[Evaluation of the concordance between guidelines and transfusion practices in neonatal intensive care units]. / Évaluation de la concordance entre recommandations et pratiques transfusionnelles en unités de soins intensifs néonataux.

OBJECTIVE: To assess the concordance rate between the prescriptions of blood products and Afssaps guidelines for transfusion practices in neonatology. STUDY DESIGN: Retrospective monocentric study. PATIENTS AND METHODS: Children transfused in the neonatology intensive care units in the Universitary Hospital of Rouen were included. Concordance rates between transfusion prescriptions, delivered and transfused products and the Afssaps guidelines were assessed. Any additional costs resulting from a theoretical discordance was also assessed. RESULTS: In 2006, 380 PSL were administered to 168 newborn children (NBC). Packed red blood cells (PRBC) represented the most often transfused products (n=290, 76%). Fifty packed platelets (PP) were transfused (13% of the blood products) and 41 fresh frozen plasmas (11%). Overall concordance rate between the Afssaps guidelines and the prescriptions was 64.9%. In 35.1% of cases, the prescription was excessive, compared to the recommendations. Excessive transfusion represented a total of 27,307 euros. CONCLUSION: Global concordance's rate between the guidelines and the prescriptions is fairly well. PRBC are the most blood product transfused. Excessive transfusions related to this concordance rate are leading to important theoretical costs. New informations to the guidelines are warranted to improve transfusional practices in this institution.

[Neurological consequences after long-term sedation in the ICU]. / Conséquences neurologiques de la sédation en réanimation.

Experiments performed in mammals, including non-human primates, have demonstrated an increase in neuronal death rates normally seen in normal brain development. Such an increase is encountered in diseases but also after exposure of the brain to various class of anaesthetics. In living animals, it can (but not always) result in persistent cognitive impairment. Most of the experiments have been conducted in animals which were never exposed to any pain, which questions their relevancy. On the clinical side, all data comes from retrospective studies. Given the multiple bias, they cannot definitely state that a protocol, if toxic, is more or less when compared to another. Until now, prospective follow-up of children exposed to anaesthetics in utero or during the first months of life do not suggest a major deleterious effect. Yet, a minor one, if existing, would be hard to detect among polluting variables (e.g. pathology requiring anaesthesia, long hospitalization after birth, preterm birth, environmental stress...). For sure, when surgery is mandatory during pregnancy, it is generally for maternal indication and should not be a motif strong enough for foetal extraction, especially in terms where the baby has few chances to survive. Second, it is known for years than anaesthesia before 1 year of age is much riskier than after 1 year, whatever the theorical neurotoxicity is. Third, this enforces the need to develop tools enhancing the precision of anaesthesia as much as possible. Meanwhile, when an infant has undergone numerous general anaesthesias, we strongly recommend a long-time neurological follow-up.

[Effects of general anaesthetics on the developing brain]. / Effets des agents anesthésiques sur le cerveau en développement.

OBJECTIVE: To expose the current knowledge about the anaesthetic effects on the developing brain. DATA SOURCES: Publications (original articles and reviews) in English and in French language from 1980 were obtained from the Medline database using alone or in combination following keywords: anaesthetics, developing brain, neurodevelopment, neurogenesis, synaptogenesis, neurotoxicity, apoptosis. DATA SYNTHESIS: Several lines of evidence resulting from animal experiments conducted in rodents and non-human primates have suggested that exposing the developing brain to anaesthetic drugs may elicit an increase a physiological programmed neuronal death (i.e. apoptosis). This neuronal death is not only seen at the cellular level but also results in alterations in some behavioural abilities in the adult animal. However, the vast majority of experiments reported have been conducted in animals not exposed to any surgical or painful stimulation. Moreover, the literature raises contradictory results, some authors not confirming this neurotoxic effect of anaesthetic drugs. Last, available clinical data are scarce and do not allow to claim that exposure to general anaesthesia definitely alters the cognitive development of children. CONCLUSION: This review raises the question of the innocuity of anaesthetic agents on the developing brain; further clinical trials are required in order to test this effect on human babies.

Neuroprotective effects vary across nonsteroidal antiinflammatory drugs in a mouse model of developing excitotoxic brain injury.

Glutamate excitotoxicity is among the main cellular mechanisms leading to perinatal insults in human newborns. We used intracerebral injection of the glutamatergic glutamate N-methyl-D-aspartate-receptor agonist ibotenate to produce excitotoxic lesions mimicking the acquired white matter lesions seen in human preterm infants. We evaluated whether nonsteroidal antiinflammatory drugs (NSAIDs) protected against glutamate excitotoxicity. Aspirin (0.01-100 microg/d), indomethacin (0.1-10 microg/d), paracetamol (10-100 microg/d), or NS-398 (12.5 microg/d) was given daily before ibotenate (P1 to P5) or after ibotenate (P5 to P9). Lesion size was measured on Cresyl Violet-stained brain sections collected on P10. None of the drugs tested alone or in combination increased lesion size. Pretreatment with low- or high-dose aspirin and post-treatment with paracetamol or NS-398 protected against white matter lesions, whereas cortical lesions were decreased by pretreatment with low- or high-dose aspirin or post-treatment with NS-398. The corticosteroid betamethasone (0.18 microg/d) was neuroprotective when given before or after ibotenate and this effect was reversed by concomitant aspirin therapy (10 microg/d). In conclusion, perinatal NSAID administration may have beneficial effects on brain injury if appropriately timed.

