Relationship Between Natriuretic Peptides and Hemodynamic Parameters Following Heart Surgery in Infancy

Critically ill states, perioperative period of major surgery, particularly cardiac operations are often encountered with large hemodynamic alterations and fluid shifts. Cardiac failure in patients with congenital heart defect has heterogeneous origin therefore diagnosis related treatment is difficult to apply. During the postoperative period, hemodynamic instability has multifactorial origin and cardiorespiratory dysfunction has several manifestation e.g. myocardial dysfunction, pulmonary hypertension etc (Laussen & Roth, 2003). Biochemical markers play an important role in the risk stratification of patients with cardiovascular disease. Elevated brain natriuretic peptide level has been shown to reveal congestive heart failure among adult patients admitted to emergency department with dyspnoe (Maisel et al, 2002; de Lemos et al, 2001), and to predict adverse events in acute coronary syndromes (de Lemos et al, 2001). Cardiac troponin, creatine kinase-MB, brain natriuretic peptide and C-reactive protein have been shown to predict mortality and morbidity in unstable coronary artery disease (Lindahl et al, 2000). In patients with pulmonary embolism, brain natriuretic peptide and other cardiac markers, such as troponin predict adverse outcomes much more accurately than any other clinical signs (Kucher et al, 2003). In the last decade, several papers investigating the prognostic, diagnostic and therapeutic relevance of natriuretic peptides in the pediatric population have been published (in rev. Cantinotti et al, 2011; Cantinotti et al, 2011).


Introduction
Critically ill states, perioperative period of major surgery, particularly cardiac operations are often encountered with large hemodynamic alterations and fluid shifts.Cardiac failure in patients with congenital heart defect has heterogeneous origin therefore diagnosis related treatment is difficult to apply.During the postoperative period, hemodynamic instability has multifactorial origin and cardiorespiratory dysfunction has several manifestation e.g.myocardial dysfunction, pulmonary hypertension etc (Laussen & Roth, 2003).Biochemical markers play an important role in the risk stratification of patients with cardiovascular disease.Elevated brain natriuretic peptide level has been shown to reveal congestive heart failure among adult patients admitted to emergency department with dyspnoe (Maisel et al, 2002;de Lemos et al, 2001), and to predict adverse events in acute coronary syndromes (de Lemos et al, 2001).Cardiac troponin, creatine kinase-MB, brain natriuretic peptide and C-reactive protein have been shown to predict mortality and morbidity in unstable coronary artery disease (Lindahl et al, 2000).In patients with pulmonary embolism, brain natriuretic peptide and other cardiac markers, such as troponin predict adverse outcomes much more accurately than any other clinical signs (Kucher et al, 2003).In the last decade, several papers investigating the prognostic, diagnostic and therapeutic relevance of natriuretic peptides in the pediatric population have been published (in rev.Cantinotti et al, 2011;Cantinotti et al, 2011).

Physiology of the natriuretic peptides
The natriuretic peptides are a family of peptides produced by the myocardium, vascular endothelium and the kidneys (Clerico et al, 2006).The "hormone" of the heart is involved in the regulation of intravascular homeostasis, myocardial function.On the other hand, natriuretic peptides counteract with the renin-angiotensin-aldosterone system, symphathetic nervous system, vasopressin release.Receptors of natriuretic peptides are mainly presented in the myocardium, kidneys, lungs and vascular endothelium.The action is mediated by c-GMP, the cytoplasmatic calcium availability will be decreased in the smooth muscles and it will result in vasodilatation.(Silberbach & Roberts, 2001).Atrial stretching triggers release of the preformed prohormone of atrial natriuretic peptide (NT-proANP) in the atrial wall.During secretion, the prohormone of atrial natriuretic peptide (ANP) is cleaved to atrial natriuretic peptide and N-terminal pro-atrial natriuretic peptide (Kangawa et al, 1984).Although brain natriuretic peptide chemically resembles atrial natriuretic peptide to some extent, it is synthetized both in the atrial and ventricular myocardium due to volume and pressure overload.The production of BNP requires time (6-12 hours), since RNA transcription of the prohormone precedes the secretion.Then, the prohormone of brain natriuretic peptide is cleaved to brain natriuretic peptide (BNP) and Nterminal pro-brain natriuretic peptide (NT-proBNP).N-terminal peptides have several times higher concentrations and longer half life time in blood circulation than atrial natriuretic peptide and brain natriuretic peptide, making them reliable markers (Ham et al, 1995).

