Diagnostic value and prognostic implications of serum procalcitonin after cardiac surgery: a systematic review of the literature

Procalcitonin (PCT) is a polypeptide consisting of 116 amino acids and is the precursor of calcitonin [1]. The role of PCT in inflammatory conditions, such as sepsis, was first described by Assicot et al. [2], who observed a rise in serum PCT levels three to four hours after a single injection of endotoxin, reaching a maximum 24 hours thereafter [3]. The origin of PCT in the inflammatory response is not yet fully understood, but it is believed that PCT is produced in the liver [4] and peripheral mononuclear cells [5], modulated by cytokines and lipopolysaccharide.

Over the last decade, PCT has become increasingly popular as a novel marker of infection in the intensive care unit (ICU) setting. Several studies have underscored its value in a variety of clinical conditions for identifying infectious processes [6‐8], characterising the severity of the underlying illness [9, 10], guiding therapy [11‐13], and risk stratification [14‐16]. Three different kits for PCT measurement are currently available: the LUMI-Test, the Q-Test, and the Kryptor Test (BRAHMS AG, Hennigsdorf, Germany). The most commonly used kit for measuring PCT, the LUMI-Test, is based on a immunoluminometric assay that binds PCT to two different antibodies in the calcitonin and katacalcin regions of the protein. Results of the measurement are available within one hour, and only 20 μl of blood serum or plasma is needed for the test. The sensitivity of the LUMI-Test is 0.1 ng/ml [17], the functional assay sensitivity (defined as the smallest value with an interassay precision of 20% coefficient of variation [CV]) is 0.3 ng/ml, and the interassay precision in the clinically relevant range is between 6% and 10% CV (data provided by BRAHMS AG). The PCT Q-Test uses a semiquantitative one-step, solid-phase immunoassay that needs 200 μl of serum or plasma, with results available within 30 minutes. The semiquantitative measurement of the test is correlated to three reference concentrations of 0.5, 2, and 10 ng/ml [18, 19]. The Kryptor Test for PCT measurement was introduced in 2004. This test is based on TRACE (time-resolved amplified cryptate emission) technology. PCT values are available within 20 minutes with a functional assay sensitivity of 0.06 ng/ml, and 50 μl of blood serum or plasma is needed for measurement [20]. At a concentration between 0.1 and 0.3 ng/ml, the Kryptor Test has an intra-assay CV of less than or equal to 7% and an interassay CV of less than or equal to 10%, and at concentrations greater than 0.3 ng/ml the intra-assay CV is less than or equal to 3% and the interassay CV is less than or equal to 6% (data provided by BRAHMS AG).

Surgical patients, especially those admitted to the ICU after cardiac surgery, represent a major diagnostic challenge in terms of identification of infectious complications. These patients have usually been subjected to intraoperative procedures that may induce various degrees of tissue inflammation and cytokine liberation [21]. Meisner et al. [22] reported that PCT concentrations were moderately increased above the normal range in 32% of patients after minor and aseptic surgery, in 59% after cardiac and thoracic surgery, and in 95% of patients after surgery of the intestine. Cardiac surgery per se and the use of cardiopulmonary bypass (CPB) lead to a more pronounced activation of cytokines than that following some other surgical procedures [23]. This cytokine 'burst' leads to a systemic response by the body's inflammatory system, well known as the systemic inflammatory response syndrome (SIRS) [24] and similar to that observed with infections, making the diagnosis of infection more difficult. Because timing is crucial in initiating therapy and determining the subsequent outcome of septic conditions [25], understanding the kinetics of PCT in various clinical conditions may improve our ability to use this marker as an early diagnostic tool.

The aims of this qualitative review were, therefore, to identify the time course of serum PCT levels after uncomplicated cardiac surgery, to characterise the possible differences in serum PCT levels with various surgical procedures, and to investigate the value of PCT levels in terms of diagnosing infection or predicting outcome in these patients.

We performed a search on MEDLINE using the keyword 'procalcitonin' crossed with 'cardiac surgery,' 'heart,' 'postoperative,' and 'transplantation.' Our search was limited to human studies published between January 1990 and June 2006. The abstracts of all articles were used to confirm our target population (patients undergoing cardiac surgery), and the corresponding full-text articles were reviewed for the presence of data with postoperative PCT levels. Two investigators (CS and YS) independently identified the eligible literature. Among the pre-defined variables collected were year of publication, study design (prospective/retrospective/case report), number of patients included, age group (adults or infants), disease group, markers other than PCT, and study results. Any inconsistencies between the two investigators in the data collected were resolved by consensus. To avoid publication bias, abstracts and full articles were eligible if PCT levels were reported. We also reviewed the bibliographies of available studies for potentially eligible studies. Of 37 articles that quoted PCT levels in patients undergoing cardiac surgery, three articles in abstract form were excluded because of insufficient data [26‐28] and 34 were included in our review. Table 1 gives an overview of the studies included.

The aims of this qualitative review were to describe the evolution of PCT after cardiac surgery and to assess the value of PCT in terms of diagnosing infection or predicting outcome in these patients. From the available literature, it is difficult to recommend universal cutoff points for PCT which clearly identify and differentiate a normal from a complicated postoperative course. PCT levels should be interpreted, therefore, according to the clinical context. After uncomplicated cardiac surgery, PCT levels increase to achieve a peak level within 24 hours postoperatively and return to normal levels within one week after surgery. The degree of PCT elevation depends on the intraoperative course and the type of the surgical procedure but is unlikely to exceed 5 ng/ml. Patients with a complicated postoperative course, with infection or sepsis syndromes, show higher PCT levels than patients with an uncomplicated course. PCT could be useful in differentiating acute graft rejection of heart and/or lung transplantation from bacterial and fungal, but not from viral, infections.

Concerning the previous limitations and interactions, PCT kinetics seems to be more attractive in identifying patients with infectious complications. There is also evidence that the evolution of PCT levels can be helpful in assessing the adequacy of antibiotic therapy in bacterial infection [12, 13].

A meta-analysis by Simon et al. [6] showed that the PCT level was more sensitive (88% versus 75%) and more specific (81% versus 67%) than the CRP level in differentiating bacterial from non-infective causes of inflammation. The sensitivity for differentiating bacterial from viral infections was also higher for PCT; the specificities were comparable. PCT also had a higher positive likelihood ratio and lower negative likelihood ratio than did CRP in both groups. The analysis included published studies that evaluated these markers for the diagnosis of bacterial infections in hospitalised patients. In a more recent meta-analysis [10] in adults in ICUs or after surgery or trauma, the summary ROC curve for PCT was better than for CRP. Unfortunately, only a few studies [30, 35, 39] have reported data on the comparative accuracy between these markers in patients who have undergone cardiac surgery, hindering a meta-analysis of this group. However, the growing body of evidence suggests a minor role for CRP compared with serum PCT in identifying infectious complications in this setting. Further studies are needed to clarify this issue.