Anaesthesia mode for caesarean section and mortality in very preterm infants: an epidemiologic study in the EPIPAGE cohort.

BACKGROUND: Little is known about the influence of anaesthesia for caesarean section on outcome in very preterm infants. METHODS: A prospective, population-based, cohort study (the EPIPAGE cohort) included all births before 33 weeks in nine French regions in 1997. Of 2360 infants live-born between 27 and 32 weeks, 1338 were delivered by caesarean section with general anaesthesia (n=711, 53.1%), spinal anaesthesia (n=419, 31.3%), or epidural anaesthesia (n=208, 15.6%). Neonatal mortality was compared among these three groups using bi- (according to gestational age and to anaesthetic technique) and multivariate analyses. RESULTS: Neonatal mortality was 10.1% with general anaesthesia, 12.2% with spinal anaesthesia and 7.7% with epidural anaesthesia. After adjustment for gestational age and characteristics of pregnancy, delivery and neonate, spinal anaesthesia was associated with a higher risk of neonatal death than general anaesthesia (adjusted odds ratio, 1.7; 95% confidence interval 1.1 to 2.6). CONCLUSION: In this population-based study, spinal anaesthesia was associated with an increased risk of neonatal mortality in very preterm infants compared to general anaesthesia (and epidural anaesthesia), independently from gestational age and characteristics of the pregnancies, deliveries and neonates. Although this multivariate analysis does not prove a causal relationship, the results suggest it could exist, particularly if maternal haemodynamics are poorly controlled. With recent significant change in the conduct of spinal anaesthesia, further studies are needed to investigate potential harmful effects of anaesthesia on very preterm infants delivered by caesarean section.

[Is it possible to protect the preterm infant brain and to decrease later neurodevelopmental disabilities?]. / Est-il possible de protéger le cerveau de l'enfant né prématuré et de diminuer le taux de séquelles neuro-développementales ?

With improving neonatal survival for very premature babies, the challenge for neonatalogists is to ameliorate outcome of surviving babies. Several pharmacological molecules have been shown to have protective effects in different types of in vitro or in vivo animal models of acquired cerebral brain damages. However translational research and conduction of therapeutic trials in human remain difficult due to failure to recognize start of deleterious cascade leading to cerebral damage and additional toxic effect of potential protective molecules. This review concentrates on best evidence emerging in recent years on prevention on brain damage by early drug administration. It has been shown in two randomised trials that prenatal low-dose of magnesium sulphate does not increase paediatric mortality in very-preterm infants and has non significant neuroprotective effects on occurrence of motor dysfunction (with a 0.62 odds ratio in the French trial Premag and 0.71 relative risk in the Australian trial ACTOMgSO4), justifying that magnesium sulphate should be discussed as a stand-alone treatment or as part of a combination treatment, at least in the context of clinical trials. Antenatal corticosteroid therapy increases the survival of very-preterm infants, including the most immature. Moreover in an observational recent study of the Epipage cohort, it has been observed a significant decrease in white matter injury in the 28-32 weeks' gestation group but no effect on long term outcome and behaviour. Conversely in the most immature of the 24-27 weeks' gestation group, no effect has been detected either in white matter injury incidence or in long term outcome rates. Caffeine has a protective effect since a decrease in cerebral palsy has been noted in the caffeine group in a randomised trial studying caffeine versus placebo. For what concern other widely used potential protective molecules during the perinatal period, there is no evidence of cerebral protection with indometacine, nitric oxide, eythropoietin, phenobarbital, and etamsylate. Due to their specific properties, a careful evaluation of aspirin, anaesthetic drugs and tocolytics should be done in the next months.

[Sedation and analgesia in the paediatric intensive care unit]. / Sédation et analgésie en réanimation--Aspects pédiatriques.

Sedation and analgesia are a constant challenging issue in paediatric intensive care units, for ethical reasons among others. Basically, goals and available treatments in that context do not differ from those in adults. For instance, while we propose midazolam as the first choice benzodiazepine, there is no evidence for encouraging the use of one morphinomimetic rather than others in children. On the other hand, numerous paediatric specificities do exist: understanding and expression of pain both different and difficult, presence and involvement of the parents, pain assessment methods, pharmacology, pathologies. It is therefore mandatory to know these specificities to ensure a proper use of evaluation tools and therapeutics. The paucity of strong evidence from the literature does not allow producing definitive consensus guidelines. However, some practices can be highlighted such as the use of written protocol on pain/sedation evaluation and therapeutics adapted to children, literature data and local habits, the training of medical/nursing staff and the constitution of local referring team. A particular attention should be paid to propofol: its use longer than several hours should be strongly discouraged in infants and children due to the risk of Propofol Infusion Syndrome. Further clinical studies should be conducted in an attempt to provide answers to routine, daily issues and questions, for example, how to tailor the level of sedation to the needs of the patient, how to stop it, which drug must be preferred or what place for non-pharmacological approaches.

