Novel Biomarkers and the Outcome from Critical Illness and Major Surgery

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and Major Surgery

D. Fallaha, G. Hillis, and B.H. Cuthbertson

Introduction

As the molecular basis for disease becomes better understood the importance of biomarkers continues to grow. Novel techniques have led to the identification of large numbers of biologically significant compounds that could act as biomarkers.

The appeal of these as diagnostic and therapeutic markers is obvious but the choice of marker for everyday clinical practice is not.

The Ideal Biomarker

In the first instance, it is necessary to consider expression in a disease state versus health. Thus levels of an ideal marker should: i) increase pathologically in a reliable fashion depending on the presence of the disease (have a high sensitivity and predictive value with a low coefficient of variation); ii) not increase in the absence of the disease (have a high specificity); iii) change in keeping with the severity and course of the clinical picture; or even better iv) anticipate clinical changes [1]. Few markers have levels at which the risk suddenly rises. Examining sensitivity versus specificity at different marker thresholds gives rise to a receiver-operating-character- istic (ROC) curve. A clinically-useful biomarker will be one with a large area under the curve. Finally, a suitable marker should of course be relatively cheap and easy to assay.

Natriuretic Peptides

Several important cardiac biomarkers have already been recognized and are being developed for the diagnosis, monitoring, and prognostics of cardiac disease in both primary and secondary care. The natriuretic peptides are a family of hormones involved in the regulation of fluid and blood pressure homeostasis where they nega- tively feed back in response to myocardial overload. Raised plasma concentrations are seen in patients with cardiac disease, particularly those with congestive heart failure. Although levels may vary widely between such individuals, it has been clearly demonstrated that persistently elevated levels strongly correlate to symptoms, cardiac events, and mortality [2]. B-type natriuretic peptide (BNP) is a 32 amino acid peptide mainly secreted from the cardiac ventricles in response to ventricular strain. On secretion, proBNP, the stored form of BNP, is cleaved into an inactive N-terminal fragment (NT-proBNP) and the endocrinologically active BNP.

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The active moiety promotes natriuresis, diuresis, and vasodilatation. These actions probably underlie its importance in the homeostasis of compensated asymptomatic heart failure. As might be expected, levels increase with age, and interestingly, levels are higher in females. Despite trending higher in patients with renal impairment, no clear independent relationship has been demonstrated between BNP and renal function [3, 4].

BNP and Chronic Congestive Heart Failure

There are approximately 120,000 clinically suspected cases of chronic congestive heart failure in the UK annually; the reliability of such diagnoses is poor, especially in primary care [2]. Current guidelines state that formal assessment and diagnosis must include echocardiographic screening [5]. There are obvious practical difficul- ties in meeting this standard of care. Evidence is growing that BNP measurement will provide the ability to markedly reduce the number of patients referred for formal cardiological assessment [2]. BNP may also give useful information to detect the presence of diastolic dysfunction [6]. In particular, it does so even in the presence of echocardiographically-preserved systolic function (ejection fraction 850 %) [7]. It has been suggested that BNP could ‘become the same to heart failure as thy- roid function tests are to hypothyroidism’ [8]. It could conceivably be used for screening significant but asymptomatic left ventricular systolic dysfunction in the general population or for the monitoring of response to therapy [8]. BNP is less labile than its sister, atrial natriuretic peptide (ANP), and this confers practical advantages in clinical use. Plasma BNP and NT-proBNP levels can routinely be measured by radioimmunoassay or immunoradiometric assay from an EDTA blood sample. A bedside assay is also now available and approved by the FDA for near- patient testing [9].

BNP and the Critically Ill Cardiac Patient Acute cardiac failure

BNP and NT-proBNP have demonstrated utility in differentiating the cause of breathlessness in the emergency room. In one seven center, prospective, multina- tional trial involving over 1,500 patients, BNP was compared against other biochemical values and historical and physical findings [10]. BNP was the single most accu- rate predictor of the presence or absence of congestive heart failure in the study group; diagnostic accuracy at a cut-off of 100ρg/ml was 83%. The negative predictive value of levels of less than 50ρg/ml was 96%. In regression analysis it additionally appeared an independently valuable adjunct to other clinical variables.

