Perinatal and perioperative factors associated with mortality and an increased need for hospital care in infants with transposition of the great arteries: A nationwide 11-year population-based cohort.

INTRODUCTION: Newborn infants with transposition of the great arteries (d-TGA) need immediate care for an optimal outcome. This study comprised a nationwide 11-year population-based cohort of d-TGA infants, and assessed whether the implementation of a nationwide systematic fetal screening program, or other perinatal, or perioperative factors, are associated with mortality or an increased need for hospital care. MATERIAL AND METHODS: The national cohort consisted of all live-born infants with simple d-TGA (TGA ± small ventricular septal defect, n = 127) born in Finland during 2004-2014. Data were collected from six national registries. Prenatal diagnosis and perinatal and perioperative factors associated with mortality and length of hospitalization were evaluated. RESULTS: Preoperative mortality was 7.9%, and the total mortality was 8.7%. The prenatal detection rate increased after introducing systematic fetal anomaly screening from 5.0% to 37.7% during the study period (P < .0001), but the total mortality rate remained unchanged. All prenatally diagnosed infants (n = 27) survived. Lower gestational age (odds ratio 0.68, P = .012) and higher maternal age at birth (odds ratio 1.16, P = .036) were associated with increased mortality in multivariable analysis. Older infant age at time of operation (P = .002), longer aortic clamp time (P < .001), and higher maternal body mass index (P = .027) were associated with longer initial hospital stay. An extended need for hospital care during the first year of life was multi-factorial. CONCLUSIONS: In our cohort, none of the prenatally diagnosed d-TGA infants died. As a result of the limited prenatal detection rates, however, the sample size was insufficient to reach statistical significance. The d-TGA infants born with lower gestational age and to older mothers had increased mortality.

Development of Human Leukocyte Antigen (HLA) Antibodies Against Vascular Homograft Donor in Pediatric Heart Transplant Recipients.

BACKGROUND The appearance of human leukocyte antigen (HLA) antibodies after solid organ transplantation predisposes recipients to graft dysfunction. In theory, vascular homografts, which are widely used in children with congenital heart defects, may cause allosensitization. MATERIAL AND METHODS In this single-center retrospective study, the presence of pre-existing HLA antibodies in pediatric heart transplant (HTx) recipients with a vascular homograft was evaluated in a cohort of 12 patients. HLA antibodies were screened before and after HTx and positive screening results were confirmed and identified using the Luminex® single antigen bead method. Endomyocardial biopsies (EMB) and coronary angiography studies were re-evaluated to assess the prevalence of acute rejections and coronary artery change in these patients. RESULTS At the time of HTx, 8 patients (67%) had HLA antibodies detected by the Luminex assay, none of which were heart donor specific (DSA). All patients had negative leukocyte crossmatch. One patient developed DSAs against homograft donor prior to HTx. After the HTx, 5 patients (42%) developed DSAs against the heart donor and 4 patients (40%) against the homograft donor. In 2 patients (17%), the antibodies were against both heart and homograft donors. The rejection rate or prevalence of coronary artery vasculopathy did not differ significantly between the homograft cohort and our historical controls. CONCLUSIONS Our results suggest that the prevalence of DSAs against homograft donor prior to HTx is relatively rare. However, almost half of the patients developed DSAs against homograft post-HTx. The clinical importance of these antibodies warrants further studies.

Complete Atrioventricular Septal Defect: Evolution of Results in a Single Center During 50 Years.

BACKGROUND: Operative mortality after complete atrioventricular septal defect (cAVSD) repair has improved vastly. Less improvement has been demonstrated regarding late mortality and reoperation rates, however. There is evident lack of comprehensive population-based studies analyzing the history and progress of the ever-changing operative results. METHODS: This is a 5-million population-based retrospective study of consecutive 388 cAVSD patients operated in Finland between 1962 and 2014. Data were collected using Children's Cardiac Surgical Registry of Children's Hospital at the Helsinki University Hospital, Finland. Mortality data and reoperation rates were analyzed on a decade-by-decade basis. RESULTS: During the early era, overall mortality was 17.4%, operative mortality constituting 10.9%. The operative results have improved significantly over the decades, and eventually, the last decade showed no mortality. A total of 23 late deaths occurred; of these, 20 were directly heart-related. Half of the late mortality occurred during the first postoperative year. The only significant risk factor for overall mortality was an earlier decade of operation (p < 0.001). Reoperation rates have not decreased but slightly increased over decades (p = 0.621), and reoperations have been performed mainly during the first year after the primary operation. Actuarial freedom from left side atrioventricular valve reoperation at 15 years was 90.9%. CONCLUSIONS: There has been an outstanding improvement in surgical results through the years even though the general operative approach has remained the same. Rates of reoperation have not been declining, but the reoperations are dated to early childhood years. The improvement in results has been ongoing.

