B-type natriuretic peptide concentrations and myocardial dysfunction in critical illness.
B-type natriuretic peptide (BNP) is the first biomarker of proven value in screening for left ventricular dysfunction. The availability of point-of-care testing has escalated clinical interest and the resultant research is defining a role for BNP in the investigation and treatment of critically ill patients.
This review was undertaken with the aim of collecting and assimilating current evidence regarding the use of BNP assay in the evaluation of myocardial dysfunction in critically ill humans. The information is presented in a format based upon organ system and disease category.
BNP assay has been studied in a spectrum of clinical conditions ranging from acute dyspnoea to subarachnoid haemorrhage. Its role in diagnosis, assessment of disease severity, risk stratification and prognostic evaluation of cardiac dysfunction appears promising, but requires further elaboration. The heterogeneity of the critically ill population appears to warrant a range of cut-off values. Research addressing progressive changes in BNP concentration is hindered by infrequent assay and appears unlikely to reflect the critically ill patient's rapidly changing haemodynamics. Multi-marker strategies may prove valuable in prognostication and evaluation of therapy in a greater variety of illnesses. Scant data exist regarding the use of BNP assay to alter therapy or outcome.
It appears that BNP assay offers complementary information to conventional approaches for the evaluation of cardiac dysfunction. Continued research should augment the validity of BNP assay in the evaluation of myocardial function inpatients with life-threatening illness.
Key Words: natriuretic peptides, 13-type natriuretic peptide, brain natriuretic peptide, critical care, critical illness, biological marker, biomarker, review
The aim of this review was to collect and assimilate current evidence regarding the use of 13-type natriuretic peptide (BNP) assay in the evaluation of myocardial dysfunction in critically ill humans.
A computerized MEDLINE search was performed using the web-based Entrez Pubmed database. Citations were considered for review if they evaluated a relationship between BNP concentration and evidence of myocardial dysfunction in critically ill patients. The bibliographies of relevant articles were subsequently studied for articles not revealed by the initial computerized literature search. Currently explored relationships between BNP concentration and myocardial dysfunction in critically ill patients are restricted to a number of clinical states. These states provided a framework for the construction of this review. Articles that related to critically ill patients generally were reviewed together and the remaining literature was classified with regard to organ systems and disease categories.
The Cochrane library was also searched but revealed no database entries regarding BNP
The cardiac natriuretic peptides have been actively researched over the past two decades (1, 2). Three types of natriuretic peptides have been described in mammals--ANP (A-type or atrial natriuretic peptide), BNP (B-type or brain natriuretic peptide) and CNP (C-type natriuretic peptide) (3). These compounds are structurally similar but genetically distinct peptides that exhibit diverse actions in cardiovascular, renal, and endocrine homeostasis.
ANP was first isolated and sequenced from human cardiac atrium in 1984 (4). Release of ANP leads to a potent natriuretic response, decreased blood pressure and increased haematocrit (5). Although initially isolated from porcine brain (6), BNP is preferentially produced and secreted by the cardiac myocyte in humans (7). Although CNP has not been detected in the heart, its production by macrophages and vascular endothelium has been demonstrated (8, 9). CNP is usually undetectable in the circulation and the autocrine/paracrine actions of the peptide in nervous system tissue and blood vessels predominate (10). The comparative features of the three mammalian natriuretic peptides are listed in Table 1.
BNP concentrations more closely correlate with left ventricular dysfunction than ANP concentrations (11). BNP assay has also become more clinically accessible, including the recent development and availability of a rapid point-of-care assay. The remainder of this review will focus specifically upon BNP
Synthesis, Storage and Secretion of BNP
The human BNP gene codes for a 134 amino acid residue BNP precursor, preproBNP PreproBNP is cleaved to the prohormone, proBNP (108 amino acids) and a signal peptide (26 amino acids). ProBNP appears to be cleaved into the 76 amino acid N-terminal proBNP (NT proBNP, also known by other acronyms including NTBNP and N-BNP) and physiologically active BNP (32 amino acids) by the enzyme furin (12, 13). BNP and NTproBNP are produced in equimolar quantities. The synthesis of BNP is summarized in Figure 2.
Plasma BNP concentrations in the coronary sinus are two to three times higher than those sampled from the aorta near the coronary ostium, demonstrating that BNP is secreted into the circulation through the coronary sinus from the heart (14).
Patterns of BNP secretion imply that only small amounts are stored in granules and that increased peptide secretion is largely dependent upon increased BNP gene expression; this is in contrast to ANP which is rapidly released from atrial granules in response to atrial stretch (15). Upon ventricular overload, rapid induction of BNP gene expression reaches peak levels within one hour, resulting in prompt secretion of BNP into the circulation (16). It has also been experimentally demonstrated that direct left ventricular wall stress-induced activation of BNP gene expression is regulated primarily at the post-transcriptional level resulting in decreased turnover, and therefore, accumulation of BNP mRNA (17).
In health, atrial secretion of BNP predominates; when tissue weight is taken into account, ventricular BNP production accounts for approximately 30% of total cardiac production. However, in the failing heart, BNP expression from the atria is largely unchanged, while expression from the ventricles more than doubles (18).
[FIGURE 1 OMITTED]
[FIGURE 2 OMITTED]
Physiological Effects of BNP
The effects of BNP have been studied by injection of BNP into intact organisms, by exposing cells or organs to increased BNP concentrations and by altering gene expression in mice. It has been demonstrated that BNP (like ANP) binds to the natriuretic peptide receptor type A (NPR-A) resulting in increased intracellular cyclic GMP production (14). The biological effects thus mediated include diuresis, vasodilation, inhibition of renin and aldosterone production, as well as altered cardiac and vascular myocyte growth (1). Mice overexpressing the BNP gene exhibit systemic hypotension and bone malformations". BNP knockout mice exhibit cardiac fibrosis, but not hypertension (20). The principal physiological role of BNP appears to be protection of the cardiovascular system from the effects of volume overload (1). Figure 3 illustrates the physiological effects of BNP.
The biological effects of NTproBNP, if any, are currently undetermined. Likewise, the ability of uncleaved prohormone to bind to peripheral receptors is yet to be elucidated (15).
[FIGURE 3 OMITTED]
Clearance of BNP
Natriuretic peptides are cleared from the plasma by binding natriuretic peptide receptors or by enzymatic degradation. It is believed that the non guanyl cyclase linked receptor, natriuretic peptide receptor type C (NPR-C), functions as a clearance receptor by binding and internalizing natriuretic peptides (21). NPR-C is distributed widely in many tissues and cells including platelets, vascular smooth muscle cells, Purkinje fibres of the cardiac conduction system, glomeruli, renal collecting ducts and central nervous system (22). BNP is also cleared from the plasma by proteolysis. The most closely studied enzyme in this respect is the extracellular membrane bound metalloprotease, neutral endopeptidase 24.11 (NEP). Compared to ANP, BNP appears to be relatively resistant to NEP degradation (23). This may explain the relatively longer plasma half-life of BNP compared to ANP
NT-proBNP has a longer plasma half-life than BNP Renal excretion is currently regarded as the principal clearance mechanism of NT-proBNP (15). However, there is a paucity of data regarding the effect of renal impairment on BNP clearance. McLean et al demonstrated a weak but significant linear correlation between the natural logarithms of BNP concentration and creatinine concentration in a critically ill population; however, this relationship became insignificant when cardiac abnormality was excluded (24). This supports the assertion that alterations in BNP concentration in renal failure are more likely to reflect altered cardiovascular function than altered renal clearance per se.
