Statewide Registry Needs Data to Succeed in Preventing Congenital Heart Defects

Andrew Pelech, MD, chairman, Wisconsin Pediatric Cardiac Registry; medical director, Catheterization Laboratory, Children's Hospital of Wisconsin; associate professor, Pediatrics, Medical College of Wisconsin.
Kathleen Hanson-Morris, RN, BSN, coordinator, Wisconsin Pediatric Cardiac Registry

As the most common birth defect in Wisconsin, congenital heart defects constitute a significant public health concern. In developed societies, congenital heart defects rank first among the causes of infant mortality and are major contributors to childhood mortality. This risk continues into adult life.

Estimated costs during the first year of a child's life often exceed $40,000 due to the frequent need for expensive diagnostic evaluation and therapeutic or palliative medical and surgical intervention.

Over the last 40 years, pediatric cardiology and cardiovascular surgery has focused on correcting structural cardiac abnormalities and relieving cardiac symptoms, but it is clear that this is a costly, palliative approach. The future of pediatric cardiology lies in identifying causal factors and preventing cardiovascular anomalies. It was with this in mind, the Wisconsin Pediatric Cardiac Registry (WPCR) was developed.

The purpose of the WPCR is to determine if there are common factors that contribute to the development of congenital heart disease. Our goals are to register all babies born in the state of Wisconsin with a confirmed congenital heart defect. The registry also hopes to cooperate with other similar registries within the country to identify causal factors of congenital and acquired pediatric heart disease.

A statewide registry requires an unprecedented level of cooperation from many institutions and offers excellent opportunities for collaborative research in the name of Wisconsin's children. While the registry is headquartered at the Medical College of Wisconsin and Children's Hospital of Wisconsin in Milwaukee, it is a statewide multi-institutional endeavor requiring the cooperation of all practitioners, hospitals and clinics caring for children with congenital heart disease.

Other regional congenital heart disease registries, such as the Baltimore-Washington Infant Study, have been extremely useful for defining epidemiological characteristics and trends, population differences, regional variations in incidence, patterns of specific disease, etiologic information, and data on the utilization of medical resources.

The concept for the WPCR was born in 1997. In May of that year an inaugural meeting was held in conjunction with the William J. Gallen Lectureship at Children's Hospital of Wisconsin. Dr. Chris Lofredo, from the Baltimore-Washington Study, spoke on the status of their study. The questionnaire was developed and a database of all cardiology patients seen at Children's Hospital was set up.

In 1998, the questionnaire was piloted on 100 families and DNA extraction and storage methods were developed. In fall of 1998 the Informatics Research Center (IFRC) at the Medical College began working on an Internet questionnaire and database for compiling information generated from families. In August 1999 a registry coordinator was hired.

Pediatric cardiologists within the state are asked to identify patients presenting for cardiac evaluation with structural congenital heart disease confirmed by echocardiogram, cardiac catheterization, surgical inspection or autopsy. These patients and families will be contacted by the registry coordinator and asked to participate in the study at one of three levels of participation: 1) registration only, 2) registration and questionnaire, 3) registration, questionnaire and DNA blood sampling.

If the family agrees to participate, they can complete the questionnaire either on-line or in print form. Registration includes inputting into the registry database infant and parents' names, address, infant's diagnosis and pediatric cardiologist.

The questionnaire is comprehensive and inquires about family history of congenital and acquired heart disease and other defects, as well as environmental exposures prior to and during pregnancy. Data from the questionnaire is then input into the database. All information provided by families is confidential.

Another dividend of the registry is to obtain, store and catalogue DNA samples from a subset of patients, their siblings and their parents for lymphocyte culture and DNA sample banking. This will allow state-of-the-art restriction endonuclease gene mapping and help to elucidate the genetic markers or patterns associated with various defects. At the present time, DNA testing is done for conotruncal abnormalities, Ebstein's anomaly and hypoplastic left heart disease.

The WPCR officially began registering patients on Jan. 1, 2000. To date, more than 150 families have completed the questionnaire, or are in the participation process.

Although the primary goal of this prospective study is to determine etiologic factors which may contribute to congenital heart defects, the results will not be available for several years. Data from the registry, without infant or parents' names, may be provided at the discretion of registry personnel to professionals researching the causes of congenital heart defects. This is done only with institutional review board (IRB) approval. Data analysis on the information provided by families will be performed at least annually.