Heart-Type Fatty Acid Binding Protein and High-Dose Methylprednisolone in Pediatric Cardiac Surgery.

OBJECTIVES: Corticosteroids possess cardioprotection in experimental cardiac ischemia/reperfusion. The authors hypothesized that if cardioprotection of corticosteroids occured during pediatric cardiac surgery, then methylprednisolone used in cardiopulmonary bypass prime would reduce postoperative concentrations of heart-type fatty-acid-binding protein, a cardiac biomarker. DESIGN: A double-blind, placebo-controlled, randomized clinical trial. SETTING: Operating room and pediatric intensive care unit of a university hospital. PARTICIPANTS: Forty-five infants and young children undergoing ventricular or atrioventricular septal defect correction. INTERVENTIONS: The patients received one of the following: 30 mg/kg of methylprednisolone intravenously after anesthesia induction (n = 15), 30 mg/kg of methylprednisolone in cardiopulmonary bypass prime solution (n = 15), or placebo (n = 15). MEASUREMENTS AND MAIN RESULTS: Plasma heart-type fatty-acid-binding protein (hFABP) was measured. Preoperatively, hFABP did not differ among the study groups. Methylprednisolone administered preoperatively and in the cardiopulmonary bypass prime solution reduced hFABP by 44% (p = 0.010) and 38% (p = 0.033) 6 hours postoperatively. hFABP significantly correlated with concomitant troponin T after protamine administration (R = 0.811, p < 0.001) and 6 hours postoperatively (R = 0.806, p < 0.001). CONCLUSIONS: Methylprednisolone in cardiopulmonary bypass prime solution administered only a few minutes before cardiac ischemia confered cardioprotection of the same magnitude as preoperative methylprednisolone as indicated by hFABP concentrations. Rapid cardioprotective actions of corticosteroids in pediatric heart surgery observed previously experimentally may have occurred.

High-Dose Methylprednisolone Has No Benefit Over Moderate Dose for the Correction of Tetralogy of Fallot.

BACKGROUND: The optimal dose of methylprednisolone during pediatric open heart surgical procedures is unknown. This study compared the antiinflammatory and cardioprotective effects of high and lower doses of methylprednisolone in children undergoing cardiac operations. METHODS: Thirty children, between 1 and 18 months old and undergoing total correction of tetralogy of Fallot, were randomized in double-blind fashion to receive either 5 or 30 mg/kg of intravenous methylprednisolone after anesthesia induction. Plasma concentrations of methylprednisolone, interleukin-6 (IL-6), IL-8, and IL-10, troponin T, and glucose were measured at anesthesia induction before administration of the study drug, at 30 minutes on cardiopulmonary bypass (CPB), just after weaning from CPB, and at 6 hours after CPB. Troponin T and blood glucose were also measured on the first postoperative morning. RESULTS: Significantly higher methylprednisolone concentrations were measured in patients receiving 30 mg/kg of methylprednisolone at 30 minutes on CBP, after weaning from CPB and at 6 hours after CPB (p < 0.001). No differences were detected in IL-6, IL-8, IL-10, or troponin concentrations at any time point. Blood glucose levels were significantly higher in patients receiving 30 mg/kg of methylprednisolone at 6 hours after CPB (p = 0.04) and on the first postoperative morning (p = 0.02). CONCLUSIONS: Based on the measured concentrations of interleukins or troponin T, a 30 mg/kg dose of methylprednisolone during pediatric open heart operations does not offer any additional antiinflammatory or cardioprotective benefit over a 5 mg/kg dose. Higher dose of methylprednisolone exposes patients more frequently to hyperglycemia.

The effect of continuous wound infusion of ropivacaine on postoperative pain after median sternotomy and mediastinal drain in children.

