**5. BNP as a biomarker following cardiac surgery**

## **5.1 Early post-operative period**

As a cardiac hormone with a relatively short circulating half life that is dynamically released in response to deranged myocardial performance, BNP appears perfectly suited for the perioperative management of pediatric patients undergoing cardiac surgery for repair or palliation of congenital cardiac defects.

A number of investigators have studied perioperative BNP levels in neonates, infants, and children undergoing cardiac surgery. Ationu and colleagues measured perioperative BNP levels in 9 children undergoing repair of congenital heart defects(Ationu et al. 1993). In that study, BNP levels decreased at 12 hours following surgery(Ationu et al. 1993). Most studies, however, have found increases in BNP and NT-proBNP levels after surgery. Costello and colleagues measured natriuretic peptide levels, including BNP, in 5 infants undergoing surgical repair of left-to-right shunts(Costello et al. 2004). As opposed to ANP and DNP, BNP concentrations increased after cardiopulmonary bypass. Sun and colleagues measured BNP levels before and after surgery in 27 infants and children undergoing biventricular

B-Type Natriuretic Peptide (BNP) in Neonates,

may differ between cardiac defects and age groups.

did not correlate with these outcomes in either group.

**5.2 BNP in patients requiring mechanical support after cardiac surgery** 

Chikovani and colleagues studied the potential utility of BNP levels in the assessment of native myocardial performance in ten neonates and infants being supported with

Infants, and Children Undergoing Cardiac Surgery 205

venous oxygen saturation differences (AVdO2) nor lactate levels (or their corresponding

In another neonatal study, Cannesson and colleagues measured perioperative BNP levels in 30 neonates undergoing the arterial switch operation (ASO) for d-transposition of the great arteries(Cannesson et al. 2007). Contrary to the findings of Hsu, BNP levels increased over the first 48 hours postoperatively. However, like the study by Hsu these investigators found that postoperative BNP levels predicted adverse clinical outcomes, including prolonged mechanical ventilation, prolonged stay in the intensive care unit, low cardiac output syndrome, and the need for inotropic support. These investigators found that a BNP level of >160 pg/ml, 6 hours postoperatively, predicted a complicated postoperative course with a sensitivity of 93% and a specificity of 67%. Similarly, Niedner and colleagues studied 102 neonates and non-neonatal controls undergoing surgical repair for various congenital cardiac defects(Niedner et al. 2010). They found that BNP levels increased after surgery, peaking at 12 hours. Levels at 24 hours were significantly higher in neonates than in nonneonates (median of 1506 vs 286 pg/ml). In addition, postoperative BNP levels correlated with the inotropic requirement, duration of mechanical ventilation, and intensive care unit and hospital length of stay. When comparing the various cardiac defects, these investigators found great variability between lesions and noted the significant impact of age, with postoperative elevations occurring earlier and to a much greater magnitude in neonates compared to older children. One might speculate that the differences between the neonatal studies of Hsu, Cannesson, and Niedner relate in part to differences between single and biventricular physiology, and the impact of surgery on ventricular volume and pressure loading. Furthermore, these studies demonstrate that the potential clinical utility for BNP determinations as a part of management after cardiac surgery may depend upon analyzing patterns of change, as opposed to single time points. Moreover, relevant patterns of change

In fact, Berry and colleagues studied 20 neonates, infants, and children undergoing various stages of palliation for cardiac defects with single ventricle physiology(Berry et al. 2007). They found that BNP levels were highest in neonates undergoing a Norwood procedure compared with patients undergoing bidirectional cavopulmonary anastomosis or a Fontan procedure. They also found that postoperative BNP levels were predictive of hospital length of stay and postoperative inotropic support.Likewise, Hsu and colleagues measured perioperative BNP levels in 36 infants and children undergoing bidirectional cavopulmonary anastomosis (n=25) or total cavopulmonary connection (n=11)(Hsu et al. 2008). Plasma BNP levels were measured before and at various time points after surgery. They found that BNP levels increased after surgery, peaking at 12 hours in most patients. In the bidirectional cavopulmonary anastomosis group, patients with a 12-hour BNP level of ≥500 pg/mL had a longer duration of mechanical ventilation, intensive care unit stay, and hospital stay. A 12-hour BNP level of ≥500 pg/mL had a sensitivity of 80% and a specificity of 80% for predicting an unplanned surgical or transcatheter cardiac intervention, including transplantation. In the total cavopulmonary connection group, preoperative BNP levels were highest in patients with total cavopulmonary connection failure compared with patients with a good outcome, whereas postoperative BNP levels were not predictive of outcome.Importantly, preoperative cardiac catheterization data

changes) were associated with postoperative outcomes in this study(Hsu et al. 2007).