BNP has even been therapeutically applied and examined in the acute setting of heart failure. The largest double-blinded placebo controlled trial, the VMAC (Vaso- dilation in the Management of Acute Congestive Heart Failure) study (489 patients) was broadly inclusive and did not exclude patients with acute coronary syndrome, preserved systolic function, arrhythmia, or renal insufficiency. BNP infusion demonstrated clear efficacy in cardiovascular offloading as confirmed by invasive monitoring. It appeared at least as effective as glyceryl trinitrate infusion but with subjec- tive benefits (chiefly less headache) and an absence of rebound effect or tachyphyla- xis [11]. However, further data analysis suggests detrimental effects. There is a need for larger studies to verify safety and demonstrate benefit based on true clinical endpoints before it can be recommended [12].

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Acute coronary syndromes

Troponin-I and creatine-kinase MB fraction (CK-MB) are the mainstay of objective diagnosis in acute coronary syndromes as direct markers of myocardial injury. This is an established role that has been well discussed previously [13].

Following acute myocardial infarction (MI), patients with clinical or invasive evidence of elevated left ventricular (LV) filling pressures have a poorer outcome as measured by mortality and the incidence of chronic congestive heart failure [14].

This may reflect a direct association between elevated filling pressures and infarct size [15] as well as related adverse effects on ventricular remodeling, neuro-hor- monal activation, and myocardial excitability [16].

The routine measurement of pulmonary artery occlusion pressure (PAOP) has obvious drawbacks. Elevated LV filling pressure after acute MI may be identified non-invasively using clinical assessment and/or chest radiography. Echocardio- graphic measures additionally provide quasi-objective non-invasive estimates of LV filling. There is now an increasing literature supporting the use of BNP measurement as a clinical marker in the period after MI. BNP identifies those patients likely to have significant LV systolic dysfunction making it very useful in centers that can- not provide echocardiography for all their infarct patients [8]. It appears at least as good as (and may even be better than) echocardiography at identifying those patients who are at high risk of progressive ventricular dilatation, heart failure or death [8]. Overall results suggest value in an integrated approach to patient work-up combining clinical, radiological and biochemical disease markers.

One such series of 378 patients examined the relative utility of BNP in predicting all-cause mortality in the immediate period following acute MI (24 – 48 hrs) as compared to the ratio of early transmitral flow to early mitral annulus velocity (E/é) and conventional clinical, radiological, and echocardiological markers (Kruszewski et al., unpublished data). E/é is a novel combined measure of early LV filling and diastolic function which has been shown to be a superior non-invasive marker of LV filling pressures [17]. Both the E/é ratio (hazard ration [HR] 1.04 per unit increase, p = 0.03) and BNP (HR 1.01 per 10ρg/ml increase, p‹ 0.001) were found to be powerful independent predictors of mortality. By receiver operator plot the optimum predictive cut-off for BNP in this cohort was 515 ρg/ml, which displayed a sensitivity of 62%

and a specificity of 92 %. BNP levels 8 515ρg/ml and E/´e ratio 8 15 added incremen- tal prognostic information to conventional variables. Likewise, both provided additional prognostic data, even when the other was available. Study limitations meant that the sickest patients could not be included. Despite this limitation, the study clearly demonstrated that powerful prognostic information could be obtained in the early period after infarction using methods representative of common clinical practice. In fact, given their more subtle clinical signs, the resulting study group might well represent the patients who would benefit most from prognostication.

While early prognostication obviously remains valuable by allowing for early intervention, the optimal sampling intervals for such parameters are still being defined. Additional evidence suggests that evaluation of serial BNP levels after infarction can refine risk stratification during follow-up. In one such study, patients with elevated baseline BNP levels who returned at four months with levels lower than 80ρg/ml displayed only a moderately increased risk compared to those with low levels throughout [18]. This further contrasted to patients with BNP levels lower than 80ρg/ml immediately post-event but with elevated levels at four months; such individuals showed a four-fold risk of death or new congestive heart failure (HR: 4.5;

95 % CI 2.3 – 8.6), findings that might relate to the effects of adverse remodeling.