For additional information about the registry, contact Kathy Hanson-Morris, RN, BSN, at 1-877-809-WPCR (9727), e-mail at wpcr@mcw.edu or log on to the WPCR web site at www.pedcar.mcw.edu

Opioid Tolerance, Physical Dependency and Withdrawal after Prolonged Analgesic Exposure

Michael T. Meyer, MD, pediatric critical care fellow, Children's Hospital of Wisconsin; instructor, Pediatrics (Critical Care) Medical College of Wisconsin.
Richard J. Berens, MD, pediatric critical care specialist and chief of staff, Children's Hospital of Wisconsin; associate professor, Anesthesiology, Medical College of Wisconsin.

Final in 3-part series

Critically ill children receive opiates and anxiolytics for comfort and to reduce morbidity and mortality. With prolonged use of analgesics and sedatives patients develop tolerance and physical dependency. Once tolerance develops, abrupt cessation of these medications can lead to a withdrawal syndrome. Effective strategies are needed to identify, treat and prevent these problems. Following are the current strategies used in the Pediatric Intensive Care Unit (PICU) at Children's Hospital of Wisconsin for the management of opioid tolerance and withdrawal.

Definitions
Tolerance: A decrease in a drug's effect over time or the need to increase the dose to achieve the same effect. This occurs at the cellular level and is not related to altered metabolism or clearance of the drug.

Physical dependency: The requirement for continued administration of a drug in order to prevent signs of withdrawal.

Withdrawal: The physical signs and symptoms after abrupt discontinuation of a drug in a physically tolerant patient.

Psychological dependency: Compulsive desire for drug administration to produce euphoria or other psychedelic effects.*

Addiction: Complex behavioral patterns characterized by the repetitive, compulsive use of a substance, antisocial or criminal behavior to obtain the drug, and a high incidence of relapse after treatment.*

*Psychological dependency and addiction rarely are seen in PICU patients after appropriate use of analgesics and sedatives. The rare occurrence and concerns regarding the development of withdrawal, tolerance, and physical dependency should not limit the use of analgesics and sedatives in the PICU.

Historically, data on withdrawal syndromes has been found either in adult literature regarding opioid-addicted patients or in neonatal literature related to infants born to drug-addicted mothers. Just recently, literature has represented reports from the PICU where problems are seen in older children after prolonged infusions of fentanyl (a synthetic opioid). These studies show that tolerance, physical dependency and withdrawal occur after prolonged exposure to opioids. In fact, tolerance may develop in animal models only hours after continuous infusions.

Fentanyl has emerged as the preferred opioid in the PICU since it has minimal hemodynamic effects, rapid onset of action and a brief duration of action. It usually is administered as a continuous infusion to provide sedation and analgesia. The cumulative dose and duration of fentanyl exposure significantly correlates to the development of opioid withdrawal. A total fentanyl dose of 1.5 mg/kg, or a five-day duration, is associated with a 50 percent risk of developing withdrawal. A total fentanyl dose of 2.5 mg/kg, or a 10-day duration, is associated with a 100 percent risk of narcotic withdrawal.

Standardized scoring systems are used to identify and grade the severity of opioid withdrawal. They also are used to assess the response to therapy. In the PICU at Children's Hospital, the Neonatal Abstinence Score (NAS) is utilized. Initially developed in 1975 to assess opioid withdrawal in neonates born to opioid-addicted mothers, it now also is used in the PICU. The NAS is a weighted scoring system of the signs and symptoms of withdrawal. A persistent score of eight or greater is indicative of withdrawal.

Once tolerance has developed, we believe that withdrawal symptoms will arise with abrupt cessation of these medications. These symptoms can be treated with one of two strategies. First, gradual tapering of the medications has been shown to minimize the withdrawal symptoms. Weaning durations of this therapy vary. Recommendations range from 10 days to six weeks.

Secondly, the rescue course of therapy differs from the above by allowing the patient to develop a withdrawal syndrome, rescue the patient from those symptoms by reinstitution of opioid therapy, and then following a weaning protocol. Various medications have been used to treat opioid withdrawal; including morphine, methadone, clonidine, and phenobarbital. However, we believe the best option to treat opioid withdrawal is to reinitiate opioid therapy.

In the PICU, consulting the Pain Service can help wean fentanyl infusions once tolerance has occurred. Patients are evaluated using both a NAS and sedation score in order to quiesce withdrawal symptoms without causing oversedation. If withdrawal symptoms already have begun, morphine rescue therapy is initiated to treat the symptoms. Once the NAS is consistently less than eight and the child is not overly sedated, the morphine is converted to methadone and then weaned over 10 days. Occasionally, clonidine is added for children with continued sleep disturbance or agitation despite adequate narcotic therapy. If their underlying condition allows, the patient may be discharged home to complete the methadone weaning process. They continue to be followed as an outpatient by phone consultations.

