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2013, Copyright the Authors Articial Organs 2013, International Center for Articial Organs and Transplantation and Wiley Periodicals, Inc.

Review Article

Monitoring Biomarkers After Pediatric Heart Surgery: A New Paradigm on the Horizon
*Mehmet Ag irbas li and Akif ndar
*Department of Cardiology, Marmara University, Istanbul, Turkey; Penn State Hershey Pediatric Cardiovascular Research Center, Department of Pediatrics, Penn State Milton S. Hershey Medical Center, Penn State Hershey College of Medicine, Penn State Hershey Childrens Hospital; and Department of Surgery and Bioengineering, Penn State Milton S. Hershey Medical Center, Penn State Hershey College of Medicine, Penn State Hershey Childrens Hospital, Hershey, PA, USA

Abstract: Until recently, risk scoring systems for adult patients consisted of only clinical criteria. Currently, we are experiencing an abundant surge of literature integrating a wide range of biomarker arrays to clinical criteria in assessing the risk in an adult. In fact, novel risk scoring systems such as Reynolds criteria have emerged by combining the validated biomarkers to the traditional risk factors. Novel biomarkers potentially improve clinical management of cardiovascular disease, but there are gaps in understanding their role during childhood. The reason might be related to relatively lower prevalence of cardiovascular disease in children compared to the adult population. One exceptional group is the children with

congenital heart disease. Recent studies indicate that novel biomarkers can alert the clinician in a timely manner about neurological and myocardial injury and their inammatory consequences. Current technologies enable us to measure several biomarkers using only a few microliters of plasma. The preliminary studies show that novel biomarkers in addition to the traditionally studied biomarkers can help the clinician to identify children at high risk following pediatric heart surgery. Future studies are needed to conrm the role of biomarkers in monitoring children after cardiopulmonary bypass. Key Words: Pediatric heart surgeryBiomarkersCardiopulmonary bypassOutcomesCongenital heart disease.

There are now more than one million adult survivors of congenital heart disease (CHD) in the USA (1,2). With advances in circulatory support systems, the number is increasing steadily. As the incidence of congenital heart defects in the USA is around eight per 1000 live births (1,2), this number of survivors could easily double over the next decade. However, improvement in the outcome can only be accomplished with timely prediction and avoidance of

doi:10.1111/j.1525-1594.2012.01573.x Received July 2012; revised September 2012. Address correspondence and reprint requests to Dr. Akif ndar, Department of Pediatrics and Department of Surgery and Bioengineering, Penn State Hershey College of Medicine, H085 500, University Drive, PO Box 850, Hershey, PA 17033-0850, USA. E-mail: aundar@psu.edu Presented in part at the 4th Istanbul Symposium on Pediatric Mechanical Circulatory Support and Pediatric Cardiopulmonary Bypass held July 28, 2012 in Istanbul, Turkey.
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complications. An important subset of patients with complex defects such as single ventricle hearts still pose a signicant challenge. They surely constitute one of the sickest populations in the hospital, yet, to a large extent, important surrogates of clinical outcome such as biomarkers are not utilized in their care. CHD has a signicant impact on morbidity, mortality, and healthcare costs in children (3) and increasingly in adults. Hospitalization rates increased by 28.5% for cardiac and circulatory congenital anomalies between 1997 and 2004 (4). As a result, the cost of care for CHD is growing tremendously. For instance, total hospital costs for congenital cardiovascular defect conditions were up to $2.6 billion in 2004 (4) and the cost will probably increase with improved long-term survival. Hence, enormous need exists for potential surrogate markers of clinical outcome in the care of children after heart surgery. Currently available criteria (such as Risk Adjustment for Congenital Heart Surgery [RACHS-1] score) consist of

BIOMARKER LEVELS IN PEDIATRIC HEART SURGERY only traditional and surgical criteria (5). Healthcare professionals need to rely on objective assessment tools to answer the increasing demand from the families and healthcare system. BIOMARKERS AFTER PEDIATRIC HEART SURGERY

