HYPERINSULINISM-HYPERAMMONEMIA: AN UNUSUAL CAUSE OF HYPOKETOTIC HYPOGLYCEMIA
HARVENGT, Julie ; LEBRETHON, Marie-Christine ; et al
Poster (2010, March)
BACKGROUND Etiological diagnosis of hypoglycaemia in infancy is a complex process, requiring careful integration of detailed history, clinical and laboratory data. The causes of recurrent infant ... [more ▼]
BACKGROUND Etiological diagnosis of hypoglycaemia in infancy is a complex process, requiring careful integration of detailed history, clinical and laboratory data. The causes of recurrent infant hypoglycaemia include excessive insulin secretion, surreptitious insulin administration, deficiency of counter-regulatory hormones and inborn errors of metabolism. CLINICAL CASE A 10 month old girl was admitted at our emergency unit for generalized seizures without fever. Routine laboratory investigations were normal but blood glucose level was at 31 mg/dl. No ketone bodies were found in the urine. Past medical history revealed failure to thrive. A first seizure episode at 8 months of age during family’s holiday is reported. Tests performed in a foreign hospital revealed glycaemia at 36mg/dl. During her stay in our paediatric unit, several hypoglycaemias (31-45 mg/dl) were documented related to irritability as initial symptom of neuroglucopaenia. Detailed medical history revealed that fast tolerance was shorten with hypoglycaemia documented between one to three hours after eating. Clinical examination showed absence of hepatomegaly and failure to thrive: weight, -3SD; height, -2SD, and cranial circumference -2SD. At the time of hypoglycaemia, urinary tests revealed absence of ketonuria, that basically evokes hyperinsulinism or fatty acid oxidation deficiencies but these deficiencies were rapidly excluded by the very short fast state. Blood acylcarnitine profile was normal. Hyperinsulinism is defined by a ratio glycaemia/insulin below 4 with insulin values not necessary high. Since hyperinsulinism can not be excluded with only one blood measure, series of taking were performed during 24 hours. One of these tests was clearly positive with ratio equal to 2.3 (glycaemia at 41 mg/dl, insulin at 18µU/ml). For this patient, ammonemia was also tested with values ranged from 242 to 275 µg/dl (normal < 125) and the diagnosis of hyperinsulinism/hyperammoniemia (hi/ha) was made and confirmed by molecular analysis (mutation c.965G>A (p.R269H) in the GLUD1 gene). The treatment consists in this case by diazoxide and reduction of leucine intakes (< 200 mg of leucine/meal). DISCUSSION Differential diagnosis of hypoglycaemia with absence of ketonuria and absence of hepatomegaly include fatty acids β-oxidation defects, ketogenesis defects and hyperinsulinisms. Short fasting and post-prandial induced hypoglycaemia pointed to hyperinsulinism in our patient. Congenital hyperinsulinism includes KATP, glucokinase or glutamate deshydrogenase mutations. Hi/ha syndrome is due to activating mutations in the GLUD1 gene, coding for the glutamate dehydrogenase (GDH). Such mutations reduce the sensitivity of the enzyme to allosteric inhibition by GTP and consequently increase its sensitivity to allosteric activation by L-leucine. Hyperactivity of the GDH is responsible for over-oxidation of glutamate in β-pancreatic cells, increase of the ATP/ADP ratio and insulin release. Hyperactivity of GDH in liver is also responsible for hyperammonemia, which is usually mild and considered harmless for the brain. Nevertheless, recent studies have shown an increased epilepsy risk in cohorts of patients with hi/ha. CONCLUSION This case points out the importance of necessity for first investigations of infant documented case of hypoglycaemia. Patient history must focus on symptoms such as shorten fast tolerance periods and neurological symptoms of glucose deprivation. Blood samples should be taken at the time of hypoglycaemia and urine samples as soon as possible after the episode of hypoglycaemia. Initial normal insulin values do not allow the exclusion of the diagnosis of hyperinsulinism. [less ▲]Detailed reference viewed: 60 (2 ULg)
Prevalence of and risk factors for perioperative arrhythmias in neonates and children after cardiopulmonary bypass: continuous holter monitoring before and for three days after surgery.
; ; et al
in Journal of cardiothoracic surgery (2010), 5
BACKGROUND: A comprehensive evaluation of postoperative arrhythmias following surgery for congenital heart disease by continuous Holter monitoring has not been carried out. We aimed, firstly, to establish ... [more ▼]
BACKGROUND: A comprehensive evaluation of postoperative arrhythmias following surgery for congenital heart disease by continuous Holter monitoring has not been carried out. We aimed, firstly, to establish the time course of pre- and early postoperative arrhythmias by beat-to-beat analysis following cardiopulmonary bypass and, secondly, to examine which surgical procedures present risk factors for specific arrhythmias. METHODS: 494 consecutive patients, including 96 neonates, were studied with serial 24-hour Holter electrocardiograms before as well as uninterruptedly during the first 72 hours after surgery and prior to discharge. RESULTS: Within 24 hours of surgery 59% of the neonates and 79% of the older children developed arrhythmias. Junctional ectopic tachycardia occurred in 9% of neonates and 5% of non-neonates and ventricular tachycardia in 3% and 15%, respectively.For neonates, male sex and longer cross-clamping time independently increased the risk for arrhythmias (odds ratios 2.83 and 1.96/minute, respectively). Ventricular septal defect repair was a strong risk factor for junctional ectopic tachycardia in neonates and in older children (odds ratios 18.8 and 3.69, respectively). For infants and children, older age (odds ratio 1.01/month) and closure of atrial septal defects (odds ratio 2.68) predisposed to arrhythmias of any type. CONCLUSIONS: We present the largest cohort of neonates, infants and children that has been prospectively studied for the occurrence of arrhythmias after cardiac surgery. Postoperative arrhythmias are a frequent and transient phenomenon after cardiopulmonary bypass, provoked both by mechanical irritation of the conduction system and by humoral factors. [less ▲]Detailed reference viewed: 45 (0 ULg)
Long-term outcome of speech and language in children after corrective surgery for cyanotic or acyanotic cardiac defects in infancy.