Plasma concentrations of BNP
In health, plasma BNP concentrations are lower than ANP concentrations. Clerico et al used a highly sensitive and specific immunoradiometric assay (IRMA) technique to measure plasma ANP and BNP in 216 healthy adults. The mean ANP value was 17.8 [+ or -] 10.9 pg/ml with no significant difference between men (16.7 [+ or -] 10.0 pg/ml) and women (18.8 [+ or -] 11.7 pg/ ml). In comparison, the mean BNP value was 9.9 [+ or -] 9.0 pg/ml with a significant difference (P<0.0001) between men (7.7 [+ or -] 7.1 pg/ml) and women (12.2 [+ or -] 10.2 pg/ml). There was a weak linear relationship between age and BNP values (r = 0.254, P = 0.0002).
On the other hand, mean BNP concentrations are much higher than simultaneously determined ANP levels in patients with severe heart failure (18). BNP concentration results are assay dependent (25).
BNP concentration can be converted from pmol/1 to pg/ml by multiplying by 3.45 (26).
BNP concentrations are influenced by a number of physiological and pathological factors but, in general, elevated concentrations are consistent with left ventricular stress (27). Physiological factors that influence circulating plasma BNP concentrations include age, gender, blood pressure, urinary salt excretion (and therefore presumably sodium intake). These changes are detailed in Table 2.
A number of pathological conditions can also impact upon plasma BNP concentrations. Disease states associated with increased BNP concentrations include heart failure, acute myocardial infarction (first 2-5 days), essential hypertension with left ventricular hypertrophy, acute dyspnoea, pulmonary embolism, obstructive pulmonary disease, hyperthyroidism, Cushing syndrome, primary hyperaldosteronism, diabetes mellitus, liver cirrhosis with ascites, acute or chronic renal failure, subarachnoid haemorrhage and paraneoplastic syndrome (28-32). BNP concentrations tend to be reduced with hypothyroidism and obesity (28-33). Drugs which impact upon BNP concentrations include corticosteroids, sex steroid hormones, thyroxine, diuretics, angiotensin-converting enzyme inhibitors and adrenergic agonists and antagonists (28). Elevated plasma BNP has also been associated with myocardial dysfunction secondary to chemotherapeutic treatment of malignancies (34, 35). In general, elevated BNP concentrations tend to be associated with raised ventricular filling pressures.
BNP Assay Characteristics
Commercially available assays exist for both BNP and NTproBNP Despite release of equimolar amounts of BNP and NTproBNP, assayed concentrations of BNP in plasma are lower (by a factor close to 10) (26). This is in part due to proteolytic degradation in blood or binding to clearance receptors and partly due to the fact that BNP is less stable at room temperature than NTproBNP BNP has a plasma half life of approximately 20 minutes, giving it greater sensitivity for acute changes than NTproBNP which has a half-life of 120 minutes (resulting in higher cumulative blood concentrations in patients with cardiac disease) (36).
Clerico et al recently compared the analytical performance of five commercially available natriuretic peptide immunoassays (37). Four methods for BNP were tested: an immunoradiometric assay (IRMA) SHIONORIA BNP (Shionogi & Co); two fully automated immunoassay systems [microparticle enzyme immunoassay (MEIA) method for the AxSYM[R] System (Abbott Laboratories Diagnostics Division), and ADVIA method for the Centaur System (Bayer Diagnostics Division)]; and a point-of-care testing (POCT) method TRIAGE[R] BNP Test (Biosite Diagnostics). A fully automated electrochemiluminescence immunoassay for NT-proBNP was also evaluated on an Elecsys[R] 2010 analyzer (Roche Diagnostics).
Results obtained by the MEIA system were significantly different from those obtained with the other BNP assays (P<0.0001). All methods clearly differentiated between healthy individuals and patients with heart failure (mild or severe). Areas under the ROC curve (AUC) ranged from 0.865 to 0.999. The best power for separating healthy individuals from patients with mild heart failure was provided by the NTproBNP immunoassay. All immunoassays also performed well in differentiating patients with severe heart failure from healthy individuals (AUC 0.9820.999).
From the above, it is evident that analytical performance and diagnostic accuracy of the immunoassays should be taken into account when interpreting a BNP result.
BNP CONCENTRATIONS AND MYOCARDIAL DYSFUNCTION IN CRITICALLY ILL PATIENTS
Heterogeneous Critical Illness
Myocardial dysfunction is common in critically ill patients (36-38). However, in this patient group, advanced age and the presence of renal failure, lung disease, pulmonary embolism, acute coronary syndromes, and diseases with high natriuretic peptide output, such as liver cirrhosis, represent potential confounders and need to be considered in the interpretation of BNP results (39). A summary of proposed BNP cut-offs described in this section is presented in Table 3 below.
A study in a surgical intensive care unit documented increased BNP concentrations in critically ill patients (40). The highest BNP concentrations were observed in patients who underwent cardiac surgical procedures and in patients with subarachnoid haemorrhage. BNP was not a predictor of the severity of illness or mortality in this cohort.
McLean et al studied a series of 84 patients serially admitted to a combined medical and surgical intensive care unit in an Australian tertiary referral hospital over a four-week period (38). Blood BNP concentration was assayed by a hand-held meter on the point of admission. Cardiac dysfunction was diagnosed in 26 of the 84 patients (30.9%). Patients with cardiac dysfunction had a significantly higher level of BNP when compared to the non-cardiac dysfunction group (516 [+ or -] 385 vs mean 67 [+ or -] 89 pg/ml; P<0.0001). A BNP cut-off value at 144 pg/ml exhibited a 92% sensitivity, 86% specificity and 96% negative predictive value. The sensitivity improved to 96% when the analysis was confined to patients [greater than or equal to] 55 years (38).
McLean et al followed this work with a prospective cross sectional study of 121 Australian intensive care patients (24). The thirty-five patients (28.9%) diagnosed to have cardiac abnormalities exhibited higher BNP concentrations than those without (518 [+ or -] 394 vs 60 [+ or -] 98 pg/ml; P<0.001). Multivariate analyses demonstrated that the presence of cardiac abnormalities was the most significant predictor of altered BNP concentration (accounting for nearly 50% of the BNP variation). They were also able to identify the impact of gender on BNP concentrations. The area under the RoC curve was slightly less for females compared to males (92.3% vs 95.6%). The cut-off point that gave the best combination of sensitivity and specificity for males was 100 pg/ml (sensitivity = 87.0%; specificity = 89.4%; accuracy = 88.5%) For females it was 200 pg/ml (sensitivity = 83.3%; specificity = 84.6%; accuracy = 84.0%).