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BRIDGING THE GAP BETWEEN BENCH AND BEDSIDE Thus, the crucial step is to integrate the lessons we learned from adult patients to the care of critically ill children. In pediatric critical care, validated biomarkers are essential for guiding drug therapy (6). Data obtained from monitoring of novel biomarkers can help to identify children with worse clinical outcome and 1-month mortality (7). The aim of this article is thus to summarize potential use of current biomarkers with a focus on the eld of circulatory support and pediatric heart surgery. This brief review will discuss the rationale for the selected biomarkers after pediatric heart surgery based on the results of prior pilot studies of monitoring biomarker array through novel technologies (i.e., multianalyte proling [MAP]) (8). This article demonstrates that there is a need for properly validated biomarkers which may offer clinical applicability after pediatric heart surgery. Remarkable advances in the monitoring technologies and circulatory support systems lead us toward a personalized treatment algorithm using genetic, proteomic, and biomarker proling instead of a small number of clinical variables (8,9). Currently available biotechnology can measure several biomarkers using only a few microliters of plasma (8,1012).

Despite recent advances in surgical outcome and circulatory support systems, perioperative myocardial and cerebral complications are the major determinants of postoperative morbidity and mortality (5,13). Therefore, the demand is increasing for surrogate markers of clinical outcome after pediatric heart surgery. The RACHS-1 method was developed to rene the contributors of morbidity and mortality associated with congenital heart surgery (5,13). The clinical need still exists to integrate clinical variables with novel technology and biomarkers to accurately predict outcome after pediatric heart surgery. RACHS-1 is widely accepted and used to evaluate mortality differences after pediatric heart surgery; however, current algorithms do not integrate pathophysiology of complications to the risk scoring systems. Biomarkers of myocardial injury, cerebral damage, and inammation can all help the clinician to assess risk accurately after pediatric heart surgery (8) (Table 1). BEST BIOMARKER TO FOLLOW? Despite the abundant literature on biomarkers, the criteria for a good biomarker is a moving target for the association studies. Hence, the discussion is open for several clinical conditions including ischemia, sepsis, and critical care. Obviously, convincing results in prospective studies and availability of standardized commercial assays are necessary to consider a biomarker in the panel. Furthermore, it should be

TABLE 1. Examples of biomarkers related to organs and systems

Early biomarkers of myocardial injury Conventional biomarkers of myocardial injury Traditional biomarkers of neurological injury Novel biomarkers of neurological injury Biomarkers expressed in the vascular wall Biomarkers related to inammation Biomarkers related to thrombosis Biomarkers related to oxidative stress Biomarkers related to heart failure Heart fatty acid-binding protein (FABP), pregnancy-associated plasma protein A (PAPP-A), myeloperoxidase (MPO) Creatine kinase myocardial band (CK-MB), myoglobin, troponin I, troponin T Creatine kinase brain band (CK-BB), neuron-specic enolase (NSE), and S100b protein Ubiquitin C-terminal hydrolase 1 (UHCL1), phosphorylated axonal neurolament heavy chain (pNF-H), tissue plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1) (7,14), glial brillary acidic protein (GFAP) Interleukin (IL)-6, monocyte chemotactic protein (MCP-1), tumor necrosis factor (TNF)-a, IL-18, IL-10, C-reactive protein (CRP), serum amyloid A (SAA), complement 3, brinogen, matrix metaloproteinase (MMP) 1,2,9, PAPP-A, type III collagen, tissue factor, PAI-1, von Willebrand factor (vWF), D-dimer, sCD40 ligand, IL-8, P-selectin, adhesion molecules, MPO CRP, B2 microglobulin, CD40, CD40 ligand, complement 3, EN-RAGE, ferritin, adhesion molecules (ICAM-1, VCAM), immunoglobulin (Ig) A, G, M, IL-1,6,8,12,16,18, MMP, TNF-a PAI-1, factor VII, brinogen, tissue factor, vWF Glutathione S transferase, -1 antitrypsin, IL-2,4,5,15, haptoglobin Brain natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), TNF-a, MMP2, 9, tissue inhibitor of metalloproteinase 1 (TIMP1), troponin I, troponin T