Adult population
In adults, diastolic dysfunction or asymptomatic aortic stenosis confirmed by echocardiography or angiography show marked correlations with brain natriuretic peptide (Gerber et al, 2003).Right-sided heart failure or complications after pulmonary embolism can accurately be detected by measuring natriuretic peptides, though the cut-off levels were only half of those for left ventricular dysfunction (Kucher et al, 2003).There are two widely accepted area for BNP testing; exclusion of non-cardiac origin of dyspnoe in emergency settings and prognostic information of various states of heart failure.NT-proBNP above 1065 pmol/l had a very high specificity and sensitivity for cardiac failure in our population, similar levels were found in decompensated heart failure, septic shock and acute pulmonary embolism with New York Heart Association III and IV symptoms (Seino et al, 2004).Additionally, lower postoperative cut-off value (513 pmol/l) bore high negative predictive power, indicating a level below which the occurrence of heart failure is unlikely.In these cases, NT-proBNP or BNP measurements are used.Levels above the cut-off level were independently associated with increased risk for mortality and cardiovascular morbidity including cardiac fibrillation.In adults, it has been shown that hyperthyroidism increases the NT-pro BNP level and could reflect cardiac dysfunction secondary to thyreotoxicosis [Kato 2008, Welisch 2011].ANP or NT-proANP reflect acute changes in atrial wall stress (Ruskoaho, 2003).Therefore, it is not suitable for long-term follow-up of congestive heart failure.Recently, a new immunoassay has been developed for a hybrid peptide (referred to as NT-proXNP) containing peptide sequences from both NT-proANP and NT-proBNP (Ala-Kopsala et al, 2005).This novel assay mimics the physiological signaling pathway since the actions of the different active natriuretic fragments on the target cells are mediated by a single natriuretic peptide receptor.The NT-proXNP assay measures the concentration of the new virtual natriuretic peptide, and thus provides combined information about the plasma levels of NT-proANP and NT-proBNP.In cardiac diseases, the neurohormonal system of the heart is activated.The diagnostic performances of NT-proXNP in adults for coronary artery disease and valvular heart disease are greater than or equal to those of NT-proANP or NT-proBNP, individually.NT-proXNP seems to combine the characteristics of the two natriuretic peptides.Therefore, NT-proXNP will increase earlier during myocardial wall stress than the NT-proBNP alone.

Pediatric population
Based on physiological considerations, BNP and NT-proBNP levels are age dependent in the first two weeks after birth (Albers et al, 2006-Schwachtgen et al, 2005).The perinatal transition from fetal to neonatal circulation is accompanied by an increase in the pulmonary blood flow and an increase in the systemic vascular resistance.These hemodynamic changes lead to pressure and volume load of the heart and it may stimulate the secretion and release of natriuretic peptides.From 31 days to 12 years of age, there is no significant change in healthy subjects (Cantinotti et al, 2010).From 14 years of age, gender related differences should be accounted and it is probably due to steroid sex hormones (Soldin et al, 2006).Agecorrected brain natriuretic peptide and NT-proBNP values should be used in the neonatal population (Cantinotti et al, 2010b), while gender should be considered in the adolescent population.Additionally, it is important to note that reference ranges, decision values are method dependent and it shows variations between the assays and consequently between the studies (Soldin et al, 2006, Cantinotti et al, 2010).These variations are seen in Figure 1.As in the adult population NT-proBNP is significantly higher in children with sepsis.In children with sepsis NT-proBNP levels are higher in some patients with leftventricular dysfunction (Fried 2006).In comparison to the adult population there are no paediatric studies in hyperthyroidism available at present (Welisch 2011).