repair and 27 patients undergoing palliation of univentricular congenital heart defects(Sun et al. 2005). Plasma BNP levels increased after bypass in patients with biventricular defects, but not in patients with univentricular defects(Sun et al. 2005). Costello and colleagues examined BNP levels before and following cardiac surgery in 25 infants and children with congenital heart disease undergoing complete or palliative repair with the use of cardiopulmonary bypass(Costello et al. 2004). BNP levels increased postoperatively, and remained elevated over the first postoperative day. The increase in BNP from baseline to 12 hours was associated with the cardiopulmonary bypass time.Koch and colleagues measured BNP levels in 65 pediatric patients (age 4 days – 17 years, mean age of 3.6), undergoing surgical repair of congenital cardiac defects preoperatively, and for one week after surgery(Koch, Kitzsteiner, et al. 2006). BNP levels increased after surgery (from a median of 31 pg/ml to 453 pg/ml) and remained elevated over the first week, with a bimodal pattern (initial peak at 1.3 days and a second peak at 5.1 days after surgery). Postoperative BNP levels correlated with cardiopulmonary bypass time and serum lactate concentrations on the first postoperative day.

Shih and colleagues conducted the first study demonstrating that BNP predicted outcome after cardiac surgery in children(Shih et al. 2006). BNP levels were determined before and after surgery in 51 patients. They found that BNP levels increased after surgery, peaking at 12 hours, and that BNP levels 12 hours following surgery were predictive of a requirement for mechanical ventilation beyond 48 hours and the presence of low cardiac output syndrome within the first 48 hours, postoperatively. Further, the study found that 12-hour BNP levels of 540 pg/ml had a sensitivity of 88.9% and a specificity of 82.5% for predicting the need for mechanical ventilation beyond 48 hours, and that a 12-hour BNP of 815 pg/ml had a sensitivity of 87.5% and a specificity of 90.2% for predicting the development of low cardiac output syndrome.

Similarly, Perez-Piaya and colleagues measured NT-proBNP levels in 68 patients (0-15 years of age) undergoing cardiac surgery(Perez-Piaya et al. 2011). They found that NT-proBNP levels increased postoperatively, peaking at 24 hours. Moreover, peak NT-proBNP levels correlated with risk adjustment congenital heart surgery-1 scores, length of cardiopulmonary bypass, inotropic score, duration of mechanical ventilation, and intensive care unit length of stay. In addition, preoperative NT-proBNP levels were independent predictors of intensive care unit length of stay. Gessler and colleagues also measured NTproBNP levels before and after cardiac surgery in 40 children(Gessler et al. 2006). In their study, higher preoperative levels were noted in patients with a complicated postoperative course.

It is well known that neonates undergoing cardiac surgery and patients with single ventricular physiology represent high-risk groups. Hsu and colleagues examined BNP levels before and after surgery in 31 consecutive neonates undergoing repair or palliation of their cardiac defects(Hsu et al. 2007). BNP levels at all time points were markedly elevated, compared to published normal values. But interestingly, as opposed to the majority of studies of older patients, they found that 24-hour postoperative BNP levels were lower than preoperative BNP levels in most patients (75%). However, in those patients whose BNP levels increased after surgery outcomes were worse. In fact, an increase in post-operative BNP was associated with an increased incidence of low cardiac output syndrome (100% vs. 36 %), and fewer ventilator-free days (17 ± 13 days vs. 25 ± 3 days), and predicted the 6 month composite endpoint of death, an unplanned operation, or cardiac transplant (57% vs. 0%). Furthermore, an increase in BNP after surgery had a sensitivity of 100% and a specificity of 87% for predicting a poor postoperative outcome. Notably, neither arterial-

repair and 27 patients undergoing palliation of univentricular congenital heart defects(Sun et al. 2005). Plasma BNP levels increased after bypass in patients with biventricular defects, but not in patients with univentricular defects(Sun et al. 2005). Costello and colleagues examined BNP levels before and following cardiac surgery in 25 infants and children with congenital heart disease undergoing complete or palliative repair with the use of cardiopulmonary bypass(Costello et al. 2004). BNP levels increased postoperatively, and remained elevated over the first postoperative day. The increase in BNP from baseline to 12 hours was associated with the cardiopulmonary bypass time.Koch and colleagues measured BNP levels in 65 pediatric patients (age 4 days – 17 years, mean age of 3.6), undergoing surgical repair of congenital cardiac defects preoperatively, and for one week after surgery(Koch, Kitzsteiner, et al. 2006). BNP levels increased after surgery (from a median of 31 pg/ml to 453 pg/ml) and remained elevated over the first week, with a bimodal pattern (initial peak at 1.3 days and a second peak at 5.1 days after surgery). Postoperative BNP levels correlated with cardiopulmonary bypass time and serum lactate concentrations on the

