Brigitte Stiller

Intravenous Sildenafil Is a Potent Pulmonary Vasodilator in Children With Congenital Heart Disease

Background—Increased pulmonary vascular resistance (PVR) because of congenital heart disease (CHD) may be caused by a dysfunction in endogenous pulmonary endothelial nitric oxide (NO) production. In other forms of pulmonary vascular disease with increased PVR, an elevated activity of a phosphodiesterase type 5 (PDE-5), responsible for the degradation of cyclic guanidine monophosphate (cGMP), the second messenger of endothelially produced NO, has been demonstrated. This study compares the effects of inhaled NO before and after the specific inhibition of the PDE-5 by intravenous sildenafil (Viagra™) in pre- and postoperative children with increased PVR because of CHD. Methods and Results—12 children with congenital heart disease (age 0.2 to 15.7 years, median 2.4 years) and increased mean pulmonary arterial pressure, and 12 postoperative children (age 0.11 to 0.65 years, median 0.32 years) with increased PVR (8.3±1.0 Wood Units*m2) were studied during cardiac catheterization (“cath laboratory”), or within 2 hours after return from cardiac surgery (“post op”), respectively. All were sedated, tracheally intubated and paralyzed. During alveolar hyperoxygenation (FiO2=0.65), the effects of inhaled NO (20 ppm) were compared before and after the stepwise infusion of sildenafil (“cath laboratory”, 1 mg/kg; post op, 0.25 mg/kg). Intravenous sildenafil more effectively reduced PVR than NO (11.5% versus 4.3% in the “cath laboratory” patient group, P <0.05, and 25.8% versus 14.6% in the post op patient group, P =0.09. The increase in cGMP in response to NO was potentiated (2- to 2.4-fold) by PDE-5 inhibition. While the vasodilating effects of sildenafil showed pulmonary selectivity, its infusion was associated with increased intrapulmonary shunting in the postoperative patients (Qs/Qt=16.5±4.7% to 25.5±18.2%P =0.04). Conclusions—Intravenous sildenafil is as effective as inhaled NO as a pulmonary vasodilator in children with congenital heart disease. Although clinically insignificant in this study, increased intrapulmonary shunting with sildenafil may be disadvantageous in some patients after CHD surgery.

Heart transplantation in children after mechanical circulatory support with pulsatile pneumatic assist device

BACKGROUND Mechanical support with a pulsatile pneumatic ventricular assist device (VAD) is a complex rescue procedure performed in children with untreatable cardiogenic shock. Its impact on early and long-term survival after subsequent heart transplantation (HTx) remains to be determined. METHODS We reviewed retrospectively the course of 95 children (median age, 8 years; range, 8 days-17 years; body weight, 24 kg; range, 3-110 kg) who underwent HTx. Group A, the elective-HTx group, consists of 33 children who were treated as outpatients before transplantation. Group B, the emergency-HTx group, has 44 children who were critically ill and hospitalized before transplantation but without ventricular assist devices, whereas Group C, the VAD-HTx group, consists of 18 children resuscitated and supported with pulsatile pneumatic VADs for a median time of 20 days. RESULTS Overall actuarial survival after cardiac transplantation was 86% at 1 month, 82% at 1 year, and 78% at 5 years, without significant differences among the 3 sub-groups. Group A had the best long-term survival rate, 88% at 1 month, 88% at 1 year, and 80% at 5 years. Group B had a survival rate of 88% at 1 month, 82% at 1 year, and 79% at 5 years. Group C had a survival rate of 72% at 1 month, 72% at 1 year, and 72% at 5 years. We found no differences in neurologic outcome, acute cardiac rejection, or transplant failure. The survival rate was significantly better in the children with cardiomyopathy compared with those with congenital heart defects (p = 0.014). CONCLUSIONS Bridging to HTx with a pulsatile pneumatic VAD is a safe procedure in pediatric patients. After HTx, overall survival of these children is similar to that of patients who were bridged with inotropes or who were awaiting heart transplantation electively.

