The natriuretic peptide family consists of three peptides: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide. ANP, the first member of this family, is primarily produced in cardiac atria (1). Increased intravascular volume and increased atrial wall tension is thought to be the predominant stimulus, along with hormones and neurotransmitters such as endothelin or catecholamines (2). BNP was originally identified in extracts of porcine brain (3). In humans, it is mainly secreted by cardiac ventricles during increased ventricular wall stress. Minor amounts have also been identified in the human brain (4). C-type natriuretic peptide is found in endothelial and vascular smooth muscle cells and throughout the central nervous system. It is likely to act in an autocrine or paracrine fashion (5,6).
The physiologic effects of the natriuretic peptides include natriuresis and diuresis, aldosterone antagonism, vasorelaxation, and reduction of cardiac preload (7–9). Furthermore, ANP and BNP are able to decrease the sympathetic outflow and inhibit vasopressin release (10–12). These properties have established the putative role of the peptides in the body’s defense against hypertension and plasma volume expansion. Increased plasma concentrations of ANP and BNP are associated with hypertension, hypervolemia, congestive heart failure, coronary artery disease, myocardial hypertrophy, arrhythmias, and renal insufficiency (13–16). However, other possible functions of ANP and BNP also cannot be entirely dismissed. For example, ANP and BNP were proposed to trigger natriuresis and diuresis in patients with cerebral disorders (17–19). The pathophysiologic role of ANP and BNP in critically ill patients is not clear, and the plasma concentrations of natriuretic peptides have not systematically been examined.
We hypothesized that ANP and BNP concentrations may be increased in critically ill patients and that there may be differences in the secretion pattern for ANP and BNP referring to the underlying disease, the severity of illness, routine variables of water and electrolyte status, or a combination of these.
The study protocol was approved by our IRB. After written informed consent was obtained from patients or their relatives, we performed a consecutive sample of 178 critically ill patients. We included all patients admitted to our surgical intensive care units who underwent major abdominal, thoracic, or cardiac surgical procedures or who had a multiple trauma, except those with preexisting endocrinologic diseases or renal or congestive heart failure, pregnant women, patients younger than 18 yr, or patients who underwent an organ transplantation. The plasma of patients was analyzed for ANP (pmol/L), BNP (pmol/L), aldosterone (pmol/L), and cortisol (nmol/L) at 6:00 am on the morning after admission. To calculate normal ranges for ANP and BNP, blood samples were collected from 42 healthy age- and sex-matched healthy volunteers. In addition, the following variables were determined: sodium excretion rate (mmol/24 h), sodium filtration fraction (%), creatinine clearance (mL/min), serum creatinine (mg/dL), serum and urine osmolality (mOsm/kg), serum sodium concentrations (mmol/L), central venous pressure (mm Hg), heart rate (bpm), and mean arterial pressure (mm Hg). Sodium excretion was defined as the urinary output of sodium during the first 24 h after sampling, and sodium filtration fraction was calculated by the following formula:MATHwhere FeNa (%) = sodium filtration fraction.
Additionally, patients’ severity of illness was assessed by the Acute Physiology and Chronic Health Evaluation System (APACHE-II score) and the Goris score for multiple organ failure. Additionally, 21 patients were examined during the first 5 days on the intensive care unit.