Tung et al studied 49 patients with shock admitted to three intensive care units at the Massachusetts general Hospital (41). No correlation was demonstrated between BNP concentrations and pulmonary artery occlusion pressure (PAOP) or between BNP concentrations and cardiac index (CI). However, a BNP <350 pg/ml had a negative predictive value of 95% for ruling out cardiogenic shock (defined as PAoP >18 mmHg and CI <2.2 4 min/[m.sup.2]). The mortality rate in the lowest BNP log-quartile was 16.7%, whereas the mortality rate in the highest log-quartile was nearly 62%. The trend between log BNP quartiles and the incidence of intensice care unit mortality achieved statistical significance (P = 0.006). A univariable analysis revealed age [greater than or equal to] 70 years, pH [less than or equal to] 7.00 and a BNP concentration in the highest log-quartile correlated with mortality. Furthermore, a multivariable analysis of these factors plus APACHE II scores (which were forced into the model) demonstrated that a BNP concentration in the highest log-quartile (relative to lowest log-quartile) was the strongest predictor of mortality (odds ratio = 4.50, 95% confidence interval = 1.87-99.0, P<0.001).
The correlation between BNP concentration and mortality was not supported by Cuthbertson et al, who recently conducted a prospective observational cohort of 78 consecutive intensive care patients in Scotland (42). The study included subgroup analysis of 35 patients with severe sepsis or septic shock. Admission and 24 hour BNP and cardiac troponin I concentrations were measured; neither assay accurately predicted 30 day mortality. Although 16 (59%) of the total 27 patients and 7 (70%) of the 10 septic patients who died within 30 days had a baseline BNP of >100 pg/ml, the relationship did not achieve statistical significance (P = 0.06 and 0.38 respectively). A kaplan-Meier survival curve for patients with severe sepsis or septic shock illustrated increased mortality in the patient group with an admission BNP [less than or equal to] 100 pg/ml; however, this relationship also failed to achieve statistical significance (P = 0.06).
Dokainish et al compared tissue Doppler echocardiography and BNP in 50 intensive care and coronary care units patients with pulmonary artery catheters. Their sample included 21 intubated patients. In patients without cardiac disease (n = 15), BNP > 250 pg/ml had a sensitivity of 81%, a specificity of 83% and an accuracy of 82% (as determined from the area under the RoC curve) for PAoP >15 mmHg compared with 74%, 72% and 67% respectively for early transmitral velocity/tissue Doppler mitral annular early diastolic velocity (E/Ea). In patients with cardiac disease (n = 35), BNP >400 pg/ml had a sensitivity of 90%, a specificity of 57% and an accuracy of 83% for PAoP >15 mmHg compared with 92%, 81% and 89% respectively for e/ea. It was concluded that BNP and e/ea have similar diagnostic accuracy for congestive heart failure (CHF) in this patient population (43).
Acute decompensated cardiac failure
Published evidence supports the usefulness of BNP concentrations in the diagnosis and prognostication of patients with acute decompensated cardiac failure. each will be considered in turn.
Diagnosis: Current data suggest that measurement of BNP plasma concentration is a useful tool in the diagnosis of acute heart failure in patients presenting to an emergency department with acute dyspnoea (44). Point-of-care BNP measurement in the emergency department discriminates well between patients with dyspnoea of cardiac and non-cardiac origin regardless of age and gender (45). A summary of studies which propose a range of BNP cut-off values used for distinguishing myocardial dysfunction as the cause of acute dyspnoea is presented in Table 4. The Breathing Not Properly Multinational Study was a seven-centre, prospective study of 1586 patients who presented to the emergency department between April 1999 and December 2000 with acute dyspnoea as the most prominent symptom (46). exclusion criteria included: age less than 18 years, dyspnoea clearly attributable to another cause (e.g. trauma or cardiac tamponade), acute myocardial infarction, unstable angina (unless the predominant symptom at presentation was dyspnoea) and renal failure. Eligible patients had BNP measured with a point-of-care assay upon arrival. BNP was accurate in making the diagnosis of CHF and correlated to severity of disease.
In summary, dyspnoea associated with cardiac dysfunction is highly unlikely in patients with concentrations of the peptide less than 100 pg/ml (47, 48). Most patients with significant congestive heart failure have concentrations of the peptide greater than 400 pg/ml. In patients with concentrations of 100 to 400 pg/ml, confounding disease states including left ventricular dysfunction without volume overload, pulmonary embolism, and cor pulmonary must be ruled out (48).
Prognostication: Plasma BNP concentrations can be useful in discriminating between normal subjects and patients in different stages of heart failure and can also be considered a prognostic indicator of long-term survival in patients with heart failure(28). In patients with reduced ejection fraction (EF), elevated BNP was a predictor of mortality (49) and a strong independent predictor of sudden death (50). Furthermore, serial BNP measurements during hospitalization also have prognostic usefulness. Failure of BNP levels to decline, or a delayed rise in BNP, were associated with readmission to hospital and excess mortality in patients with New York Heart Assocation (NYHA) Class III-IV heart failures (51). Subgroup analysis of the Valsartan Heart Failure Trial also supports the conclusion that serum BNP is an important predictor of morbidity and mortality in patients with heart failure (52).
Multimarker strategies have also been proposed as an effective means of risk assessment in patients with heart failure (53). Heart failure patients with detectable cardiac troponin I (cTnI) and high BNP concentrations have been shown to have a 12-fold increased mortality risk compared with those with both undetectable cTnI and lower BNP (54). Troponin T (cTnT) and BNP have also been demonstrated as independent predictors of cardiac events in heart failure (55). BNP plasma concentrations in end-stage heart failure patients decrease in the presence of ventricular unloading by ventricular assist devices and may be indicative of recovery of ventricular function during mechanical circulatory supportt (56).
Acute myocardial infarction/acute coronary syndromes
In patients referred for stress testing, BNP concentrations are elevated during, and remain elevated 30 minutes after, exercise in the presence of angiographic coronary disease compared with healthy controls. The magnitude of this BNP increase is proportional to the size of the ischaemic territory (57). However, the utility of BNP as a marker of coronary ischemia is limited owing to its limited specificity (58).
In patients with ST-segment elevation myocardial infarction (STEMI), higher BNP and NT proBNP concentrations have been shown to predict a greater likelihood of death or heart failure, independent of other prognostic variables (59, 60). When measured within 1-4 days of acute myocardial infarction, plasma BNP has been shown to be a powerful independent predictor of left ventricular function, heart failure, or death over the subsequent 14 months, and was superior to ANP, N-terminal ANP, cGMP and plasma catecholamines (61).