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Cardiac surgery

In the UK over 30,000 patients per year undergo cardiac surgery, with a hospital mortality of approximately 2.5 % for coronary artery bypass grafting (CABG) and 4.1 % for cardiac valvular surgery increasing to 12.6 % after one year. Cardiac surgery is also associated with major morbidities, such as stroke, myocardial infarction and malignant arrhythmia, with a quoted incidence of up to 22 % [19]. The most common methods of risk stratification are clinical scoring systems such as the Par- sonnet score and EuroSCORE [20, 21]. These and other existing methods of predicting outcome following cardiac surgery are imprecise. All scoring systems may over- estimate mortality in ‘high-risk’ patients, but underestimate mortality in low to moderate risk groups. Although such scores may be helpful when comparing outcome between cardiac surgical units, none has sufficient predictive accuracy to identify individuals who will die or experience an adverse event with an acceptable level of sensitivity and specificity. They, therefore, function as clinical audit tools and are not widely used in clinical risk prediction and risk modification strategies [22].

Sensitive and specific biochemical tests are, thus, being sought to augment the accuracy of risk assessment and to ultimately improve outcome. At present, both cardiac troponin-I (cTnI) and BNP levels are actively being studied in this respect.

There is good reason to explore these markers; existing evidence suggests that both cTnI and BNP levels reflect the state of the myocardium after surgery. Cardiac troponin levels directly reflect myocardial cell necrosis, whereas BNP levels primarily reflect ventricular filling and pressure and rise in response to myocardial ischemia [23]. They, therefore, correlate with aortic cross-clamp time and the duration of car- diopulmonary bypass (CPB). Prolonged ischemia will also result in myocyte necrosis and for this reason levels of BNP and cTnI closely correlate with each other [24].

Troponin-I in CABG

In one large cohort study in Aberdeen (1,356 patients), the significance of cTnI levels measured at 2 and 24 hours following surgery was examined in relation to subsequent short, medium and long-term mortality [22]. Troponin generally appeared a powerful predictive variable. Although significant in univariate analysis, two-hour measurements had no power of prediction once adjusted for operation complexity.

However, risk remained highly significant for 24 hour troponin levels even when adjusted for all other variables, suggesting a relationship based on pathological events rather than inherent operative factors. cTnI levels measured at 24 hours were independently predictive of mortality at 30 days (odds ratio [OR] 1.02, 95 % CI 1.01 – 1.02; p ‹0.001), 1 year (OR 1.02, 95 % CI 1.01 – 1.03; p ‹0.001), and 3 years (OR 1.01, 95 % CI 1.01 – 1.02; p = 0.002). This association was strongly enhanced in the upper quartile, which might suggest a useful cut-off at around 8 l g/ml (OR adjusted for operation type 3.24, 95 % CI 1.55 – 6.77). These data are backed up by other similar studies which suggest troponin levels do not separate well in relation to mortality until beyond the 12 – 24 hour mark [25, 26]. One study did in fact show a significant relationship of operating room troponin levels to adverse events, although this was chiefly as a result of subsequent infarction rather than mortality [27].

Attempts to try and establish universally accepted at-risk thresholds for troponin remain challenging. Figure 1 highlights the influence of operation type on interpretation of troponin levels, with complexity of surgery being strongly related to increased troponin release. Thus, a troponin level in the lowest quartile for valve surgery may have very different interpretation if found in a patient receiving one vessel CABG. The complexity of surgery will undoubtedly be related to a host of

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Fig. 1. The relationship between number of coronary grafts and cardiac troponin I (TnI) release at two and 24 hours after surgery [22]

influences on troponin rise, including pre-operative condition and time on bypass.

Added to this are more local variables such as surgical technique, patient case-mix, and inter-assay variability; all must be taken into account when trying to interpret troponin levels. At present it seems most appropriate for individual centers to establish their own limits. There is also the need to better examine other adverse events within this general cohort to try and build a fuller picture of the post-operative period.

