Ann Thorac Surg 2002;73:1582-1586
© 2002 The Society of Thoracic Surgeons
Original article: general thoracic
Natriuretic peptides after pulmonary resection
Kohsuke Tayama, MD*a,
Shinzo Takamori, MDa,
Masahiro Mitsuoka, MDa,
Akihiro Hayashi, MDa,
Kohichi Tamura, MDa,
Hiroharu Mifune, PhDb,
Kazuo Shirouzu, MDa
a Department of Surgery, Kurume University School of Medicine, Kurume, Japan
b Institute of Animal Experimentation, Kurume University School of Medicine, Kurume, Japan
Accepted for publication January 4, 2002.
* Address reprint requests to Dr Tayama, Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
e-mail: ktayama{at}kkr.sasebo.nagasaki.jp
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Abstract
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Background. Little is known about alterations in the levels and influence of natriuretic peptide (NP) on cardiopulmonary function after pulmonary resection for lung cancer. This study was designed to investigate the patterns and activity of NP after pulmonary resection.
Methods. We investigated changes in plasma A-type (atrial) NP and B-type (brain) NP (BNP) using radioimmunoassay, in lung cancer patients before and after lobectomy (n = 15) or pneumonectomy (n = 10). Patient characteristics, respiratory function, operative time, blood loss, intraoperative fluid administration, and intraoperative urine output in both groups were also compared. Pulmonary hemodynamic variables were monitored continuously.
Results. Plasma concentrations of A-type NP and BNP did not differ between the two groups preoperatively. However, the group undergoing pneumonectomy exhibited higher concentrations of A-type NP and BNP than the group undergoing lobectomy on postoperative days 3 and 7. Alterations in A-type NP and BNP after pulmonary resection therefore differed according to the volume of lung tissue resected. Both mean pulmonary artery pressure and total pulmonary vascular resistance increased significantly in the pneumonectomy group. The total pulmonary vascular resistance on postoperative day 3 correlated with the plasma BNP concentration in the pneumonectomy group.
Conclusions. A-type NP and BNP effectively compensate for the right ventricular dysfunction noted after pulmonary resection, and this is more evident after pneumonectomy than after lobectomy. Changes in ventricular activity associated with changes in plasma BNP and total pulmonary vascular resistance are indicative of cardiopulmonary adjustments after pneumonectomy.
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Introduction
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The relationship between right ventricular function and altered pulmonary vascular tone after pulmonary resection has been well documented [1–3]. Pulmonary vascular tone is regulated by many vasoactive mediators produced by pulmonary vascular endothelium, vascular smooth muscle, and blood.
Natriuretic peptides are vasodilator hormones involved in the regulation of blood pressure and volume homeostasis. A-type natriuretic peptide (ANP) is released from the right auricle in response to right atrial stretch [4] or pulmonary vasoconstriction [5], and dilates pulmonary artery smooth muscles [6]. B-type natriuretic peptide (BNP) has peripheral and central actions similar to ANP and is secreted into the circulation from the cardiac ventricles [7]. Vasodilatory activity of both ANP and BNP is mediated through the cyclic guanosine monophosphate (cGMP)-linked receptor on vascular smooth muscle cells. Plasma concentrations of these peptides are higher in patients with heart failure than in normal patients [8]. In our previous experimental study in beagle dogs, pneumonectomy resulted in a significant rise in ANP levels in the plasma and contralateral lung and elevation of pulmonary artery pressure [9]. However, the effects of these vasoactive natriuretic peptides after pulmonary resection are still not clearly understood. The aim of this study was to determine the effects of lobectomy, as compared with pneumonectomy, on ANP and BNP levels.
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Material and methods
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Patients
After obtaining institutional approval and the patients’ informed consent, 15 patients underwent lobectomy and 10 patients underwent pneumonectomy for lung cancer at Kurume University Hospital. None of the patients had symptomatic coronary artery disease, hypertension, or atrial arrhythmias, or had undergone induction chemotherapy or radiotherapy. All patients had unremarkable cardiac examinations. Surgical resections included five right upper lobectomies, two right middle lobectomies, three right lower lobectomies, two left upper lobectomies, three left lower lobectomies, four right pneumonectomies, and six left pneumonectomies. In all patients, the pulmonary vein was dissected first. In pneumonectomy, the superior pulmonary vein and inferior pulmonary vein were ligated and dissected separately. All patients underwent intubation with a double-lumen endotracheal tube and insertion of radial arterial catheters for constant blood pressure monitoring.