Shih and colleagues conducted the first study demonstrating that BNP predicted outcome after cardiac surgery in children(Shih et al. 2006). BNP levels were determined before and after surgery in 51 patients. They found that BNP levels increased after surgery, peaking at 12 hours, and that BNP levels 12 hours following surgery were predictive of a requirement for mechanical ventilation beyond 48 hours and the presence of low cardiac output syndrome within the first 48 hours, postoperatively. Further, the study found that 12-hour BNP levels of 540 pg/ml had a sensitivity of 88.9% and a specificity of 82.5% for predicting the need for mechanical ventilation beyond 48 hours, and that a 12-hour BNP of 815 pg/ml had a sensitivity of 87.5% and a specificity of 90.2% for predicting the development of low

Similarly, Perez-Piaya and colleagues measured NT-proBNP levels in 68 patients (0-15 years of age) undergoing cardiac surgery(Perez-Piaya et al. 2011). They found that NT-proBNP levels increased postoperatively, peaking at 24 hours. Moreover, peak NT-proBNP levels correlated with risk adjustment congenital heart surgery-1 scores, length of cardiopulmonary bypass, inotropic score, duration of mechanical ventilation, and intensive care unit length of stay. In addition, preoperative NT-proBNP levels were independent predictors of intensive care unit length of stay. Gessler and colleagues also measured NTproBNP levels before and after cardiac surgery in 40 children(Gessler et al. 2006). In their study, higher preoperative levels were noted in patients with a complicated postoperative

It is well known that neonates undergoing cardiac surgery and patients with single ventricular physiology represent high-risk groups. Hsu and colleagues examined BNP levels before and after surgery in 31 consecutive neonates undergoing repair or palliation of their cardiac defects(Hsu et al. 2007). BNP levels at all time points were markedly elevated, compared to published normal values. But interestingly, as opposed to the majority of studies of older patients, they found that 24-hour postoperative BNP levels were lower than preoperative BNP levels in most patients (75%). However, in those patients whose BNP levels increased after surgery outcomes were worse. In fact, an increase in post-operative BNP was associated with an increased incidence of low cardiac output syndrome (100% vs. 36 %), and fewer ventilator-free days (17 ± 13 days vs. 25 ± 3 days), and predicted the 6 month composite endpoint of death, an unplanned operation, or cardiac transplant (57% vs. 0%). Furthermore, an increase in BNP after surgery had a sensitivity of 100% and a specificity of 87% for predicting a poor postoperative outcome. Notably, neither arterial-

first postoperative day.

cardiac output syndrome.

course.

venous oxygen saturation differences (AVdO2) nor lactate levels (or their corresponding changes) were associated with postoperative outcomes in this study(Hsu et al. 2007).

In another neonatal study, Cannesson and colleagues measured perioperative BNP levels in 30 neonates undergoing the arterial switch operation (ASO) for d-transposition of the great arteries(Cannesson et al. 2007). Contrary to the findings of Hsu, BNP levels increased over the first 48 hours postoperatively. However, like the study by Hsu these investigators found that postoperative BNP levels predicted adverse clinical outcomes, including prolonged mechanical ventilation, prolonged stay in the intensive care unit, low cardiac output syndrome, and the need for inotropic support. These investigators found that a BNP level of >160 pg/ml, 6 hours postoperatively, predicted a complicated postoperative course with a sensitivity of 93% and a specificity of 67%. Similarly, Niedner and colleagues studied 102 neonates and non-neonatal controls undergoing surgical repair for various congenital cardiac defects(Niedner et al. 2010). They found that BNP levels increased after surgery, peaking at 12 hours. Levels at 24 hours were significantly higher in neonates than in nonneonates (median of 1506 vs 286 pg/ml). In addition, postoperative BNP levels correlated with the inotropic requirement, duration of mechanical ventilation, and intensive care unit and hospital length of stay. When comparing the various cardiac defects, these investigators found great variability between lesions and noted the significant impact of age, with postoperative elevations occurring earlier and to a much greater magnitude in neonates compared to older children. One might speculate that the differences between the neonatal studies of Hsu, Cannesson, and Niedner relate in part to differences between single and biventricular physiology, and the impact of surgery on ventricular volume and pressure loading. Furthermore, these studies demonstrate that the potential clinical utility for BNP determinations as a part of management after cardiac surgery may depend upon analyzing patterns of change, as opposed to single time points. Moreover, relevant patterns of change may differ between cardiac defects and age groups.

