Immunosuppressive Therapy After Heart Transplantation

Jane Zlotocha, RN, heart transplant coordinator

In order to be successful, pediatric heart transplants require a major commitment to long-term care by patients and their families. Avoiding serious complications and living a long life after transplant are dependent upon the ability of the patient and family to follow a complex medical regimen.

A critical part of postoperative management for these children is the delicate balance between preventing rejection and the serious consequences of immunosuppression. Inadequate immunosuppression can lead to graft rejection, while excessive immunosuppression can lead to infection or malignancy.

The family is responsible for administering the child's medications on time and detecting side effects early. The child also should participate in the medical regimen as much as possible. This gives the child, who was forced into a dependent role during much of the transplant process, a sense of independence and control. We find compliance increases when children are involved in their own care.

The child and family also need to be prepared for the unpleasant side effects of immunosuppressant medications, including those that cause body changes such as hirsutism and cushionoid appearance. These side effects often cause noncompliance in school-age and adolescent patients. It may help to have these patients meet other children who have had transplants and had to deal with these issues. A psychosocial professional also is a part of the Children's Hospital heart transplant team and is available to children, families and other team members to help with these issues.

Immunosuppressive drug therapy usually consists of a triple drug protocol. At Children's Hospital this usually includes cyclosporine, azathioprine and prednisone. New drugs - tacrolimus and mycophenolate mofetil - may be substituted for cyclosporine and azathioprine, respectively. Our goal always is to reduce the use of steroids over time.

Episodes of rejection are treated with higher dose steroids or OKT3. Agents also are used to prevent and treat cytomegalovirus (CMV). IV or oral gancyclovir may be prescribed for patients at high risk of CMV, such as seronegative recipients who receive an organ from a seropositive donor.

Corticosteroids - prednisone and methylpredniosone - have blood immunosuppressive activity. They stabilize macrophages and prevent them from perpetuating the chemical and cell-mediated immune response. Corticosteroids cause T-cell suppression and a decrease in B-cell response. Among the most common side effects are greatly increased susceptibility to infection, glucose intolerance, GI bleeding, slowed wound healing, hirsutism, cushionoid appearance, impaired growth, sun sensitivity, fluid retention, hypertension, cataracts, increased appetite, mood swings and sodium retention. IV solumedrol is started immediately after the operation with transition to prednisone, when tolerated.

Cyclosporine first was used for organ recipients in 1972, after it was discovered to have antifungal activity. Neoral, a new microenvulsion formulation of cyclosporine (CSA), is used for its improved bioavailability. Many factors can increase and decrease CSA absorption and certain medications can increase CSA serum levels.

Adverse effects of CSA include nephrotoxicity, hypertension, hepatotoxicity, neurologic effects, nausea, vomiting and hyperlipedemia. Although the effect of CSA on renal function appears to be directly related to CSA blood levels, the use of other nephrotoxic medications or pre-existing renal dysfunction may potentiate CSA nephrotoxic effects. BUN and creatinine levels, as well as trough monoclonal CSA levels, are followed regularly on post-transplant patients. Other side effects include hyperkalemia, gingival hyperplasia, fluid retention, hirsutism, tremors, mouth ulcers, nausea, joint pain, night sweats and susceptibility to infection. A continuous IV infusion of cyclosporine is maintained until oral medications are tolerated. Cyclosporine then is given orally two to three times a day to maintain serum levels of 200 to 300.

Azathropirine (imuran) has activity more specific for T lymphocytes than for B lymphocytes and has been shown to decrease the rate of synthesis of IgM and IgG antibodies. One of the most common adverse effects is bone marrow suppression. Azathioprine is given IV, then orally once daily.

Tacrolimus (FK506, Prograf) has actions similar to cyclosporine in that it binds to the petidyl-prolylcis-trans isomerase receptor and blocks secretion of IL-2 and other lymphokinesis. The immosuppressive properties are due to its inhibitory effects both on the production of various interleukins and on T-cell preparation. Adverse effects are similar to cyclosporine and include neurotoxicity, nephrotoxicity, diabetes and infection. However, tacrolimus does not seem to cause hirsutism or gingival hyperplasia, which makes it an especially desirable alternative to cyclosporine for adolescents.

Mycophenolate Mofetil (cellcept) is the newest immunosuppressant drug approved by the FDA for preventing acute graft rejection. It inhibits proliferative responses of T and B lymphocytes, suppresses the antibody formation of B lymphocytes and may inhibit migration of leukocytes into inflammatory sites involved in graft rejection. Principle adverse effects include increased risk of infection, leukopenia, abdominal cramping, diarrhea, nausea and vomiting. Cellcept may be used in place of imuran.

Muromonab CD3 (orthoclone OKT3) is the final therapeutic monoclonal antibody produced for suppressing T-cell mediated rejection. It commonly is used for the prevention or treatment of steroid-resistant acute allograft rejection. Patients are premedicated for flu-like symptoms such as fever, chills, headache, nausea, vomiting, diarrhea and myalgia before the first three IV doses. Less frequent side effects include pulmonary edema, hypotension and seizures. Higher incidences of infection and malignancy have been observed following OKT3 therapy. A 10- to 14-day course is the usual protocol.