; ; et al
in European Journal of Paediatric Neurology : Official Journal of the European Paediatric Neurology Society (2008), 12(5), 378-386
The purpose of this prospective study was to assess whether outcome of speech and language in children 5-10 years after corrective surgery for tetralogy of Fallot (TOF) or ventricular septal defect (VSD ... [more ▼]
The purpose of this prospective study was to assess whether outcome of speech and language in children 5-10 years after corrective surgery for tetralogy of Fallot (TOF) or ventricular septal defect (VSD) in infancy was influenced by the preoperative condition of hypoxemia or cardiac insufficiency and whether it was associated with perioperative risk factors and neurodevelopmental outcome. A total of 35 unselected children, 19 with TOF and hypoxemia and 16 with VSD and cardiac insufficiency, operated with combined deep hypothermic circulatory arrest and low-flow cardiopulmonary bypass at mean age 0.7+/-0.3 (mean+/-standard deviation) years, underwent, at mean age 7.4+/-1.6 years, standardized evaluation of speech and language functions. Results were compared between subgroups and related to perioperative factors, sociodemographic and neurodevelopmental status. Age at testing, socioeconomic status and history of speech and language development were not different between the subgroups. In contrast, total scores on oral and speech motor control functions (TFS) as well as on oral and speech apraxia (Mayo Test) were significantly reduced (p<0.02 to <0.05), and scores on anatomical oral structures tended to be lower (p<0.09) in the TOF group as compared to the VSD group. No differences were found for auditory word recognition and phonological awareness as assessed by the Auditory Closure subtest of the Illinois Test of Psycholinguistic Abilities and the test of auditory analysis skills, respectively. In all children, higher age at testing and better socioeconomic status were associated with better results in all domains of assessment (p<0.001 to <0.04). Consistent impairments of all oral and speech motor control functions (TFS and Mayo Test) were present in 29% of all children with a mean age of 6.5 years in contrast to 43% with normal performance and a mean age of 8.3 years. On the receptive speech tasks, only 6% scored below the normal range of their age group. TFS subscores were significantly correlated with age, bypass duration and motor function, but not correlated with socioeconomic status, duration of cardiac arrest, intelligence and academic achievement. Children with preoperative hypoxemia due to cyanotic cardiac defects in infancy are at higher risk for dysfunction in speech and language than those with cardiac insufficiency due to acyanotic heart defects. Age at testing, socioeconomic status, and duration of cardiopulmonary bypass influenced test results. Long-term outcome in speech and language functions can be considered as a sensitive indicator of overall child development after cardiac surgery. [less ▲]Detailed reference viewed: 42 (1 ULg)
Congenital cystic adenomatoid malformation type 0-a rare cause of neonatal death.
; ; et al
in Pediatric Critical Care Medicine (2007), 8(6), 580-581
OBJECTIVE: We give the first account of failure of extracorporeal membrane oxygenation therapy secondary to congenital cystic malformation of the lung (CCAM) type 0. DESIGN: Case report. SETTING ... [more ▼]
OBJECTIVE: We give the first account of failure of extracorporeal membrane oxygenation therapy secondary to congenital cystic malformation of the lung (CCAM) type 0. DESIGN: Case report. SETTING: Pediatric intensive care unit. PATIENT: A female neonate, appropriate for gestational age, with respiratory failure immediately after delivery. INTERVENTIONS: : Cardiopulmonary support with venoarterial extracorporeal membrane oxygenation. RESULTS: There was no improvement of pulmonary function, and the patient died. CCAM type 0 was diagnosed postmortem. CONCLUSIONS: CCAM type 0 should be considered as a rare differential diagnosis of irreversible lung pathologies leading to failure of extracorporeal membrane oxygenation therapy for neonatal respiratory failure. [less ▲]Detailed reference viewed: 17 (0 ULg)
Long-term behavior and quality of life after corrective cardiac surgery in infancy for tetralogy of Fallot or ventricular septal defect.