In fact, Berry and colleagues studied 20 neonates, infants, and children undergoing various stages of palliation for cardiac defects with single ventricle physiology(Berry et al. 2007). They found that BNP levels were highest in neonates undergoing a Norwood procedure compared with patients undergoing bidirectional cavopulmonary anastomosis or a Fontan procedure. They also found that postoperative BNP levels were predictive of hospital length of stay and postoperative inotropic support.Likewise, Hsu and colleagues measured perioperative BNP levels in 36 infants and children undergoing bidirectional cavopulmonary anastomosis (n=25) or total cavopulmonary connection (n=11)(Hsu et al. 2008). Plasma BNP levels were measured before and at various time points after surgery. They found that BNP levels increased after surgery, peaking at 12 hours in most patients. In the bidirectional cavopulmonary anastomosis group, patients with a 12-hour BNP level of ≥500 pg/mL had a longer duration of mechanical ventilation, intensive care unit stay, and hospital stay. A 12-hour BNP level of ≥500 pg/mL had a sensitivity of 80% and a specificity of 80% for predicting an unplanned surgical or transcatheter cardiac intervention, including transplantation. In the total cavopulmonary connection group, preoperative BNP levels were highest in patients with total cavopulmonary connection failure compared with patients with a good outcome, whereas postoperative BNP levels were not predictive of outcome.Importantly, preoperative cardiac catheterization data did not correlate with these outcomes in either group.

#### **5.2 BNP in patients requiring mechanical support after cardiac surgery**

Chikovani and colleagues studied the potential utility of BNP levels in the assessment of native myocardial performance in ten neonates and infants being supported with

B-Type Natriuretic Peptide (BNP) in Neonates,

deterioration in this patient population.

postoperative weight gain (weight z-score change per month).

correlated with ventricular function, particularly diastolic function.

6 months after surgery.

imaging.

Infants, and Children Undergoing Cardiac Surgery 207

23 patients with repaired tetralogy of Fallot, severe pulmonary insufficiency, and increased right ventricular end-diastolic volume that were undergoing pulmonary valve replacement(Dodge-Khatami et al. 2006). Log-NT-proBNP levels were inversely correlated with right ventricular ejection fraction before and 6 months after surgery. NT-proBNP levels, right ventricular end-diastolic volume, and pulmonary insufficiency all decreased by

These three studies differed from a study by Apitz and colleagues. These investigators measured BNP levels and recorded pressure-volume loops using conductance catheters in 16 adolescents (median age of 14.2 years) with a known history of right ventricular dilation (NYHA class I, and Ross class 0) secondary to pulmonary regurgitation after repair of tetralogy of Fallot(Apitz et al. 2009). Latent right ventricular dysfunction was defined as impaired contractility (calculated by the slope of the end-systolic pressure-volume relation) in response to a dobutamine infusion. Latent right ventricular dysfunction was identified in 5 patients, but no clear relationship with BNP levels could be observed. The difference between this study and those of Koch, Pietrzak, and Dodge-Khatami may relate to the severity of disease, suggesting that BNP may not be useful in detecting subclinical

In a small pilot study, Paul and colleagues measured BNP levels before and after surgical repair of ventricular septal defects in 14 patients who were less than 2 years of age(Paul et al. 2009). Mean BNP levels decreased by 94 pg/ml after repair. Longitudinal analysis found that there was a weak inverse correlation between the postoperative change in BNP and

