Gaute Døhlen

Achievements in Congenital Heart Defect Surgery: A Prospective, 40 Year Study of 7038 Patients

Background— This article presents an update of the results achieved by modern surgery in congenital heart defects (CHDs) over the past 40 years regarding survival and the need for reoperations, especially focusing on the results from the past 2 decades. Methods and Results— From 1971 to 2011, all 7038 patients <16 years of age undergoing surgical treatment for CHD at Rikshospitalet (Oslo, Norway) were enrolled prospectively. CHD diagnosis, date, and type of all operations were recorded, as was all-cause mortality until December 31, 2012. CHDs were classified as simple (3751/7038=53.2%), complex (2918/7038=41.5%), or miscellaneous (369/7037=5.2%). Parallel to a marked, sequential increase in operations for complex defects, median age at first operation decreased from 1.6 years in 1971 to 1979 to 0.19 years in 2000 to 2011. In total, 1033 died before January 1, 2013. Cumulative survival until 16 years of age in complex CHD operated on in 1971 to 1989 versus 1990 to 2011 was 62.4% versus 86.9% (P<0.0001). In the comparison of patients operated on in 2000 to 2004 versus 2005 to 2011, 1-year survival was 90.7% versus 96.5% (P=0.003), and 5-year cumulative survival was 88.8% versus 95.0% (P=0.0003). In simple versus complex defects, 434 (11.6%) versus 985 (33.8%) patients needed at least 1 reoperation before 16 years of age. In complex defects, 5-year cumulative freedom of reoperation among patients operated on in 1990 to 1999 versus 2000 to 2011 was 66% versus 73% (P=0.0001). Conclusions— Highly significant, sequential improvements in survival and reductions in reoperations after CHD surgery were seen. A future challenge is to find methods to reduce the need for reoperations and further reduce long-term mortality.Background— This article presents an update of the results achieved by modern surgery in congenital heart defects (CHDs) over the past 40 years regarding survival and the need for reoperations, especially focusing on the results from the past 2 decades. Methods and Results— From 1971 to 2011, all 7038 patients <16 years of age undergoing surgical treatment for CHD at Rikshospitalet (Oslo, Norway) were enrolled prospectively. CHD diagnosis, date, and type of all operations were recorded, as was all-cause mortality until December 31, 2012. CHDs were classified as simple (3751/7038=53.2%), complex (2918/7038=41.5%), or miscellaneous (369/7037=5.2%). Parallel to a marked, sequential increase in operations for complex defects, median age at first operation decreased from 1.6 years in 1971 to 1979 to 0.19 years in 2000 to 2011. In total, 1033 died before January 1, 2013. Cumulative survival until 16 years of age in complex CHD operated on in 1971 to 1989 versus 1990 to 2011 was 62.4% versus 86.9% ( P <0.0001). In the comparison of patients operated on in 2000 to 2004 versus 2005 to 2011, 1-year survival was 90.7% versus 96.5% ( P =0.003), and 5-year cumulative survival was 88.8% versus 95.0% ( P =0.0003). In simple versus complex defects, 434 (11.6%) versus 985 (33.8%) patients needed at least 1 reoperation before 16 years of age. In complex defects, 5-year cumulative freedom of reoperation among patients operated on in 1990 to 1999 versus 2000 to 2011 was 66% versus 73% ( P =0.0001). Conclusions— Highly significant, sequential improvements in survival and reductions in reoperations after CHD surgery were seen. A future challenge is to find methods to reduce the need for reoperations and further reduce long-term mortality. # CLINICAL PERSPECTIVE {#article-title-36}

Reoxygenation of hypoxic mice with 100% oxygen induces brain nuclear factor-kappa B.

Oxidative stress is closely related to inflammation, a pathologic process characterized by activation of the transcriptional factor nuclear factor-kappa B (NF-κB). We have used transgenic NF-κB luciferase reporter mice to assess brain NF-κB activity noninvasively in living mice. We have studied NF-κB activation in hypoxic mice reoxygenated with either 21% O2 (room air) or 100% O2. Forty-one mice exposed for 2 h to 4% oxygen and then randomized to reoxygenation with pure oxygen or room air were investigated. A control mouse was dedicated to every mouse exposed to hypoxia. In vivo luminescence originated from brain was measured from mice 2 d before hypoxia, and 3 h after reoxygenation. A change in luminescence between the mouse exposed to hypoxia and its control demonstrates an alteration in NF-κB activity. Because of high mortality among males, only females were included. Six female mice died. Nineteen female mice were reoxygenated with room air, 16 with pure oxygen. We observed a significantly higher luminescence in the brain of the 100% O2 group versus the 21% O2 group. Our data indicate that brain NF-κB activity is increased in mice subjected to 4% oxygen followed by reoxygenation with 100% oxygen. However, when reoxygenation occurs with 21% O2 (room air), no elevation in NF-κB activity is observed. Thus, reoxygenation with room air may induce less brain inflammation than reoxygenation with pure oxygen.

