Fontan physiology and the natriuretic peptides

Joseph Cava, MD, PhD, pediatric cardiologist, Herma Heart Center, Children's Hospital of Wisconsin; assistant professor, Pediatrics (Cardiology), Medical College of Wisconsin.

The natriuretic peptides are a family of neurohormones that share a common 17 amino acid ring structure. The unique feature of these peptides is that they are produced and secreted by the heart in response to specific physiologic and hemodynamic stimuli. Two of these peptides have been studied extensively in adults and are an excellent indicator of cardiac failure such that treatment strategies can be altered based on levels that are detected. In addition, therapeutic intervention in adult patients with heart failure, using genetically engineered natriuretic peptides, have begun with encouraging early results.

Atrial natriuretic peptide (ANP) is a naturally occurring diuretic and vasodilator primarily secreted from the cardiac atria with the major stimulus being atrial stretch. Vasodilitation of both the systemic and pulmonary vascular beds have been shown to occur in response to ANP action. Brain natriuretic peptide (BNP) also has natriuretic and vasodilatory properties and is secreted from the atria with normal cardiac physiology but primarily from the left ventricle in the pathologic state of congestive heart failure. BNP has become a sensitive indicator of heart failure in adult studies. Indeed, elevated levels of BNP have been seen before significant clinical symptoms have developed. In addition to fluid regulation and vasodilitation, other clinically relevant actions of the natriuretic peptides include inhibition of the renin-angiotension and sympathoadrenal systems.

With the Fontan procedure (total cavopulmonary connection) there is high central venous pressure, which causes systemic venous congestion leading to fluid retention and subsequent pleural effusion, ascites and peripheral edema. Manipulation of the high pulmonary vascular resistance and maintaining sufficient urine output is important for hemodynamic stability following the Fontan operation. Fluid and vasoactive regulatory peptide hormones have the potential to influence the hemodynamic response to this altered physiologic state. A few studies have looked at ANP levels in patients undergoing the Fontan operation. In general there is a significant increase immediately following surgery and this level, although it drops briefly when immediate stores are released, remains high during the immediate postoperative period. This is thought to occur because of the significant atrial volume overload seen after right atrial to pulmonary artery anastomosis. Intermediate and long-term ANP levels following Fontan are not clear. Preliminary results suggested that ANP infusion following the Fontan operation had positive findings with decreases in pulmonary vascular resistance and central venous pressures. The relationship to prolonged pleural drainage still is unclear. Little is known about BNP and its correlation to post-Fontan hemodynamics, although preliminary studies have shown alterations in BNP levels. Despite changes, the extent, if any, to which BNP contributes to pathophysiologic perturbations in the Fontan circulation is not known. This especially is true in light of more recent surgical modifications in which the right atrium no longer is connected directly to the pulmonary arteries and instead, a lateral right atrial tunnel or extracardiac conduit now is employed. It is likely that changes in BNP levels may signal an adaptive response of the myocardium to the altered hemodynamics. Like is seen in heart failure, an initial adaptive response resulting in a hemodynamic defense response results in short-term improvement and survival. Unfortunately, over the long term maladaptive changes can occur that result in "remodeling" of the myocardium and eventually complete heart failure and death. 
BNP levels may serve as a sensitive indicator of the univentricular heart's health. Correlation to clinical outcomes such as early Fontan failure, prolonged chest tube drainage and congestive heart failure may enable us to predict those patients who are at increased early risk and in which more aggressive and appropriate medical therapy will need to be used. In this way, we can avoid putting many patients who otherwise would do well through a strict medical regimen but could not be previously identified. There is active research in identifying the causes of  the maladaptive remodeling response seen in biventricular adult heart failure. Strategies to limit or reverse this remodeling are currently being implemented in this population. Identification of similar mechanisms in the Fontan population could, in addition to identifying early risk, provide prognostic information for late outcome, thereby allowing earlier intervention and if needed timely evaluation for heart transplantation. Finally, knowing the specific changes that occur after the Fontan operation eventually may allow us to test recombinant analogs of the natriuretic peptides to improve cardiovascular function and hemodynamics with potential improvement in quality of life for those patients with single ventricular physiology.