Thermodilution measurements
A multilumen thermodilution catheter mounted with a rapid-response thermistor (7.5F; Baxter Healthcare Corp, Irvine, CA) was positioned 3 to 4 cm distal to the pulmonary valve. The output from this thermistor and the analog electrocardiographic signal were interfaced to a thermodilution ejection fraction computer (REF-1; Baxter Healthcare Corp). The following hemodynamic variables were measured: mean pulmonary artery pressure (PAP), cardiac output, and total pulmonary vascular resistance (TPVR). Cardiac output was determined in triplicate by thermodilution. Total pulmonary vascular resistance was calculated using the following formula: TPVR = mean PAP/CI x 80, where CI is cardiac index. Hemodynamic variables and plasma ANP and BNP levels in arterial blood were determined at six different points: preoperatively (after insertion of the Swan-Ganz catheter but before thoracotomy), 0 hours (immediately postoperatively), 6 hours, and on postoperative days (POD) 1, 3, and 7. Hemodynamic variables were not measured on POD 7, as the patients were restricted to bed after the operation for 7 days to calculate the hemodynamic variables using a Swan-Ganz catheter.
Radioimmunoassay
Blood was collected from the peripheral end of the pulmonary artery occluded in the unilateral pulmonary artery occlusion study to determine the difference in ANP and BNP between the pulmonary circulation and the systemic circulation. As a result, because there was no difference between them and it took time to collect sufficient amounts of blood from the peripheral end of the occluded pulmonary artery, the determination was conducted in the systemic circulation.
Blood samples were drawn from the femoral artery into a syringe containing 1 mg of ethylenediaminetetraacetic acid and 1,000 U of the kallikrein-inhibitor aprotinin (Bayer, Leverkusen, Germany). The plasma samples were rapidly frozen and stored at -80°C until the measurement of plasma ANP and BNP levels. Plasma ANP and BNP levels were measured using a radioimmunoassay kit (Peninsula Laboratories, Belmont, CA).
Statistical analysis
All data are expressed as the mean ± standard deviation and were analyzed using StatView 4.0 software (Abacus Concepts, Berkeley, CA). Analysis of variance and paired or unpaired Student’s t tests were used for comparison of data as appropriate. Correlations between variables were assessed using linear regression analysis. Differences were considered significant at a probability level of less than 0.05.
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Results
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Patient characteristics
Pneumonectomy was performed in 10 patients (median age, 63.5 years; range, 41 to 76 years), and lobectomy was performed in 15 patients (median age, 65.7 years; range 45 to 78 years). There was no significant difference between the two groups with respect to age, sex, body weight, height, body surface area, and pulmonary function tests (Table 1).
Perioperative conditions
There were no differences in operative time, blood loss, intraoperative fluid administration, intraoperative urine output, or median 24-hour postoperative fluid balance (lobectomy, 3 mL · kg-1 · h-1; pneumonectomy, 1 to 1.5 mL · kg-1 · h-1) between the two groups (Table 2).
Oral ingestion was started on the day after operation, but the amount was not determined exactly. In addition, the body weight was not determined either. An epidural catheter was preoperatively inserted in all patients for the purpose of postoperative analgesia, and continuous administration of 0.25% bupivacaine hydrochloride was administered at a dose of 2 mL/h for 3 days.
Hemodynamics
Mean PAP was significantly elevated immediately after pulmonary resection at 0 hours (Fig 1a).
This was especially marked after pneumonectomy on POD 3; mean PAP was significantly higher in the pneumonectomy group compared with the lobectomy group (Fig 2a).
Cardiac output was not altered by pulmonary resection (Fig 1b), and it was comparable in both groups (Fig 2b). Total pulmonary vascular resistance was significantly elevated at 0 hours after pulmonary resection (Fig 1c), and it was significantly higher after pneumonectomy than after lobectomy (Fig 2c). There was no significant difference in urine output between the lobectomy and pneumonectomy groups (Table 3).
