Pediatric heart transplantation across a positive crossmatch: First year results from the CTOTC-04 multi-institutional study.

Sensitization is common in pediatric heart transplant candidates and waitlist mortality is high. Transplantation across a positive crossmatch may reduce wait time, but is considered high risk. We prospectively recruited consecutive candidates at eight North American centers. At transplantation, subjects were categorized as nonsensitized or sensitized (presence of ≥1 HLA antibody with MFI ≥1000 using single antigen beads). Sensitized subjects were further classified as complement-dependent cytotoxicity crossmatch (CDC-crossmatch) positive or negative and as donor-specific antibodies (DSA) positive or negative. Immunosuppression was standardized. CDC-crossmatch-positive subjects also received perioperative antibody removal, maintenance corticosteroids, and intravenous immunoglobulin. The primary endpoint was the 1 year incidence rate of a composite of death, retransplantation, or rejection with hemodynamic compromise. 317 subjects were screened, 290 enrolled and 240 transplanted (51 with pretransplant DSA, 11 with positive CDC-crossmatch). The incidence rates of the primary endpoint did not differ statistically between groups; nonsensitized 6.7% (CI: 2.7%, 13.3%), sensitized crossmatch positive 18.2% (CI: 2.3%, 51.8%), sensitized crossmatch negative 10.7% (CI: 5.7%, 18.0%), P = .2354. The primary endpoint also did not differ by DSA status. Freedom from antibody-mediated and cellular rejection was lower in the crossmatch positive group and/or in the presence of DSA. Follow-up will determine if acceptable outcomes can be achieved long-term.

Incidence, characterization, and impact of newly detected donor-specific anti-HLA antibody in the first year after pediatric heart transplantation: A report from the CTOTC-04 study.

Data on the clinical importance of newly detected donor-specific anti-HLA antibodies (ndDSAs) after pediatric heart transplantation are lacking despite mounting evidence of the detrimental effect of de novo DSAs in solid organ transplantation. We prospectively tested 237 pediatric heart transplant recipients for ndDSAs in the first year posttransplantation to determine their incidence, pattern, and clinical impact. One-third of patients developed ndDSAs; when present, these were mostly detected within the first 6 weeks after transplantation, suggesting that memory responses may predominate over true de novo DSA production in this population. In the absence of preexisting DSAs, patients with ndDSAs had significantly more acute cellular rejection but not antibody-mediated rejection, and there was no impact on graft and patient survival in the first year posttransplantation. Risk factors for ndDSAs included common sensitizing events. Given the early detection of the antibody response, memory responses may be more important in the first year after pediatric heart transplantation and patients with a history of a sensitizing event may be at risk even with a negative pretransplantation antibody screen. The impact on late graft and patient outcomes of first-year ndDSAs is being assessed in an extended cohort of patients.

Prognostic value of B-type natriuretic peptide in surgical palliation of children with single-ventricle congenital heart disease.

The objective of this prospective study was to assess the prognostic role of perioperative B-type natriuretic peptide (BNP) levels in infants and children with single-ventricle congenital heart disease undergoing Norwood, bidirectional cavopulmonary anastomosis (BCPA), or Fontan operation. BNP levels were measured at baseline, after cardiopulmonary bypass, 6 to 12 hours after surgery, and then daily until indwelling vascular catheters were removed. Outcome measures included length of mechanical ventilation, inotropic support, and hospital stay. Twenty subjects underwent 23 surgical procedures (13 Norwood, 5 BCPA, and 5 Fontan). BNP levels were significantly higher in patients undergoing a Norwood procedure compared with a BCPA or Fontan procedure (p < 0.01). BNP levels measured 6 to 12 hours after surgery were predictive of duration of hospitalization (p = 0.005) and inotropic support (p = 0.01). An increase in BNP level within 48 hours of extubation was observed in 92% of patients undergoing a Norwood procedure. Early postoperative BNP levels correlate significantly with the ensuing duration of inotropic support and length of hospitalization. An increase in BNP after extubation may be reflective of the degree of underlying cardiopulmonary instability. Further investigation is necessary to define this important relation.