; ; et al
in Pediatric Cardiology (2007), 28(5), 346-354
The objective of this study was to evaluate behavior and quality of life in children after corrective cardiac surgery in infancy. Twenty cyanotic (tetralogy of Fallot) and 20 acyanotic children ... [more ▼]
The objective of this study was to evaluate behavior and quality of life in children after corrective cardiac surgery in infancy. Twenty cyanotic (tetralogy of Fallot) and 20 acyanotic children (ventricular septal defect), operated at a mean age of 0.7 years with deep hypothermic circulatory arrest (DHCA) and low-flow cardiopulmonary bypass (CPB), were assessed at a mean age of 7.4 years by the Child Behavior Checklist (CBCL) and the German KINDL. Test results were related to perioperative and neurodevelopmental outcome. Compared to healthy children and not significantly different between the groups, internalizing and externalizing problems were elevated, school performance and total competence were reduced, and self- and parent-reported quality of life was not reduced. Parent-reported problems and reduced physical status were correlated with longer durations of DHCA and CPB. Internalizing and externalizing problems, reduced school competence, and reduced self-esteem were associated with reduced endurance capacity. Externalizing problems were related to reduced gross motor function. Poor school competence was related to reduced intelligence and academic achievement. Children with preoperative hypoxemia in infancy due to cyanotic cardiac defects are not at significantly higher risk for behavioral problems and reduced quality of life than those with acyanotic heart defects. The risk of long-term psychosocial maladjustment after corrective surgery in infancy is increased compared to that for normal children and related to the presence of neurodevelopmental dysfunction. [less ▲]Detailed reference viewed: 15 (0 ULg)
The hypoxia-inducible factor HIF-1 promotes intramyocardial expression of VEGF in infants with congenital cardiac defects.
; ; SCHUMACHER, Katharina et al
in Basic Research in Cardiology (2007), 102(3), 224-232
OBJECTIVES: The response to hypoxia is primarily mediated by the transcription factor hypoxia-inducible factor-1 (HIF-1) which leads to the induction of a variety of adaptive gene products including ... [more ▼]
OBJECTIVES: The response to hypoxia is primarily mediated by the transcription factor hypoxia-inducible factor-1 (HIF-1) which leads to the induction of a variety of adaptive gene products including vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). This study was designed to test the hypothesis that HIF-1 and its target genes would be upregulated in the ventricular myocardium of infants with cyanotic congenital cardiac defects. METHODS: 14 infants with cyanotic (n = 7) or acyanotic cardiac defects (n = 7) were investigated. Samples from the right ventricular myocardium taken immediately after aortic clamping were studied for protein expression and DNA-binding activity. RESULTS: Protein levels of HIF-1alpha were significantly elevated in patients with cyanotic compared to acyanotic congenital heart disease and inversely correlated with the degree of hypoxemia. This response was accompanied by significantly enhanced HIF-1 DNA binding activity. Furthermore, protein levels of VEGF and eNOS were significantly higher in the myocardium of cyanotic than of acyanotic infants. To test the potential involvement of upstream regulatory pathways, activation of MAP kinases was determined. Intramyocardial levels of phosphorylated p38 MAP kinase, but not of ERK1/2 were significantly higher in infants with cyanotic compared to those with acyanotic congenital heart disease and inversely correlated to hypoxemia. CONCLUSIONS: These findings show that chronic hypoxemia is associated with the induction and stabilization of the transcription factor HIF-1 as well as its target genes VEGF and eNOS in the myocardium of infants with cyanotic cardiac defects. Thus, stabilization of HIF-1 and induction of the adaptive hypoxia response could particularly participate in myocardial remodeling in children with congenital cardiac defects and chronic hypoxemia. [less ▲]Detailed reference viewed: 16 (0 ULg)
Magnetic guide-wire navigation in pulmonary and systemic arterial catheterization: initial experience in pigs.
; ; SEGHAYE, Marie-Christine
in Journal of Vascular and Interventional Radiology (2007), 18(4), 545-551
PURPOSE: Cardiovascular catheterization can be challenging whenever a stenosis or an abnormal vascular course interferes with probing the target vessel. This study addresses the feasibility of navigating ... [more ▼]
PURPOSE: Cardiovascular catheterization can be challenging whenever a stenosis or an abnormal vascular course interferes with probing the target vessel. This study addresses the feasibility of navigating a guide wire with a magnetic tip by an external magnetic field through pulmonary and systemic arteries in an experimental porcine model. MATERIALS AND METHODS: We investigated six piglets using magnetic guide-wire navigation. Two pulmonary arteriograms were taken from different angles in order to reconstruct the three-dimensional vessel anatomy. A computer interface then calculated three-dimensional coordinates for the vessel in space. Using these coordinates, two external magnets were positioned to create magnetic vectors along the expected vessel course. Magnetically enabled guide wires were then navigated into the vessels using the magnetic field to orient the guide-wire tips. Aortic and renal branches were addressed in a similar fashion. Difficulty in reaching the target vessel was reflected by the number of attempts that were necessary. After 10 failed attempts, the maneuver was recorded to have failed. RESULTS: Thirty-five of 37 (94.6%) arteries with branches at acute angles were reached successfully using magnetic navigation. In two pigs, the left upper lobe artery could not be probed. Peripheral arteries of small diameter were easier to reach than large central arteries, requiring less attempts. CONCLUSIONS: Magnetic guide-wire navigation is feasible in the arteries of the lungs, the head and neck, and the kidneys. It is particularly useful in entering small arterial branches at acute angles and may facilitate interventional therapy in a variety of vascular diseases in children and adults. [less ▲]Detailed reference viewed: 20 (0 ULg)
Atherosclerosis lifestyle risk factors in children with congenital heart disease.