BNP in CABG

The pattern of release of BNP during CABG has been characterized in several small studies. Very early (one to two hours) after surgery, BNP levels tend to fall, rising thereafter to levels considerably higher than baseline. The two most detailed studies have both found that BNP levels peak around one day following CABG, falling thereafter but remaining significantly above baseline for several days [24, 28]. However, others have found the highest post-operative levels at one week [29]. This group additionally demonstrated significantly higher pre-operative BNP levels in the 14 patients who required inotropic support against the twelve patients who did not (mean 77 vs. 34ρg/ml, respectively, p=0.03).

A number of more recent studies continue to suggest value in the pre-operative measurement of BNP. Chello and colleagues studied 31 patients with moderate to severe LV dysfunction undergoing CABG [30]. Mean BNP levels were significantly lower by the time of follow-up (at a mean of ten months) and the extent of these changes also correlated with alterations in systolic function. In the sub-group whose ejection fraction did not improve following surgery (‹5 % increase) pre-operative levels of BNP were higher, suggesting utility in predicting functional recovery. In another study of 60 patients undergoing elective CABG, elevated pre-operative levels of BNP were associated with an increased mortality after two-year follow-up (mean levels 65ρg/ml in non-survivors (n=10) versus 29 ρg/ml in survivors (n=50) [24].

Likewise, above a threshold of 80ρg/ml, two-year survival was only 66% (eight of 12 patients) versus 87 % (42 of 48) with levels below this cut-off. This prognostic utility was independent of pre-operative ejection fraction and modified Cleveland scoring.

Our work on several surgical cohorts has examined both intensity of care and mortality as outcomes in relation to pre- and post-operative NT-proBNP and BNP levels. In the larger unpublished cohort, 255 patients were recruited and subse-

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Fig. 2. The Kaplan-Meier curves for the relationship between N terminal pro-B-type natriuretic peptide quartiles and cumulative survival after coronary artery bypass surgery with a median follow-up of one year. The median BNP being 357 ρg/ml with a 25^thcentile level of 127ρg/ml and a 75^thcentile level of 1359ρg/ml.

quently presented for elective cardiac surgery. At baseline, NT-proBNP levels correlated well to age (p‹0.001), risk scoring (euroSCORE, Parsonnet [p‹0.001]) and LV dysfunction (p ‹0.003). Figure 2 shows the Kaplan-Meier survival curves compared by NT-proBNP quartiles. Of note, individuals in the fourth quartile displayed an approximate four-fold relative risk (a threshold of 1359 ρg/ml). Requirements for peri- and post-operative inotropic and peri-operative mechanical support all strongly correlated to NT-proBNP levels as did extended length of hospital stay (all p‹0.001). Work on a smaller cohort (50 patients) that examined post-operative BNP levels at six and 24 hours also predicted most of these events [31]. The only similar previous study also found pre-operative BNP levels to be strongly predictive of mortality in keeping with this body of work. It did not however demonstrate a correla- tion between twelve-hour post-operative BNP levels and this specific outcome [23].

Overall, current data suggest that pre-operative measurement of BNP has real potential not only to assist in the counseling of patients and relatives but also to provide a strategic benefit. Scheduling of high risk patients for when other demands on intensive care services are likely to be lower (for example on days when other sched- uled patients are at low risk) should reduce the need to cancel operations due to the non-availability of intensive care beds. Pre-operative levels might also be used to identify patients who require more intensive pre-operative medical therapy before presentation for surgery. As already discussed, there is evidence that BNP levels can be used to guide the therapy of patients with heart failure and that such an approach reduces adverse cardiac events [32]. The expectation of the need for increased perioperative support should also allow the elective provision of mechanical cardiovascular support for weaning from CPB and assist in the early recognition of patients requiring intense medical management after surgery.

BNP in the Non-Cardiac Surgical Patient Elective surgery

Examining major surgery, nearly 30,000 patients die around the time of operation each year in the UK alone [33, 34]. As with cardiac surgery, the majority of these deaths are clearly related to cardiac events together with significant long-term morbidities, such as stroke, non-fatal myocardial events, and malignant arrhythmia. In

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high-risk patients, cardiac ischemic events may occur in over 30 % of those undergoing major vascular surgical procedures, with an early cardiac death rate of 17 % [35].