Prolonged exposure to opioids may lead to tolerance and the onset of tolerance places the child at high risk for the development of withdrawal symptoms if the opioids are abruptly discontinued. However, we believe the above strategy is effective in recognizing tolerance, physical dependency and withdrawal and in guiding therapy to help treat these conditions.

Children's Transport Well Equipped to Care for Cardiac Patients

Judi Stoegbauer, RN, transport nurse clinician, Children's Hospital of Wisconsin

A Children's Transport Team has been available 24 hours a day, seven days a week since February 1988, transporting more than 8,000 patients to Children's Hospital. This includes an average of 85 infants/children per year with cardiac-related diagnoses. To help us care for these patients, our specialized equipment includes a zoll defibrillator, which also enables us to provide pacing capabilities, umbilical and CVL catheters, heated humidification system for intubated patients and blended gases for transport. Drugs used include prostaglandins, dopamine, dobutamine, epinephrine, adenosine and digoxin. We also have the ability to monitor two invasive pressure lines in addition to monitoring non-invasive blood pressure. Each nurse has extensive critical care training and is PALS/NRP certified.

Due to an increased demand for our service, we now have two teams available 24 hours a day. As always, we provide emergency pediatric and neonatal transport service for patients from throughout Wisconsin, northern Illinois and Michigan's Upper Peninsula.

In addition to a second team, Children's Transport recently has filmed a transport of a neonate available on video for referring hospitals to show new parents whose infant needs to be transported to Children's Hospital. The 8-minute video introduces transport team members, shows parents how their infant will be cared for in transit, and introduces them to our Neonatal Intensive Care Unit.

By calling our transport hotline (800-266-0366 or 414-266-2460) you will be connected to a transport nurse clinician. The nurse will gather information, notify team members and within 20 minutes the team is mobilized. A referring hospital or clinic can be in constant contact with a nurse clinician until the team arrives, if needed.

Children are admitted directly to the Pediatric Intensive Unit, Neonatal Intensive Care Unit or to a general care unit at Children's Hospital.

If you would like more information about Children's Transport, call Leslie Talbert, transport manager, at 414-266-2471.

Myocarditis

Alexis Sullivan, RN, Pediatric Intensive Care Unit, Children's Hospital of Wisconsin

According to Jeffrey Towbin, MD, professor of Cardiology and Molecular Genetics at Baylor University, Texas, the cause of myocarditis usually is an enteroviral infection (coxsackie or adenorvirus). He said, of the patients who present with acute myocarditis one-third will die, one-third develop chronic myocarditis and one-third will recover.

Towbin was the guest speaker at the fourth annual William Gallen lecture series held at Children's Hospital in June. He specializes in cardiomyopathy and the treatment of heart transplant patients, and is investigating the causes of muscle inflammation at the cellular level. He believes that there are similarities between rejection in transplant patients and the inflammation in myocarditis.

Diagnostic tests
Endomyocardial biopsy can be dangerous to perform in young patients with myocarditis because they have thin, dilated hearts. Histological findings can vary depending on the stage of disease making them difficult to interpret. Also, myocardial involvement may be focal so it can be missed with biopsy. Towbin cited a study on right ventricular endomyocardial biopsy that reported a 50/50 chance of diagnosing myocarditis by this method. In patients that are too unstable to undergo biopsy, diagnosing by pleural effusion fluid if present or endotracheal aspirate enabled identification of viruses. Other diagnostic methods, such as stool sampling and serum cultures do not correlate well, while throat washings or pericardial fluid are only marginally better. Recent diagnostic advances look at viral DNA and RNA with polymerized chain reaction (PCR) testing. Extra tissue is taken at the time of biopsy to look at DNA and RNA Templates and nucleotides. DNA and RNA is extracted from the tissue and placed in a test tube with PCR multiplication primers. Then the it is run out on a gel and compared to controls to see if bands formed are consistant with a specific virus, for example enterovirus. Every virus has a unique series of base pairs of adenine, thymine, cytosine, and guanine, that identify it. Looking at dilated forms of cardiomyopathy, 20 to 40 percent of these patients have an identifiable virus by PCR techniques.