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IRBAS M. AG LI AND A. NDAR recently, CK-MB was the only biomarker to detect and quantify myocardial injury. However, recent progress in the eld of biomedical research discovered several biomarkers that rise much earlier after injury. With recent clinical advances, structural myobrillar proteins, such as troponin T and troponin I and their cardiospecic isoforms, have entered the clinical eld in routine diagnostics (1618). The troponin test became a standard of care in acute coronary syndrome patients (1618). Yet, CK-MB and troponin are not suitable for monitoring as these biomarkers come with a delay between surgical damage and the detection of a measurable amount of protein in plasma. In the critical care unit, this delay gives rise to difculties in the rapid evaluation of the degree of myocardial injury. Therefore, selecting the biomarkers to be tested after CPB or pediatric heart surgery requires ongoing research. As the eld advances rapidly, there will be new technology and biomarkers which can also be added to the clinical practice. Besides, the best biomarker to be monitored might depend on the individual patient or timing after surgery. For instance, in our pilot study, novel markers of injury (pregnancyassociated plasma protein A [PAPP A], myeloperoxidase [MPO], and fatty acid-binding protein [FABP]) were the earliest to rise after CPB (8). In addition to the kinetics, the peak levels of biomarker remain as the prognostic indicator (19). In our experience, heart-type FABP levels displayed a striking increase after CPB with 25-fold increase 3 min after initiation of CPB (8). Hasegawa et al. reported that serum heart FABP reached a peak level at 1 h after declamping (19). The peak FABP level is likely to be the most relevant risk determinant of outcome, while the early rise and kinetics of biomarker release can also alert the clinician about the clinical course. Hasegawa group concluded that several factors altered FABP release after pediatric heart surgery (19). The signicant covariates and intraoperative variables that inuenced the release of heart FABP were aortic crossclamp time, the presence of a ventriculotomy, and the lowest hematocrit level during CPB (19). Hence, avoidance of hemodilution appeared important to prevent further myocardial injury. More importantly, peak FABP levels yielded prognostic information on extended stays in the critical care unit (19). Serum peak heart FABP levels correlated with postoperative inotropic support, duration of intubation, and intensive care unit stay (19). The major goal is to prevent acute organ deciency, that is, to decrease injury related to CPB and/or myocardial ischemia. Peak FABP levels can form a potential target to

additive to other risk factors and risk scoring systems (i.e., RACHS-1) in prospective studies. The clinical applicability will be questioned if biomarkers do not add further information to the traditional risk criteria. The assay methods should be cheap, easy, and widely available and, more importantly, reproducible. After pediatric heart surgery, important characteristics of a biomarker include specicity for myocardial or cerebral damage, cellular localization, aqueous solubility, clearance from blood circulation, detectability in plasma, presence of valid assay methods, and prior clinical trials indicating the utility. The majority of the current biomarker literature attempts to advocate the use of a single biomarker for a pathophysiologically complex condition. Unfortunately, no single biomarker can accomplish all these ambitious goals expected from a good biomarker. Hence, simultaneously evaluating several biomarkers or a biomarker array approach can help to fulll these goals to provide additional risk stratication. Besides, rather than relying on a