New strategies of invasive and noninvasive monitoring

Nancy Ghanayem, MD, pediatric intensivist, Pediatric Intensive Care Unit, Children's Hospital of Wisconsin; assistant professor, Pediatrics (Critical Care), Medical College of Wisconsin.

The utility of continuous venous oximetry in postoperative care of complex congenital heart disease has underscored the limitations associated with conventional monitoring of oxygen delivery. Saturation of venous blood (SvO2) whether obtained from the superior vena cava or the pulmonary artery (true mixed venous saturation in structurally normal heart) more commonly is used in pediatric and cardiac intensive care units as another means to assess the adequacy of oxygen delivery. Interpretation of the Fick equation highlights the relationship of SvO2 to arterial saturation, oxygen consumption and oxygen delivery (SvO2 = SaO2-VO2/DO2) and suggests ways in which SvO2 may be increased. Experience with SvO2 in the postoperative care of hypoplastic left heart syndrome (HLHS) after stage one palliation has been the single most important factor that has contributed to survival now exceeding 95 percent. In adults, a SvO2 less than 50 percent is associated with anaerobic metabolism and ischemia, whereas in neonates with cyanotic and acyanotic heart disease, anaerobic metabolism occurs at an SvO2 nearing 30 percent. These data by Hoffman (George Hoffman, MD, medical director, Anesthesiology, Children's Hospital of Wisconsin; associate professor, Anesthesiology, Medical College of Wisconsin) and others accepted for publication in the Journal of Thoracic and Cardiovascular Surgery, suggest that monitoring and adjusting therapies for low SvO2 not only improves survival, but may improve neurodevelopmental outcomes. These preliminary data of 4-to-6-year-old children with HLHS supports that adverse neurodevelopmental outcomes occur at a SvO2 less than 50 percent. Hence, increased detection and treatment of brain hypoxia during high-risk periods may improve long-term outcomes. Invasive SvO2 monitoring is not without risk given the potential for thrombus formation and bleeding, as well as its limited ability to detect regional ischemia.

The limitations of SvO2 can be addressed with other technology, specifically near infrared spectroscopy (NIRS). NIRS technology detects oxyhemoglobin saturation and given that most blood is in capillaries and veins, it reflects venous-weighted hemoglobin saturation. NIRS technology has been used for regional monitoring of oxygen saturation in various organ beds and is used as an adjunct during shock resuscitation. Goal-directed therapy with NIRS has improved outcomes in adult patients. In both adults and children, a regional cerebral saturation (rScO2) less than 50 percent or fall from baseline of greater than 20 percent has correlated with hypoxic-ischemic injury. Our experience with NIRS technology is as a two-site detection device for assessment of global and regional ischemia. Specifically, the two probes of the NIRS device (INVOS, Somanetics) are placed on the forehead and back between T10-L2 for assessment of cerebral and somatic-renal saturations. The two-site monitoring clearly delineates the differences in tissue oxygenation between organ beds with a difference that is generally 15 to 20 percent; cerebral saturations greater than somatic saturations as expected given the high flow-low extraction at the kidney. Narrowing of this expected difference correlates with an increased risk anaerobic metabolism, similar to what has been observed with a SvO2 that approaches 30 percent. More recent data, which correlates somatic saturation and renal function as defined by a rise in creatinine, demonstrates the best predicter of renal dysfunction in postoperative stage one palliation patients is low somatic saturation. Despite the novelty of two-site NIRS technology, its use for routine monitoring of critically ill children rapidly is expanding as it is noninvasive and effective in monitoring global and regional perfusion abnormalities.

Second research study of prophylaxis against RSV in children with CHD

Raymond Fedderly, MD, pediatric cardiologist, Herma Heart Center, Children's Hospital of Wisconsin; associate professor, Pediatrics (Cardiology), Medical College of Wisconsin.

This fall, we are participating in our second study of prophylaxis against respiratory syncytial virus (RSV) called "A study to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of MEDI-524, a humanized-enhanced potency monoclonal antibody against respiratory syncytial virus, in children with hemodynamically significant congenital heart disease."