BACKGROUND: Postoperative pain after median sternotomy is usually treated with i.v. opioids. We hypothesized that continuous wound infusion of ropivacaine decreases postoperative morphine consumption and improves analgesia in children who undergo cardiac surgery. METHODS: This randomized, double-blind study comprised 49 children aged 1-9 years who underwent atrial septal defect (ASD) closure. Patients received continuous local anesthetic wound infiltration either with 0.2% ropivacaine, 0.3-0.4 mg·kg(-1) ·h(-1) (Group R) or with saline (Group C). Rescue morphine consumption, Objective Pain Scale (OPS), time to mobilization, time to enteral food intake, and time to discharge were recorded. RESULTS: There were no statistically significant differences in morphine consumption at 24, 48, and 72 h postsurgery between R and C groups. There was a weak evidence for a difference in the time to the first morphine administration after tracheal extubation to be longer for Group R than Group C (186.2 vs 81.0 min; 95% CI (-236.5, 26.2), P = 0.114). The incidence of nausea and vomiting were comparable between the groups. No signs or symptoms of local anesthetic toxicity were registered. CONCLUSIONS: Contrary to our hypothesis, continuous ropivacaine wound infusion did not reduce morphine consumption, pain score values, or nausea and vomiting in children who underwent ASD closure with median sternotomy and mediastinal drain.

Interleukin-7 promotes human regulatory T cell development at the CD4+CD8+ double-positive thymocyte stage.

Although mature human FOXP3(+) regulatory T cells are CD127 (IL-7Rα) negative, CD4(+)CD8(+) FOXP3(+) thymocytes express relatively high levels of CD127 and are responsive to IL-7. However, the role of IL-7 in human regulatory T cell development is poorly known. We show that at the CD4(+)CD8(+) stage, FOXP3(+) thymocytes are highly susceptible to apoptosis, and IL-7 selectively rescues them from death, leading to an increased frequency of FOXP3(+) cells. IL-7 also promotes the development of regulatory T cell phenotype by inducing up-regulation of FOXP3(+) and CTLA-4 expression. In contrast, IL-7 does not enhance proliferation of FOXP3(+)thymocytes or induce demethylation of FOXP3(+) regulatory T cell-specific demethylated region. After the CD4(+)CD8(+) stage, the FOXP3(+) thymocytes down-regulate CD127 expression but despite very low levels of CD127, remain responsive to IL-7. These results suggest that IL-7 affects human regulatory T cell development in the thymus by at least 2 distinct mechanisms: suppression of apoptosis and up-regulation of FOXP3(+) expression.

Resection of the stenotic segment with individually tailored anastomosis for symptomatic congenital tracheal stenosis in infants.

OBJECTIVES: To analyse retrospectively population-based results of congenital tracheal stenosis (CTS) repair in infants in Finland. METHODS: Data on infants who were operated on for CTS in Helsinki Children's Hospital between August 1988 and May 2013 were analysed retrospectively. Fibreoptic bronchoscopy was performed perioperatively and in follow-up of all the surviving patients. The median follow-up time was 7 (range 1-20) years. RESULTS: Thirteen infants were operated on for CTS. Resection of the stenotic segment with individually tailored anastomosis was used in 12 patients and slide tracheoplasty in 1 patient. The median age at the operation was 2.9 (range 0.2-19) months. Eight (62%) patients had associated cardiovascular defects, which were corrected during the same operation. The median length of stenosis was 35% (range 25-60%) of the total length of the trachea. The median length of time of postoperative mechanical ventilation was 10 (range 5-19) days. The median length of time of intensive care treatment was 15 (range 7-40) days. One patient died from hypoplastic lung tissue and fibrosis, and multiorgan failure. One patient required reoperation, and 3 other patients received balloon bronchodilatations postoperatively. There was no late mortality. All of the 12 survivors had a good outcome. CONCLUSION: Resection with individually tailored anastomosis with up to 55% of the stenotic segment of the trachea presented a good long-term outcome.

Outcome of pediatric heart transplantation recipients treated with ventricular assist device.

This study was conducted to evaluate the long-term prognosis of pediatric HTx patients treated with VAD before transplantation. The clinical data of six patients bridged to HTx with Berlin Heart EXCOR pediatric device were analyzed retrospectively. Information about graft function, CA results, and EMB findings as well as appearance DSA was collected. Also, information about growth and cognitive function was analyzed. These findings were compared with age-, gender-, and diagnosis-matched HTx patients. During the median follow-up time of four and half yr after HTx, the prognosis including graft function, number of rejection episodes, and incidence of coronary artery vasculopathy, growth and cognitive development did not differ between VAD-bridged HTx patients compared with control patients. In both groups, one patient developed positive DSA titer after HTx. Our single-center experience suggests that the prognosis of pediatric HTx patients treated with VAD before transplantation is not inferior to that of other HTx patients.

Prevention of postoperative pericardial adhesions in children with hypoplastic left heart syndrome.