Anecdotal evidence suggests that in the absence of overt myocardial dysfunction in the setting of acute myocardial function, sudden elevations in BNP might forewarn of impending myocardial rupture (62).
Recently, the prognostic value of BNP has also been extended to patients with non-STEMI (63). Elevated concentrations of BNP were associated with early death. Subgroup analysis from the TACTICS TIMI 18 study evaluated BNP at baseline in 1,676 patients with non-STEMI randomized to early invasive versus conservative management. It demonstrated that BNP elevation was closely associated with death and progression of heart failure. Patients with elevated BNP (> 80 pg/ml) were at higher risk of death at seven days and six months. Those with elevated BNP also had a fivefold higher risk of developing new congestive cardiac failure by 30 days. However, BNP concentrations were not a predictor of response to early invasive treatment (64).
Coronary artery bypass grafting
Terazawa et al studied 27 consecutive patients undergoing coronary artery bypass grafting. Preoperative BNP concentrations differed markedly between patients in the various ASA physical status categories with higher concentrations in the ASA III and IV groups. In ASA III and IV patients, plasma BNP concentrations decreased during cardiopulmonary bypass (CPB), returning toward preoperative concentrations after bypass. The lower concentration of BNP in the ASA III and IV group during CPB may have been a reflection of decreased cardiac volume and pressure status immediately after the initiation of CPB. After bypass the BNP concentrations in this group returned toward the preoperative concentrations (65).
BNP plasma concentrations are elevated in heart transplant recipients compared to the normal population (66).
Hervas et al have also confirmed that the magnitude of BNP elevation is greater in patients with higher rejection grades on endomyocardial biopsy and greater impairment of left ventricular function (67).
Plasma BNP concentrations correlate with the severity of stenosis and degree of left ventricular dysfunction in patients with valvular aortic stenosis (68, 69) and hypertrophic obstructive cardiomyopathy (69).
Plasma BNP concentrations also correlate with the severity of mitral regurgitation (70).
Scant data are available regarding the influence of altered ventilatory/intrathoracic pressures upon plasma BNP concentrations. Two published data have presented results of BNP concentration during positive pressure ventilation for acute pulmonary oedema (71, 72). However, given the confounding factors in this study, the impact of IPPV alone on plasma BNP is difficult to decipher.
Acute pulmonary embolus
In patients with acute pulmonary embolus, it has been shown that BNP concentrations are frequently increased in the presence of right ventricular dysfunction (73, 74). However, its role as a prognostic indicator of outcome in this setting is less clear. Kruger et al did not demonstrate a correlation between BNP concentrations at presentation and in-hospital adverse events or mortality (73). Kucher et al found that low BNP concentrations (<90 pg/ml) at presentation did not guarantee an uncomplicated hospital course in patients with acute pulmonary embolus; however, a lower cut-off concentration of <50 pg/ml identified 95% of patients with a benign clinical course (75). ten Wolde et al demonstrated that high BNP concentrations (measured at presentation) were associated with increased mortality from pulmonary embolism during the three-month follow-up period (76). It is difficult to compare studies in this area because of different population samples, different standards for diagnosing pulmonary embolism, differing BNP thresholds, different outcome assessment and different lengths of follow-up.
Acute lung injury and acute respiratory distress syndrome
There are reports of elevations in BNP in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) (77, 78). These probably reflect the presence of right heart dysfunction. The limited sample size precludes drawing any further conclusions on the prognostic implications of elevated BNP.
Elevated BNP is associated with septic myocardial dysfunction (79). Witthaut et al have also confirmed the association between elevated BNP and myocardial dysfunction in sepsis. However, in their study, no correlation was demonstrable between markers of inflammation or sickness severity (80).
A study of 24 patients following subarachnoid haemorrhage found that excessive secretion of BNP occurred in all subjects, unrelated to severity, stress hormone activation or markers of cardiac injury (81). Whilst elevated BNP concentrations were thought to reflect underlying myocardial dysfunction, no formal assessment of LV function was made.
Biochemical detection of myocardial dysfunction has previously been demonstrated in subarachnoid haemorrhage by Parekh and Venkatesh (82). The sensitivity and specificity of cTnI to predict myocardial dysfunction as defined by echocardiography was documented at 100% and 91% respectively. The association between cardiac troponins and BNP in the setting of myocardial infarction and myocardial ischaemia might be found to extend into this critical care setting. Further research may address this possibility.
Acute Renal Failure and CVVHDF
There are scant data regarding the role of BNP assay in acute renal failure. As mentioned previously, elevated BNP concentrations in renal failure patients probably reflect cardiovascular changes rather than altered BNP kinetics.
Balik et al measured A-naturetic peptide (ANP) and BNP concentrations in 23 mechanically ventilated patients before and during the first 48 hours of continuous venovenous haemodiafiltration (CVVHDF). Samples were drawn both from the ports proximal and distal to the filter. The concentrations of both peptides were grossly elevated in comparison to controls (10 patients exposed to abdominal surgery). It was demonstrated that the elimination of ANP and BNP by the CVVHDF was negligible and that ANP and BNP concentrations correlated with left ventricular function even during acute renal failure and CVVHDF (83).
Chronic Liver Disease
Elevated plasma concentrations of BNP have been demonstrated in patients with cirrhosis. In a study of 51 patients with liver cirrhosis, it was found that circulating BNP was related to severity of liver disease (Child score, serum albumin, coagulation factors 2, 7, and 10, and hepatic venous pressure gradient) and to markers of cardiac dysfunction (QT interval, heart rate, plasma volume). Hepatic extraction ratios and disposal rates of plasma BNP were not significantly different in cirrhotic patients compared to controls (84). This finding prompted the authors to conclude that elevated BNP reflects increased cardiac ventricular generation of these peptides and thus cardiac dysfunction, rather than altered hepatic disposal. Data from Wong et al also appear to support this conclusion (85).
The availability of a rapid point-of-care BNP assay has escalated clinical interest and the resultant research is defining a role for BNP in the investigation and treatment of critically ill patients. BNP assay has been studied in a spectrum of clinical conditions ranging from acute dyspnoea to subarachnoid haemorrhage. Its role in diagnosis, assessment of disease severity, risk stratification and prognostic evaluation of cardiac dysfunction appears promising, but requires further elaboration. Indeed, BNP is the first biomarker to prove its value in screening for left ventricular dysfunction. However, there are a number of caveats.
First of all, the utility of BNP for evaluation of cardiac function in critically ill patients requires consensus on the optimal cut-off value/s to be used. The heterogeneity of the critically ill population appears to warrant several cut-off values depending upon demographic variables and comorbidities. Continued research may well prove the usefulness of an algorithmic approach based on a number of variables including age, gender, renal function and principal pathophysiological disturbance.