It is also important to note that the majority of post-operative cardiac complications are in fact asymptomatic. Scoring systems and imaging strategies have been developed to predict adverse cardiovascular events in patients undergoing major non-cardiac surgery with the aim of reducing this risk [36, 37]. This may involve the effective targeting of pre-operative investigations such as non-invasive or invasive cardiac testing [36] or the use of therapies such as q -blockade [38] but again, as with cardiac surgery, low predictive accuracies, variations in the constituent parameters and poor clinical utility has limited the use of such scores in practice.

The usefulness of BNP in predicting such peri-operative cardiac complications has been assessed in several scenarios. In Glasgow, a small high-risk cohort of vascular surgical patients (American Society of Anesthesiologists (ASA) Grade 3/4) was followed post-operatively for evidence of MI [39]. Pre-operative BNP concentrations appeared highly predictive of peri-operative cardiac events irrespective of other variables. Median plasma BNP levels in patients who experienced a fatal or non-fatal MI (n = 11) were 240ρg/ml (interquartile range 172–344) versus 39 ρg/ml (interquartile range 15 – 70) in those who did not (n = 30). As compared to the Eagle clinical scoring system [36], BNP with a threshold of 100ρg/ml showed greater predictive value (area under the ROC curve: BNP 0.957 versus Eagle 0.714, p = 0.001). Sensitivity and negative predictive value were similar (100 % for both) but with BNP showing a superior specificity (90 % vs. 40 %) and a greater positive predictive value (78 % vs. 38 %). All patients who experienced events had pre-operative BNP levels 8 120ρg/ml. Patients with a formal history of ischemic heart disease trended towards an almost two-fold risk of cardiac events but only half of those who experienced events had a previous history. Patients receiving q -blockade showed a trend towards a lower event rate in keeping with the suggested cardioprotective role of these drugs [40].

Two-hundred and four patients undergoing major elective non-cardiac surgery in Aberdeen were studied (unpublished data). Peri-operative death or new MI (cTnI 8 0.32 l g/ml) was defined as a combined primary endpoint. Troponin threshold was set as per local assay to provide a coefficient of variation for infarction of less than 10 % without pre-operative cTnI elevation or a non-cardiac etiology (such as pulmonary embolism) [37]. Pre-operative BNP levels were raised in patients who died or suffered a peri-operative MI (median 52.2ρg/ml vs. 22.2 ρg/ml, p=0.01). BNP predicted this outcome with an area under the ROC curve of 0.72 (95 % CI 0.59 – 0.86).

An optimal cut-off point of 40 ρg/ml for pre-operative BNP differentiated patients with an almost seven-fold increased risk of cardiac events in the early post-operative period (OR 6.8, 95 % CI 1.8 – 25.9, p = 0.003). A pre-operative BNP above this cut-off point was also associated with an increased postoperative hospital stay.

In a similar cohort in Japan, 190 patients undergoing major or minor surgery under general anesthesia were studied with pre-operative sampling for NT-proBNP in addition to routine pre-operative work-up [41]. Cardiac death together with acute coronary syndrome, heart failure, and sustained cardiac arrhythmias (8 30 secs) were defined as ‘cardiac complications’. Fifteen of the 190 patients experienced complications; four had acute coronary syndrome and 13, congestive heart failure. NT- proBNP concentration was significantly higher in patients with a cardiac complication; a level greater than 450ρg/ml was predictive of cardiac complications with a sensitivity of 100 % and a specificity of 82.9 %. Other factors associated with cardiac complications were a higher ASA grade, age, and clinical cardiac impairment, but in a multivariate analysis NT-proBNP level was the only independent factor. Of note,

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the rate of cardiac complications was not affected by whether the operation was major or minor (twelve of 158 [7·6 %] versus three of 32 [9 %], p = 0·733).

As with cardiac surgery, these data already show the usefulness of pre-operative BNP levels in identifying patients who are at risk of peri-operative cardiac complications in this setting.

