Henrik Holmstrøm

Plasma levels of natriuretic peptides and hemodynamic assessment of patent ductus arteriosus in preterm infants.

The main purpose of this study was to investigate whether circulating natriuretic peptides in premature infants reflect the hemodynamic significance of a patent ductus arteriosus (PDA). The study comprises 120 examinations in 55 premature infants with a mean gestational age of 27.2 wk and a mean birthweight of 933 g. Based on clinical and echocardiographic findings, the hemodynamic influence of ductal shunting was classified as small, moderate or large. Blood samples for N‐terminal proatrial natriuretic peptide (Nt‐proANP) and brain natriuretic peptide (BNP) were analysed after completion of the clinical part of the study. Linear regression indicated a very strong association between Nt‐proANP and BNP (adjusted R2= 0.89). The mean levels of Nt‐proANP and BNP increased with the size of the shunt through a PDA, and peptide values followed hemodynamic alterations. The size of PDA accounted for 50% and 47% of the total variation in the plasma values of Nt‐proANP and BNP, respectively. In detecting an echocardio‐graphically significant PDA, the area under a ROC curve was 0.94 for Nt‐proANP and 0.90 for BNP.

Low‐dose warfarin for the prevention of central line‐associated thromboses in children with malignancies—a randomized, controlled study

Background: Central venous lines (CVLs) are essential in the care of children with malignancies, but are associated with venous thromboembolism (VTE) and infections. Effective and safe prophylactic approaches are deficient. Aim: To perform a study of adjusted low‐dose warfarin for the prevention of CVL‐related VTE in children with malignancies. Methods: Children with newly diagnosed cancer, a CVL in a jugular vein and an expected treatment period of over 6 mo were eligible for the study. Participants were randomized to low‐dose warfarin, with intended international normalized ratio (INR) 1.3–1.9, or to a control group. Primary outcome was VTE in a jugular vein diagnosed by ultrasonography at 1, 3 and 6 mo after inclusion. Secondary outcome was CVL‐related infections, mainly measured as days on antibiotics or positive blood cultures. Results: The study enrolled 73 children, and 62 completed it fully. Asymptomatic CVL‐related VTE was frequent (42%), but often transient. Regardless of severity, timing and duration, CVL‐related VTE was equally frequent among children on warfarin as compared to controls (p=0.44). Low‐dose warfarin (p=0.59) or jugular CVL‐related VTE (p=0.91) did not have any impact on days on antibiotics, but we observed a tendency towards an association between CVL‐related VTE and positive blood cultures (p=0.15).

Central line-associated venous late effects in children without prior history of thrombosis

Background: The frequency of asymptomatic central line‐associated thromboses is high and well recognized among children with cancer, while the long‐term consequences are mainly unknown. Aim: In a cross‐sectional study, we evaluated clinical and radiological venous outcome in children with previous long‐standing intravascular catheters. Methods: The study enrolled 71 children previously treated for malignant or haematological diseases, 4–180 (median 37) mo after removal of their central lines. Inclusion criteria were a prior central line in a jugular vein for a minimum of 6 mo and no previous history of thrombosis. The children had clinical examination for post‐thrombotic syndrome (PTS) and Doppler ultrasonography of the central neck veins. Twelve children had additional venous magnetic resonance imaging (MRI). But no kind of venography was performed in the remaining. Results: We observed mild PTS with increased superficial collaterals in four children (6%), but no cases of more severe PTS. None complained of symptoms related to venous late effects. By ultrasonography, post‐thrombotic venous alterations were detected in 17 children (24%), and five of these had complete occlusion of the veins. The sensitivity for pathologically increased collaterals to identify occlusive thrombosis was 0.6, while the specificity was 0.98. Occlusive venous thromboembolism was associated with the total number of central venous lines (CVLs; p=0.002), previous severe CVL‐associated infections (p=0.001) and duration of central line in place (p=0.042).

Diagnostic value of family histories of thrombosis to identify children with thrombophilia.