A gain-of-function TBX20 mutation causes congenital atrial septal defects, patent foramen ovale and cardiac valve defects

Background Ostium secundum atrial septal defects (ASDII) account for approximately 10% of all congenital heart defects (CHD), and mutations in cardiac transcription factors, including TBX20, were identified as an underlying cause for ASDII. However, very little is known about disease penetrance in families and functional consequences of inherited TBX20 mutations. Methods The coding region of TBX20 was directly sequenced in 170 ASDII patients. Functional consequences of one novel mutation were investigated by surface plasmon resonance, CD spectropolarymetry, fluorescence spectrophotometry, luciferase assay and chromatin immunoprecipitation. Results We found a novel mutation in a highly conserved residue in the T-box DNA binding domain (I121M) segregating with CHD in a three generation kindred. Four mutation carriers revealed cardiac phenotypes in terms of cribriform ASDII, large patent foramen ovale or cardiac valve defects. Interestingly, tertiary hydrophobic interactions within the mutant TBX20 T-box were significantly altered leading to a more dynamic structure of the protein. Moreover, Tbx20-I121M resulted in a significantly enhanced transcriptional activity, which was further increased in the presence of co-transcription factors GATA4/5 and NKX2-5. Occupancy of DNA binding sites on target genes was also increased. Conclusions We suggest that TBX20-I121M adopts a more fluid tertiary structure leading to enhanced interactions with cofactors and more stable transcriptional complexes on target DNA sequences. Our data, combined with that of others, suggest that human ASDII may be related to loss-of-function as well as gain-of-function TBX20 mutations.

Primary cardiac tumours: when is surgery necessary?

OBJECTIVE Primary cardiac tumours are rare. The literature predominantly contains series on myxomas in adults and only a few long-term series that involve the very different primary cardiac tumours in early childhood. As foetal ultrasonography has continued to improve, cardiac tumours are increasingly detected early before significant symptoms develop. It is a challenge for paediatric cardiologists and surgeons to ascertain which patients need surgery and which will benefit from conservative follow-up. METHODS A retrospective review of a 10-year period revealed 51 tumours in 26 children (median age: 1 month). Analysis was by presentation, location, associated findings, interventions, histological findings, and clinical course. RESULTS The most common tumours were rhabdomyomas (29), fibromas (nine), teratomas (two), and haemangiomas (two). The tumour location was the right ventricle in 24 and the left ventricle in 22 patients. The symptoms varied between abnormal heart murmur (20), arrhythmia and conduction abnormalities (ten), obstruction of the outflow tract >30 mmHg (nine), severe cyanosis (three) and congestive heart failure (two). Fourteen children with haemodynamic compromises underwent surgery. There was one post-operative death and one heart transplantation after bridging with an assist device. There was no tumour recurrence even when resection was incomplete. Nine of 13 children with rhabdomyomas had spontaneous tumour regression without intervention. CONCLUSIONS Most of the cardiac tumours in children are benign. Spontaneous regression is possible not only in rhabdomyoma. Surgical intervention is only required for children who develop relevant clinical symptoms. Total resection of the tumour is not the only therapeutic aim; more important is the restoration of the best possible heart function.

Mutations in GATA4, NKX2.5, CRELD1, and BMP4 Are Infrequently Found in Patients With Congenital Cardiac Septal Defects