Emergency surgery

Major emergency surgery has a mortality rate considerably greater than that of elective surgery [33]. In the National Confidential Enquiry into Peri-operative Deaths (NCEPOD) in 2002 [33], 57 % of reported deaths were after urgent or emergency operations despite non-elective operations constituting only 16 % of total surgical workload. This figure disguises considerable inter-specialty differences. Orthopedics and general surgery were the specialties with the largest number of non-elective cases (25.9 % and 21.2 % cases, respectively). This is perhaps unsurprising given the greatly increased risk of fractured neck of femur and acute abdominal pathology in the older age groups. The initial disease that requires surgery may be complicated by a number of factors. Tissue hypoperfusion and acidosis can result from vomiting and loss of fluid into the gastrointestinal tract or malignant disease [42]. Chronic co-mor- bid disease, documented or otherwise, is more common in this group with a decreased physiological reserve. It thus also unsurprising that the Scottish Audit of Surgical Mortality (SASM) indicates that 72 % of operative deaths in patients undergoing emergency surgery are in patients aged over 70 years [34]. Despite these varied elements, the single largest cause of morbidity and mortality in patients undergoing major emergency surgery is the development of post-operative cardiac events [35].

Mangano et al. determined that cardiac complications are two to five times more likely to occur with emergency surgical procedures than with elective operations [35]. This finding is not surprising because the necessity for immediate surgical intervention may make it impossible to evaluate and treat such patients optimally.

Consequently, it was suspected that BNP would be an even more powerful predictor of outcome in this patient group. A cohort of 40 patients undergoing major non-cardiac emergency surgery in Aberdeen was studied (unpublished data). Blood samples were taken pre-operatively and on days one and three after surgery for BNP and cTnI analysis. Twelve-lead electrocardiograms (EKGs) were performed at the same time as blood sampling. The patients were followed-up until hospital discharge for the development of cardiac complications. The primary outcome was the predictive power of BNP for the combined end-point of cardiac death or early post-operative cardiac event (defined as de novo cTnI & 0.10 l g/ml and/or the development of EKG changes suggestive of significant acute myocardial ischemia/infarction within 72 hours of surgery). Pre-operative BNP levels were significantly higher in patients who experienced a post-operative cardiac event (median 400.1ρg/ml vs. 89.6 ρg/ml, p=0.011).

Pre-operative BNP levels were also shown to be a good predictor of post-operative morbidity, as determined by the Day 3 Post-Operative Morbidity Survey (POMS) [43]. Pre-operative BNP levels were higher in patients classified at greater risk by pre-existing risk assessment indices. The study displayed a number of inherent limitations chiefly related to sample size. A low cTnI threshold ( ‹0.1 l g/ml) is a poor discriminator between true thrombo-occlusive events and other more benign causes of cTnI elevation. The use of such a broad combined endpoint was necessary to gen- erate significant outcomes in this small pilot study. Study size also precluded a sub- group analysis to compare the effectiveness of measurements across specialties.

Patients too unwell to give consent were excluded, thus, creating an inclusion bias

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with a likely underestimation of post-operative cardiac events. Limitations notwith- standing, this preliminary study was suggestive of a useful relationship that merits more definitive investigation. Interestingly, a significant number of subjects had elevated pre- operative troponin levels, therefore, indicating pre-existing myocardial injury. cTnI levels are not currently routinely measured in the pre-operative assessment of a patient but in light of these observations further work may wish to examine their utility.

BNP in the General Intensive Care Unit

Sepsis represents one of the major challenges in medicine. Despite the widespread use of intensive care units (ICUs), broad-spectrum antibiotics, surgical interven- tions, nutritional support, and more modern therapies, its incidence continues to rise, with an unacceptably high mortality (30 – 70 %) [44]. This is, in part, due to a high degree of heterogeneity due to variables such as age, weight, gender, underly- ing disease, immunological factors, and the severity of infection.