Etiology
Adenovirus type 2 may be a more common cause of myocarditis than the enteroviruses (coxsackie types A and B, echovirus, poliovirus). Cytomegalo virus usually is not the source in younger patients, but may be seen more in adolescents and adults. Other viral causes include herpes, influenza, Ebstein-Barr virus, varicella, hepatites, mumps and rubella.

Therapy
Standard therapy for acute myocarditis has included the use of steroids. This is controversial as it can suppress symptoms while masking the underlying cause and can allow viral replication. IVIG has been shown to be effective, but limited supplies may restrict its use. Antiviral therapies include gancyclovir and acyclovir. Drug therapy advances cite protease inhibitors as potential therapeutic agents and new anti-enteroviral drugs now are coming on the market. The U.S. military currently has a vaccine for the adenovirus type 7. Towbin said the hope is to develop vaccines for coxsackie type B and adenovirus type C. Immunosupressants and interferon also may play therapeutic roles in the treatment of myocarditis. Gene therapy has gained a lot of attention recently, but Towbin cautioned the potential problem of a hyperinflammatory response to the viral vectors used to do gene therapy has to date limited utility (for example, a common vector used is adenovirus because it gets into cells easily).

Transplant patients
In both heart and lung transplant patients, there is a fine line between rejection and infection. These patients are followed with serial biopsies and rejection can appear very similar to myocarditis on biopsy. Towbin noted a strong correlation between PCR+ and PCR- patients for adenovirus in late rejection with PCR- patients having a much better outcome in both heart and lung transplant patients.

Single Ventricle: The Heterotaxy Variants

Eliot May, PA, Cardiovascular Surgery, Children's Hospital of Wisconsin

One of the most captivating aspects of studying congenital heart disease is the tremendous variety of defects. Consider the diagnosis of single ventricle. We all have a mental picture of this heart defect. One main ventricle, which will be assigned the task of systemic pump, and a bidirectional Glenn shunt and Fontan completion to provide pulmonary blood flow. Single ventricle, however, is a diagnosis that encompasses numerous subtypes. Hypoplastic left heart syndrome, unbalanced atrioventricular canal, double inlet single left ventricle, and tricuspid atresia are just some of the varieties we see. Heterotaxy variants of single ventricle are addressed below.

The term heterotaxia or heterotaxy refers to a complex syndrome of congenital defects affecting the organs of the abdomen and chest. Other names used to describe this spectrum of disorders are cardiosplenic syndrome and Ivemark's syndrome. Two main types exist - asplenia and polysplenia syndromes. While there is significant variability in the expression of these syndromes, common themes appear in each.

Asplenia syndrome
The term asplenia refers to the congenital absence of the spleen. Asplenia occurs in about one percent of congenital cardiovascular malformations. Abdominal organs usually are abnormally oriented. Cardiovascular manifestations are fairly characteristic. Dextrocardia is present in more than one-third of cases. Bilateral superior vena cavae, rather than a single right superior vena cava, occurs in nearly half of these patients. Anatomically, these patients exhibit bilateral right-sidedness, where the morphology of the chest structures like the atria, pulmonary arteries and bronchi is right sided. This means the patient has two right atria, two right lungs, and two superior vena cavae. Total anomalous pulmonary venous connection occurs in three-quarters of cases. Malposition of the great vessels, such as transposition, occurs in most cases. Severe pulmonary stenosis or atresia also is very common. A large atrial septal defect, or common atrium is usual, and endocardial cushion defects with a common atrioventricular valve is nearly universal. The ventricular septum usually is poorly formed, and various types of single ventricle anatomy are common. Laboratory findings are consistent with an absent spleen, including increased number of nucleated red blood cells, target cells, and Howell-Jolly and Heinz bodies on the peripheral smear.

The spleen is an important organ filtering out old cells and bacteria, particularly encapsulated organisms like streptococci and hemophilus. Absence of the spleen results in an increased risk of overwhelming infection. Prophylactic antibiotics are used to decrease this incidence.

Polysplenia
Polysplenia is characterized by the presence of multiple spleens. Abnormalities of abdominal orientation occur frequently. Cardiovascular manifestations typical of patients with polysplenia are similar to those described for asplenia with a few notable exceptions. Congenital polysplenia usually is associated with azygous continuation of the inferior vena cava. Here, the inferior vena cava enters the azygous venous system and eventually enters the superior vena cava, rather than entering the right atrium directly. With normal anatomy, the azygous system only drains venous blood from the chest wall, thus, azygous continuation of the IVC results in the majority of the systemic venous return entering the heart via the SVC. Bilateral Glenn shunting in this setting results in a near-completion Fontan.