Sudden unexpected death in children with congenital heart defects

AIMS Congenital heart defects (CHDs) are the most common birth defects and are an important cause of death in children. The fear of sudden unexpected death has led to restrictions of physical activity and competitive sports. The aim of the present study was to investigate the rate of sudden unexpected deaths unrelated to surgery in children 2-18 years old with CHDs and, secondarily, to determine whether these deaths were related to cardiac disease, comorbidity, or physical activity. METHODS AND RESULTS To identify children with CHDs and to determine the number of deaths, data concerning all 9 43 871 live births in Norway in 1994-2009 were retrieved from the Medical Birth Registry of Norway, the Cardiovascular Disease in Norway project, the Oslo University Hospitals Clinical Registry for Congenital Heart Defects and the Norwegian Cause of Death Registry. Survivors were followed through 2012, and information for the deceased children was retrieved from medical records at Norwegian hospitals. Among 11 272 children with CHDs, we identified 19 (0.2%) children 2-18 years old who experienced sudden unexpected deaths unrelated to cardiac surgery. A cardiac cause of death was identified in seven of these cases. None of the children died during physical activity, whereas two children survived cardiac arrest during sports. CONCLUSION Sudden unexpected death was infrequent among children with CHDs who survived 2 years of age. Comorbidity was common among the children who died. This study indicates that sudden unexpected death in children with CHDs rarely occurs during physical activity.

Antioxidant activity in the newborn brain: a luciferase mouse model.

Introduction: Oxidative stress in the newborn period may cause cell injury and inflammation if the antioxidant capacity is insufficient. To monitor antioxidant and inflammatory activity we examined by in vivo imaging various strains of luciferase reporter mice whose light-emitting properties were regulated by response elements or complete promoters related to oxidative stress and/or inflammation. The aim of this study is to present a model that can monitor genetic activity in vivo during pregnancy and the first 10 days of life. Methods: One mouse strain reports the activity of nuclear factor-ĸB (NF-ĸB) activity, a transcription factor essential for modulating inflammation, apoptosis, differentiation and cell growth. A second mouse strain reports on superoxide dismutase 1-promoter activity. A third strain reports the promoter activity of γ-glutamylcysteine synthetase, the rate limiting enzyme in glutathione production, and the last strain reports on antioxidant responsive element (ARE)/electrophil responsive element. Wild-type female mice mated with NF-ĸB mice were imaged through pregnancy to monitor intrauterine NF-ĸB activation. Results: Intrauterine NF-ĸB activity increased dramatically from day 17 towards labor. During the first 4 days of life luminescence measured was intense in all mice with distinct strain differences. All strains had high luminescence levels at day 1 and a considerably lower level at day 10. Conclusion: This model allows investigation of the transcriptional regulation of key proteins related to oxidative stress and inflammation in pregnancy and the first days of life. With very little stress to the newborn animals genetic activity can be monitored day by day.

Mortality and complications in 3495 children with isolated ventricular septal defects