Thrombophilia screening is a time-consuming and expensive procedure. Information about thromboembolism among relatives may be a simple method to identify those at risk of having thrombophilia. In a cross-sectional clinical study the authors have investigated the role of such family histories to detect children with thrombophilia. In 202 children a family history of venous or arterial thromboembolism was recorded. The participants were either children with congenital heart defects at the time of a scheduled cardiac catheterization (n = 134) or children with newly diagnosed cancer (n = 68). Questions were answered, on the spot, by the parents, at the same time as blood samples for thrombophilia screening were taken. Questions about family history of thromboembolism were completed in 184 children, of whom 114 children (62%) were positive, and 35 of these had relatives with venous thromboembolic events. Only one child had an affected first-degree relative. Thrombophilic alterations were observed in 60 children (30%), and 25 of these were defined as inherited. A positive family history of venous origin increased the relative risk of a child having inherited thrombophilia to 2.35 (95% confidence interval 1.1–5.2). Information about familial arterial thromboembolism was not useful in spotting children with prothrombotic risk factors. These results indicate that questioning about family history of venous thromboembolism may identify children with genetic thrombophilia, but the association is not strong. The authors encourage similar larger-scale studies to enlighten the issue fully.

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.

Symptoms of communication and social impairment in toddlers with congenital heart defects

BACKGROUND With the advances in congenital cardiac surgery and medical management, mortality rates for congenital heart defects (CHD) have declined remarkably. As the number of CHD survivors have increased there is a growing focus on developmental morbidity. The objective of the current study is to compare symptoms of communication and social impairment in 18-month-old children with different severity of CHD with those of controls. METHOD We linked prospective data from the Norwegian Mother and Child Cohort Study, conducted by the Norwegian Institute of Public Health, with a nationwide medical CHD registry and identified 198 18-month-olds with CHD in a cohort of 47,692. Three groups of CHD were distinguished: mild/moderate (n= 122), severe (n= 54) and CHD with comorbidity (n= 22). Mothers reported on the childs communication and social skills by completing items from the Ages and Stages Questionnaire as part of the Norwegian Mother and Child Cohort Study. RESULTS Children aged 18 months old with CHD differed significantly from controls in levels of symptoms of communication impairment (P≤ 0.0001) and social impairment (P≤ 0.0001). The largest differences were found in children with CHD and comorbidity. Children with severe CHD also showed higher levels of both symptoms of communication and social impairment. Children with mild/moderate CHD showed a small difference only in symptoms of communication impairment. CONCLUSION Children with severe CHD and CHD with comorbidity show more symptoms of communication and social impairment compared with a large cohort at the age of 18 months. It is important to broaden the scope of inquiry to involve communication and social developmental domains.

Oral anticoagulation with warfarin is significantly influenced by steroids and CYP2C9 polymorphisms in children with cancer.

Clinical management of warfarin therapy is complex, and dosing algorithms do not include genetic factors or interactions with other drugs for warfarin dose determinations. We evaluated the interaction of warfarin and CYP2C9 polymorphisms and concomitant corticosteroids in 29 children with cancer. Children with heterozygous polymorphisms of CYP2C9 achieved target INR sooner and more frequently had INR above the target level, compared to children without mutations. Children on concomitant steroids had significantly lower warfarin requirements. Thus, awareness of CYP2C9 genotype and steroid‐induced responsiveness to warfarin may be important when administrating oral anticoagulation in children. Pediatr Blood Cancer 2008;50:710–713.

Motor and Social Development in 6-Month-Old Children with Congenital Heart Defects

OBJECTIVE To assess whether the development of children with varying severity of congenital heart defect (CHD) differs from that of children without CHD at age 6 months. STUDY DESIGN A total of 236 children with CHD were compared with 61 032 children from the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health. Diagnostic and treatment information was retrieved from a nationwide CHD registry. Four groups of CHD were distinguished: mild (n = 92), moderate (n = 50), severe (n = 70), and CHD with comorbidity (n = 24). At child age 6 months, the childrens mothers reported on motor and social development by using the Mother and Child Questionnaire. RESULTS After adjusting for confounders (ie, birth weight), severe CHD increased the odds of gross motor impairment (odds ratio [OR], 3.78; 95% CI, 1.97-7.25) and fine motor impairment (OR, 2.04; 95% CI, 0.96-4.33). CHD with co-morbidity (eg, intestinal malformations) increased the odds of gross motor impairment (OR, 3.00; 95% CI, 0.95-9.51), fine motor impairment (OR, 5.47; 95% CI, 2.03-14.74), and social impairment (OR, 3.43; 95% CI, 1.40-8.41). CONCLUSION Increased odds of motor impairment are present already in infancy in severe CHD and CHD with comorbidity. CHD with comorbidity increases the odds of social impairment.