Towards the development of a pediatric ventricular assist device.

The very limited options available to treat ventricular failure in children with congenital and acquired heart diseases have motivated the development of a pediatric ventricular assist device at the University of Pittsburgh (UoP) and University of Pittsburgh Medical Center (UPMC). Our effort involves a consortium consisting of UoP, Children's Hospital of Pittsburgh (CHP), Carnegie Mellon University, World Heart Corporation, and LaunchPoint Technologies, Inc. The overall aim of our program is to develop a highly reliable, biocompatible ventricular assist device (VAD) for chronic support (6 months) of the unique and high-risk population of children between 3 and 15 kg (patients from birth to 2 years of age). The innovative pediatric ventricular assist device we are developing is based on a miniature mixed flow turbodynamic pump featuring magnetic levitation, to assure minimal blood trauma and risk of thrombosis. This review article discusses the limitations of current pediatric cardiac assist treatment options and the work to date by our consortium toward the development of a pediatric VAD.

The PediaFlow pediatric ventricular assist device.

The very limited options available to treat ventricular failure in patients with congenital and acquired heart diseases have motivated the development of a pediatric ventricular assist device (VAD). Our effort involves a consortium consisting of the University of Pittsburgh, Carnegie Mellon University, Children's Hospital of Pittsburgh, World Heart Corporation, and LaunchPoint Technologies, LLC. The overall aim of our program is to develop a highly reliable, biocompatible VAD for chronic support (6 months) of the unique and high-risk population of children between 3 kg and 15 kg (patients from birth to 2 years of age). The innovative pediatric VAD we are developing (PediaFlow) is based on a miniature mixed-flow turbodynamic pump featuring magnetic levitation, with the design goal being to assure minimal blood trauma and risk of thrombosis. This article discusses the limitations of current pediatric cardiac assist treatment options and the work to date by our consortium toward the development of a pediatric VAD.

Effect of ViscoStat and ViscoStat Plus on composite shear bond strength in the presence and absence of blood.

PURPOSE: To examine the effects of the hemostatic agents ViscoStat and ViscoStat Plus on the shear bond strength (SBS) of composite resin (CR) to dentin in the presence and absence of blood. MATERIALS AND METHODS: Sixty permanent teeth mounted in acrylic were randomly divided into 5 groups (n = 12): (1) control, C; (2) ViscoStat, VS; (3) ViscoStat Plus, VS+; (4) ViscoStat and blood, VS/B; (5) ViscoStat Plus and blood, VS+/B. Groups 2 and 3 were exposed to VS and VS+, respectively. Freshly drawn human blood was placed on groups 4 and 5 immediately followed by VS and VS+, respectively. Specimens remained undisturbed for 1 min and were rinsed with tap water for 1 min. All groups were etched with 35% phosphoric acid and were bonded utilizing the Ultradent bonding clamp, Optibond Solo Plus, and Z-250 composite resin. Following water storage for 48 hrs at 37 degrees C, specimens were debonded in an Instron test frame at a crosshead speed of 0.5 mm/min. Statistical analysis was done with one-way analysis of variance. RESULTS: The mean SBS+/-SD in MPa were C: 44.2+/-4.8, VS: 42.3+/-8.7, VS+: 46.2+/-7.8, VS/B: 43.0+/-6.4, VS+/B: 44.0+/-8.1. ANOVA revealed no significant difference (p > 0.05) between SBS of VS or VS+ and the control with or without blood present. ostatic CONCLUSION: This controlled laboratory study concluded that the use of ViscoStat or ViscoStat Plus as a hem agent does not have a significant effect on the shear bond strength of composite resin to dentin when using Optibond Solo Plus.

B-type natriuretic peptide levels in congenital heart disease.

