Surgery induces an intense inflammatory response [8]. The release of inflammatory markers has been documented following cardiac surgery [9], and major noncardiac surgeries such as joint replacement, major vascular surgery, and colorectal surgery [10]. The perioperative inflammatory response is believed to contribute to poor perioperative outcomes. For example, 17% of postoperative deaths are attributed to cardiovascular causes [11]. Inflammation has been implicated in the pathophysiology of myocardial infarction; it is associated with the development of arterial plaque, starting with lipid deposition to plaque rupture and the resulting complications. If the underlying mechanism of perioperative myocardial infarction (PMI) is plaque rupture, then a negative stress test (which indicates that there is no flow-limiting stenosis) may fail to detect a nonobstructing plaque that may potentially rupture and cause cardiac ischemia or infarction [12]. In such circumstances, inflammatory markers such as CRP may more accurately predict perioperative cardiac morbidity and mortality [13]. There are many available markers of inflammation such as tumor necrosis factor (TNF) and the interleukins (IL) IL-2, IL-4. IL-6, IL-8, IL-10, and IL-14; however, this article focuses on CRP.

CRP, an acute-phase reactant produced in the liver, is a well-known marker of systemic inflammation; it greatly increases in response to acute injury. Its stable concentration over a long period of time is governed chiefly by the rate of hepatic production rather than by factors connected with its clearance [14]. CRP assays, being cost-effective, reliable, and fairly sensitive [15,17], seem to meet all criteria for the ideal biomarker. Indeed, the sensitivity of the high sensitivity CRP (hsCRP) assay seems to exceed even that of the original CRP assay.

In nonsurgical settings, CRP functions as a marker of atherosclerosis; when increased, it is considered a biochemical cardiovascular risk factor [18,20].

Congestive heart failure (CHF) has been shown to be a predictor of PMI following vascular surgery [3,35–37]. It increases the odds of dying from a PMI 12-fold if diagnosed within 12 months of a vascular surgery [1]. Diagnosis of CHF is a clinical challenge. Traditionally, the diagnostic approach begins with a thorough history and physical examination, complemented by chest radiographic examination and echocardiography. However, the history and physical examination can be misleading [38], and chest radiographic examination has its own limitations [39]. Echocardiography can also be misleading, in that 30% to 70% of patients with CHF present with a normal (>50%) or only mildly depressed left ventricular ejection fraction. Diastolic dysfunction may underlie CHF in many of these patients [40]. Most patients with asymptomatic left ventricular dysfunction remain undiagnosed [38]. Brain natriuretic peptide (BNP) and NT-proBNP have emerged as promising biomarkers, as simple and reliable tests that may be useful in establishing the diagnosis of CHF and correlating with its severity [38,41].

BNP is a 32-amino acid polypeptide secreted by cardiomyocytes in response to excessive ventricular or atrial stretching, or during ischemia. NT-proBNP is a 76-amino acid N-terminal fragment that is biologically inactive and is coreleased in the same conditions as BNP [42,43]. Biologically, they are distinguished by a significantly different half-life: NT-ProBNP has a longer half-life, 1 to 2 hours, in contrast with 20 minutes for BNP.

In nonsurgical settings, clinical studies have shown that plasma BNP is a powerful predictor of adverse cardiovascular events in patients with heart failure, acute coronary syndromes, primary pulmonary hypertension, and valvular disease [44,46].

Noncardiac Surgery

In noncardiac surgery, many investigators have confirmed that either preoperative BNP [52–56] or NT-proBNP [57–60] are helpful in predicting outcomes (Fig. 1). A clear example comes from Breidhardt and colleagues [61], who showed that preoperative increase of BNP predicts major perioperative cardiovascular complications in patients undergoing orthopedic surgery, and that the combination of BNP and the American Society of Anesthesiologists score is superior to BNP alone in predicting in-hospital cardiac events.

Fig. 1 The area under the curve (95% confidence interval) for each study and overall, evaluating the usefulness of BNP and NT-proBNP in noncardiac surgery.

(From Karamchandani K, Abdelmalak B, Sun Z, et al. Pre-op BNP as a predictor for post-op cardiac morbidity after non-cardiac surgery – a meta-analysis. Anesthesiology 2008:A470; with permission.)

In light of these studies, both BNP and NT-proBNP are promising markers for postoperative cardiac outcomes. The current evidence does not support a universal cutoff point for BNP or NT-proBNP levels beyond which poor outcomes are anticipated, because existing studies have used different assays and various statistical methods to obtain their cutoffs; moreover, some did not indicate how they obtained their cutoff [62]. The specified cutoff points have varied between 40 and 189 pg/mL for BNP [52–56] and between 280 and 533 pg/mL for NT-proBNP [57–60]. Additional investigations are needed in order for consensus to be reached on what constitutes increased and predictive levels of both markers. Interventions should be sought that reduce concentrations of these 2 markers, and trials designed to assess the effects of these interventions on surgical outcomes.