Recently, Atz and colleagues described their findings in a study of 510 children (6-18 years of age), who were enrolled in the Pediatric Heart Network Fontan cross-sectional study(Atz et al. 2011). The patients had all undergone 3rd stage palliation of single ventricle cardiac defects with a Fontan procedure (median time from Fontan of 8.2 years). The distribution of BNP levels in these patients were highly skewed, but were generally within the normal range (median 13 pg/ml). However, logBNP levels were independently associated with a history of pre-Fontan systolic dysfunction, and post-Fontan complications, including thrombosis. LogBNP levels were higher in patients with atrial-to-pulmonary connections compared to extracardiac conduits. Furthermore, increased logBNP levels were associated with a lower level of physical functioning, chronotropic index during exercise, diastolic dysfunction, and greater ventricular mass measured by cardiac magnetic resonance

In a similar study, Koch and colleagues measured plasma BNP levels in 67 patients after a modified Fontan procedure(Koch et al. 2008). Although there was a wide range, BNP levels were normal in 81% of the patients, with a median value of 13 pg/ml. Levels were not different between patients with right or left ventricular morphology. BNP levels were higher in patients in NYHA class II compared to those in class I, and were positively correlated with the severity of AV valve regurgitation. Likewise, Man and colleagues measured plasma BNP levels and assessed ventricular function (by tissue Doppler assessments, acoustic quantification, and myocardial performance index) in 35 asymptomatic patients who had previously undergone a Fontan procedure(Man and Cheung 2007). Comparisons were made to 34 healthy controls. Although BNP levels were low in the Fontan group (median 21 pg/ml), they were higher than the control group. Moreover, BNP levels were inversely

extracorporeal life support (ECLS) after cardiac surgery(Chikovani et al. 2007). In particular, alterations in BNP during weaning trials off of ECLS were determined and compared to other biochemical markers, including lactate and the AVDO2.This study did not find associations between long-term outcome and alterations in lactate and the AVDO2 during trials off ECLS. However, an increase in BNP during the final trial off ECLS had a sensitivity of 80% and a specificity of 100% for predicting the need for an unplanned operation or death within 3 months. A notable finding of this study was that BNP levels decreased during trials off of ECLS support (which were accomplished through the use of a bridge placed in the ECLS circuit, allowing mechanical support to be diverted away from the patient before the ECLS cannulae were removed) in patients who were successfully separated from ECLS after a trial. Since trials off ECLS were associated with increased cardiac filling (increased central venous pressures) in all patients, this study suggests that BNP levels may be regulated by additional mechanisms (other than just myocyte stretch). Furthermore, during trials off of ECLS, inotropic support, lactate levels and the AVDO2 increased in all patients (both those who successfully separated from ECLS and those who did not), suggesting that BNP levels may capture myocardial performance in a unique manner.

In a similar earlier study, Huang and colleagues studied fifteen pediatric patients requiring ECLS for cardiogenic shock(Huang et al. 2006). Eleven of the fifteen patients developed shock after cardiac surgery. These investigators did not find an association between BNP levels during the course of ECLS and survival after ECLS. However, they did find that BNP levels on the first and fourth day following separation from ECLS were significantly higher in nonsurvivors than survivors(Huang et al. 2006).

#### **5.3 Long-term outcomes**

Koch and colleagues measured BNP levels in 130 children and adolescents (mean age of 16.1 years) with a history of surgically repaired tetralogy of Fallot, at a mean time of 13±6.5 years after repair. They also performed exercise testing and echocardiograms. BNP levels were increased above normal gender and age specific values in 60% of the patients, but were less than 200 pg/ml in all patients(Koch et al. 2010). BNP levels were higher in patients awaiting pulmonary valve replacement, and in those in NYHA class II compared to class I. Furthermore, BNP levels correlated with right ventricular dilatation and the severity of tricuspid and pulmonary valve regurgitation, and were inversely correlated with exercise time. In addition, BNP levels increased over time in patients awaiting pulmonary valve replacement and decreased after surgery. The authors suggested that BNP levels might aid in the long-term management of these patients, particularly in the timing of pulmonary valve replacement.

Pietrzak and Werner conducted a similar study, in which they measured NT-proBNP levels in 20 adolescents (10 to 17 years of age) during a follow-up period of 7 to 16 years after repair of tetralogy of Fallot(Pietrzak and Werner 2009). They found that NT-proBNP levels were higher in those patients than in age matched healthy controls. NT-proBNP levels were higher in patients who had undergone repair with a transannular patch compared to those who underwent repair without a transannular patch. Furthermore, NT-proBNP levels were increased in patients with: QRS prolongation during exercise testing, severe pulmonary regurgitation, and severe triscuspid regurgitation. Likewise, Dodge-Khatami and colleagues measured plasma NT-proBNP levels and obtained cardiac magnetic resonance imaging in