; ; SEGHAYE, Marie-Christine
in European Journal of Cardiovascular Prevention and Rehabilitation : Official Journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology (2007), 14(2), 349-351
OBJECTIVE: To assess lifestyle risk factors for atherosclerotic cardiovascular disease in children with congenital heart disease. MATERIALS AND METHODS: Surveys were distributed to 329 unselected cardiac ... [more ▼]
OBJECTIVE: To assess lifestyle risk factors for atherosclerotic cardiovascular disease in children with congenital heart disease. MATERIALS AND METHODS: Surveys were distributed to 329 unselected cardiac children. RESULTS: Many patients were taking an unhealthy diet and did not eat fruit (68%), vegetables (60%) or low-fat milk products (60%) every day, whereas 41% drank sweetened beverages and 89% ate foods high in fats at least three times a week. Only 15% spent half an hour daily involved in after-school physical activity, whereas 7.6% were overweight, 4.3% had arterial hypertension, 50% were passive smokers and 12% of teenagers were active smokers. CONCLUSION: Most cardiac children have modifiable cardiovascular risk factors. This highlights the importance of enhancing actions to promote a healthy lifestyle addressed to that population. [less ▲]Detailed reference viewed: 3 (0 ULg)
Extravasation of albumin after cardiopulmonary bypass in newborns.
; ; et al
in Journal of Cardiothoracic and Vascular Anesthesia (2007), 21(2), 174-178
OBJECTIVE: The systemic inflammatory response to cardiopulmonary bypass (CPB) possibly increases microvascular permeability to plasma proteins, leading to capillary leak syndrome. The study was conducted ... [more ▼]
OBJECTIVE: The systemic inflammatory response to cardiopulmonary bypass (CPB) possibly increases microvascular permeability to plasma proteins, leading to capillary leak syndrome. The study was conducted to elucidate any protein leakage in newborns using Evans blue dye as tracer. DESIGN: Prospective controlled study. SETTING: University-affiliated heart center. PARTICIPANTS: Eleven neonates with transposition of the great arteries. INTERVENTIONS: Plasma interleukin-6 (IL-6), IL-10, fractional escape rate (FER) of an intravenous bolus of Evans blue, and colloid osmotic pressure (COP) were assessed before and after surgery (statistics: median and 25th-75th percentile, Friedman's 2-way analysis of variance, and Wilcoxon matched-pairs signed-rank test [before and after surgery]). MEASUREMENTS AND MAIN RESULTS: All patients had an uneventful intraoperative course. The demographic and operative data were age 11 (10-13) days, body weight 3.2 (3.0-3.3) kg, CPB time 132 (123-144) minutes, and aortic cross-clamp time 66 (64-78) minutes. The proinflammatory IL-6 increased 60-fold and the anti-inflammatory IL-10 only 3-fold after CPB. FER, however, was not changed, whereas COP was significantly reduced after CPB. CONCLUSIONS: In contrast to the expectation, the escape rate of Evans blue, reflecting the extravasation of albumin, was not increased after CPB. However, reduced COP, hypothermia, and also a reduced lymphatic drainage may contribute to edema formation. The present data do not support the hypothesis of a capillary leak after CPB in newborns. [less ▲]Detailed reference viewed: 25 (0 ULg)
Attentional dysfunction in children after corrective cardiac surgery in infancy.
; ; et al
in Annals of Thoracic Surgery (2007), 83(4), 1425-1430
BACKGROUND: Attentional dysfunction in children after corrective cardiac surgery in infancy has rarely been evaluated and is the topic of the present work. METHODS: Forty unselected children, 20 with ... [more ▼]
BACKGROUND: Attentional dysfunction in children after corrective cardiac surgery in infancy has rarely been evaluated and is the topic of the present work. METHODS: Forty unselected children, 20 with tetralogy of Fallot and hypoxemia and 20 with ventricular septal defect and cardiac insufficiency, operated on at a mean age 0.7 (SD 0.3) years with deep hypothermic circulatory arrest and low flow cardiopulmonary bypass, were evaluated at mean age 7.4 (SD 1.6) years by the computerized form of the Attention Network Test providing performance measures of three networks of attention: alerting, orienting, and executive control. Parental ratings of attentional dysfunction were derived from the Child Behavior Checklist. Results were compared with healthy controls, between patient groups, and correlated with perioperative risk factors and current neurodevelopmental status. RESULTS: Executive control was reduced in the tetralogy of Fallot group, alerting and orienting were found normal and not different between patient groups. Durations of aortic cross clamping inversely correlated with orienting; durations of cardiopulmonary bypass correlated with mean reaction time and inversely correlated with executive control. Motor function and acquired abilities correlated with executive control and orienting. Parent-reported problems on the Child Behavior Checklist inversely correlated with executive control and mean accuracy. CONCLUSIONS: Children with preoperative hypoxemia in infancy due to cyanotic cardiac defects are at increased risk for attentional dysfunction in the field of executive control, compared with normal children and with those who have acyanotic heart defects. Besides unfavorable perioperative influences, preoperative hypoxemia is considered responsible for additional damage to the highly oxygen sensitive regions of the prefrontal cortex and striate body assumed to be associated with the executive control network of attention. [less ▲]Detailed reference viewed: 25 (1 ULg)
Multiple types of cardiac arrhythmias in a child with head injury and raised intracranial pressure.