The objective of this study was to evaluate the potential role of B-type natriuretic peptide (BNP) levels in children with congenital heart disease undergoing cardiac catheterization. Measurement of plasma BNP concentration has been shown to be useful in the diagnosis, risk stratification, and management of adult patients with congestive heart failure, but little is known about the role of BNP in children with structural congenital heart disease. We measured plasma BNP levels using the Triage BNP test in patients with congenital heart disease referred for diagnostic or interventional cardiac catheterization. Plasma BNP concentration was measured in 96 children and 11 adults > or = 19 years old (7.9+/-8.3 years) undergoing heart catheterization for underlying congenital heart disease. BNP levels ranged from < 5 to > 1300 pg/ml, with a median BNP concentration of 19.0 pg/ml. Baseline BNP concentrations were > 100.0 pg/ml on 19 occasions in 17 patients. The pressure difference between the left ventricle and ascending aorta was 10-110 mmHg in 21 patients. BNP concentrations for this cohort ranged from < 5.0 to 1060.0 pg/ml and correlated with the degree of left ventricular outflow obstruction (correlation coefficient, 0.661; p = 0.001). This study suggests that with additional research, BNP concentration may prove to be a useful clinical tool in managing children and adults with congenital heart disease.

Complete follow-up echocardiograms are needed to detect stenosis of normally connecting pulmonary veins.

Reimbursement for limited echocardiograms focusing on known pathology rather than complete studies has recently received widespread attention. Few data are available to determine if these limited examinations provide enough information to adequately evaluate many forms of congenital heart disease. Stenosis of normally connecting pulmonary veins is a congenital or acquired cardiac anomaly that is difficult to diagnose clinically and may be detectable only by echocardiography. To evaluate the yield of complete versus limited echocardiograms for detecting the presence and development of stenosis in pulmonary veins with anatomically normal connections, the cardiology database was searched for all patients with this diagnosis presenting between June 1990 and January 2000. Charts were reviewed for demographic data, associated defects, surgeries, and outcomes. Angiograms and echocardiograms were reviewed for location and severity of pulmonary vein stenosis. A pulsed-wave Doppler signal of > 1.6 mm/sec with loss of phasic flow was used to define stenosis. Eighteen patients were identified and ranged in age at first evaluation from 1 day to 17 years (median 15 days). All 18 patients had associated cardiac anomalies, and 4 (22%) of 18 had Trisomy 21. Pulmonary vein stenosis was detected on the initial evaluation in 5 patients, detected 8 +/- 5 months after the initial echocardiogram in 11 patients, and missed by echocardiography in 2 patients who were diagnosed by cardiac catheterization. The initial echocardiograms were complete, with pulsed-Doppler sampling of all four pulmonary veins in 17 of 18 patients. Of the 12 patients who had echocardiographic evidence of late stenosis, 10 had 17 limited interim studies prior to eventually having a complete diagnostic follow-up study. Of the two patients in whom the diagnosis was missed by echocardiography, one initial study was technically inadequate (17-year-old) and one had only limited interim studies after the initial echocardiogram. Of the 9 patients in whom repair of the pulmonary vein stenosis was attempted, 3 had no residual obstruction and 6 had progressive stenosis (three deaths). Of the remaining nine patients who had no intervention for their pulmonary venous stenosis, four have died from progressive pulmonary hypertension. Stenosis of normally connecting pulmonary veins is an uncommon lesion that has a significant impact on clinical outcome. The stenoses might be undetectable on limited echocardiograms that focus on evaluating only specified pathology. Complete follow-up examinations might be warranted to diagnose this lesion. This may be an important consideration when formulating reimbursement policies.

Optimizing treatment for chronic congestive heart failure in children.

Treatment strategies for chronic heart failure in children have generally been extrapolated from studies in adults with heart failure. This presentation reviews the existing knowledge and recommendations regarding the treatment of chronic heart failure in adults and the information that is available in children. Medications currently recommended for use in adults include diuretics, digoxin, angiotensin-converting enzyme inhibitors, and beta-blockers. These recommendations are based on results from large, randomized, multicenter trials. Anecdotal evidence suggests similar beneficial effects of these medications in children. The fact that the etiologies, pathophysiology, and physiologic consequences of heart failure in children often differ greatly from those in adults, however, justifies the development of prospective, randomized trials to evaluate these medications specifically in children. Findings from these types of studies will provide critical information for developing guidelines for the appropriate treatment of children with chronic heart failure.