ANP and BNP plasma concentrations were analyzed by radioimmunoassays (Peninsula Laboratories, Belmont, CA) by using polyclonal rabbit immunoglobulin G antisera increased to the following peptides: α-ANP 1–28 (human) and BNP-32 (human). For measurements, 10 mL of venous blood was taken into a chilled syringe, transferred into polypropylene tubes containing edetic acid (3 mmol/L) and aprotinin (500 kallikrein-inhibiting units per milliliter) at 4°C, and centrifuged at 900 g for 15 min at 4°C. Plasma was stored at −70°C until analysis. Peptides were extracted from 5 mL of plasma (Sep-Pak C-18; Waters Associates, Milford, MA) and eluted with 3 mL of a mixture of 60% acetonitrile, 0.1% trifluoroacetic acid, and 39% distilled water (by volume). All samples were assayed in triplicate and analyzed as a batch to minimize assay variations. Standard curves were constructed with standard human ANP and BNP in radioimmunoassay buffer. The mean recovery of added natriuretic peptides from plasma was 60%–80%, and the lower detection limits as defined by 95% of the upper plateau of the standard curve were 0.1 nmol per tube for ANP and 0.5 nmol per tube for BNP. Cross-reactivity between natriuretic peptides was <0.1%. The intraassay and interassay coefficients of variation were 3.8% and 9.6% for ANP and 6.1% and 7.9% for BNP, respectively. The concentrations used to calculate coefficients of variation were 10 pmol/L for ANP and 3 pmol/L for BNP.
Plasma aldosterone and cortisol concentrations were measured with commercially available radioimmunoassay kits (Sereno Diagnostics, Biodata S.p.A., Rome, Italy) with antialdosterone and anticortisol antibodies and immunoglobulin G from rabbits in accordance with the manufactures’ recommendations. The intraassay and interassay coefficients of variation were 3.5% and 6.4% for aldosterone and 4.0% and 7.6% for cortisol, respectively. The concentrations used to calculate coefficients of variation were 112 pmol/L for aldosterone and 57 nmol/L for cortisol, respectively.
The data were analyzed with nonparametric tests (Friedman and Wilcoxon’s matched-pair rank test and Mann-Whitney U-test). Linear regression analysis by the least-squares method was used to examine correlations. Data are presented as mean ± sd. P < 0.05 was considered statistically significant.
The plasma concentrations of ANP and BNP were measured in 115 men and 63 women. The mean age of overall patients was 53 ± 16.8 yr, the mean height was 171 ± 8.4 cm, and the mean weight was 74 ± 14.1 kg. Overall, the patients’ plasma concentrations of ANP were 1.6-fold (14.3 ± 5.8 pmol/L versus 8.8 ± 3.2 pmol/L, P < 0.05) and those of BNP were 5.7-fold (26.2 ± 10.7 pmol/L versus 4.6 ± 2.8 pmol/L, P < 0.0001) increased compared with those of healthy controls (Fig. 1).
Patients were assigned to the following disease groups: 1) multiple trauma (ANP, 11.8 ± 2.1 pmol/L, P = 0.13 versus controls; BNP, 19.9 ± 3.6 pmol/L, P < 0.01 versus controls;n = 34), 2) major abdominal surgery, thoracic surgery, or both (ANP, 15.9 ± 1.0 pmol/L, P < 0.05 versus controls; BNP, 25.4 ± 5.1 pmol/L, P < 0.01 versus controls;n = 59), 3) cardiac surgical procedures with cardiopulmonary bypass (ANP, 15.1 ± 1.7 pmol/L, P < 0.05 versus controls; BNP, 35.6 ± 7.7 pmol/L, P < 0.001 versus controls;n = 52), 4) traumatic and aneurysmal subarachnoid hemorrhages (ANP, 12.7 ± 1.6 pmol/L, P = 0.07 versus controls; BNP, 29.8 ± 7.3 pmol/L, P < 0.001 versus controls;n = 12), and 5) brain disorders without subarachnoid hemorrhage (ANP, 11.9 ± 2.2 pmol/L, P = 0.17 versus controls; BNP, 9.7 ± 2.6 pmol/L, P < 0.05 versus controls;n = 21). ANP increases were comparable in all patients, but BNP increases showed a larger variety, depending on the underlying disease. The largest BNP concentrations were observed in patients who underwent cardiac surgical procedures and in patients with subarachnoid hemorrhage. Relatively smaller BNP increases were found in patients with brain disorders without subarachnoid hemorrhage (Fig. 2).