extracorporeal life support (ECLS) after cardiac surgery(Chikovani et al. 2007). In particular, alterations in BNP during weaning trials off of ECLS were determined and compared to other biochemical markers, including lactate and the AVDO2.This study did not find associations between long-term outcome and alterations in lactate and the AVDO2 during trials off ECLS. However, an increase in BNP during the final trial off ECLS had a sensitivity of 80% and a specificity of 100% for predicting the need for an unplanned operation or death within 3 months. A notable finding of this study was that BNP levels decreased during trials off of ECLS support (which were accomplished through the use of a bridge placed in the ECLS circuit, allowing mechanical support to be diverted away from the patient before the ECLS cannulae were removed) in patients who were successfully separated from ECLS after a trial. Since trials off ECLS were associated with increased cardiac filling (increased central venous pressures) in all patients, this study suggests that BNP levels may be regulated by additional mechanisms (other than just myocyte stretch). Furthermore, during trials off of ECLS, inotropic support, lactate levels and the AVDO2 increased in all patients (both those who successfully separated from ECLS and those who did not), suggesting that

In a similar earlier study, Huang and colleagues studied fifteen pediatric patients requiring ECLS for cardiogenic shock(Huang et al. 2006). Eleven of the fifteen patients developed shock after cardiac surgery. These investigators did not find an association between BNP levels during the course of ECLS and survival after ECLS. However, they did find that BNP levels on the first and fourth day following separation from ECLS were significantly higher

Koch and colleagues measured BNP levels in 130 children and adolescents (mean age of 16.1 years) with a history of surgically repaired tetralogy of Fallot, at a mean time of 13±6.5 years after repair. They also performed exercise testing and echocardiograms. BNP levels were increased above normal gender and age specific values in 60% of the patients, but were less than 200 pg/ml in all patients(Koch et al. 2010). BNP levels were higher in patients awaiting pulmonary valve replacement, and in those in NYHA class II compared to class I. Furthermore, BNP levels correlated with right ventricular dilatation and the severity of tricuspid and pulmonary valve regurgitation, and were inversely correlated with exercise time. In addition, BNP levels increased over time in patients awaiting pulmonary valve replacement and decreased after surgery. The authors suggested that BNP levels might aid in the long-term management of these patients, particularly in the timing of pulmonary

Pietrzak and Werner conducted a similar study, in which they measured NT-proBNP levels in 20 adolescents (10 to 17 years of age) during a follow-up period of 7 to 16 years after repair of tetralogy of Fallot(Pietrzak and Werner 2009). They found that NT-proBNP levels were higher in those patients than in age matched healthy controls. NT-proBNP levels were higher in patients who had undergone repair with a transannular patch compared to those who underwent repair without a transannular patch. Furthermore, NT-proBNP levels were increased in patients with: QRS prolongation during exercise testing, severe pulmonary regurgitation, and severe triscuspid regurgitation. Likewise, Dodge-Khatami and colleagues measured plasma NT-proBNP levels and obtained cardiac magnetic resonance imaging in

BNP levels may capture myocardial performance in a unique manner.

in nonsurvivors than survivors(Huang et al. 2006).

**5.3 Long-term outcomes** 

valve replacement.

23 patients with repaired tetralogy of Fallot, severe pulmonary insufficiency, and increased right ventricular end-diastolic volume that were undergoing pulmonary valve replacement(Dodge-Khatami et al. 2006). Log-NT-proBNP levels were inversely correlated with right ventricular ejection fraction before and 6 months after surgery. NT-proBNP levels, right ventricular end-diastolic volume, and pulmonary insufficiency all decreased by 6 months after surgery.

These three studies differed from a study by Apitz and colleagues. These investigators measured BNP levels and recorded pressure-volume loops using conductance catheters in 16 adolescents (median age of 14.2 years) with a known history of right ventricular dilation (NYHA class I, and Ross class 0) secondary to pulmonary regurgitation after repair of tetralogy of Fallot(Apitz et al. 2009). Latent right ventricular dysfunction was defined as impaired contractility (calculated by the slope of the end-systolic pressure-volume relation) in response to a dobutamine infusion. Latent right ventricular dysfunction was identified in 5 patients, but no clear relationship with BNP levels could be observed. The difference between this study and those of Koch, Pietrzak, and Dodge-Khatami may relate to the severity of disease, suggesting that BNP may not be useful in detecting subclinical deterioration in this patient population.