Background Ventricular septal defects (VSDs) are the most common congenital heart defects (CHDs). Previous studies indicate an increased risk of endocarditis, aortic regurgitation, left ventricular outflow tract obstructions, pulmonary hypertension, arrhythmias and sudden death in patients with isolated VSDs. The present nationwide cohort study reports mortality and cardiac complications requiring hospitalisation or intervention in children with isolated VSDs. Methods and results Medical information concerning all 943 871 live births in Norway in 1994–2009 was retrieved from the Medical Birth Registry of Norway, the Cardiovascular Disease in Norway project, the Oslo University Hospitals Clinical Registry of Congenital Heart Defects and the Norwegian Cause of Death Registry. Isolated VSDs were identified in 3495 children without known chromosomal aberrations or extracardiac malformations. Surgical or catheter-based treatment of VSD was performed in 181 (5.2%) cases. Twelve (0.3%) children with VSDs died before 2013. There was no operative mortality, and no excess mortality in children with isolated VSDs compared with children without VSDs (adjusted HR 0.8 (0.5 to 1.4), p=0.48). The following conditions were recorded as possible cardiac complications of the VSDs: endocarditis in 3 children (0.9‰), aortic regurgitation in 12 children (3.4‰), left ventricular outflow tract obstructions in no children (0.0‰), pulmonary hypertension in 1 child (0.3‰) and arrhythmias in 16 children (4.6‰). Conclusions The entire group of children with isolated VSDs had a favourable prognosis without excess mortality. Cardiac complications requiring hospitalisation or intervention, including endocarditis, aortic regurgitation, left ventricular outflow tract obstructions, pulmonary hypertension and arrhythmias, were infrequent during childhood. Trial registration number NCT02026557.

Trends in Mortality of Congenital Heart Defects.

OBJECTIVE The aim of the present nationwide cohort study was to describe trends in 1-year mortality in live-born children with congenital heart defects in Norway 1994-2009 and to assess whether changes in the proportion of terminated pregnancies and altered operative mortality have influenced these trends. METHODS Medical information concerning all 954 413 live births, stillbirths, and late-term abortions in Norway, 1994-2009, was retrieved from the Medical Birth Registry of Norway, the Cardiovascular Disease in Norway project, the Oslo University Hospitals Clinical Registry for Congenital Heart Defects and the Norwegian Cause of Death Registry. Survivors were followed through 2012. RESULTS The 1-year cumulative mortality proportion during the study period was 17.4% for children with severe congenital heart defects and 3.0% for children with nonsevere congenital heart defects. The 1-year cumulative mortality proportion among live born children with severe congenital heart defects decreased 3.6% (95% CI: -5.4, -1.5) per year. The total mortality of severe congenital heart defects was unchanged when including stillbirths and late-term abortions with severe congenital heart defects. The proportion of stillbirths or terminated pregnancies with severe congenital heart defects among all pregnancies with severe congenital heart defects, was on average 8.8% over the entire period with an annually increase of 16.6% (11.4, 18.0). The mean operative mortality in children with severe congenital heart defects was 8.4% and decreased by 9.0% (-11.9, -5.9) per year. CONCLUSIONS The 1-year mortality of severe congenital heart defects among live births, 1994-2009, declined in Norway. The downward trend in mortality may be explained by a more frequent use of termination of affected pregnancies, and the reduced operative mortality of severe congenital heart defects.

Cerebral microemboli detection and differentiation during transcatheter closure of atrial septal defect in a paediatric population.

INTRODUCTION The aim of this prospective study was to determine the frequency and composition of cerebral microemboli in a paediatric population during transcatheter atrial septal defect closure. METHODS Multi-frequency transcranial Doppler was used to detect microembolic signals in the middle cerebral artery of 24 patients. Embolic signals were automatically identified and differentiated according to their composition, gaseous or solid. The procedure was divided into five periods: right cardiac catheterisation; left cardiac catheterisation; pulmonary angiography; balloon sizing; and device placement. RESULTS Microemboli were detected in all patients. The median number of signals was 63 and over 95% gaseous. The total number of microembolic signals detected during two periods - balloon sizing and sheath placement and device placement - was not significantly different (median: 18 and 25, respectively) but was significantly higher than each of the other three periods (p<0.001). In eight patients, the device was opened more than once and the number of embolic signals decreased with each successive device deployment. There was no correlation between the number of microembolic signals and fluoroscopic time, duration of procedure, age, or device size. CONCLUSION This is the first study to investigate the timing and composition of cerebral microemboli in a paediatric population during cardiac catheterisation. Microembolic signals were related to specific catheter manipulations but were not associated with fluoroscopic time or duration of procedure.