Reoperations for congenital cardiac defects are associated with an increased surgical risk due to adhesions. We compared the capability of a polytetrafluoroethylene (PTFE) membrane, synthetic polyethyleneglycol hydrogel (PEG), and a combination of them to prevent postoperative pericardial adhesions in patients with hypoplastic left heart syndrome (HLHS). Eighteen consecutive patients with HLHS were included. At the end of the Norwood I operation the cranial and the caudal half of the heart of each patient was randomized to receive a PTFE membrane, a synthetic PEG, a combination of them, or no treatment (control). Tenacity and density of adhesions, epicardial visibility, and adhesions between the heart and the sternum were analyzed semiquantitatively at a subsequent bidirectional Glenn operation. The PTFE membrane significantly decreased adhesion formation between the heart and the sternum (P<0.001). However, the PTFE membrane, with or without synthetic PEG, impaired epicardial visibility (P<0.05) when compared to synthetic PEG or controls. Synthetic PEG alone did not significantly reduce the formation of pericardial adhesions. Tenacity and density of adhesions were not affected by any of the treatment modalities. The PTFE membrane significantly decreases postoperative adhesions between the heart and the sternum, but impairs epicardial visibility. Synthetic PEG does not prevent formation of pericardial adhesions.

Cutting edge: human CD4-CD8- thymocytes express FOXP3 in the absence of a TCR.

The best candidate for regulatory T (Treg) cell lineage-determining factor is currently the Forkhead box transcription factor FOXP3. FOXP3 up-regulation has been linked to TCR-mediated signals, and in mice the abrogation of TCR expression or signals also prevents FoxP3 expression. In contrast, the TCR dependence of human FOXP3 is assumed but not established. In this study we show on a single cell level that 1.4% (range 0.1-3.8%) of CD4(-)CD8(-) thymocytes in healthy humans express FOXP3, two thirds of them without any detectable alphabeta TCR. These TCR(-)FOXP3(+) cells were mostly CD25(-) and did not express gammadelta TCR or B cell, NK cell, or monocyte-associated markers. Like mature Treg cells, they were mostly CD2(+)CD127(low) and expressed cytoplasmic CTLA-4. Our results suggest that in immature human thymocytes the expression of FOXP3 precedes surface TCR, in which case TCR-mediated signals cannot be responsible for the thymic up-regulation of FOXP3.

Coronary sinus orifice atresia with left superior vena cava in patients with univentricular heart.

Two patients with hypoplastic left heart syndrome had coronary sinus orifice atresia with persistent left superior vena cava. Both patients underwent successfully coronary sinus unroofing. One underwent surgery at the time of the bidirectional Glenn procedure and the other before creation of a total cavopulmonary connection. According to our population-based database, 10.3% of patients with univentricular heart have persistent left superior vena cava, and 2.3% have associated coronary sinus orifice atresia. Our cases highlight the importance of recognizing this anomaly in patients with univentricular heart to avoid high coronary venous pressure, which is potentially lethal.

Positive genetic test led to an early diagnosis of myxoma in a 4-year-old boy.

Less than 10% of cardiac myxomas are familial. These familial cases are related to Carney complex, a multiple neoplasia and lentiginosis syndrome. Mutations in the PRKAR1alpha gene are the cause of Carney complex in most patients. We report a boy, who had PRKAR1alpha gene mutation, and atrial myxoma that was diagnosed in a routine echocardiographic study at the age of four years. Surgical excision of myxoma was performed. This case demonstrates the benefit of screening genetically the kindreds of patients with familial myxomas, and the importance of close follow-up of individuals affected with this mutation irrespective of age.

MRI in the assessment of growth arrest.

OBJECTIVE: To compare MRI with X-ray tomography in the assessment of bone bridges across the growth plate. MATERIALS AND METHODS: The investigation consisted of two parts. (1) Eleven children with 13 epiphyses suspected of physeal growth arrests were examined with conventional X-ray tomography and MRI. The bar was post-traumatic in eight children, postinfectious in two and due to a congenital, operated pes equinovarus in one. Three blinded radiologists separately evaluated the examinations retrospectively. (2) The images of four children with known physeal bars in the ankle were mixed with 36 normal examinations obtained 1-year after trauma and evaluated blindly by three radiologists. RESULTS: In 5 of 13 epiphysis, the bony bridge was considered smaller on MRI than on X-ray tomography, in 7 of 13 it was considered equal, while it was larger only in one. The interobserver agreement (weighted kappa) was 0.8 (very good) for MRI, 0.76 (good) for X-ray tomography and 0.60 (moderate) for radiographs. The four bony bridges were easily detected on MRI. CONCLUSIONS: Compared to MRI, the size of bridges was estimated larger by tomography in about half of the patients.