Myocardial dysfunction is a common complication of all critical illness, particularly severe sepsis, and is associated with poor outcome. This may not always be ini- tially apparent due to adaptive responses, but is often followed by overt myocardial dysfunction and failure [45]. Measures of myocardial dysfunction are varied, but lack accuracy and validation in clinical practice. The utility of the pulmonary artery catheter has been questioned lately by research suggesting negative effects on outcome [46]. Two-dimensional echocardiography is a valuable investigation, but the clinical usefulness depends on the experience of the operator and the quality of the images obtained. Measurements of cardiac output or cardiac index may be useful but are highly dependent on load conditions and heart rate [47]. Once again the appeal of a biomarker that would aid management or even potentially predict outcome is obvious. Previous work has already established that levels of BNP (and also ANP) are elevated in septic shock [48]. However, the relationship between BNP and LV filling pressure is an imperfect one, particularly in heterogeneous populations with the potential for rapid fluctuations in hemodynamic status [49]. One reason for this may be the tendency for BNP levels to remain elevated despite reductions in PAOP. This may in turn reflect the half-life of BNP within the circulation and/or the potential for factors other than acute filling pressure to influence its production.

Indeed, this may underpin the powerful prognostic utility of BNP which may integrate data both on acute and more chronic filling pressures. These and other data have led to the suggestion that BNP is principally a measure of raised intra-cardiac pressures and, as such, may be an excellent indicator of ‘global’ myocardial function [50].

McLean and colleagues have examined the ability of BNP to detect myocardial dysfunction in the general ICU [3]. All patients admitted to a combined medical and surgical ICU over a four-week period were included in the study with BNP measured on the point of admission. Cardiac dysfunction was defined as LV systolic or diastolic dysfunction, right ventricular (RV) systolic dysfunction or as a hemodynami- cally overloaded RV. Diagnosis was based on past history, symptoms, EKG, chest X- ray, echocardiography, blood tests, and physical examination. BNP was a powerful independent predictor of cardiac dysfunction. Such patients displayed significantly higher mean BNP levels as compared to the non-cardiac dysfunction group:

516 +/– 385ρg/ml (n=26) vs. 67+/–89 ρg/ml (n=58) (p‹0.0001). At a threshold of 144ρg/ml, BNP exhibited 92% sensitivity, 86% specificity, and 96% negative predictive value with a total area under the ROC curve of 0.96. The sensitivity further improved to 96 % when the analysis was confined to patients over 55 years of age.

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The actual prognostic utility of BNP in a heterogeneous population of critically ill patients admitted to intensive care, or in those admitted with severe sepsis, had not previously been investigated. The hypothesis that, as a measure of global myocardial health, admission levels of BNP would be predictive of 30-day mortality, was suggested and tested. Our cohort comprised 78 consecutive patients admitted to the general ICU [4]. BNP levels correlated with age, sex, and non-significantly with cre- atinine clearance as seen in previous work [3]. However, BNP levels measured on ICU admission and at 24 hours were not found to be significantly higher in patients who died within 30 days as compared to survivors (all p 8 0.05). Despite admission BNP levels being higher in patients with severe sepsis and septic shock, again they were not higher in those who died. Indeed, using a cut-off point of 100 ρg/ml for BNP (a value described to be useful in identifying patients with heart failure [10]), there was a trend towards lower BNP levels in all non-survivors. Although this trend was not significant in patients who died of severe sepsis and septic shock, their admission BNP values also tended to be lower than in survivors. These results are difficult to explain and require confirmation. It is known that patients with sepsis who fail to exhibit LV dilatation have a reduced ejection fraction and stroke work indices and ultimately a worse prognosis [51]. It could be that a rise in BNP levels is associated with appropriate ventricular dilatation and thus it is a failure of this response that is associated with reduced BNP levels and a greater mortality. Further work will be required to test this interesting hypothesis.

Conclusion

With an aging population and an increasing ability to perform complex interven- tions, cardiac complications have become the primary cause of death after major surgery and a major contributor to death in the critically ill. Myocardial injury in both these settings, as measured by troponin, now appears to have clear long-term sequelae as well as implications for immediate levels of care. BNP appears to be a powerful integrator of myocardial dysfunction with the ability to assess the likeli- hood of such injury at the same time as providing the means to monitor disease progression and response to treatment. All of the above is with the aim of more appropriate monitoring and investigation with intervention at the earliest possible stage. This should have positive implications for healthcare efficiency, clinical resource utilization, and ultimately patient outcome. However, these markers still await true verification in interventional studies. In the interim, we suggest they should be considered as valuable adjuncts to current clinical practice.

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