NF‐κB Activity in Perinatal Brain During Infectious and Hypoxic‐Ischemic Insults Revealed by a Reporter Mouse

Infants suffering from infection or hypoxia–ischemia around the time of birth can develop brain damage resulting in life‐long impairment such as cerebral palsy, epilepsy and cognitive disability. Inflammation appears to be an important contributor irrespective of whether the primary event is infection or hypoxia–ischemia. Activation of the transcription factor NF‐κB is a hallmark of inflammation. To study perinatal brain inflammation, we developed a transgenic reporter mouse for imaging NF‐κB activity in live animals and tissue samples. The reporter genes firefly luciferase and a destabilized version of enhanced GFP (dEGFP) were regulated by common NF‐κB sites using a bidirectional promoter. Luciferase activity was imaged in vivo, while dEGFP was detected at cellular level in tissue sections. In newborn mice subjected to experimental models of infections or hypoxia–ischemia; luciferase signal increased in brains of live animals. In brain sections dEGFP expression, revealing NF‐κB activation was observed in the endothelial cells of the blood–brain barrier in all disease models. In meningitis and hypoxia–ischemia expression of dEGFP was also induced in perivascular astrocytes. In conclusion, by using this transgenic reporter mouse in experimental models of perinatal complications, we could assess NF‐κB activity in vivo and subsequently determine the cellular origin in the tissues.

[Percutaneous catheter-based implantation of artificial pulmonary valves in patients with congenital heart defects].

BACKGROUND Percutaneous catheter-based implantation of artificial heart valves is a new technique that may supplement surgery and which may be used more in the future. We here report our first experience with implantation of artificial pulmonary valves in children with congenital heart defects. MATERIAL AND METHODS Eligible patients were those with symptoms of heart failure combined with stenosis and/or insufficiency in an established artificial right ventricular outflow tract. The valve was inserted through a catheter from a vein in the groin or neck. Symptoms, echocardiography, invasive measurements and angiography were assessed for evaluation of treatment effect. Our treatment results are reported for the period April 2007-September 2009. RESULTS Ten patients (seven men and three women, median age 17 years) were assessed. The procedure reduced pressure in the right ventricle (p = 0.008) and resolved the pulmonary insufficiency in all patients. The median time in hospital was two days. No patients had complications that were directly associated with the implantation procedure. One patient developed a pseudoaneurysm in the femoral artery, another had a short-lasting fever two days after the procedure and one patient experienced a stent fracture that required surgery 9 months after the implantation. After 6 months all patients had a reduced pressure gradient in the right ventricular outflow tract (p = 0.008), the pulmonary insufficiency had improved (p = 0.006) and they all reported improval of symptoms. These results persisted for at least 24 months for the four patients who were monitored until then. INTERPRETATION Percutaneous catheter-based implantation of artificial pulmonary valves improves hemodynamics in the right ventricle of selected patients with congenital heart defects. A randomized controlled study should be undertaken to provide a stronger evidence-base for usefulness of this procedure.

Pulmonary Valve Replacement With a Bovine Pericardial Valve A Five Year Follow-Up Study

Objectives: From a population of 90 patients after pulmonary valve replacement with a biological valve (Carpentier-Edwards Perimount valve), 56 of 80 available patients were examined five years after surgery. Background: Pulmonary valve replacement is needed in many patients with congenital heart disease. Homografts have limited availability and predictable degeneration, and mechanical valves require anticoagulation. No superiority of one kind of pulmonary valve replacement has been shown. Biological valves that are readily available are being used and evaluated in increasing numbers. Methods: In this cross-sectional study, five years following surgery, data were gathered from hospital charts, echocardiography, stress echocardiography, magnetic resonance imaging, and exercise testing. Results: In 90 patients, there were three new valve replacements, one early cardiac death, and four late noncardiac deaths. Echocardiographic assessment of the study group showed pulmonary Doppler velocities (m/s) before, after operation, and at five-year follow-up of 2.8 ± 1.1, 1.6 ± 0.4, and 2.3 ± 0.7, respectively. The assessed insufficiencies (0-3) at the same times were 2.3 ± 1.0, 0.3 ± 0.4, and 1.1 ± 0.8. Maximal oxygen uptake increased from 65.6% ± 10.1% to 77.1% ± 18.2% of predicted and QRS width increased by 7 ± 23ms. Valve degeneration could be associated with young age but not with diagnosis or valve size. Conclusion: In our study, the biological valve in the pulmonary position showed excellent mid-term results with few reoperations, low gradients, and mild to moderate insufficiency. Oversizing, in contrast to young age, was not a risk factor for valve degeneration. In younger patients, this allows later percutaneous replacement, reducing the need for further surgery. However, longer follow-up is needed.