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Fig 1. (a) Mean pulmonary artery pressure (PAP) was significantly increased postoperatively above the preoperative (pre) value at 0 hours and 6 hours, and on postoperative days (pod) 1, 2, and 3 (#p < 0.01; *p < 0.05). (b) Cardiac output did not change after pulmonary resection. (c) Total pulmonary vascular resistance (TPVR) was significantly increased from the preoperative value (*p < 0.05). Data are the mean ± standard deviation.
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Fig 2. (a) Mean pulmonary artery pressure (PAP) was increased postoperatively and the increase after pneumonectomy was significantly greater than after lobectomy on postoperative day (pod) 3 (*p < 0.05). (pre = preoperative value.) (b) Cardiac output was not significantly different between the lobectomy and pneumonectomy groups. (c) Total pulmonary vascular resistance (TPVR) was significantly increased after pneumonectomy compared with lobectomy at postoperative 0 hours and on pod 1, 2, and 3 (#p < 0.01). Data are the mean ± standard deviation.
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Radioimmunoassay
Plasma ANP concentration was significantly higher after pulmonary resection, and it was still higher on POD 7 (Fig 3a).
Preoperative ANP levels did not differ significantly between the groups; however, after pneumonectomy, ANP levels on POD 3 and 7 were significantly higher than those in the lobectomy group (Fig 4a). Plasma BNP concentrations were not elevated until POD 1, and continued to be significantly higher on POD 3 and 7 (Fig 3b). Preoperative plasma BNP levels did not differ significantly between the two groups (Fig 4b). Plasma BNP levels did not alter significantly after lobectomy; however, BNP was significantly elevated on POD 3 and 7 in pneumonectomy group (Fig 4b). There was a clearly positive correlation between TPVR and plasma BNP on POD 3 in the pneumonectomy group (Fig 5b);
however, this correlation was not evident in the lobectomy group at the same determination point (Fig 5a).
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Fig 3. (a) Plasma A-type natriuretic peptide (ANP) concentrations were significantly elevated at 0 hours and 6 hours, and on postoperative days (pod) 1 and 3, compared with preoperative (pre) levels (* p < 0.05). (b) Plasma B-type natriuretic peptide (BNP) concentrations were significantly elevated on pod 3 and 7, compared with preoperative levels (* p < 0.05). Data are the mean ± standard deviation.
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Fig 4. (a) Plasma A-type natriuretic peptide (ANP) concentrations were significantly higher after pneumonectomy than after lobectomy on postoperative days (pod) 3 and 7 (* p < 0.05). (b) Plasma B-type natriuretic peptide (BNP) concentrations were significantly higher after pneumonectomy than after lobectomy on pod 3 and 7 (* p < 0.05). Data are the mean ± standard deviation. (pre = preoperative value.)
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Fig 5. Correlation between total pulmonary vascular resistance (TPVR) index on postoperative day (POD) 3 and plasma B-type natriuretic peptide (BNP) concentration at the same determination point in patients who underwent a lobectomy (a:r = 0.06, p > 0.05) or a pneumonectomy (b:r = 0.56, p < 0.01).
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Comment
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In the present study, we have demonstrated that postoperative alterations in the natriuretic peptide system, as determined by plasma concentrations of ANP and BNP, depended on the extent of pulmonary resection. This phenomenon may contribute to the right ventricular dysfunction observed after lung resection.
Right ventricular dysfunction and altered pulmonary vascular tone after pulmonary resection have been discussed previously [3, 4]. Clinical and experimental reports have suggested that the cause of the early increase in right ventricular pressure after pulmonary resection is most likely the decreased volume of the pulmonary vascular bed [10]. Reed and colleagues [3] reported that, in most lobectomy patients with lung cancer, right ventricular end-diastolic volume was significantly increased in the postoperative period with a slight decrease in right ventricular ejection fraction. In contrast, Amar and associates [1] found no significant difference in right or left atrial size, right atrial pressure, or estimated right ventricular systolic pressure between lobectomy and pneumonectomy groups, at the preoperative stage or on POD 1. The same group also demonstrated by echocardiography that right ventricular systolic pressure was higher after pneumonectomy than lobectomy from POD 2 to 6. Furthermore, the linear velocity of blood in the pulmonary microcirculation was shown to increase when a reduced vascular bed is subjected to a constant cardiac output, which increases tangential and shear stresses and may physically injure the endothelium, leading to increased membrane permeability [11]. However, compensation for dysfunction in cardiopulmonary circulation in the heart or the lung after pulmonary resection remains obscure.