; ; SEGHAYE, Marie-Christine
in Pediatric Cardiology (2006), 27(2), 286-8
Arrhythmias occur as a life-threatening complication in adults with severe head injuries. A wide spectrum of brady- and tachyarrhythmias and different pathogenetic mechanisms have been described. We ... [more ▼]
Arrhythmias occur as a life-threatening complication in adults with severe head injuries. A wide spectrum of brady- and tachyarrhythmias and different pathogenetic mechanisms have been described. We report an 8-year-old boy with traumatic brain injury who developed a variety of independent types of arrhythmias during the course of his illness, including supraventricular and ventricular extrasystoles, prolonged QT duration and ventricular fibrillation, accelerated junctional rhythm, and reentry tachycardia. Each arrhythmia may have had a distinct pathogenic pathway, and not all were associated with raised intracranial pressure. [less ▲]Detailed reference viewed: 19 (1 ULg)
Children undergoing cardiac surgery for complex cardiac defects show imbalance between pro- and anti-thrombotic activity.
; ; et al
in Critical Care (2006), 10(6), 165
INTRODUCTION: Cardiac surgery with cardiopulmonary bypass (CPB) is associated with the activation of inflammatory mediators that possess prothrombotic activity and could cause postoperative haemostatic ... [more ▼]
INTRODUCTION: Cardiac surgery with cardiopulmonary bypass (CPB) is associated with the activation of inflammatory mediators that possess prothrombotic activity and could cause postoperative haemostatic disorders. This study was conducted to investigate the effect of cardiac surgery on prothrombotic activity in children undergoing cardiac surgery for complex cardiac defects. METHODS: Eighteen children (ages 3 to 163 months) undergoing univentricular palliation with total cavopulmonary connection (TCPC) (n = 10) or a biventricular repair (n = 8) for complex cardiac defects were studied. Prothrombotic activity was evaluated by measuring plasma levels of prothrombin fragment 1+2 (F1+2), thromboxane B2 (TxB2), and monocyte chemoattractant protein-1 (MCP-1). Anti-thrombotic activity was evaluated by measuring levels of tissue factor pathway inhibitor (TFPI) before, during, and after cardiac surgery. RESULTS: In all patients, cardiac surgery was associated with a significant but transient increase of F1+2, TxB2, TFPI, and MCP-1. Maximal values of F1+2, TxB2, and MCP-1 were found at the end of CPB. In contrast, maximal levels of TFPI were observed at the beginning of CPB. Concentrations of F1+2 at the end of CPB correlated negatively with the minimal oesophageal temperature during CPB. Markers of prothrombotic activity returned to preoperative values from the first postoperative day on. Early postoperative TFPI levels were significantly lower and TxB2 levels significantly higher in patients with TCPC than in those with biventricular repair. Thromboembolic events were not observed. CONCLUSION: Our data suggest that children with complex cardiac defects undergoing cardiac surgery show profound but transient imbalance between pro- and anti-thrombotic activity, which could lead to thromboembolic complications. These alterations are more important after TCPC than after biventricular repair but seem to be determined mainly by low antithrombin III. [less ▲]Detailed reference viewed: 10 (1 ULg)
The use of moderate hypothermia during cardiac surgery is associated with repression of tumour necrosis factor-alpha via inhibition of activating protein-1: an experimental study.
; ; et al
in Critical Care (2006), 10(2), 57
INTRODUCTION: The use of moderate hypothermia during experimental cardiac surgery is associated with decreased expression of tumour necrosis factor (TNF)-alpha in myocardium and with myocardial protection ... [more ▼]
INTRODUCTION: The use of moderate hypothermia during experimental cardiac surgery is associated with decreased expression of tumour necrosis factor (TNF)-alpha in myocardium and with myocardial protection. In order to identify the cellular mechanisms that lead to that repression, we investigated the effect of hypothermia during cardiac surgery on both main signalling pathways involved in systemic inflammation, namely the nuclear factor-kappaB (NF-kappaB) and activating protein-1 pathways. METHOD: Twelve female pigs were randomly subjected to standardized cardiopulmonary bypass with moderate hypothermia or normothermia (temperature 28 degrees C and 37 degrees C, respectively; six pigs in each group). Myocardial probes were sampled from the right ventricle before, during and 6 hours after bypass. We detected mRNA encoding TNF-alpha by competitive RT-PCR and measured protein levels of TNF-alpha, inducible nitric oxide synthase and cyclo-oxygenase-2 by Western blotting. Finally, we assessed the activation of NF-kappaB and activating protein-1, as well as phosphorylation of p38 mitogen-activated protein kinase by electrophoretic mobility shift assay with super shift and/or Western blot. RESULTS: During and after cardiac surgery, animals subjected to hypothermia exhibited lower expression of TNF-alpha and cyclo-oxygenase-2 but not of inducible nitric oxide synthase. This was associated with lower activation of p38 mitogen-activated protein kinase and of its downstream effector activating protein-1 in hypothermic animals. In contrast, NF-kappaB activity was no different between groups. CONCLUSION: These findings indicate that the repression of TNF-alpha associated with moderate hypothermia during cardiac surgery is associated with inhibition of the mitogen-activated protein kinase p38/activating protein-1 pathway and not with inhibition of NF-kappaB. The use of moderate hypothermia during cardiac surgery may mitigate the perioperative systemic inflammatory response and its complications. [less ▲]Detailed reference viewed: 34 (1 ULg)
Long-term neurodevelopmental outcome and exercise capacity after corrective surgery for tetralogy of Fallot or ventricular septal defect in infancy.