Pediatric population -Congenital heart disease
Different requirements have been formulated for the natriuretic peptide assays in the pediatric population.One major area is the exclusion of cardiovascular disease particularly below one year of age.The clinical signs are poor or share the ones with other noncardiac diseases.The major symptoms are dyspnea, tachypnea, cold extremities, murmurs, tachycardia, hypotension, etc.The assay is easy to carry out and requires only 0.5 ml blood.
The recent studies showed convincing results that the BNP test could be performed without difficulties from capillary stick and it had a high negative power both in neonates and infants (Law et al, 2009,Maher et al, 2008).
The anatomy of the congenital heart diseases is heterogenous.Additionally, the situation after different types of surgery complicates the hemodynamic state.An arbitrary classification is the following: ventricle volume overload, including left-right shunts, ventricular septal defects, patent ductus arteriosus, atrial septal defect, atrioventricular malformations, truncus arteriosus, etc; pressure overload, as a consequence of outflow tract obstruction or valvular stenosis, such as tetralogy of Fallot, pulmonary or aorta stenosis; univentricular physiology and non-clusterable complex malformations.Despite the age related BNP elevation in the neonatal period, the severity of heart failure can be determined and diagnosed (Cantinotti et al, 2010b, Law et al, 2009).Other studies have been described the linear relationship between BNP or NT-proBNP levels and the magnitude of left-right shunting (Kunii et al, 2003) and BNP levels were able to predict the need for ductus arteriosus closure (Paul et al, 2009).Echocardiographic studies have been confirmed the association between pressure gradient and natriuretic peptide levels (Cowley et al, 2004).In right sided pressure overload, the BNP levels were lower compared to left sided pressure overload (Cantinotti et al, 2009, Holmgren et al, 2005).In Table 1 and 2 pediatric studies measuring BNP and NT-proBNP levels are shown.