single biomarker, monitoring multiple biomarkers may be more informative on different systems (i.e., neuroprotection, myocardial blood ow, inammation, etc.) (8). BIOMARKERS AND CARDIOPULMONARY BYPASS (CPB) In most cases, pediatric heart surgery requires CPB which can cause signicant changes in the biomarkers of myocardial and cerebral damage, inammation, thrombosis, and other tissue pathologies (8). Early and accurate assessment of biomarkers can therefore offer clinical applicability. We previously tested the efcacy and suitability of MAP (Rules Based Medicine, Austin, TX, USA) in pediatric cardiac surgery as a potential surrogate marker of clinical outcome (8). This novel technology enables us to serially and simultaneously detect the changes among several biomarkers with 100 mL of plasma (8). Our pilot study shows that this novel technology can simultaneously monitor biomarker arrays after pediatric heart surgery. Different pathophysiology and systems such as neuroprotection, myocardial blood ow, inammation, and wound healing can take part in the biomarker array (Table 1). EARLY BIOMARKERS OF MYOCARDIAL INJURY (35 MIN AFTER INITIATION OF CPB) Traditional and classic biomarkers of myocardial injury include creatine kinase and its isoform, creatine kinase-myocardial band (CK-MB) (15,16). Until
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BIOMARKER LEVELS IN PEDIATRIC HEART SURGERY achieve by alterations in the patient management during surgery, that is, by avoiding hemodilution during surgery. The early rise of novel biomarkers may relate to the membrane-associated localization of these molecules. In that sense, PAPP-A is another potential early biomarker of myocardial injury (20). Peak PAPP-A levels have previously been reported as a predictor of clinical outcome in unstable coronary artery disease (21). In our pilot study, PAPP-A levels increased nearly 50-fold 35 min after CPB (21). MPO is another biomarker for injury and necrosis (19). MPO was predictive of death and myocardial infarction in patients with acute coronary syndromes (22). Among the biomarker arrays, FABP, MPO, and PAPP-A can be valuable clinical parameters to follow after pediatric heart surgery (8,19). BIOMARKERS OF NEUROLOGICAL INJURY Undoubtedly, neurological injury is the leading complication and concern after pediatric cardiac surgery, despite major progress in circulatory support systems over the last decade (23,24). Developing robust biomarkers of neural injury is crucial to indicate the extent of the neurological injury and prognosis. Furthermore, to accomplish an effective neuroprotection, biomarkers can identify patients that are likely to benet, and to display a surrogate for outcome. Nearly half of the children experience impaired neurological outcomes after complex heart surgery (23,24). Enhanced monitoring during the perioperative period in pediatric cardiac surgery can potentially alert the clinician and help to prevent some of the neurological injuries after pediatric heart surgery. Devastatingly, affected children may display severe debilitation including motor decits and speech and language impairment (25). There is an increasing demand for novel biomarkers that can predict neurological outcome in these patients. Novel neuroprotective strategies such as pulsatile ow and/or improved bubble detection can be implemented to improve the outcome. As the pathophysiology of brain injury in the perioperative period is still not completely understood, the area of valid biomarkers as predictors of acute neurological injury is a novel concept which remains in its infancy. An early diagnosis of brain injury does not modify clearly the prognosis at this stage, but is clearly crucial for the clinician in charge of the patient. Long-term studies are needed to correlate with the clinical outcome.