Patients with Pulmonary Hypertension Related to Congenital Systemic‐to‐Pulmonary Shunts are Characterized by Inflammation Involving Endothelial Cell Activation and Platelet‐mediated Inflammation

OBJECTIVE We examined inflammatory mediators in patients with pulmonary hypertension related to congenital systemic-to-pulmonary shunts and the change in these markers during treatment with bosentan. BACKGROUND Inflammatory mechanisms probably play a pathogenic role in idiopathic pulmonary arterial hypertension. Their involvement in pulmonary hypertension related to congenital systemic-to-pulmonary shunts is largely unknown. PATIENTS AND METHODS Plasma levels of several inflammatory mediators were determined by enzyme immunoassays in 14 children and adolescents with pulmonary hypertension related to congenital systemic-to-pulmonary shunts before and after 12 months treatment with bosentan, and compared with levels in 54 healthy controls. RESULTS The patients were characterized by increased plasma levels of von Willebrand factor ( approximately 2.5-fold), C-reactive protein ( approximately 3.5-fold), and soluble CD40 ligand ( approximately 2.5-fold) as compared with controls, representing markers of endothelial cell activation, systemic inflammation, and platelet-mediated inflammation, respectively. Patients also had significantly elevated plasma levels of osteoprotegerin ( approximately 1.6-fold). Within the study group, N-terminal pro-brain natriuretic peptide levels correlated significantly with the concentrations of C-reactive protein (r= 0.61, P < .027) and von Willebrand factor (r= 0.74, P= .004). Except for a decline in monocyte chemoattractant protein-1 and receptor activator of nuclear factor-kappaB ligand, bosentan therapy did not attenuate the systemic inflammation. CONCLUSION Children and adolescents with pulmonary hypertension related to congenital systemic-to-pulmonary shunts are characterized by enhanced systemic inflammation involving increased endothelial cell activation and platelet-mediated inflammation. These inflammatory responses seem essentially to be unmodified by bosentan, potentially representing new targets for therapy in this disorder.

Children with acute lymphoblastic leukaemia have high plasma levels of total homocysteine at time of diagnosis

Objective. Cancer can induce venous thromboembolic complications for various reasons. As part of a greater study, acquired and congenital prothrombotic risk factors were investigated in children with leukaemia or non‐Hodgkins lymphoma and compared with similar investigations in children with congenital heart defects. Material and methods. Blood samples were taken from 60 children with newly diagnosed leukaemia or lymphoma and 133 children with congenital heart defects in the course of a scheduled cardiac catheterization. When children with cancer were in remission, analyses of acquired prothrombotic risk factors were repeated. Children with cancer were observed for symptoms of thromboembolism throughout their treatment period. Results. Total homocysteine levels were significantly raised in children with cancer (median value 10.0 µmol/L) as compared with the levels in children with congenital heart diseases (5.0 µmol/L) (p<0.001), while children with acute lymphoblastic leukaemia had the highest values. The median level of lipoprotein(a) was slightly increased in children with newly diagnosed leukaemia or lymphoma (105 mg/L versus 100 mg/L, p<0.001), and levels of coagulation inhibitors were higher (p<0.001). Total homocysteine levels normalized when children attained remission of cancer disease. Two children had symptoms of acute thrombosis. Conclusions. Raised concentrations of total homocysteine were frequent in children with newly diagnosed cancer, but this normalized when the children were in remission. The clinical significance of our observations and the impact on venous thromboembolism have yet to be defined.