Patients’ mean values of the APACHE-II score and Goris score were 11 ± 3.7 and 1.6 ± 0.8, respectively, indicating a medium degree of severity of illness and predicting a mortality of 10%–15%. We found no correlation between values of scores and ANP or BNP concentrations (Table 1). Fourteen (7.9%) of the 178 patients died. ANP and BNP plasma concentrations in patients who died did not differ from those of patients who survived.
Biometric data and underlying diseases of patients within these groups and of the 21 continuously examined patients are presented in Table 2 and Table 3. The five patients with cerebral tumor were treated with 16 mg of dexamethasone three times daily to avoid perifocal edema and were not continuously examined. In patients who underwent cardiac surgical procedures, the weaning from cardiopulmonary bypass was usually performed without vasoactive substances. Only 8 of the 52 patients were afforded short-term inotropic support with dobutamine at the sampling time point (mean dosage, 6.4 ± 1.5 μg · kg−1 · min−1).
None of the patients developed acute renal failure. Patients’ mean sodium filtration fraction (2.1% ± 0.7%; normal value, 1.0%) was increased. Mean values of the other variables were within the normal range: aldosterone (94 ± 19.1 pg/mL), cortisol (154 ± 67.7 ng/mL), serum sodium (140 ± 4.3 mmol/L), sodium excretion (206 ± 87.4 mmol/24 h; normal range, 80–250 mmol/24 h), serum osmolality (305 ± 16.3 mOsm/kg), urine osmolality (489 ± 122 mOsm/kg), serum creatinine (1.1 ± 0.6 mg/dL), creatinine clearance (122 ± 43 mL/min), mean arterial pressure (78 ± 16.7 mm Hg), heart rate (87 ± 14.3 bpm), and central venous pressure (7 ± 4.1 mm Hg).
Significant correlations were obtained between ANP and the following variables: aldosterone (r = 0.4, r2 = 0.16, P < 0.001), serum sodium (r = 0.42, r2 = 0.18, P < 0.001), sodium filtration fraction (r = 0.3, r2 = 0.1, P < 0.001), serum osmolality (r = 0.25, r2 = 0.06, P < 0.01), urine osmolality (r = −0.24, r2 = −0.06, P < 0.01), and central venous pressure (r = 0.22, r2 = 0.05, P < 0.01). No significant correlation was found between BNP and one of the above-mentioned or other routine laboratory variables (Table 1).
In the 21 patients with a prolonged stay on the intensive care unit, the following variables were increased on the day of admission: concentrations of ANP (15.4 ± 5.0 pmol/L, P < 0.05), BNP (46.1 ± 19.1 pmol/L, P < 0.001), and aldosterone (552.6 ± 150.4 pmol/L), as well as sodium filtration fraction (1.6% ± 0.7%). Other variables of water and electrolyte status were within normal ranges. During the following days, ANP and aldosterone concentrations, as well as sodium filtration fraction, returned to normal values. Although BNP concentrations significantly decreased at the fifth postoperative day, they remained increased sixfold compared with controls at this time point (Fig. 3).
This study provides evidence for the first time that both ANP and BNP are markedly increased in many patients on a surgical intensive care unit. Natriuretic peptides are thought to play an important role in the defense against excess salt and water retention. It is assumed that natriuretic peptides act by inhibiting the production and action of vasoconstrictor peptides, by promoting vascular relaxation, and by inhibiting the sympathetic outflow (2). Therefore, it was not unexpected that the natriuretic peptides were increased in our patients who tended to have disturbances in water and electrolyte balance (20–22). However, our study demonstrated several divergences between ANP and BNP in all patients. The ANP increase was only mild and was similar in all patient groups. BNP, by contrast, was markedly increased (5.7-fold), especially in patients who underwent cardiac surgical procedures (7.7-fold) and in patients with subarachnoid hemorrhage (6.4-fold). Moreover, ANP, but not BNP, concentrations correlated with variables of water and electrolyte status, and ANP, in contrast to BNP, remained significantly increased throughout the entire observation period.