Cardiac septal defects constitute the majority ofcongenitalheartdisease(CHD)inhumansandfamilialrecurrenceisreportedtoexceed5%[Burnetal.,1998].Previously, mutations in GATA4 and NKX2.5 havebeendescribedtobepathogenicforostiumsecundumatrial septal defects (ASDII) and ventricular septaldefects(VSD)[Schottetal.,1998;Gargetal.,2003].Incontrast, CRELD1 and BMP4 constitute functionalcandidatesforregulardevelopmentoftheendocardialcushionandmutationsinthesegenescause atrioven-tricular septal defects (AVSD) in animal models andhumans [Jiao et al., 2003; Robinson et al., 2003]. Wehypothesizedthatmutationsin GATA4(NM_002052),NKX2.5 (NM_004387), CRELD1 (NM_015513), andBMP4(NM_001202)canbeidentifiedinalargecohortof patients withcongenital septal defects with a focusonASDII.Weanalyzedthecodingregionofthesefourgenesin205patientswithcongenitalseptaldefectsbysinglestrandedconformationalpolymorphism(SSCP)and sequencing. The patient cohort was assembledout of 110 patients with isolated ASDII. Of these,four subjects (3.6%) mentioned a familial history andformal segregation analysis of pedigrees suggestedan autosomal dominant inheritance. However, familyrelatives were not studied systematically. To thishomogenous ASDII patient cohort we added agroupof95individualswithdifferentcongenitalseptaldefects (60 ASDII, 22 perimembranous VSD, and13 AVSD) and concomitant minor cardiac malforma-tions (Aortic coarctation ¼CoA, persistent ductusarteriosus¼PDA or partial anomalous venousreturn¼PAPVR). These patients were included as asubgroup in a candidate gene approach reportedpreviously [Ozcelik et al., 2006]. All patients wereattending the Department for Congenital Heart Dis-ease, German Heart Institute Berlin (GHIB). Patientswith syndromic appearance and/or limb malforma-tions were excluded from the genetic study andcontrolsubjectswerematchedforethnicity.Thestudyprotocol was approved by the Institutional ReviewBoard of the GHIB and Charite´.A heterozygous c.1750C>T mutation of GATA4,which predicts p.A411V, was identified in a cauca-sian patient with multiperforated ASDII and PAPVR.After exclusion in 600 control chromosomes weconsideredthevarianttobeanovelASDIIassociatedmutation representing the fifth GATA4 mutationidentified in a patient with ASDII. The carrier was a73-year-old female with ASDII and sustained atrial

Ventricular assist devices in children: Current achievements and future perspectives

Abstract:   Mechanical circulatory support systems for the treatment of acute and chronic heart failure are now available for use in several clinical situations and are designed for different indications and support times. In children, particularly in small infants, extracorporeal membrane oxygenation and centrifugal pumps have been most widely used in the past. These systems are preferred for support after cardiac operations and for use in patients who have concomitant respiratory failure, but they are suitable for short‐term application only and intensive care is obligatory. VADs are designed for long‐term application and allow patients to be discharged home. Pneumatic pulsatile VADs have been available in pediatric sizes since 1992. Currently at our institution, 74 children have been supported with pediatric extracorporeal VADs for up to 14 months. In the past five yr, a notable rise in survival has been achieved by improvements in pump design and pre‐ and post‐operative management. We have been able to discharge 78% of the infants under one yr old. In this review, our current VAD experience in children will be presented in the light of improvements in decision‐making, device technology, and implantation techniques, and in coagulation monitoring and anticoagulation. Additionally, new developments in the field of pediatric assist devices will be presented.

Peritoneal dialysis after infant open heart surgery: observations in 27 patients

BACKGROUND The role of peritoneal dialysis (PD) in the management of infants after heart operation is under discussion. The aim of this study was to investigate the effect of PD on fluid balance and outcome. METHODS Twenty-seven (33%) of 81 consecutive infants who underwent heart operation required PD. In 22 patients (81%), PD was started prophylactically at the end of the operation. We recorded hemodynamic data and fluid balance. Patients experiencing acute renal failure (ARF) were compared with the remaining infants. RESULTS Eleven of 81 patients (14%) experienced ARF; 3 of them died (4% of all patients undergoing operation, 27% of those with ARF). Complications of PD, present in 33%, were transitory and of minor significance. Patients with ARF had decreased cardiac function compared with those without ARF but similar fluid balance. CONCLUSIONS Peritoneal dialysis is an effective and safe method for the treatment of ARF in infants after open heart operation. As PD is helpful in modulating postoperative fluid balance, prophylactic use of PD can be recommended for selected patients who are at risk for low cardiac output syndrome.

Relation of cerebral tissue oxygenation index to central venous oxygen saturation in children

