discontinued shortly afterward. However, continuous hANP infusion occupies the deleting system of natriuretic peptides such as natriuretic peptide receptor C and neutral endopeptidase, 33,34 and the deleting system is immediately resumed after the discontinuation of hANP infusion resulting in the rebound phenomenon. Therefore, phased and deliberate discontinuation is preferable, especially for patients requiring a high-dose of hANP infusion.

The hANP-treated patients in the present study showed significantly lower plasma renin-activity and aldosterone were on the first postoperative day. These results imply that intraoperative RAS activation may contribute to the incidence of postoperative HT and RD after AAA operation, which has not yet been demonstrated even in the experimental fields. Effects of ANP on renin-activity and aldosterone may be secondary to improved hemodynamics. To confirm the role of RAS activation in the incidence of postoperative HT and RD, further examinations should be done using appropriate RAS inhibitors such as angiotensin-converting enzyme inhibitors and angiotensin-I receptor blockers.

The mechanism of hANP-mediated renal protection in terms of renal circulation remains unclear. Similar to nitric oxide (NO), hANP provides its vasodilation effect through the activation of cyclic guanosine monophosphate. 35–37 Pathophysiologically, arteriosclerosis is thought to deteriorate endogenous NO production and impair vasoreactivity. 38–40 In addition, recent studies have demonstrated a link between plasma natriuretic peptide and NO in the pathogenesis of arteriosclerosis. 41–46 These facts imply that hANP infusion may compensate NO-mediated impairment of vasoreactivity and participate in postoperative renal protection more effectively in patients with both renal impairment and arteriovascular disease. The results of the present study appear to support this assumption, but statistical analysis was not available because the number of patients with preoperative renal impairment was small.

In summary, we first applied hANP infusion to the management after AAA operation and examined the efficacy in the prevention of HT and RD after aneurysmectomy. The present study implies that RAS may play a role in the incidence of postoperative HT and RD, as well as demonstrated that hANP infusion simplified the postoperative management with satisfactory effects on the prevention of HT and RD. These results suggest that hANP infusion is a simple, reliable, and effective method for the management during the immediate period after AAA operation.

ACKNOWLEDGMENT

We gratefully thank Daiichi Pharmaceutical Co., Ltd., for their critical suggestions on this manuscript.

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Keywords:

abdominal aortic aneurysms; atrial natriuretic peptide; hypertension; renal dysfunction; renin-angiotensin system

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