; ; et al
in Annals of Thoracic Surgery (2006), 81(3), 958-66
BACKGROUND: The purpose of this prospective study was to assess whether neurodevelopmental status and exercise capacity of children 5 to 10 years after corrective surgery for tetralogy of Fallot or ... [more ▼]
BACKGROUND: The purpose of this prospective study was to assess whether neurodevelopmental status and exercise capacity of children 5 to 10 years after corrective surgery for tetralogy of Fallot or ventricular septal defect in infancy was different compared with normal children and influenced by the preoperative condition of hypoxemia or cardiac insufficiency. METHODS: Forty unselected children, 20 with tetralogy of Fallot and hypoxemia and 20 with ventricular septal defect and cardiac insufficiency, operated on with combined deep hypothermic circulatory arrest and low flow cardiopulmonary bypass at a mean age of 0.7 +/- 0.3 years (mean +/- SD), underwent, at mean age 7.4 +/- 1.6 years, standardized evaluation of neurologic status, gross motor function, intelligence, academic achievement, language, and exercise capacity. Results were compared between the groups and related to preoperative, perioperative, and postoperative status and management. RESULTS: Rate of mild neurologic dysfunction was increased compared with normal children, but not different between the groups. Exercise capacity and socioeconomic status were not different compared with normal children and between the groups. Compared with the normal population, motor function, formal intelligence, academic achievement, and expressive and receptive language were significantly reduced (p < 0.01 to p < 0.001) in the whole group and in the subgroups, except for normal intelligence in ventricular septal defect patients. Motor dysfunction was significantly higher in the Fallot group compared with the ventricular septal defect group (p < 0.01) and correlated with neurologic dysfunction, lower intelligence, and reduced expressive language (p < 0.05 each). Reduced New York Heart Association functional class was correlated with lower exercise capacity and longer duration of cardiopulmonary bypass (p < 0.05 each). Reduced socioeconomic status significantly influenced dysfunction in formal intelligence (p < 0.01) and academic achievement (p < 0.05). Preoperative risk factors such as prenatal hypoxia, perinatal asphyxia, and preterm birth, factors of perioperative management such as cardiac arrest, lowest nasopharyngeal temperature, and age at surgery, and postoperative risk factors as postoperative cardiocirculatory insufficiency and duration of mechanical ventilation were not different between the groups and had no influence on outcome. Degree of hypoxemia in Fallot patients and degree of cardiac insufficiency in ventricular septal defect patients did not influence the outcome within the subgroups. CONCLUSIONS: Children with preoperative hypoxemia in infancy are at higher risk for motor dysfunction than children with cardiac insufficiency. Corrective surgery in infancy for tetralogy of Fallot or ventricular septal defect with combined circulatory arrest and low flow bypass is associated with reduced neurodevelopmental outcome, but not with reduced exercise capacity in childhood. In our experience, the general risk of long-term neurodevelopmental impairment is related to unfavorable effects of the global perioperative management. Socioeconomic status influences cognitive capabilities. [less ▲]Detailed reference viewed: 27 (0 ULg)
Physical activity patterns of children after neonatal arterial switch operation.
; ; Gérard, Paul et al
in Annals of Thoracic Surgery (2006), 81(2), 665-70
BACKGROUND: Physical inactivity is a major atherosclerosis risk factor. The exercise tolerance is usually excellent after neonatal arterial switch operation, but those patients in whom coronary anomalies ... [more ▼]
BACKGROUND: Physical inactivity is a major atherosclerosis risk factor. The exercise tolerance is usually excellent after neonatal arterial switch operation, but those patients in whom coronary anomalies remain the main late complication, risk developing atherosclerotic coronary disease owing to perceived physical activity restrictions. METHODS: We investigated physical activity patterns of 52 unselected children 7 to 14 years after neonatal arterial switch operation for transposition of the great arteries by 24-hour continuous heart rate monitoring. The percentage of heart rate reserve was used to measure the amounts of activities. Comparisons were made with 35 children with repaired atrial or ventricular septal defect and with 127 age-matched healthy children. RESULTS: Children after arterial switch operation accumulated 167.3 +/- 70.6, 25.3 +/- 12.9, and 15.7 +/- 11.3 minutes a day (mean +/- SD) of light, moderate, and vigorous physical activities, respectively. At the same activity levels, children with repaired septal defect accumulated 165.2 +/- 82.2, 26.2 +/- 11.7, and 16.2 +/- 9.1 minutes a day, and their healthy peers 164.8 +/- 74.5, 31.8 +/- 13.9, and 21.9 +/- 11.3 minutes a day. Both cardiac groups were significantly less active than the control group when considering moderate (p = 0.026) and vigorous activities (p = 0.006). Only 19% and 27% of the children after arterial switch operation engaged, respectively, in more than 30 minutes a day of moderate activity and 20 minutes a day of vigorous activity. CONCLUSIONS: Children after arterial switch operation, just like other cardiac children, do not meet the guidelines for physical activity. We should encourage regular physical activity to offset adult sedentary behavior and to prevent atherosclerotic cardiovascular disease in those patients whose long-term function of the coronary arteries remains a matter of concern. [less ▲]Detailed reference viewed: 12 (0 ULg)
Does cardiac surgery in newborn infants compromise blood cell reactivity to endotoxin?