In a small pilot study, Paul and colleagues measured BNP levels before and after surgical repair of ventricular septal defects in 14 patients who were less than 2 years of age(Paul et al. 2009). Mean BNP levels decreased by 94 pg/ml after repair. Longitudinal analysis found that there was a weak inverse correlation between the postoperative change in BNP and postoperative weight gain (weight z-score change per month).

Recently, Atz and colleagues described their findings in a study of 510 children (6-18 years of age), who were enrolled in the Pediatric Heart Network Fontan cross-sectional study(Atz et al. 2011). The patients had all undergone 3rd stage palliation of single ventricle cardiac defects with a Fontan procedure (median time from Fontan of 8.2 years). The distribution of BNP levels in these patients were highly skewed, but were generally within the normal range (median 13 pg/ml). However, logBNP levels were independently associated with a history of pre-Fontan systolic dysfunction, and post-Fontan complications, including thrombosis. LogBNP levels were higher in patients with atrial-to-pulmonary connections compared to extracardiac conduits. Furthermore, increased logBNP levels were associated with a lower level of physical functioning, chronotropic index during exercise, diastolic dysfunction, and greater ventricular mass measured by cardiac magnetic resonance imaging.

In a similar study, Koch and colleagues measured plasma BNP levels in 67 patients after a modified Fontan procedure(Koch et al. 2008). Although there was a wide range, BNP levels were normal in 81% of the patients, with a median value of 13 pg/ml. Levels were not different between patients with right or left ventricular morphology. BNP levels were higher in patients in NYHA class II compared to those in class I, and were positively correlated with the severity of AV valve regurgitation. Likewise, Man and colleagues measured plasma BNP levels and assessed ventricular function (by tissue Doppler assessments, acoustic quantification, and myocardial performance index) in 35 asymptomatic patients who had previously undergone a Fontan procedure(Man and Cheung 2007). Comparisons were made to 34 healthy controls. Although BNP levels were low in the Fontan group (median 21 pg/ml), they were higher than the control group. Moreover, BNP levels were inversely correlated with ventricular function, particularly diastolic function.

B-Type Natriuretic Peptide (BNP) in Neonates,

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bedside assay for plasma B-type natriuretic peptide as a biomarker in the management of patent ductus arteriosus in premature neonates." *J Pediatr* no. 147

## **6. Conclusion**

The essential relationship between BNP production by the cardiac ventricle and increased myocyte stretch is the foundation for the potential use of BNP as a biomarker in any condition in which abnormal ventricular loading conditions are primarily involved in the pathophysiology. To date, plasma BNP determinations have not attained the same clinical prominence in pediatric patients as in adults. The growing utilization of BNP determinations in the care of adult patients likely stems from the ability to make clinical decisions, indeed to titrate therapy, in response to BNP levels(Troughton et al. 2000). Thus, a widespread use of BNP in pediatric patients is restrained by the scarcity of data that supports BNP guided therapies. It is likely that this discrepancy between the adult and pediatric experience relates, in part, to the number of investigations. However, compared to adult CHF, pediatric cardiac diseases resulting in ventricular dysfunction and CHF are far more heterogeneous. In fact, coronary artery disease is the leading cause of CHF in adults, whereas pediatric CHF may result from a wide spectrum of congenital cardiac defects and various cardiomyopathies. Moreover, clinically relevant cutoff values for plasma BNP levels within these various disease processes are not well established or are completely unknown. Nonetheless, the ability to readily quantify plasma BNP levels is attractive as few markers are so directly related to the pathobiology of the cardiac ventricle. This is particularly true in the management of critically ill pediatric patients, where we often employ surrogate markers of disease severity, such as serum lactate levels, that reflect global processes as opposed to organ specific functioning.

Based on the studies outlined above, it is clear that BNP determinations can offer valuable clinical information to aid in the management of neonates, infants, and children undergoing surgical repair of cardiac defects. It is also clear, however, that the information is unlikely to come from single cut-off values that can be generalized across populations. Rather, a clinical utility for BNP determinations will likely come from an advanced understanding of expected perioperative patterns of change in BNP levels – patterns that will differ between age groups and specific cardiac defects. Furthermore, future studies must begin to evaluate the utility of guiding therapy in response to plasma BNP values. Fortunately, the ease of measuring BNP levels should facilitate these studies. For now the available data demonstrate that BNP has emerged as a novel biomarker with great potential.