Second, the temporal changes in BNP concentrations in critically ill patients warrant further attention. Serial BNP measurements have been undertaken by a number of investigators. However, the serial BNP assays tend to be infrequent and at best can be assumed to represent a snapshot of the critically ill patient's rapidly changing haemodynamics. It is of interest that in one study, two septic patients with exceptionally high BNP concentrations, but normal baseline echocardiography, went on to develop cardiomyopathy (24). Also, the impact of medical interventions, including fluid resuscitation and inotropic/ vasopressor support, upon serial BNP concentrations in the critically ill patient is, to date, largely undefined. To some extent the feasibility of serial BNP assay is inhibited by the financial and time constraints of frequent repetition of the assay.
Third, multiple marker strategies including BNP require further evaluation. Combinations including BNP, as a marker for myocardial dysfunction, in parallel with markers of myocyte injury, such as cardiac troponin, have been applied in certain specific conditions, including acute coronary syndromes; however, the broad base of pathophysiological states in a typical intensive care unit presents a valuable resource for proposing and testing this and other combinations of biological markers. Multi-marker strategies may prove valuable in prognostication of a variety of illnesses and perhaps even in evaluation of therapeutic interventions.
Finally, the clinical usefulness of BNP assay in the critically ill is yet to be tested with regard to altering outcome. Current research is challenged by the lack of a gold standard for the evaluation of myocardial dysfunction. Each clinically available standard has its own limitations (86). Scant data exist to justify the use of BNP assay to alter therapy. The possibility that the outcomes of critically ill patients may be improved by clinical decisions based upon BNP assay is speculative and further research in all of the aforementioned areas will be important to address this.
In conclusion, it appears that BNP assay can offer complementary information to conventional approaches for the evaluation of cardiac dysfunction and clinical disease. It is expected that further research will reinforce the value of BNP assay for evaluating myocardial dysfunction in patients with life-threatening illness.
This literature review was undertaken at the Department of Intensive Care and the School of Medicine (Southern Division), University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
Accepted for publication on December 16, 2005.
(1.) Azzazy HM, Christenson RH. B-type natriuretic peptide: physiologic role and assay characteristics. Heart Fail Rev 2003; 8:315-320.
(2.) Venugopal J. Cardiac natriuretic peptides-hope or hype? J Clin Pharm Ther 2001; 26:15-31.
(3.) Hirose S, Hagiwara H, Takei Y. Comparative molecular biology of natriuretic peptide receptors. Can J Physiol Pharmacol 2001; 79:665-672.
(4.) Kangawa K, Matsuo H. Purification and complete amino acid sequence of alpha-human atrial natriuretic polypeptide (alphah-ANP). Biochem Biophys Res Commun 1984; 118:131-139.
(5.) de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci 1981; 28:89-94.
(6.) Sudoh T, Kangawa K, Minamino N, Matsuo H. A new natriuretic peptide in porcine brain. Nature 1988; 332:78-81.
(7.) Yasue H, Yoshimura M, Sumida H et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 1994; 90:195-203.
(8.) Sudoh T, Minamino N, Kangawa K, Matsuo H. C-type natriuretic peptide (CNP): a new member of natriuretic peptide family identified in porcine brain. Biochem Biophys Res Commun 1990; 168:863-870.
(9.) Matsuo H. Discovery of a natriuretic peptide family and their clinical application. Can J Physiol Pharmaco12001; 79:736-740.
(10.) Baxter GE The natriuretic peptides. Basic Res Cardiol 2004; 99:71-75.
(11.) Yamamoto K, Burnett JC Jr., Jougasaki M et al. Superiority of brain natriuretic peptide as a hormonal marker of ventricular systolic and diastolic dysfunction and ventricular hypertrophy. Hypertension 1996; 28:988-994.
(12.) Maisel AS, McCullough PA. Cardiac natriuretic peptides: a proteomic window to cardiac function and clinical management. Rev Cardiovasc Med 2003; 4 Suppl 4:S3-12.
(13.) Sawada Y, Suda M, Yokoyama H et al. Stretch-induced hypertrophic growth of cardiocytes and processing of brain-type natriuretic peptide are controlled by proprotein-processing endoprotease furin. J Biol Chem 1997; 272:20545-20554.
(14.) Nakao K, Mukoyama M, Hosoda K et al. Biosynthesis, secretion, and receptor selectivity of human brain natriuretic peptide. Can J Physiol Pharmacol 1991; 69:1500-1506.
(15.) Hall C. Essential biochemistry and physiology of (NT pro)BNP Eur J Heart Fail 2004; 6:257-260.
(16.) Nakagawa O, Ogawa Y, Itoh H et al. Rapid transcriptional activation and early mRNA turnover of brain natriuretic peptide in cardiocyte hypertrophy. Evidence for brain natriuretic peptide as an "emergency" cardiac hormone against ventricular overload. J Clin Invest 1995; 96:1280-1287.
(17.) Tenhunen O, Szokodi I, Ruskoaho H. Posttranscriptional activation of BNP gene expression in response to increased left ventricular wall stress: role of calcineurin and PKC. Regul Pept 2005; 128:187-196.
(18.) Mukoyama M, Nakao K, Hosoda K et al. Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide. J Clin Invest 1991; 87:1402-1412.
(19.) Ogawa Y, Itoh H, Tamura N et al. Molecular cloning of the complementary DNA and gene that encode mouse brain natriuretic peptide and generation of transgenic mice that overexpress the brain natriuretic peptide gene. J Clin Invest 1994; 93:1911-1921.
(20.) Tamura N, Ogawa Y, Chusho H et al. Cardiac fibrosis in mice lacking brain natriuretic peptide. Proc Natl Acad Sci USA 2000; 97:4239-4244.
(21.) Maack T, Suzuki M, Almeida FA et al. Physiological role of silent receptors of atrial natriuretic factor. Science 1987; 238:675-678.
(22.) Anand-Srivastava MB. Natriuretic peptide receptor-C signaling and regulation. Peptides 2005; 26:1044-1059.
(23.) Smith MW, Espiner EA, Yandle TG, Charles CJ, Richards AM. Delayed metabolism of human brain natriuretic peptide reflects resistance to neutral endopeptidase. J Endocrinol 2000; 167:239-246.
(24.) McLean AS, Huang SJ, Nalos M, Tang B, Stewart DE. The confounding effects of age, gender, serum creatinine, and electrolyte concentrations on plasma B-type natriuretic peptide concentrations in critically ill patients. Crit Care Med 2003; 31:2611-2618.
(25.) Emdin M, Clerico A, Clemenza F et al. Recommendations for the clinical use of cardiac natriuretic peptides. Ital Heart J 2005; 6:430-446.
(26.) Troughton RW, Richards AM, Yandle TG, Nicholls G. Routine measurement of natriuretic peptide to guide the diagnosis and management of chronic heart failure. Circulation 2004; 109: e325-6; author reply e-6.
(27.) Yancy CW Practical considerations for BNP use. Heart Fail Rev 2003; 8:369-373.
(28.) Clerico A, Emdin M. Diagnostic accuracy and prognostic relevance of the measurement of cardiac natriuretic peptides: a review. Clin Chem 2004; 50:33-50.