ObjectiveTo evaluate the relationship between the cerebral tissue oxygenation index measured by near-infrared spectroscopy and central venous oxygen saturation (SvO2) after corrective surgery of congenital heart defects in children.DesignProspective observational clinical study.SettingA tertiary neonatal and paediatric intensive care unit for paediatric cardiology.PatientsNeonates and children consecutively admitted to the paediatric cardiology intensive care unit after corrective surgery of non-cyanotic congenital heart defects.Measurements and resultsForty-three children were studied. Cerebral tissue oxygenation index, measured non-invasively by near-infrared spectroscopy, was compared to SvO2, measured by a catheter placed in the right atrium, and to haemodynamic and respiratory parameters. Pearson’s correlation coefficients and p values were calculated. Simultaneously measured values for SvO2 (62.2±9.8%, 39.8–80.4%) and cerebral tissue oxygenation index (56.7±8.8%, 35.8–71.2%) showed a significant correlation (r=0.52, p<0.001).ConclusionCerebral tissue oxygenation index and SvO2 are not interchangeable parameters, but cerebral tissue oxygenation index reflects the haemodynamic influence on cerebral oxygenation after cardiovascular surgery. Further work is necessary to confirm the clinical role of continuous non-invasive measurement of cerebral tissue oxygenation index with regard to the variations of global systemic oxygen consumption after cardiac surgery in children.

Complement and Contact Activation During Cardiovascular Operations in Infants

BACKGROUND By comparing the results of cardiac operations with or without cardiopulmonary bypass (CPB) in infants in a prospective study, we sought to determine which part of the postoperative systemic inflammatory response was caused by CPB. METHODS Thirty-five patients were divided into two groups: 11 infants operated on without CPB and 24 infants operated on with CPB. Blood samples were drawn before, during, and after the operation. We assessed complement function and the concentrations or activities of C1q, C3, C4, C1 inhibitor, factor B, the activated split product C3a, and prekallikrein and factor XIIa of the contact system. RESULTS All of the patients exhibited a decrease of complement proteins. This was greater in infants who underwent CPB. A increase in C3a and factor XIIa and changes in prekallikrein activity occurred only in infants during CPB. CONCLUSIONS Complement activation occurs in all infants, but is significantly higher in the group with CPB. Contact activation only occurs in patients who undergo CPB. Thus, the inflammatory response is caused by the use of a CPB circuit and to a lesser degree by surgical procedures and anesthesia.

Extracorporeal membrane oxygenation for intraoperative cardiac support in children with congenital heart disease

OBJECTIVES Extracorporeal membrane oxygenation (ECMO) is commonly used in children to allow recovery from ischemic injury or cardiac surgery, to support the circulation in case of end-stage cardiomyopathy, as bridge-to-bridge therapy and as bridge to transplantation as well. It has achieved success in providing cardiac support for these kind of patients with expected mortality due to severe myocardial dysfunction. In this modern era, ECMO support should be considered an important option for children with cardiopulmonary failure refractory to medical therapy or resuscitation. We report our experience in pediatric patients supported by ECMO for intraoperative cardiac failure between November 1991 and December 2006. METHODS AND RESULTS Sixty-six patients with a mean age of 5.2+/-4 years (range: 1 day-17 years) and mean weight of 14.3+/-11 kg (range: 2.8-69 kg) had intraoperative ECMO support for failure to wean off cardiopulmonary bypass (n=46, 69.7%), low cardiac output syndrome (n=8, 12.1%), isolated right ventricular failure (n=6, 9.1%), isolated left ventricular failure (n=3, 4.5%), malignant arrhythmia (n=1, 1.5%) and pulmonary hypertension (n=2, 3.1%). Mean duration of ECMO support was 5.1+/-3 days. Overall 30 (45.4%) patients were successfully weaned off ECMO and survived to decannulation. Overall 6 (9.1%) patients were successfully bridged to heart transplantation while on ECMO support. Thirty patients died (54.4%) (16 while on ECMO and 14 after decannulation) because of multi-factorial complications, i.e. cerebral hemorrhage, pulmonary failure, consumption coagulopathy and therapy-resistant myocardial insufficiency, leding to an overall hospital mortality rate of 45.4%. Mean survival time after decannulation was 28+/-16 h. Overall survival rate on ECMO as bridge to recovery and transplantation has been 54.5% with successful hospital discharge of patients. CONCLUSIONS Our experience shows that ECMO support can be offered intraoperatively to any children after palliative or corrective surgery for congenital heart disease with potentially reversible pulmonary, cardiac or cardiopulmonary failure. In the majority of patients who did not survive late after weaning from ECMO support, significant myocardial dysfunction persisted or pulmonary hypertensive events. Nevertheless, an acceptable proportion of patients who were successfully weaned from ECMO ultimately survived to leave the hospital.