#### **7. References**


The essential relationship between BNP production by the cardiac ventricle and increased myocyte stretch is the foundation for the potential use of BNP as a biomarker in any condition in which abnormal ventricular loading conditions are primarily involved in the pathophysiology. To date, plasma BNP determinations have not attained the same clinical prominence in pediatric patients as in adults. The growing utilization of BNP determinations in the care of adult patients likely stems from the ability to make clinical decisions, indeed to titrate therapy, in response to BNP levels(Troughton et al. 2000). Thus, a widespread use of BNP in pediatric patients is restrained by the scarcity of data that supports BNP guided therapies. It is likely that this discrepancy between the adult and pediatric experience relates, in part, to the number of investigations. However, compared to adult CHF, pediatric cardiac diseases resulting in ventricular dysfunction and CHF are far more heterogeneous. In fact, coronary artery disease is the leading cause of CHF in adults, whereas pediatric CHF may result from a wide spectrum of congenital cardiac defects and various cardiomyopathies. Moreover, clinically relevant cutoff values for plasma BNP levels within these various disease processes are not well established or are completely unknown. Nonetheless, the ability to readily quantify plasma BNP levels is attractive as few markers are so directly related to the pathobiology of the cardiac ventricle. This is particularly true in the management of critically ill pediatric patients, where we often employ surrogate markers of disease severity, such as serum lactate levels, that reflect global processes as

Based on the studies outlined above, it is clear that BNP determinations can offer valuable clinical information to aid in the management of neonates, infants, and children undergoing surgical repair of cardiac defects. It is also clear, however, that the information is unlikely to come from single cut-off values that can be generalized across populations. Rather, a clinical utility for BNP determinations will likely come from an advanced understanding of expected perioperative patterns of change in BNP levels – patterns that will differ between age groups and specific cardiac defects. Furthermore, future studies must begin to evaluate the utility of guiding therapy in response to plasma BNP values. Fortunately, the ease of measuring BNP levels should facilitate these studies. For now the available data

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**6. Conclusion** 

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**Part 3** 

**Aortic Surgery** 

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**12** 

*USA* 

**Cerbral Protection Strategies for** 

Surgical therapy for aortic arch disease involves partial or complete replacement of the aortic arch with reimplantation of the great vessels while the cerebral blood flow is temporarily altered. Patients undergoing this mandatory period of circulatory arrest during arch replacement are at an increased risk for adverse neurologic outcomes, and strategies for cerebral protection must be implemented to achieve successful results. The optimal strategy for management of the circulation during aortic arch surgery remains controversial. Arch reconstruction has historically been associated with significant morbidity and mortality due to global ischemic end-organ damage occurring during the circulatory arrest period. As surgical techniques have evolved, survival has improved; however, neurologic dysfunction

Profound hypothermia was the initial method of cerebral protection utilized during the period of circulatory arrest. The first successful series of arch reconstructions using deep hypothermic circulatory arrest (DHCA) with body temperatures of 18°C was reported in 1975 (1). Further efforts to improve cerebral protection during arch reconstruction have led to the development of antegrade cerebral perfusion (ACP) and retrograde cerebral perfusion (RCP). Both techniques provide continuous blood flow to the brain and are used in conjunction with hypothermic circulatory arrest (HCA). The optimal method of cerebral perfusion (antegrade vs. retrograde) is a controversial topic and has yet to be determined. In the this chapter, the indications for aortic arch surgery will be delineated, and the various

The most common indication for arch replacement is the presence of aneurysmal disease. The most common type of arch aneurysm is a degenerative aneurysm. The media of the aortic wall in degenerative aneurysms develops cellular necrosis which results in a loss of smooth muscle cells that are replaced by cystic spaces filled with mucoid material. Dr. Cooley coined the phrase cystic medial necrosis to describe this characteristic histologic pattern found in degenerative aneurysms (2). These aneurysms also have a significant reduction in elastin content due to a poorly understood increase in elastin fragmentation. The second most common cause of arch aneurysms is atherosclerosis. The development of invasive atheromas is thought to destroy the elastin fibers and smooth muscle cells of the

methods of cerebral protection strategies and their results will be reviewed.

due to cerebral ischemia remains a significant concern.

**2. Pathology/indications for aortic arch surgery** 

**1. Introduction** 

Bradley G. Leshnower and Edward P. Chen

**Aortic Arch Surgery** 

*Division of Cardiothoracic Surgery, Emory University School of Medicine,* 