Beta-adrenergic receptor blockers as therapy in pediatric chronic heart failure.

Beta-adrenergic receptor blocking agents (beta-blockers) are now considered to be standard of care for the treatment of chronic congestive heart failure in adults. Studies in adults with chronic heart failure have shown that beta-blockers improve left ventricular ejection fraction, symptoms, and survival when compared to placebo. New mechanisms of actions in individual beta-blockers are being continually elucidated, but the primary mechanism of action of beta-blockers in chronic heart failure is thought to be the prevention and/or reversal of adrenergically-mediated intrinsic myocardial dysfunction and remodeling. Experience with the use of beta-blockers in children with heart failure is limited but growing. Although no randomized, placebo-controlled data yet exists, anecdotal evidence suggests that children with chronic congestive heart failure may also benefit from this therapy. There are now uncontrolled safety and efficacy studies showing possible benefit from both metoprolol and carvedilol in children with heart failure due to either large left-to-right shunt or systemic ventricular dysfunction. Large prospective, randomized trials in children are currently underway in order to attempt to determine the indications, dosages, and optimal use of beta-blockers in children with chronic congestive heart failure.

Intra-aortic balloon pumping in children with dilated cardiomyopathy as a bridge to transplantation.

Children with dilated cardiomyopathy awaiting transplantation who fail maximal pharmacologic therapy may benefit from intra-aortic balloon pumping. Between July 1993 and August 1999, a total of 4 children with dilated cardiomyopathy underwent pre-transplant balloon pumping for 6.0 +/- 5.8 (1 to 12) days. One child (pumped for 12 days) died awaiting transplant, and the remaining 3 were successfully transplanted. Intra-aortic balloon pumping timed precisely with M-mode echocardiographic markers offers a relatively simple and safe intermediate level of mechanical support for children with dilated cardiomyopathy who fail pharmacologic support.

Carvedilol as therapy in pediatric heart failure: an initial multicenter experience.

OBJECTIVE: The objective was to determine the dosing, efficacy, and side effects of the nonselective beta-blocker carvedilol for the management of heart failure in children. STUDY DESIGN: Carvedilol use in addition to standard medical therapy for pediatric heart failure was reviewed at 6 centers. RESULTS: Children with dilated cardiomyopathy (80%) and congenital heart disease (20%), age 3 months to 19 years (n = 46), were treated with carvedilol. The average initial dose was 0.08 mg/kg, uptitrated over a mean of 11.3 weeks to an average maintenance dose of 0.46 mg/kg. After 3 months on carvedilol, there were improvements in modified New York Heart Association class in 67% of patients (P =.0005, chi2 analysis) and improvement in mean shortening fraction from 16.2% to 19.0% (P =.005, paired t test). Side effects, mainly dizziness, hypotension, and headache, occurred in 54% of patients but were well tolerated. Adverse outcomes (death, cardiac transplantation, and ventricular-assist device placement) occurred in 30% of patients. CONCLUSIONS: Carvedilol as an adjunct to standard therapy for pediatric heart failure improves symptoms and left ventricular function. Side effects are common but well tolerated. Further prospective study is required to determine the effect of carvedilol on survival and to clearly define its role in pediatric heart failure therapy.

Prospective randomized trial of azathioprine in cryopreserved valved allografts in children.