; ; et al
in Critical Care (2005), 9(5), 549-55
INTRODUCTION: Neonatal cardiac surgery is associated with a systemic inflammatory reaction that might compromise the reactivity of blood cells against an inflammatory stimulus. Our prospective study was ... [more ▼]
INTRODUCTION: Neonatal cardiac surgery is associated with a systemic inflammatory reaction that might compromise the reactivity of blood cells against an inflammatory stimulus. Our prospective study was aimed at testing this hypothesis. METHODS: We investigated 17 newborn infants with transposition of the great arteries undergoing arterial switch operation. Ex vivo production of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), of the regulator of the acute-phase response IL-6, and of the natural anti-inflammatory cytokine IL-10 were measured by enzyme-linked immunosorbent assay in the cell culture supernatant after whole blood stimulation by the endotoxin lipopolysaccharide before, 5 and 10 days after the operation. Results were analyzed with respect to postoperative morbidity. RESULTS: The ex vivo production of TNF-alpha and IL-6 was significantly decreased (P < 0.001 and P < 0.002, respectively), whereas ex vivo production of IL-10 tended to be lower 5 days after the operation in comparison with preoperative values (P < 0.1). Ex vivo production of all cytokines reached preoperative values 10 days after cardiac surgery. Preoperative ex vivo production of IL-6 was inversely correlated with the postoperative oxygenation index 4 hours and 24 hours after the operation (P < 0.02). In contrast, postoperative ex vivo production of cytokines did not correlate with postoperative morbidity. CONCLUSION: Our results show that cardiac surgery in newborn infants is associated with a transient but significant decrease in the ex vivo production of the pro-inflammatory cytokines TNF-alpha and IL-6 together with a less pronounced decrease in IL-10 production. This might indicate a transient postoperative anti-inflammatory shift of the cytokine balance in this age group. Our results suggest that higher preoperative ex vivo production of IL-6 is associated with a higher risk for postoperative pulmonary dysfunction. [less ▲]Detailed reference viewed: 43 (2 ULg)
Intrahepatic synthesis of tumor necrosis factor-alpha related to cardiac surgery is inhibited by interleukin-10 via the Janus kinase (Jak)/signal transducers and activator of transcription (STAT) pathway.
; ; et al
in Critical Care Medicine (2003), 31(12), 2769-75
SUMMARY: OBJECTIVES To identify the signaling pathways involved in the anti-inflammatory shift of the cytokine balance due to hypothermia during cardiopulmonary bypass. DESIGN Experimental animal study ... [more ▼]
SUMMARY: OBJECTIVES To identify the signaling pathways involved in the anti-inflammatory shift of the cytokine balance due to hypothermia during cardiopulmonary bypass. DESIGN Experimental animal study. SETTING Department of experimental surgery of a university hospital. SUBJECTS Young pigs. INTERVENTIONS Animals underwent normothermic (37 degrees C) or hypothermic (28 degrees C) cardiopulmonary bypass (n = 6 each). Samples of liver tissue were taken before and 6 hrs after cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS Intrahepatic expression of tumor necrosis factor-alpha, interleukin-10, inducible nitric oxide synthase, and suppressor of cytokine signaling-3 was detected by reverse transcriptase polymerase chain reaction and/or Western blotting. Concentrations of the inhibitory protein of nuclear factor-kappaB, IkappaB, and of the signal transducer and activator of transcription (STAT)-3 were measured by Western blotting. The DNA-binding activity of nuclear factor-kappaB and STAT-3 was assessed by electrophoretic mobility shift and supershift assays. Liver cell necrosis and apoptosis were assessed by histology and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay, respectively. Pigs operated on in hypothermia showed significantly higher intrahepatic concentrations of interleukin-10 and lower concentrations of tumor necrosis factor-alpha than the others. They also showed a lower percentage of hepatic cell necrosis but not of apoptosis. This anti-inflammatory reaction observed in the hypothermic group was associated with a higher expression of suppressor of cytokine signaling-3 and with increased activation of STAT-3. Activation of nuclear factor-kappaB and expression of inducible nitric oxide synthase, however, were not significantly different between both groups. CONCLUSION Our results show that hypothermia during cardiopulmonary bypass up-regulates interleukin-10 via STAT-3 activation, which in turn leads to the attenuation of tumor necrosis factor-alpha expression and to hepatic protection. [less ▲]Detailed reference viewed: 7 (1 ULg)
Long-term results of cardiac and general health status in children after neonatal arterial switch operation.