Pediatric cardiac population postoperative period
Monitoring of cardiac output is still a problematic issue, although early recognition of hemodynamic complications is essential in pediatric critical care.During the postoperative period, hemodynamically unstable patients are characterized by high volume intake, the need for considerable inotropic support, edema formation, hepatic congestion, lung dysfunction or the combination of them (Laussen & Roth, 2003).High lactate levels and low base excess on the first postoperative day have been reported to predict mortality and outcome in pediatric cardiac patients (Tibby et al, 1999, Carmona et al, 2008).Mir et al.found limited value of NT-proBNP levels in the perioperative period.In their study, dosage and duration of catecholamines and length of mechanical ventilation correlated with postoperative troponin T and arterial lactate levels, but not with NT-proBNP (Mir et al, 2006).Since catecholamine therapy is a consequence of hemodynamic instability and prolonged mechanical ventilation can be influenced by certain non-cardiac factors, the direct relationship might be concerned.Indeed, clinical signs and scores of congestive heart failure is difficult to apply as diaphoresis, respiratory rate, heart rate in the early postoperative period are strongly modified by inotropic, analgesic and sedative medication (Tibby et al, 1999).Preoperative NT-proBNP was associated with adverse postoperative outcome in children undergoing heart surgery, like duration of mechanical ventilation, dose of inotropic support, length of intensive care unit stay (33-Hsu et al, 2007).BNP and NT-proBNP levels usually exceed the peak maximum at 12 hours, and a second peak may occur about five days after surgery (Koch et al, 2007).Postoperative BNP and NT-proBNP levels have also been shown to have prognostic value after pediatric cardiac surgery.After cavopulmonary anastomosis a decrease in natriuretic peptides level compared to preoperative level were correlated with better outcomes (Hsu et al, 2008).Prognostic role of BNP was also reported after switch surgery in neonates (Lehot et al, 1992).
Our study investigated the prognostic role of NT-proXNP, a hybride analyte.NT-proXNP level correlated significantly with the simultaneously measured NT-proANP level (r = 0.60, p < 0.001), but more strongly with NT-proBNP level (r = 0.89, p < 0.001) and the arithmetic sum of both peptides throughout the perioperative period (r = 0.88, p < 0.001).Baseline NT-proXNP level correlated with the age (r = -0.72,p < 0.001) and the weight of the patients (r = -0.47,p = 0.026).Preoperative creatinine level (53.3 ± 13.1 μmol/l) correlated with baseline NT-proXNP (r = 0.53, p = 0.013).The duration of operation and the duration of CPB were associated with the preoperative NT-proXNP level (r = 0.58, p = 0.005 and r = 0.62 p = 0.002, www.intechopen.comFig. 2. Correlation between logarithmic transformed NT-proXNP levels and cardiopulmonary bypass time respectively) and the peak postoperative NT-proXNP level (r = 0.64, p < 0.001 and r = 0.67, p < 0.001, respectively).NT-proBNP showed similar correlations with the duration of operation and CPB (Breuer et al, 2010).In the postoperative period, natriuretic peptide levels correlated significantly with the simultaneously assessed hemodynamic parameters.NT-proXNP correlated stronger with the hemodynamic parameters except for extravascular lung water index than the arithmetic sum of NT-proANP and NT-proBNP.The correlation between NT-proXNP and CI remained significant after adjusting for age (r = 0.60, p = 0.018) or weight (r = 0.81, p < 0.001).The hemodynamic parameters improved during the postoperative period as the myocardium recovered.The application of transpulmonary thermodilution was safe and reliable and it added useful information to the conventionally measured pressure values in neonates and infant following open heart surgery.We found lower global enddiastolic volume indices and higher extravascular lung water indices compared to adult ranges, whereas the cardiac indices were the same.Age related and disease specific reference values of the transpulmonary thermodilution parameters are yet to be determined in children.In ROC analysis, a postoperative NT-proBNP level of 2051 pmol/l was diagnostic for cardiac index (CI) lower than 3 l/min/m2 with 79% sensitivity and 95% specificity (AUC: 0.87 ± 0.06), whereas a postoperative NT-proXNP level of 079 pmol/l was diagnostic for that with 89% sensitivity and 90% specificity (AUC: 0.91 ± 0.05).The length of mechanical ventilation and ICU stay did not correlate with the baseline or the peak natriuretic peptide levels.NT-proBNP and NT-proXNP, but not NT-proANP level at 24 hours after surgery were correlated to the length of mechanical ventilation (r = 0.51, p = 0.015 and r = 0.47, p = 0.027, respectively).The area under the curve (AUC) of NT-proBNP and NT-proXNP at 24 hours after surgery for prolonged mechanical ventilation (> 72h) in ROC analysis was 0.81 ± 0.10 and 0.72 ± 0.11, respectively.The new analyte, NT-proXNP seems to have promising characteristics, because it reflects the cardiac output changes earlier than the BNP, NT-proBNP assay.

Fig. 1 .
Fig. 1.Refence mean and median values of healthy subjects

Fig. 3 .
Fig. 3. Relationship between logarithmic transformed NT-proXNP levels and Cardiac indexConventionally measured parameters such as heart rate, mean arterial pressure and pulsepressure product exhibited weaker correlations with CI than natriuretic peptide levels.Parameters measured by echocardiography i.e. fractional shortening and calculated pressures of the right ventricle were not correlated to CI. Clinical and laboratory values, except for creatinine level and creatinine clearance, showed no correlation with CI or NT-proXNP.According to our findings, natriuretic peptides and NT-proXNP are indicators of hemodynamic parameters following pediatric cardiac surgery that can only be measured by invasive hemodynamic monitoring.
are age dependent and show significant variability according to the type of the cardiac malformation and the actual hemodynamic condition.Recently, age related normal values have been established in the neonatal period and it allows detection of the congental heart disease in different age groups.Right sided hemodynamic ventricular stress is encountered with lower BNP values.Preoperative and postoperative application of natriuretic peptides provides a useful tool for the detection of postoperative complications.