BACKGROUND: The purpose of this study was to prospectively assess the effects of azathioprine on the humoral immune response to HLA alloantigens and allograft function in children receiving cryopreserved valved allografts. METHODS: We randomized 13 children to receive azathioprine or not to receive azathioprine (controls) after receiving a cryopreserved valved allograft. Azathioprine patients received intraoperatively 4 mg/kg of azathioprine and 2.0 +/- 0.5 mg/kg once daily for 3 months after operation. Panel reactive antibodies against HLA class I and class II alloantigens were measured before, 1 month, and 3 months after operation. RESULTS: Panel reactive antibodies were not significantly different between the azathioprine and control groups before (0.0% +/- 0% versus 1.6% +/- 1%), 1 month (59% +/- 17% versus 71% +/- 12%), or 3 months (84% +/- 15% versus 96% +/- 1.3%) after operation. There were no differences in degree of allograft valve stenosis between azathioprine (31.5 +/- 26 mm Hg, 13.4 +/- 7 months postoperatively) and control groups (25.4 +/- 11 mm Hg, 17.2 +/- 10 months postoperatively) or allograft valve insufficiency. CONCLUSIONS: Azathioprine does not significantly decrease the immune response to HLA alloantigens or affect the function of cryopreserved valved allografts used in children to repair congenital heart defects.

Cardiomyopathies in adolescents: dilated, hypertrophic, and restrictive.

Three major types of cardiomyopathies affect adolescents: dilated, hypertrophic, and restrictive. At the present time the etiologies of the majority of these cardiomyopathies in children remain elusive. Treatment of these diseases is generally directed toward improving symptoms, survival, myocardial performance, and hemodynamics. Most treatment strategies are extrapolated from studies in adults with these types of cardiomyopathies, although prospective, randomized therapeutic trials are currently underway in children. All three types of cardiomyopathy can be associated with a wide range of symptoms (from none to severe) and also are associated with sudden death. For those in whom medical management fails, heart transplantation is a therapeutic option with an excellent intermediate-term success rate.

Evidence for early vessel involvement in the dysfunctional myocardium of Takayasu's arteritis.

A 15-year-old girl presented with persistent fevers, night sweats, leukocytosis, an elevated erythrocyte sedimentation rate, and a 13-pound weight loss over 2 months. Duplex Doppler scans, computed tomographic scan, and magnetic resonance imaging studies were suggestive of Takayasu's arteritis. Left ventricular dysfunction occurred during the episode of active disease, and an endomyocardial biopsy demonstrated increased HLA-DR (human leukocyte antigen-DR) on the endothelium and evidence of immune complex deposition in the walls of small vessels. One year later, after treatment with corticosteroids and resolution of clinical symptoms, repeat endomyocardial biopsy revealed focal interstitial fibrosis and persistent immune complex deposition. These results indicate that the inflammatory, vasculitic process affecting the large vessels in Takayasu's arteritis may also involve the endomyocardium and its small vessels resulting in ventricular dysfunction.

A prospective analysis of the immunogenicity of cryopreserved nonvalved allografts used in pediatric heart surgery.

BACKGROUND: The purpose of this study was to prospectively determine the immunogenicity of nonvalved allograft tissue used to repair congenital heart defects. METHODS AND RESULTS: We prospectively analyzed the immune response of 11 children, 1.4 months to 10 years of age, who required nonvalved allografts to alleviate stenosis during repair of congenital heart defects. In 7 patients, pulmonary arterial grafts were used; in 3 patients, monocusp pulmonary artery grafts were used; and in 1 patient, a section of glutaraldehyde-preserved allograft pericardium was used. We measured the level of HLA panel-reactive antibody (PRA) before surgery, 1 week after, 1 month after, and 3 months after surgery. PRA was determined by the antiglobulin technique and flow cytometry. HLA class I and class II antibodies measured by either technique were negligible before and 1 week after surgery. Nine of 11 patients (82%) exhibited a significant immune response at 1 month after surgery that further increased at 3 months. The measured PRA for class I antibodies with the antiglobulin technique increased to 43+/-36% at 1 month and to 69+/-38% at 3 months after surgery. Flow cytometry class I PRA measurements were similar. Class II PRA increased to 26+/-34% at 1 month and to 41+/-36% at 3 months. Age negatively correlated with the degree of elevation of PRA, but neither allograft area nor the area indexed to patient body surface area correlated with PRA. CONCLUSIONS: Cryopreserved nonvalved allografts induce a strong HLA antibody response in the majority of children.