A-type natriuretic peptide is a cardiac hormone and a typical vasodilator, which has been localized in various tissues, including the lung, by immunohistochemical examination and by radioimmunoassay [12]. Alteration in the atrial natriuretic peptide system has been described in several pathophysiologic conditions associated with abnormal regulation of body fluids and blood pressure control, particularly in edematous disorders, and ANP has been shown to induce pulmonary vasodilation in the perfused pulmonary vascular bed in vitro [13]. We have previously shown that ANP synthesis and release were enhanced in plasma and in the contralateral lung after pneumonectomy in beagle dogs, and have postulated that ANP from plasma and the remnant lung may contribute to improve the cardiopulmonary circulation [9].
B-type natriuretic peptide, isolated from porcine brain, has peripheral and central actions similar to ANP, and is secreted into the circulation from cardiac ventricles [7]. A simple blood test for BNP has been used to distinguish patients in whom heart failure is extremely unlikely from those in whom the probability of heart failure is high [14]. Synthesis of BNP has also been detected in the lungs of humans and rats, and lung BNP may thus contribute to the pool of circulating hormone [15, 16]. However, the vasoregulatory role of these peptides when the cardiopulmonary circulation is changed by pulmonary resection has remained obscure. Thus, we hypothesized that plasma ANP and BNP may play compensatory roles in cardiopulmonary function after pulmonary resection, in particular after the more radical pneumonectomy procedure compared with lobectomy.
Alterations in cardiopulmonary function differed after lobectomy and pneumonectomy. Mean PAP and TPVR were both significantly more elevated after pneumonectomy than after lobectomy. This phenomenon was also observed in a previous study [3]. Plasma ANP concentrations were higher after pneumonectomy than lobectomy, but this increase did not correlate with that of mean PAP and TPVR. In contrast, plasma BNP concentrations were not altered on POD 1 after lobectomy or pneumonectomy; however, there was a clear difference in BNP levels on POD 3 and 7. Only the plasma BNP concentration correlated with TPVR on POD 3. Because TPVR was not determined until POD 3, we cannot tell from this study what the high BNP value in the pneumonectomy group observed until POD 7 means. However, the correlation between TPVR and BNP on POD 3 may indicate that BNP corrects the increase in the pulmonary vascular resistance or that the increase in BNP leads to an increase of TPVR. However, with such little data we can only say that the increase in BNP may have influenced that of TPVR. This will be the subject of a future study.
We were unable to follow the PAP in this study as the patients were restricted to bed for 7 days after the operation to calculate PAP using a Swan-Ganz catheter. The chest tube was placed for 3 to 5 PODs, and during that period, the patients were resting in bed; placement of the Swan-Ganz catheter inserted through the neck was also conducted after obtaining the approval of the patient. Usually, patients were eating on POD 3, and transfusions became unnecessary on POD 5 in most patients. Therefore, it would be a burden for patients to have a catheter inserted only for the purpose of determining hemodynamic variables on POD 7. Reed and coworkers [3] reported PAP and right ventricular functional changes in the early period after lobectomy in a clinical study. The postoperative right ventricular end-diastolic volume did not change by 4 to 6 hours after lobectomy, but markedly increased on POD 1 and 2. These changes in right ventricular movement reflecting changes in plasma BNP and TPVR may be associated with cardiopulmonary circulatory adjustments after pneumonectomy.
In conclusion, ANP and BNP may be associated with the right ventricular dysfunction noted after pulmonary resection, owing to the decrease in the volume of the pulmonary vascular bed. Further investigations on the different elevations of ANP and BNP after pneumonectomy and lobectomy are required. It is also necessary to study the relationship of ANP and BNP with the altered permeability of the alveolar-capillary membrane after pulmonary resection.
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Abstract
Introduction