As asplenic patients have characteristics of bilateral right-sidedness, the polysplenic patient has characteristics of bilateral left-sidedness. They have two left atria and two left lungs. Pulmonary venous return often is anomalous with right-sided pulmonary venous drainage entering the right-sided atrium and left-sided pulmonary venous drainage entering the left-sided atrium. Great arterial anomalies are much less common. Presence of intracardiac defects is similar to the asplenic patient, with atrioventricular canal occurring frequently. Lab findings show little or no abnormality of the peripheral smear. Susceptibility to infection is not increased and prophylactic antibiotics are not needed routinely.

A case study
An interesting case in point is a patient who presented in the neonatal period with the following anatomic features: abnormal abdominal situs, with a midline liver, rightward stomach bubble and asplenia. Cardiac features include abnormal systemic venous return with bilateral superior vena cavae, moderate-sized innominate vein with the left-sided superior vena cava entering the left atrium. This left superior vena cava enters the left-sided atrium the way a right SVC would enter the right atrium, rather than taking the usual course of an LSVC by draining into the coronary sinus. The pulmonary venous return is anomalous with a posterior pulmonary venous confluence draining into a vertical vein that connects to the left superior vena cava and drains into the left atrium. The pulmonary venous connection is obstructed at the level of its insertion into the left superior vena cava. The intracardiac defects include: unbalanced atrioventricular canal with hypoplasia of the right ventricle, and double outlet right ventricle with side-by-side great vessels arising from the anterior aspect of the heart. The aortic arch is right-sided (fig. 1).

Surgical approach to the treatment of all single ventricle patients is the same conceptually. The first stage requires that the patient have the correct amount of pulmonary blood flow, without dependence on a patent ductus arteriosus. Many subtypes require the placement of a systemic-to-pulmonary artery shunt (if there is pulmonary valve atresia or stenosis), or pulmonary artery banding (if there is non-restrictive pulmonary blood flow). In this specific case, pulmonary artery banding was required (fig. 2).

Second stage surgery was performed later in the first year of life and included removal of the pulmonary artery band with over sewing of the pulmonary valve, ligation of the LSVC and creation of a right bidirectional Glenn shunt (fig. 3). In this case, the patient has both bilateral vena cavae as well as a bridging vein (usually presence of a persistent LSVC is associated with absence of a bridging innominate vein). A single bidirectional Glenn shunt was sufficient, rather than bilateral bidirectional Glenn shunts.

Final stage surgery was Fontan completion, with an extracardiac conduit connecting the inferior vena cava to the pulmonary artery system. The conduit was fenestrated to the common atrium with a four-millimeter communication. The fenestration allows for a "pop-off" effect, thus decompressing the Fontan conduit at the expense of right-to-left shunting (fig. 4). Recovery from this final stage was uneventful.

Some experts would argue that obstructed pulmonary venous return in the presence of single ventricle heterotaxia would result in pulmonary vascular changes and limited success of the Fontan single ventricle repair. While it is true that even short periods of obstruction of pulmonary venous drainage can result in pulmonary vascular obstructive disease with increased pulmonary vascular resistance, rapid intervention and staged palliation can result in success, as was seen with this patient.

Heterotaxy variants of single ventricle present us with some of the most interesting challenges. Every case is different, and elucidating the specifics of the anatomy is important. Modern echocardiography has made this task more accurate and less invasive. Good results can be obtained with this group of patients, provided adherence to the concepts of single ventricle treatment is maintained.

Heart Center Welcomes New Cardiologist and Surgeon

Joseph Cava, MD, joins eight established pediatric cardiologists offering services to children throughout the region at The Heart Center at Children's Hospital of Wisconsin.

Cava also is an assistant professor, Pediatrics (Cardiology) at the Medical College of Wisconsin.

He received his medical degree from Loyola University and received his training in pediatric cardiology from Hope Children's Hospital Heart Institute for Children.

Robert Jacquiss, MD, has joined James Tweddell, MD, S. Bert Litwin, MD, and The Heart Center offering service to children with heart disease or congenital defects at Children's Hospital of Wisconsin.

In addition to his hospital appointment, Jacquiss is an assistant professor of Surgery (Cardiothoracic) at the Medical College of Wisconsin. He received his medical degree from Vanderbilt University and completed his pediatric cardiothoracic surgery training at St. Louis Children's Hospital and Washington University School of Medicine.