In addition, transplant recipients take a variety of other medications. OTC drugs should be avoided when possible. The cardiac transplant team should be notified of any illness, to rule out a rejection episode and to make recommendations before any OTC meds are taken.

Proper administration of immunosuppressive therapy and prompt recognition of potentially dangerous side effects are essential for long-term survival of these patients. Research continues to try to identify more specific modes of immunosuppression with fewer side effects.

The Genetics of Congenital Heart Disease

Christine Sauer, genetics associate

No parent plans to have a child with a congenital defect. Unfortunately, about 3 percent of children - no matter the family, pregnancy, or history - are born with a congenital anomaly, and about 1 percent of live births are babies with a congenital heart defect.

It is not unusual for parents to go through a period of grief after receiving news of a congenital defect. They may have several questions including, "Why did this happen?" "Did I do something to cause this?" "Will it happen again?" "Do my other children need to worry about having a child with this condition?"

Heart defects, especially those that occur without other health problems, usually are not inherited in the typical ways, nor are they caused by environmental factors. Because of this, isolated heart defects are said to be a result of multifactorial causes. In other words, there is an abnormal interaction between the genetic code controlling heart development and the environment.

Aside from the isolated heart problem seen in DiGeorge syndrome, there is no single gene responsible for a specific heart defect. Many genes are thought to have a role in heart development, and there are several known genetic conditions that have a higher chance for developing heart abnormalities (see Table I). The heart defect in these conditions is only one feature of the condition and the chance that it will happen again in a future pregnancy is as high as 50 percent.

Using population studies, we can define recurrence risks for isolated heart defects. For example, these studies show about eight in 1,000 babies born have a congenital heart defect. Although not all children with heart defects are identified, these studies can be used as a baseline for counseling purposes.

The overall chance a couple will have another child with a congenital heart defect after one child is born with an isolated congenital heart defect is 2 to 4 percent. However, it is important to examine the specific pregnancy and history of the child, since certain exposures are known to cause congenital heart defects. These include alcohol, maternal diseases such as german measles, diabetes, lupus and phenylketonuria, and medications such as Dilantin, valproic acid, retinoic acid, lithium and thalidomide. A history of exposure to a teratogenic agent, for example, would affect the risk of bearing another child with a heart defect.

Recurrence risks also are different when the parents themselves are affected. In general, if one of the parents has a congenital heart defect, there is as high as a 10 percent chance that their child might be born with a heart defect. A fetal echocardiogram is recommended for families wanting more information about future pregnancies.

A fetal echocardiogram can accurately show fetal heart structures by 20 weeks gestation. Although some heart problems can be missed by this test, families usually are reassured that the fetus does not have a significant heart problem. If a serious defect is present, the family can make informed decisions about medical intervention.

Knowledge of the causes of heart defects is expanding constantly. The Human Genome Project, an international group of scientists working on mapping out every gene in the body, is expected to result in more information for families in the future.

Physical and Occupational Therapy in Post-surgical Patients

Chris Casey, occupational therapist;
Jackie Shay, physical therapist

Physical and occupational therapy services are important components in postsurgical heart patients.

Therapy decreases the effects of postsurgical immobilization, assists with patient positioning, promotes early mobility and developmental skills, facilitates infant state control and self regulation, empowers parents to interact and bond with their baby and performs developmental assessments.

Immobilization after surgery can cause pooling of pulmonary secretions and tissue fluids (especially on the dependent side), decreased circulation and edema, shallow breathing and poor ventilation, muscle weakness and overall discomfort. Muscle tissue and joint capsules can become contracted, and adhesions may develop between joint surfaces. Patients need early passive range of motion exercise, progressing to active assisted range of motion to decrease these effects. Edema massage helps mobilize tissue fluid into the circulatory system, and tactile stimulation of the skin surface stimulates the lymphatic system.

Positioning is based on postsurgical needs as well as the patient's developmental level. For example, it is normal for a newborn to be in a position of physiological flexion - the basis of stability for early movement skills. In this position babies are able to utilize their self-regulatory skills. However, a postoperative baby usually is placed supine with widely abducted extended extremities, which removes all physiological flexion and overstretches the anterior muscles, decreasing his or her ability to contract and provide postural support or movement. In addition, the head often is in an extended rotated asymmetric position to accommodate endotrachael tubing. Initially, this position may be medically necessary, but should be changed as soon as possible to avoid atelectesis, decreased ventilation, muscle contractures and muscle weakness. Therapists work with positioning techniques to promote neutral flexion of the lower extremities, protracted shoulder girdle position allowing hands to come toward midline and a midline head. These techniques include placing the infant on his or her side, in a semi-prone position, or partially upright. These positions increase the infant's comfort and feeling of security and improve breathing patterns and oxygen saturation levels.

Movement is important as soon as medically appropriate after surgery. Normal, early movement improves circulation, promotes deeper respirations, which may improve atelectesis, and helps minimize later developmental delays. Movement can be difficult, since it requires adequate cardiac output and oxygen levels. Also, tight joint capsules and muscle tissues may resist movement.