(29.) Epshteyn V, Morrison K, Krishnaswamy P et al. Utility of B -type natriuretic peptide (BNP) as a screen for left ventricular dysfunction in patients with diabetes. Diabetes Care 2003; 26:2081-2087.
(30.) Asakawa H, Fukui T, Tokunaga K, Kawakami E Plasma brain natriuretic peptide levels in normotensive Type 2 diabetic patients without cardiac disease and macroalbuminuria. J Diabetes Complications 2002; 16:209-213.
(31.) Ohsaki Y, Gross AJ, Le PT, Oie H, Johnson BE. Human small cell lung cancer cells produce brain natriuretic peptide. Oncology 1999; 56:155-159.
(32.) Walter M, Berendes E, Claviez A, Suttorp M. Inappropriate secretion of natriuretic peptides in a patient with a cerebral tumor. JAMA 1999; 282:27-28.
(33.) Wang TJ, Larson MG, Levy D et al. Impact of obesity on plasma natriuretic peptide levels. Circulation 2004; 109:594-600.
(34.) Nousiainen T, Vanninen E, Jantunen E et al. Natriuretic peptides during the development of doxorubicin-induced left ventricular diastolic dysfunction. J Intern Med 2002; 251:228-234.
(35.) Snowden JA, Hill GR, Hunt P et al. Assessment of cardiotoxicity during haemopoietiic stem cell transplantation with plasma brain natriuretic peptide. Bone Marrow Transplant 2000; 26:309-313.
(36.) Giannitsis E, Katus HA. Still unresolved issues with brain-type natriuretic peptide measurement in the critically ill patient. Crit Care Med 2003; 31:2703-2704.
(37.) Clerico A, Prontera C, Emdin M et al. Analytical performance and diagnostic accuracy of immunometric assays for the measurement of plasma B-type natriuretic peptide (BNP) and N-terminal proBNP Clin Chem 2005; 51:445-447.
(38.) McLean AS, Tang B, Nalos M, Huang SJ, Stewart DE. Increased B-type natriuretic peptide (BNP) level is a strong predictor for cardiac dysfunction in intensive care unit patients. Anaesth Intensive Care 2003; 31:21-27.
(39.) Maisel A. B-type natriuretic peptide measurements in diagnosing congestive heart failure in the dyspneic emergency department patient. Rev Cardiovasc Med 2002; 3 Suppl 4:S10-17.
(40.) Berendes E, Van Aken H, Raufhake C, Schmidt C, Assmann G, Walter M. Differential secretion of atrial and brain natriuretic peptide in critically ill patients. Anesth Analg 2001; 93:676-682.
(41.) Tung RH, Garcia C, Morss AM et al. Utility of B-type natriuretic peptide for the evaluation of intensive care unit shock. Crit Care Med 2004; 32:1643-1647.
(42.) Cuthbertson BH, Patel RR, Croal BL, Barclay J, Hillis GS. B-type natriuretic peptide and the prediction of outcome in patients admitted to intensive care. Anaesthesia 2005; 60:16-21.
(43.) Dokainish H, Zoghbi WA, Lakkis NM et al. Optimal noninvasive assessment of left ventricular filling pressures: a comparison of tissue Doppler echocardiography and B-type natriuretic peptide in patients with pulmonary artery catheters. Circulation 2004; 109:2432-2439.
(44.) de Denus S, Pharand C, Williamson DR. Brain natriuretic peptide in the management of heart failure: the versatile neurohormone. Chest 2004; 125:652-668.
(45.) Knudsen CW, Riis JS, Finsen AV et al. Diagnostic value of a rapid test for B-type natriuretic peptide in patients presenting with acute dyspnoe: effect of age and gender. Eur J Heart Fail 2004; 6:55-62.
(46.) Maisel AS, Krishnaswamy P, Nowak RM et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002; 347:161-167.
(47.) McCullough PA, Sandberg KR. Sorting out the evidence on natriuretic peptides. Rev Cardiovasc Med 2003; 4 Suppl 4: S13-9.
(48.) Prahash A, Lynch T B-type natriuretic peptide: a diagnostic, prognostic, and therapeutic tool in heart failure. Am J Crit Care 2004; 13:46-53; quiz 4-5.
(49.) Tsutamoto T, Wada A, Maeda K et al. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation 1997; 96:509-516.
(50.) Berger R, Huelsman M, Strecker K et al. B-type natriuretic peptide predicts sudden death in patients with chronic heart failure. Circulation 2002; 105:2392-2397.
(51.) Cheng V, Kazanagra R, Garcia A et al. A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: a pilot study. J Am Coll Cardio12001; 37:386-391.
(52.) Anand IS, Fisher LD, Chiang YT et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation 2003; 107:1278-1283.
(53.) Ishii J, Nomura M, Nakamura Y et al. Risk stratification using a combination of cardiac troponin T and brain natriuretic peptide in patients hospitalized for worsening chronic heart failure. Am J Cardio12002; 89:691-695.
(54.) Fonarow GC, Horwich TB. Combining natriuretic peptides and necrosis markers in determining prognosis in heart failure. Rev Cardiovasc Med 2003; 4 Suppl 4:520-28.
(55.) Ishii J, Cui W, Kitagawa F et al. Prognostic value of combination of cardiac troponin T and B-type natriuretic peptide after initiation of treatment in patients with chronic heart failure. Clin Chem 2003; 49:2020-2026.
(56.) Sodian R, Loebe M, Schmitt C et al. Decreased plasma concentration of brain natriuretic peptide as a potential indicator of cardiac recovery in patients supported by mechanical circulatory assist systems. J Am Coll Cardiol 2001; 38:1942-1949.
(57.) Marumoto K, Hamada M, Hiwada K. Increased secretion of atrial and brain natriuretic peptides during acute myocardial ischaemia induced by dynamic exercise in patients with angina pectoris. Clin Sci (Lond) 1995; 88:551-556.
(58.) de Lemos JA, Morrow DA. Combining natriuretic peptides and necrosis markers in the assessment of acute coronary syndromes. Rev Cardiovasc Med 2003; 4 Supp14:S37-46.
(59.) Omland T, Aakvaag A, Bonarjee VV et al. Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction. Comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide. Circulation 1996; 93:1963-1969.
(60.) Richards AM, Nicholls MG, Espiner EA et al. B-type natriuretic peptides and ejection fraction for prognosis after myocardial infarction. Circulation 2003; 107:2786-2792.
(61.) Richards AM, Nicholls MG, Yandle TG et al. Neuroendocrine prediction of left ventricular function and heart failure after acute myocardial infarction. The Christchurch Cardioendocrine Research Group. Heart 1999; 81:114-120.
(62.) Arakawa N, Nakamura M, Endo H, Sugawara S, Suzuki T, Hiramori K. Brain natriuretic peptide and cardiac rupture after acute myocardial infarction. Intern Med 2001; 40:232-236.