Can Doppler systemic venous flow indices predict central venous pressure in children?

Tricuspid valve, superior vena cava (SVC), and hepatic vein Doppler patterns may be abnormal in right heart anomalies and have been used to predict high central venous pressure (CVP) in adults. The purpose of this study was to evaluate the relationship of these systemic venous flow indices to CVP in children. Children undergoing cardiac catheterization were studied prospectively using simultaneous recordings of mean CVP with pulsed-Doppler tracings of SVC, hepatic vein, and tricuspid valve flow. Systemic venous Doppler measurements included peak velocities and velocity time integrals for ventricular systole (S), ventricular diastole (D), and ventricular systole (B), and atrial systole (A). Tricuspid inflow Doppler E and A waves were recorded also. Patients with significant tricuspid stenosis or regurgitation, systemic venous obstruction, and nonsinus rhythm were excluded. The 42 patients ranged in age from 0.2 to 21.0 years and in weight from 3.0 to 68.0 kg. Mean CVPs ranged from 1 to 17 mmHg. Catheterization indications included hemodynamic evaluation (25 patients), transplant biopsy, (11 patients), and interventional procedures (6 patients). No SVC or tricuspid valve Doppler measurement correlated with CVP. Hepatic vein peak D, peak B, and peak A significantly correlated with CVP (r = 0.34 - 0.55; P < 0.05, linear regression). For all correlations, the r values were low with significant overlap among patients. Thus, in children, only hepatic vein peak velocities correlate with CVP. Because of the low r values and significant overlap among patients, the currently used Doppler indices have a low sensitivity for predicting CVP in this age group.

Usefulness of the preoperative tricuspid/mitral valve ratio for predicting outcome in pulmonary atresia with intact ventricular septum.

Although tricuspid valve z-scores have been used to predict outcome in pulmonary atresia with intact ventricular septum, they are statistically generated from local populations, and widespread generalization may not be appropriate. To determine if there are echocardiographic predictors of outcome that can be universally used, the records of all infants with this diagnosis since 1988 were reviewed for age, weight, type of surgery, and outcome. Preoperative and follow-up echocardiograms were reviewed for valve diameter and z-scores, and valve ratios were calculated. Thirty-six patients were divided into 2 groups: group 1 included 23 infants who had a successful biventricular repair; group 2 included the remaining 13 infants who did not have a successful repair. Preoperatively, both groups had similar ages, pulmonary, aortic, and mitral z-scores, and pulmonary/aortic ratios, but the patients in group 2 had significantly lower weight (3.5 +/- 0.6 vs 2.9 +/- 0.5 kg), tricuspid z-scores (-0.7 +/- 1.5 vs -2.3 +/- 1.2), and tricuspid/mitral ratios (0.8 +/- 0.2 vs 0.5 +/- 0.1). At similar follow-up, both groups of patients had similar weight, aortic and mitral z-scores, and pulmonary/aortic ratios, but group 2 infants had significantly lower pulmonary and tricuspid z-scores and tricuspid/mitral ratios. Compared with the preoperative echocardiograms, group 1 had significant increases only in pulmonary z-scores, and pulmonary/aortic and tricuspid/mitral ratios. Group 2 had no significant change in any echocardiographic variable. The tricuspid/mitral ratio was >0.5 in all group 1 infants, and in 6 of 13 group 2 infants (2 sepsis deaths, 4 palliations). Compared with a tricuspid valve z-score >-3, a tricuspid/mitral ratio >0.5 was a better predictor of biventricular repair. Thus, infants who have a successful biventricular repair have significantly greater preoperative weight, tricuspid valve z-scores, and tricuspid/mitral valve ratios. A tricuspid/mitral ratio >0.5 was the best predictor of a biventricular repair.