To support a fragile breathing pattern, postsurgical babies with pulmonary compromise frequently are placed in a stiff holding posture with the extremities or trunk against the bed. Therapists can elongate tight tissues, support breathing patterns and facilitate appropriate movement with minimal energy expended. Attention also must be directed toward early head control and postural tone of the trunk as stronger flexor postural control can improve oral-motor function and feeding.

For toddlers, standing and becoming ambulatory as soon as medically appropriate improves ventilation and a faster recovery period.

After heart surgery, babies often are overwhelmed with invasive treatments and stimulation and deprived of the comfort of being held by their parents, which severely challenges their ability to calm themselves. When the baby is continuously anxious, it causes shallow breathing, and crying easily depletes cardiac reserves. Therapists use several techniques to enhance regulatory skills, the most important being touch input. These babies may develop a negative response to all touch and can become hypersensitive to handling, making even routine care difficult. Parents also may feel their baby is rejecting them when they try to touch him or her. Therapists use deep, firm, non-moving touch, especially to the soles of the feet, palms of the hands and head. This decreases the baby's negative sensitivity. Deep touch is strengthened when used with a soft voice, soothing music and low lighting. Babies also can learn to calm themselves by using a visual focus such as a mobile or parent's face.

Therapists also teach parents these techniques and how to read their baby's cues, so they can respond appropriately. Parents often feel a sense of loss, anxiety and helplessness when their baby is hospitalized and can have trouble connecting with their child. Empowering parents with information and techniques helps them bond with their infant and helps the infant thrive.

When postsurgical heart patients are medically stable and nearing discharge, physical and occupational therapists assess their developmental status and facilitate a referral to a 0 to 3 program, if needed.

Research under way

Kathy Mussatto, RN, CV outcomes research coordinator
Beth Newbury Whitstone, RN, Cardiology clinical research nurse

Children's Hospital Heart Center professionals are active in several ongoing research projects and have presented findings at both regional and national level meetings. Some of our current research protocols include:

"Factors Affecting the Longevity of Homograft Valves Utilized in Right Ventricular Outflow Tract Reconstruction for Congenital Heart Disease" - presented at the American Heart Association's Scientific Sessions, Atlanta, Ga., November 1999 and the Midwest Pediatric Cardiology Conference, Ann Arbor, Mich., September 1999.

Ongoing aspects of this research include phone interview follow-up with all valve recipients to investigate health-related quality-of-life and functionality issues.

"Ventilatory Control of Pulmonary Vascular Resistance is Not Necessary to Achieve a Balanced Circulation in the Postoperative Norwood Patient" - presented at the American Heart Association's Scientific Sessions, Atlanta, Ga., November 1999. Produced from clinical data prospectively collected on all Norwood patients since July 1996.

"Use of Parenteral Phenoxybenzamine in Infants and Children During Surgery for Congenital Heart Disease - Phenoxybenzamine (POB) continues to be utilized under a FDA IND (Investigational New Drug) status." The producer of the drug does not anticipate applying for full approval of parenteral POB, making it essentially an "orphan drug." We can continue to use it with informed consent of participants and an institutionally approved usage protocol.

"Evaluation of the Safety and Efficacy of Seprafilm II Adhesion Barrier in Pediatric Cardiac Surgery." We recently enrolled in this multi-center clinical trial designed to evaluate an adhesion barrier in children who undergo multiple sternotomies. The study will enroll Norwood patients only and is anticipated to last approximately one year.

"Cardioprotection by K ATP Channels During Chronic Hypoxia." An examination of cellular responses to chronic hypoxia in human heart tissue with the hypothesis that there may be protective enzymatic changes that occur to protect the heart from ischemia.

"Wisconsin Pediatric Cardiac Registry." WPCR is a long-term prospective database of all patients born in the state of Wisconsin as of January 1, 2000. The goal is to identify genetic and environmental factors that may be causally related to forms of congenital heart disease. Families are asked to fill out an extensive questionnaire and some are also asked to donate blood for DNA sampling.

"Synagis for Prophylaxis of RSV in Children with Congenital Heart Disease." This is the second year Children's Hospital has participated in this clinical trial, which continues through the RSV season. It is a double-blinded, randomized, placebo-controlled study looking at the efficacy of IM Synagis to prevent or minimize RSV infection.

"Randomization of Oral Afterload Reducers in Infants after the Norwood Procedure." This is a randomized trial comparing the efficacy of oral phenoxybenzamine and captopril after the Norwood. It requires the PICU staff to document blood pressures after each dose of the medication. It is believed that phenoxybenzamine will be shown to decrease morbidity and mortality after the Norwood. This study will be ongoing.

"The Effects of Prenatal versus Postnatal Diagnosis of Severe Congenital Heart Disease on Parental Coping." This qualitative study compares the impact of prenatal diagnosis on how parents cope with severe congenital heart disease. The goal of the study is to improve support to families diagnosed both prenatally and postnatally. A total of 10 prenatally diagnosed and 10 postnatally diagnosed families will be enrolled and interviewed, with the study about half complete at this time.