(63.) Omland T, de Lemos JA, Morrow DA et al. Prognostic value of N-terminal pro-atrial and pro-brain natriuretic peptide in patients with acute coronary syndromes. Am J Cardiol 2002; 89:463-465.
(64.) Morrow DA, de Lemos JA, Sabatine MS et al. Evaluation of B-type natriuretic peptide for risk assessment in unstable angina/non-ST-elevation myocardial infarction: B-type natriuretic peptide and prognosis in TACTICS TIMI 18. J Am Coll Cardiol 2003; 41:1264-1272.
(65.) Terazawa E, Dohi S, Akamastsu S, Ohata H, Shimonaka H. Changes in calcitonin gene-related peptide, atrial natriuretic peptide and brain natriuretic peptide in patients undergoing coronary artery bypass grafting. Anaesthesia 2003; 58:223-232.
(66.) Masters RG, Davies RA, Veinot JP, Hendry PJ, Smith SJ, de Bold AJ. Discoordinate modulation of natriuretic peptides during acute cardiac allograft rejection in humans. Circulation 1999; 100:287-291.
(67.) Hervas I, Almenar L, Perez-Pastor JL et al. Radioimmunometric assay of B-type natriuretic peptide (BNP) in heart transplantation: correlation between BNP determinations and biopsy grading of rejection. Nucl Med Commun 2003; 24:925-931.
(68.) Gerber IL, Stewart RA, French JK et al. Associations between plasma natriuretic peptide levels, symptoms, and left ventricular function in patients with chronic aortic regurgitation. Am J Cardiol 2003; 92:755-758.
(69.) Fukuda N, Shinohara H, Sakabe K, Nada T, Tamura Y. Plasma levels of brain natriuretic peptide in various forms of obstruction to the left ventricular outflow tract. J Heart Valve Dis 2003; 12:333-340.
(70.) Sutton TM, Stewart RA, Gerber IL et al. Plasma natriuretic peptide levels increase with symptoms and severity of mitral regurgitation. J Am Coll Cardio12003; 41:2280-2287.
(71.) Kelly CA, Newby DE, McDonagh TA et al. Randomised controlled trial of continuous positive airway pressure and standard oxygen therapy in acute pulmonary oedema; effects on plasma brain natriuretic peptide concentrations. Eur Heart J 2002; 23:1379-1386.
(72.) Thorens JB, Ritz M, Reynard C et al. Haemodynamic and endocrinological effects of noninvasive mechanical ventilation in respiratory failure. Eur Respir J 1997; 10:2553-2559.
(73.) Kruger S, Graf J, Merx MW et al. Brain natriuretic peptide predicts right heart failure in patients with acute pulmonary embolism. Am Heart J 2004; 147:60-65.
(74.) Bilkovski RN, Kulstad EB. Elevations of B-type natriuretic peptide in pulmonary embolism: a case series. J Emerg Med 2003; 25:415-420.
(75.) Kucher N, Printzen G, Goldhaber SZ. Prognostic role of brain natriuretic peptide in acute pulmonary embolism. Circulation 2003; 107:2545-2547.
(76.) ten Wolde M, Tulevski II, Mulder JW et al. Brain natriuretic peptide as a predictor of adverse outcome in patients with pulmonary embolism. Circulation 2003; 107:2082-2084.
(77.) Mitaka C, Hirata Y, Nagura T, Tsunoda Y, Itoh M, Amaha K. Increased plasma concentrations of brain natriuretic peptide in patients with acute lung injury. J Crit Care 1997; 12:66-71.
(78.) Maeder M, Ammann P, Rickli H, Diethelm M. Elevation of B-type natriuretic peptide levels in acute respiratory distress syndrome. Swiss Med Wkly 2003; 133:515-518.
(79.) Charpentier J, Luyt CE, Fulla Y et al. Brain natriuretic peptide: A marker of myocardial dysfunction and prognosis during severe sepsis. Crit Care Med 2004; 32:660-665.
(80.) Witthaut R, Busch C, Fraunberger P et al. Plasma atrial natriuretic peptide and brain natriuretic peptide are increased in septic shock: impact of interleukin-6 and sepsis-associated left ventricular dysfunction. Intensive Care Med 2003; 29:1696-1702.
(81.) Espiner EA, Leikis R, Ferch RD et al. The neuro-cardioendocrine response to acute subarachnoid haemorrhage. Clin Endocrinol (Oxf) 2002; 56:629-635.
(82.) Parekh N, Venkatesh B, Cross D et al. Cardiac troponin I predicts myocardial dysfunction in aneurysmal subarachnoid hemorrhage. J Am Coll Cardio12000; 36:1328-1335.
(83.) Balik M, Jabor A, Kolar M et al. Relationship between natriuretic peptides and residual diuresis during continuous hemodiafiltration. Blood Purif 2003; 21:401-408.
(84.) Henriksen JH, Gotze JP, Fuglsang S, Christensen E, Bendtsen F, Moller S. Increased circulating pro-brain natriuretic peptide (proBNP) and brain natriuretic peptide (BNP) in patients with cirrhosis: relation to cardiovascular dysfunction and severity of disease. Gut 2003; 52:1511-1517.
(85.) Wong F, Siu S, Liu P, Blendis LM. Brain natriuretic peptide: is it a predictor of cardiomyopathy in cirrhosis? Clin Sci (Lond) 2001; 101:621-628.
(86.) Bellomo R, Uchino S. Cardiovascular monitoring tools: use and misuse. Curr Opin Crit Care 2003; 9:225-229.
(87.) Suttner SW, Boldt J. Natriuretic peptide system: physiology and clinical utility. Curr Opin Crit Care 2004; 10:336-341.
(88.) Jensen KT, Carstens J, Ivarsen P, Pedersen EB. A new, fast and reliable radioimmunoassay of brain natriuretic peptide in human plasma. Reference values in healthy subjects and in patients with different diseases. Scand J Clin Lab Invest 1997; 57:529-540.
(89.) Kanda H, Kita Y, Okamura T et al. What factors are associated with high plasma B-type natriuretic peptide levels in a general Japanese population? J Hum Hypertens 2005; 19:165-172.
(90.) Kjaer A, Appel J, Hildebrandt P, Petersen CL. Basal and exercise-induced neuroendocrine activation in patients with heart failure and in normal subjects. Eur J Heart Fail 2004; 6:29-39.
(91.) Mottram PM, Haluska BA, Marwick TH. Response of B-type natriuretic peptide to exercise in hypertensive patients with suspected diastolic heart failure: correlation with cardiac function, hemodynamics, and workload. Am Heart J 2004; 148:365-370.
(92.) Margulies KB, Jaffer S, Pollack PS, Ennis KJ. Physiological significance of early deceleration time prolongation in asymptomatic elderly subjects. J Card Fail 1999; 5:92-99.
(93.) Wilkins MA, Su XL, Palayew MD et al. The effects of posture change and continuous positive airway pressure on cardiac natriuretic peptides in congestive heart failure. Chest 1995; 107:909-915.