The initial study was done over several years in the process of approving the use of Synagis to help protect our patients from RSV bronchiolitis. Lower respiratory tract disease due to RSV accounts for more than 125,000 pediatric hospitalizations and approximately 6.3 deaths per 100,000 among children up to 4 years of age in the United States. Overall, the hospitalization rate due to RSV in infants younger than 1 year of age is approximately 2 percent. Premature infants, infants with BPD and infants with complicated congenital heart disease are admitted four to five times more frequently than non high-risk children and have increased morbidity and mortality.

The new drug, MEDI-524 (Numax), is an enhanced potency RSV-specific monoclonal antibody derived from Synagis. Numax differs by 13 amino acids from Synagis. Preclinical data from the cotton rat model of RSV infection demonstrate that Numax has 50 to 100 times the activity against RSV compared to palivizumab in the lower respiratory tract.  We hope to enroll four to six children younger than age 2 with hemodynamically significant heart disease beginning in November. Approximately 600 children will be enrolled world wide. The children will receive five shots monthly as they would with the standard protocol of Synagis. They will randomly be assigned to receive either Numax or Synagis.  An important point to remember about Synagis and Numax is that cardiac bypass effectively removes the drug from the body and the children should receive a "booster" shot post bypass but predischarge from cardiac surgical admissions that require cardiac bypass. Steven Zangwill, MD, pediatric cardiologist, Herma Heart Center, Children's Hospital of Wisconsin, and assistant professor, Pediatrics (Cardiology), Medical College of Wisconsin, and I will be the primary investigators with the help of Martha Fillinger, RN, pediatric nurse practitioner and research coordinator. If you have any questions about Synagis, Numax or this study please contact me at (414) 266-2380.

Cytokine/Corticosteroid study

Kathy Murkowski, RN, Pediatric Intensive Care Unit, Children's Hospital of Wisconsin.

As one of many varied research projects involving children undergoing cardiac surgery, Pediatric Intensive Care Unit Fellow Jake Kane, MD, is spearheading a study looking at cytokine production in 20 neonates undergoing cardiopulmonary bypass during surgery. Under the direction of the study's principal investigator, Nancy Ghanayem, MD, Kane is trying to assess whether high-dose corticosteroids administered to infants prior to cardiopulmonary bypass decrease inflammatory mediators better than low-dose corticosteroids.

Cardiopulmonary bypass-induced inflammation is considered a leading cause of death for neonates who undergo cardiac surgery. Corticosteroids administered prior to cardiopulmonary bypass attenuate the inflammatory process. The purpose of this double-blinded, randomized study is to determine whether 60 mg/kg (high dose) has a significantly different effect than 20 mg/kg (low dose) of methylprednisolone on serum concentrations of cytokine concentrations of IL-1, IL-6, TNF-alpha, and IL-10 during the first 24 hours postcardiopulmonary bypass. Besides the mentioned cytokine concentrations, cortisol levels and clinical data will be collected preop in the Neonatal Intensive Care Unit and postop in the Pediatric Intensive Care Unit at scheduled intervals. To date, 14 neonates have been enrolled in the study.

Robert (Jake) Jaquiss, MD, leaves Herma Heart Center

James Tweddell, MD, medical director, Cardiothoracic Surgery, Herma Heart Center, Children's Hospital of Wisconsin; professor, Surgery (Cardiothoracic), Medical College of Wisconsin.

It is with mixed emotions I announce the resignation of Robert ("Jake") Jaquiss, MD, pediatric cardiothoracic surgeon. As a friend, I am proud to say that Jake has been named chief of Cardiothoracic Surgery at Arkansas Children's Hospital in Little Rock. This appointment provides Jake with an enhanced career opportunity and well-deserved leadership role.

As a colleague, I regret his leaving, but am grateful for the skill and leadership he has provided our program and patients since he started here in 2000. Jake helped us maintain our status as one of the world leaders in correcting one of the most complex and serious congenital heart defects. He also was committed to research as well as resident and medical student education. 

Because of our national recognition and program growth, we had been actively recruiting for an additional pediatric cardiothoracic surgeon. With Jake's resignation, we have expanded that search to two new surgeons. We hope to have them both on board soon. We wish Jake all the best in his new role and thank him for his service to our patients.