; SEGHAYE, Marie-Christine ; et al
in Annals of Thoracic Surgery (2003), 75(3), 935-43
BACKGROUND: The purpose of this study was to assess cardiac and general health status 8 to 14 years after neonatal arterial switch operation for transposition of the great arteries. METHODS: Sixty ... [more ▼]
BACKGROUND: The purpose of this study was to assess cardiac and general health status 8 to 14 years after neonatal arterial switch operation for transposition of the great arteries. METHODS: Sixty unselected children with intact ventricular septum (78.3%) or ventricular septal defect (21.7%) without or with aortic isthmic stenosis (5.1%) were examined 10.5 +/- 1.6 (mean +/- SD) years after neonatal switch and 5.3 +/- 1.6 years after mid-term evaluation. Complete clinical examination, standard and 24-hour Holter electrocardiogram, M-mode, 2D-, Doppler, and color Doppler echocardiography were performed. Results were compared with normal values and to mid-term follow-up results. RESULTS: Rates of reoperation after arterial switch operation and operation to correct concomitant coarctation were 3.3% and 5.1%, respectively. No patient needed medication, and 93.3% had no limitation of physical activity. All children had normal height and weight; 31.6% had abnormal thoracic configuration after median sternotomy. Most patients (91.7%) were in sinus rhythm. Incidence of complete right bundle branch block (10.0%) was unchanged, as was prevalence of ectopic activity (occasional atrial ectopy 20.0%, ventricular ectopy: occasional 21.7%; frequent 1.7%). Left ventricular dimensions and shortening fraction did not change over time. Diameters of neo-aortic valve annulus and neo-aortic root did not increase, and z-scores decreased between mid-term and present evaluation. Incidence of neo-aortic insufficiency was 13.3% and remained unchanged in comparison with the pre-examination value. Neo-aortic stenosis was not seen. Compared with mid-term follow-up, incidence (41.6%) and degree of supravalvular pulmonary stenosis increased. CONCLUSIONS: Good cardiac results persist 10 years after neonatal arterial switch operation for transposition of the great arteries. Encouraging findings include preservation of left ventricular function, low incidence of rhythm disturbances, lack of further neo-aortic root dilatation, and unchanged incidence of neo-aortic insufficiency compared with mid-term follow-up. Increased incidence and degree of supravalvular pulmonary stenosis are of concern. [less ▲]Detailed reference viewed: 13 (0 ULg)
Results of exercise testing at a mean age of 10 years after neonatal arterial switch operation.
; ; Seghaye, Marie-Christine et al
in Acta paediatrica (Oslo, Norway : 1992) (2003), 92(2), 190-6
AIM: This prospective follow-up study investigated long-term exercise capacity at a mean age of 10 y after neonatal arterial switch operation for transposition of the great arteries in a large group of ... [more ▼]
AIM: This prospective follow-up study investigated long-term exercise capacity at a mean age of 10 y after neonatal arterial switch operation for transposition of the great arteries in a large group of homogeneous unselected children. METHODS: 56 asymptomatic children, aged 7.9-14.3 y (10.5 +/- 1.6, mean +/- SD), were examined with respect to exercise tolerance, electrocardiographic (ECG) response and activity of biochemical markers for myocardial injury. The protocol included standard electrocardiography, M-mode and two-dimensional echocardiography at rest, a Bruce walking treadmill test to voluntary exhaustion, and determination of cardiac troponin I and T, creatine kinase and myoglobin from venous blood samples at rest and 4 h after exercise. Heart rate, blood-pressure response to exercise stress and endurance time were compared with published results of age-matched normal children. RESULTS: 54 patients (96.4%) had normal exercise capacity; a reduction in 2 patients was not due to cardiac disease. Heart rate and systolic blood pressure rose significantly between rest and peak exercise and did not differ from normal controls, whereas diastolic blood pressure was lower. ECG remained normal at rest and on exercise in 54 children (96.4%). Serum values of cardiac troponin I and T, creatine kinase and myoglobin were normal at rest and after exercise in all patients. CONCLUSION: The study demonstrates excellent long-term exercise capacity after neonatal arterial switch operation. Exercise testing is a useful and non-invasive screening method to detect patients with clinically relevant exercise-induced myocardial ischaemia and should be routinely performed in growing patients. [less ▲]Detailed reference viewed: 8 (0 ULg)
Intramyocardial synthesis of pro- and anti-inflammatory cytokines in infants with congenital cardiac defects.
; ; et al
in Journal of the American College of Cardiology (2003), 41(12), 2266-74
OBJECTIVES: We sought to test the hypothesis that cytokines would be expressed in the myocardium of infants with congenital cardiac defects and to identify the signaling pathways involved. BACKGROUND ... [more ▼]
OBJECTIVES: We sought to test the hypothesis that cytokines would be expressed in the myocardium of infants with congenital cardiac defects and to identify the signaling pathways involved. BACKGROUND: Mechanical stress upregulates pro-inflammatory cytokines in the myocardium. METHODS: Fifteen infants with tetralogy of Fallot (TOF) (n = 7) or with ventricular septal defects (VSDs) (n = 8) were investigated. Concentrations of pro- and anti-inflammatory cytokines and of the inducible nitric oxide synthase (iNOS) were measured by enzyme-linked immunosorbent assay and/or Western blotting in the right ventricular myocardium taken during cardiac surgery. Activation of the nuclear factor-kappa-B (NF-kappa-B) and p38 mitogen-activated protein kinase (MAPK) pathways was assessed by electrophoretic mobility shift assay with supershift and/or Western blotting, respectively. RESULTS: The pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1-beta, and IL-6 and the anti-inflammatory cytokine IL-10 were detected in the myocardium of all patients. Concentrations of the pro-inflammatory cytokines and also of phosphorylated p38 MAPK were higher in patients with TOF than in those with VSD and correlated with the degree of pressure overload of the right ventricle. Levels of phosphorylated I-kappa-B-alpha, iNOS, and IL-10 were similar in patients with TOF and in those with VSD. CONCLUSIONS: Our results show intramyocardial synthesis of pro-inflammatory cytokines in infants with congenital cardiac defects. This is associated with activation of both the NF-kappa-B and p38 MAPK pathways. The latter could be particularly important for the transduction of mechanical signals in the infant's myocardium. Synthesis of IL-10 indicates an intramyocardial anti-inflammatory potential in this age group. [less ▲]Detailed reference viewed: 6 (0 ULg)