(94.) McCullough PA, Duc P, Omland T et al. B-type natriuretic peptide and renal function in the diagnosis of heart failure: an analysis from the Breathing Not Properly Multinational Study. Am J Kidney Dis 2003; 41:571-579.
(95.) Davis M, Espiner E, Richards G et al. Plasma brain natriuretic peptide in assessment of acute dyspnoea. Lancet 1994; 343:440-444.
Address for correspondence: Dr David Sturgess, Fellow in Clinical Research, University of Queensland School of Medicine (Southern Division), Princess Alexandra Hospital, Ipswich Road, Wolloongabba, Qld 4102.
D. J. STURGESS *, T H. MARWICK ([dagger]), C. J. JOYCE ([double dagger]), B. VENKATESH ([section]) Department of Intensive Care and Department of Medicine, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia
* M.B., B.S., F.R.A.C.G.P, Fellow in Clinical Research, Department of Intensive Care, Princess Alexandra Hospital, Brisbane, Queensland, Australia. Associate Lecturer, University of Queensland, Brisbane, Queensland.
([dagger]) M.B., B.S., Ph.D., F.R.A.C.P, F.E.S.C., F.A.C.C., Professor of Cardiology, Princess Alexandra Hospital, Department of Medicine, University of Queensland, Brisbane, Queensland.
([double dagger]) M.B., B.S., Ph.D., F.A.N.Z.C.A., F.J.F.I.C.M., Director of Intensive Care, Princess Alexandra Hospital, Associate Professor of Intensive Care, University of Queensland, Brisbane, Queensland.
([section]) M.B., B.S., M.D., F.F.A.R.C.S.I., F.R.C.A., E.D.I.C.M., F.J.F.I.C.M., Staff Specialist in Intensive Care, Princess Alexandra Hospital. Associate Professor of Intensive Care, University of Queensland. Deputy Director in Intensive Care, Wesley Hospital, Brisbane, Queensland, Australia.
TABLE 1 Comparative physiology of mammalian natriuretic peptides. Based upon information from: Suttner SW, Boldt J. Natriuretic peptide system: physiology and clinical utility. Curr Opin Crit Care 2004; 10:336-341 (87) ANP BNP CNP Origin Predominantly Predominantly Nervous system, atrial myocytes ventricular macrophages and myocytes vascular endothelium Plasma half 1-5 minutes Approximately 20 Does not life minutes function as a circulating hormone Main trigger Atrial Myocyte Ventricular myocyte Poorly defined for release Stretch stretch (increased intracardiac pressure & volume expansion) Mechanism of Secretory upregulation of Not applicable increased granule release proBNP gene plasma expression concentration Receptor Bind Binds B type responsible preferentially receptor (NPR-B) for principle to Natriuretic physiological Peptide actions Receptor--Type A (NPR-A) Physiological Diuresis, natriuresis, decreased Limited roles renin, angiotensin, aldosterone, diuretic and adreneline and endothelin natriuretic effects. Autocrine/ paracrine functions appear to include vasodilation and inhibition of vascular cell proliferation TABLE 2 Physiological influences upon plasma BNP concentrations Physiological Effect on BNP Variable Concentrations Reference Age Increase with age Jensen KT et al (88) Gender Higher in females Jensen KT et al (88) Blood Pressure Increased with Jensen KT et al (88) increasing BP High Urinary Salt Increased Kanda H et al (89) Excretion Exercise No change in Kjaer A et al (90), normal subjects. Mottram et al (91) Increased BNP levels in presence of heart failure Water Immersion No significant Margulies KB et al (92) change Circadian Rhythm No change Jensen KT et al (88) Body Posture No change Wilkins MA et al (93) Plasma Lipids No change Kanda H et al (89) TABLE 3 Proposed BNP cut-off values from studies of heterogeneous, critically ill patient samples Reference Protocol Standard Assay McLean et Patients admitted Myocardial systolic or TRIAGE al (38) to general ICU diastolic dysfunction BNP (n=84) based on past history, (Biosite symptoms, ECG, CXR, Diagnostics) echocardiography, blood tests and physical examination McLean et Patients admitted Cardiac abnormality TRIAGE al (24) to general ICU defined as presence of BNP (n=121) anatomical or functional abnormality based on past history, ECG, CXR and echocardiography Tung et Consecutive ICU Cardiogenic shock (CI TRIAGE al (41) patients with <2.2 l/min/[m.sup.2] BNP hypotension and and PAOP >18 mmHg) PAC inserted for clinical reasons (n=49) Dokainish ICU and Coronary Pulmonary Capillary TRIAGE et al (43) Care Unit patients Wedge Pressure BNP with pulmonary >15 mmHg artery catheters (n=50) Sensi- Speci- Reference Cut-off tivity ficity PPV NPV Accuracy McLean et 144 92 86 75 97 86 al (38) McLean et 100 [male] 87 89.4 80 93.3 88.5 al (24) 200 [female] 83.3 84.6 62.5 94.3 84 Tung et 350 NR NR NR 95 NR al (41) Dokainish 250 [no 81 83 NR NR 82 et al (43) cardiac disease] 90 57 NR NR 83 400 [cardiac] disease] PPV = positive predictive value, NPV = negative predictive value, NR = not reported. Cut-off values for BNP assay are in pg/ml. Sensitivity, specificity, PPV, NPV and accuracy are reported as percentages. TABLE 4 Proposed BNP cut-off values (pg/ml) from studies of patients with acute dyspnoea Reference Protocol Standard Assay Maisel et Multicentre Diagnosis of CHF TRIAGE al (46) trial. Patients made by two BNP presenting to cardiologists (Biosite emergency Diagnostics) department with acute dyspnoea (n=1586) McCullough Patients with Diagnosis of CHF TRIAGE et al (94) estimated gFR made by two BNP <60 ml/min/ cardiologists 1.73[m.sup.2] (n=432) from Maiselet al (46) Davis et Patients Diagnosis of heart Research al (95) admitted to failure made assay hospital with retrospectively by acute dyspnoea a committee of (n=52) physicians and a radiologist Sensi- Speci- Reference Cut-off tivity ficity PPV NPV Accuracy Maisel et 100 90 76 79 89 83 al (46) McCullough 200 NR NR NR NR 80 et al (94) Davis et 76 93 90 NR NR NR al (95) PPV = positive predictive value, NPV = negative predictive value, NR = not reported. Sensitivity, specificity, PPV, NPV and accuracy are reported as percentages. (CHF = congestive heart failure, GFR = glomerular filtration rate.)
|Printer friendly Cite/link Email Feedback|
|Author:||Sturgess, D.J.; Marwick, T.H.; Joyce, C.J.; Venkatesh, B.|
|Publication:||Anaesthesia and Intensive Care|
|Date:||Apr 1, 2006|
|Previous Article:||Peripheral Regional Anesthesia. An Atlas of Anatomy and Techniques.|
|Next Article:||An introductory guide to survey research in anaesthesia.|