Troponins are proteins of the contractile system of the cardiac cells that act together through the tropomyosin complex to regulate muscle contraction [63]. Cardiac troponins have become the biomarker of choice for the diagnosis of acute myocardial ischemia and infarction [64]. Cardiac troponin T (cTnT) levels are detectable 3 to 12 hours after myocardial injury, and the concentration is in direct proportion to the extent of myocardial injury [65,67].

Cardiac troponins have also been used in the perioperative period to evaluate myocardial ischemia and infarction. Early studies considered them the best tool for diagnosing PMI in patients having noncardiac and cardiac surgery. Several investigators have shown that increased preoperative and postoperative levels of cTnI are associated with poor postoperative clinical outcomes [68]. However, at present, no single cutoff value has been recommended for use in the diagnosis of PMI. Moreover, cTnI may increase even before aortic cross-clamping and cardiac manipulation [69]. Martin and colleagues [70] suggested that cTnI levels lower than 0.15 μg/L were not associated with myocardial ischemia in the perioperative period of cardiac surgery. In contrast, cTnI levels higher than 0.15 μg/L were a strong indicator of ischemic damage.

Thielmann and colleagues [71] showed that preoperative cTnI levels higher than 1.15 ng/mL were associated with longer ICU stay and with higher in-hospital mortality. Moreover, levels of 0.15 ng/mL or higher were associated with higher morbidity and mortality 6 months after surgery [72]. In a study conducted by Lehrke and colleagues [73], cTnT measurement 48 hours after surgery was a strong predictor of severe cardiac failure and high postoperative mortality. A cTnT value exceeding 0.46 μg/L 48 hours after surgery carried a 6.7-fold risk of cardiac death.

Cardiac troponins have also been used to identify clinical outcomes in patients undergoing major vascular surgery [74]. Early studies by Lee and colleagues [75] and Meltzer and colleagues [76] suggested an association between increased levels of cTn and postoperative outcomes. More recently, Landesberg and colleagues [77] showed that levels of cTnI greater than 0.6 ng/mL and cTnT greater than 0.03 ng/mL were independently associated with a respectively 2.15-fold and 1.89-fold increase in mortality. The investigators of the Coronary Artery Revascularization Prophylaxis (CARP) trial used cTnI to define PMI. They found that cTnI levels of 0.1 μg/L or higher occurred in 27% of patients undergoing elective vascular surgery and that these levels were a strong predictor of long-term risk of death among patients with diabetes [78]. Preoperative concentrations of cTnI were predictive of postoperative cardiac outcomes in major noncardiac surgery patients and their predictive power was mildly improved by adding preoperative BNP concentration into the model (Fig. 2).

Fig. 2 The predictive value of preoperative BNP, troponin I, individually and combined for postoperative cardiac outcomes in patients having major noncardiac surgery.

(From Abdelmalak B, You J, Tang W, et al. Combining pre-operative BNP and cTnI in predicting cardiac outcomes from major non-cardiac surgery. Anesthesiology 2009:A1229; with permission.)

In agreement with these last 2 studies, Filipovic and colleagues [79] found an association between cTnI levels and all-cause mortality 1 year after major noncardiac surgery, but a subsequent study by the same group of investigators could not show this association [80]. Controversies surround the validity of cTnT in patients with impaired renal function. However, Feringa and colleagues [81] showed that, after adjustment for estimate of the glomerular filtration rate, minor increases in troponin T from 0.03 to 0.09 ng/mL were strongly associated with late mortality and major adverse cardiac events after major vascular surgery.

In summary, cTn assays are important diagnostic tools in the perioperative period. The most recently developed assays are much more sensitive than the older generations; however, what their absolute cutoff values should be as markers for myocardial infarction remains unclear, because very low levels of cTn may represent increased permeability of myocytes resulting from inflammation.

Procalcitonin (PCT) is a 116-amino acid peptide produced by the c-cells in the thyroid. Its concentration in the serum of healthy individuals is low (<0.1 ng/mL); however, it may be considered an acute-phase reactant because of its production and release during inflammatory stress [63,82]. Traditionally identified as a marker for infectious conditions, PCT at increased levels has been shown more recently to be associated with noninfectious processes such as trauma, surgery, cardiogenic shock, burns, heat stroke, acute respiratory distress syndrome, and rejection after transplantation [83–87]. In these conditions it is produced outside the thyroid by the liver and circulating mononuclear cells.

Acute kidney injury (AKI) remains a common postoperative complication. The incidence of dialysis-dependent acute renal failure after cardiac surgery is approximately 1%, and approximately half of these patients die from this complication [101,103]. Early detection of AKI in the perioperative period may permit early renoprotective interventions, which may in turn translate into more favorable postoperative outcomes; thus, simple and specific biomarkers would be useful to monitor AKI.