We found a positive correlation between ANP and sodium filtration fraction. In humans, infusions of ANP at doses increasing their plasma concentration slightly above normal levels result in diuresis and natriuresis and reduce plasma aldosterone and angiotensin-II concentrations. ANP may inhibit aldosterone-mediated sodium and water reabsorption in proximal convoluted tubules. In our patients, increased sodium filtration and urinary loss of sodium within the upper normal range are most likely the result of increased plasma levels of natriuretic peptides, particularly ANP. Because none of the patients had acute renal failure, the urinary loss of sodium may at least partly result from ANP secretion (23). Volume overload and mild secondary hyperaldosteronism is a frequent disturbance in patients on a surgical intensive care unit. We hypothesize that volume overload and consecutive hyperaldosteronism may result in this subsequent increase in ANP. This interpretation could explain the positive correlation between ANP and aldosterone and sodium filtration fraction. This possibility is further supported by the parallel time courses of ANP and aldosterone plasma levels. Because only five patients with cerebral tumors were treated with steroids and none of these patients was continuously examined, this result is most likely not affected by steroid therapy.
By contrast, we found no indication for the possible involvement of BNP in water, electrolyte, and volume homeostasis in critically ill patients. Accumulation of endogenous vasoconstrictors and catecholamines or endotoxemia are other proposed mechanisms for the secretion of natriuretic peptides. In this context, we were interested to note that most of the cardiac surgical procedures in our patients were coronary artery bypass graftings. The markedly increased BNP concentrations in these patients could be the result of myocardial ischemia during cross-clamp, suggesting a temporary short-term myocardial dysfunction. This possibility is further supported by previous studies showing that increased BNP concentrations may be a better predictor of the stage and prognosis of ischemic heart disease than ANP (24–26). An increased preload after termination of cardiopulmonary bypass, an intermittent hemodynamic instability, or both of these during the weaning from cardiopulmonary bypass are other potential mechanisms for BNP secretion.
A BNP increase in patients with traumatic or subarachnoid hemorrhage has previously been described (17–19). Although primarily of cardiac origin, ANP and BNP have also been localized to the brain (10). Damage to BNP-containing cells and passage of BNP across the blood-brain barrier, loss of regulation, local hyperirritability, or increased BNP secretion as a part of the general stress response may contribute to BNP secretion. However, the exact mechanism of BNP release in cerebral disorders is not clear. Differences in the action of ANP and BNP may also at least partly be explained by the differential affinity of ANP and BNP to natriuretic peptide receptors and different rates of catabolism. The receptors of ANP and BNP are guanylyl cyclases, which mediate the cardiovascular and renal effects of natriuretic peptides (27).
Because most of the variables measured, other than ANP and BNP, are within normal ranges because of the intensive care therapy itself, and because there is a high variability within the overall group of patients and various subgroups, the interpretation of our data with regard to the exact pathophysiologic role of the peptides is difficult. Another limitation is the fact that the study was designed as a consecutive sample. Thus, we cannot discriminate whether the observed increases in ANP and BNP are primarily caused by perioperative stress, by the disease itself, or by abnormalities in water balance. However, the observation that ANP was increased much more homogenously in all patients in contrast to BNP suggests that ANP secretion may occur more or less independently of the underlying disease. Although the significance level is low, the correlations between ANP, aldosterone concentrations, and sodium filtration fraction make an involvement of ANP in water balance more likely. Thus, our study stresses some important features, such as the divergence between ANP and BNP in critically ill patients and the pronounced alteration in BNP in patients undergoing cardiac surgical procedures with cardiopulmonary bypass. In our opinion, these findings are worthy of follow-up.
In summary, both ANP and BNP plasma concentrations are significantly increased in critically ill patients. ANP increases were comparable in all patients, but BNP increases showed a larger variety depending on the underlying disease. ANP, but not BNP, may have a regulatory role in the maintenance of water and electrolyte balance. The extent of ANP and BNP increase, however, is apparently not predictive of the severity of illness in critically ill patients. (23)
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