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Several studies tested biomarkers as an indicator of neurological outcome. Traditionally tested biomarkers of neurological injury include creatine kinase brain band (CK-BB), neuron-specic enolase, and S100b protein (14,2628). The limitation of previously studied biomarkers is related to specicity to brain tissue (26). Therefore, we require more robust and novel biomarkers that are more specic for the brain. After hypoxic-ischemic encephalopathy from birth asphyxia, ubiquitin C-terminal hydrolase 1 and phosphorylated axonal neurolament heavy chain offered clinical applicability as specic biomarkers of brain injury (2931). On the other hand, prior studies focused on the late neurological outcome. Neurological complications after surgery have a complex pathophysiology with a variety of pre-, intra-, and postoperative and socioeconomic variables entering into the equation producing a late neurological or psychomotor outcome (32). As a result, brain protection during pediatric CPB remains as an important area of experimental and clinical research (32). Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) directly inuence thrombus formation and degradation and, thus, risk for arterial thrombosis. PAI-1 is a procoagulant, proinammatory, and probrotic molecule (33). PAI-1 is frequently expressed in injured tissues including myocardium and brain and the PAI-1/t-PA ratio is indicative of a patients brolytic balance which can indicate thrombus and stroke risk (33,34). Studies indicate evidence for the endothelial activation in small-vessel brain injury, associated with low levels of PAI-1 (35). In a small pilot study, we in fact observed that PAI-1 levels drop signicantly minutes after CPB in the pediatric population (9). Glial brillary acidic protein (GFAP) is a biomarker candidate indicative of intracerebral hemorrhage (ICH) in patients with symptoms of acute stroke (3638). Prior studies indicate that children with brain ischemia or cerebral infarct had GFAP elevations above the 95th percentile of healthy pediatric controls (37). GFAP is released rapidly in the presence of expanding intracerebral bleeding, whereas a more gradual release occurs in ischemic stroke. A GFAP cutoff of 0.29 mg/L provided diagnostic sensitivity of 84.2% and diagnostic specicity of 96.3% for differentiating ICH from ischemic stroke and stroke mimic. GFAP is associated with hemodilution and low blood pressure during CPB. INFLAMMATORY BIOMARKERS Inammatory cytokine markers such as interleukins (IL) 1b, 6, 8, and tumor necrosis factor, taken
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IRBAS M. AG LI AND A. NDAR help in the diagnosis of heart failure, with a high specicity and sensitivity. Clinicians can use biomarkers to differentiate heart failure from respiratory distress. LIMITATIONS The current review aims to summarize current understanding on the use of biomarkers after pediatric heart surgery and comes with several limitations. First of all, most studies are cross sectional, and it is hard to prove that the selected study populations are representative of all children undergoing pediatric heart surgery. Obviously, larger prospective studies are needed to assess temporal changes in biomarker levels after the surgical procedure. In addition to the procedural variables, genetic and environmental risk factors are important in the onset of complications after pediatric heart surgery. Socioeconomic status, diet, and shortcomings of the health systems can all potentially affect the success after pediatric heart surgery. Most studies focus on a single biomarker of interest. Unlike Mendelian diseases that are associated with a single protein, complications after pediatric heart surgery are likely to be caused by the nonlinear interactions of numerous genetic and environmental risk pathways. Therefore, a multifactorial approach is necessary to study risk interactions. Novel bioinformatic methods and risk scoring systems are crucial to assess the ever-growing amount of variables that do or can relate to adverse outcome after pediatric heart surgery. CONCLUSIONS Current technologies enable us to measure different biomarkers using only a very small sample of plasma (1012). The preliminary studies show that novel biomarkers in addition to the traditionally studied biomarkers can help to identify children at high risk following pediatric heart surgery. Future studies are needed to conrm the role of biomarkers in monitoring children after CPB. Carefully designed studies can compare biomarker levels for comparison of pulsatile versus nonpulsatile CPB and other neural or myocardial protective strategies. We need long term follow-up studies to determine the relationship between novel biomarkers and neurological and cardiovascular outcomes after pediatric heart surgery. REFERENCES
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together with markers of myocardium and CNS injury, have the potential to help as a surrogate of adverse outcomes after pediatric heart surgery (8) (Table 1). Inammation is an important component of response to CPB and cardiac surgery. Elevations in serum levels of IL-1b, 6, 8 have been shown to correlate with long-term adverse neurodevelopmental outcomes in full-term neonates (26). The new and novel biomarkers of inammation yield more specic tests which could discriminate patients at high risk for long-term adverse outcomes. Such subjects are candidates for early myocardium and cerebral protective therapies (i.e., pulsatile ow or avoidance of hemodilution). In our pilot study, the proinammatory biomarkers IL-6 and IL-8 were elevated signicantly during CPB (8). Even at 1 h after CPB, the level of IL-6 was 45 times higher than the baseline (8). Inammatory markers (C-reactive protein, ferritin, and MPO) also underwent signicant changes. C-reactive protein increased by 161fold even at 24 h post-CPB (P = 0.001). Ferritin increased by six times of baseline level at 24 h post-CPB (P = 0.0011). IL-10, an anti-inammatory marker, increased by 12.5-fold at the end of CPB (P = 0.015). Selection of a biomarker array may depend on the individual patient and timing in the course of the perioperative period (8). Peak PAPP-A, MPO, and FABP levels can assess and monitor the extent of myocardial injury. As discussed earlier, several biomarkers can monitor inammation and coagulation following injury in the course (Table 1). For instance, in our pilot study, CRP increased nearly 200-fold 24 h after CPB (8). IL-6 and IL-10 displayed a similar trend (8). THYROID HEMOSTASIS AND PULSATILE VERSUS NONPULSATILE FLOW Previous studies indicate that pulsatile ow during CPB can in fact maintain physiologic thyroid balance (39). In our pilot study, the thyroid stimulating hormone (TSH) gradually decreased as the patients underwent CPB. Then, there was a large drop in the TSH level going from 1 h post-CPB to 24 h post-CPB (P = 0.0129) which resulted in an eight-fold decrease of TSH overall (P = 0.0019). Hormonal and inammatory biomarkers induced by initial injury may predict complications in the early recovery period. Hormonal and hemostatic biomarkers can direct further therapeutic options. Similarly, brain natriuretic peptide (BNP) and N-terminal brain natriuretic peptide (NTproBNP) are important biomarkers after pediatric heart surgery (40). BNP and NT-proBNP levels can
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