Interactions of PACAP and ceramides in the control of granule cell apoptosis during cerebellar development.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that belongs to the secretin/glucagon/vasoactive intestinal polypeptide superfamily. The PACAPergic system is actively expressed in the developing cerebellum of mammals. In particular, PACAP receptors are expressed by granule cell precursors suggesting a role of the peptide in neurogenesis of this cell type. Consistent with this hypothesis, several studies reported antiapoptotic effects of PACAP in the developing cerebellum. On the other hand, the sphingomyelin metabolites ceramides are recognized as important signaling molecules that play pivotal roles during neuronal development. Ceramides, which production can be induced by death factors such as FasL or TNFalpha, are involved in the control of cell survival during brain development through activation of caspase-dependent mechanisms. The present review focuses on the interactions between PACAP and ceramides in the control of granule cell survival and on the transduction mechanisms associated with the anti- and proapoptotic effects of PACAP and ceramides, respectively.

Bax siRNA promotes survival of cultured and allografted granule cell precursors through blockade of caspase-3 cleavage.

Transplantation of neuronal precursor cells (NPCs) into the central nervous system could represent a powerful therapeutical tool against neurodegenerative diseases. Unfortunately, numerous NPCs die shortly after transplantation, predominantly due to caspase-dependent apoptosis. Using a culture of cerebellar neuronal precursors, we have previously demonstrated protective effect of the neuropeptide PACAP, which suppresses ceramide-induced apoptosis by blockade of the mitochondrial apoptotic pathway. The main objective of this study was to determine whether Bax repression can promote survival of NPCs allotransplanted into a host animal. In vivo and ex vivo experiments revealed that C2-ceramide increases Bax expression, while PACAP reverses this effect. In vitro tests using cerebellar NPCs demonstrated that the Bax-specific small interfering RNA (siRNA) could reduce their death and caspase-3 cleavage within the first 24 h. BrdU-labelled NPCs were subjected to transfection procedure with or without siRNA introduction before using for in vivo transplantation. Twenty-four hours after, the allografted NPCs containing siRNA showed significantly reduced level of caspase-3 cleavage, and the volume of their implants was almost twofold higher than in the case of empty-transfected precursors. These data evidence an important role of Bax in life/death decision of grafted NPCs and suggest that RNA interference strategy may be applicable for maintaining NPCs survival within the critical first hours after their transplantation.

Role of tissue-plasminogen activator (t-PA) in a mouse model of neonatal white matter lesions: interaction with plasmin inhibitors and anti-inflammatory drugs.

Ibotenic acid injected intracerebrally over a broad dose range to 5-day-old mice induces cystic white matter (WM) lesions that mimic periventricular leukomalacia (PVL) of preterm infants. With both low (0.1 mug) and high (5 mug) ibotenic acid doses, tissue-plasminogen activator (t-PA) is involved in cyst formation. Subsequent cyst growth depends on high doses. We evaluated the effects of human recombinant tissue-plasminogen activator (hrt-PA), plasmin inhibitors (tranexamic acid, alpha2-antiplasmin, and aprotinin), and anti-inflammatory drugs (betamethasone, NS-398) in wild-type and t-PA(-/-) mice given high-dose or low-dose ibotenic acid. Intracerebral hrt-PA induced WM cystic lesions in t-PA(-/-) mice and had an additive effect when co-injected with high-dose ibotenic acid. Plasmin inhibitors reduced lesion growth in wild-type mice given high-dose, but not low-dose, ibotenic acid but had no effect in t-PA(-/-) mice. Similarly the anti-inflammatory drugs betamethasone and NS-398 (a cyclooxygenase 2 and NFkappaB inhibitor) were neuroprotective in wild-type animals exposed to high-dose, but not low-dose, ibotenic acid. Thus, the t-PA-dependent effect of low-dose ibotenic acid on cyst formation appeared independent from plasmin activity or inflammation. Conversely, a t-PA-dependent inflammatory process occurred with high-dose ibotenic acid. Potential strategies for PVL in preterm neonates may include fibrinolytic monitoring for prevention and anti-inflammatory agents for treatment.

[Early spontaneous ileal perforations in preterm infants: report of 4 cases]. / Perforations iléales précoces sans signes d'entérocolite ulcéronécrosante: à propos de quatre cas survenus chez des prématurés.

An ileal perforation occurred shortly after birth in 4 very premature newborns. Diagnosis was made on an abdominal distension with a pneumoperitoneum on X-ray. There were no biological, radiological nor histological signs of necrotizing enterocolitis. There were no digestive short- or long-term complications. According to the few authors who described this syndrome, there are some risk factors, but they were not clearly involved in our cases. Ileal perforation in the absence of signs of necrotizing enterocolitis is rarely reported but should be well known because of its good prognosis.

Ontogenic study of the influence of tissue plasminogen activator (t-PA) in neonatal excitotoxic brain insult and the subsequent microglia/macrophage activation.

Intracerebral injections of ibotenic acid in neonatal mice produced white and gray matter lesions that mimic some aspects of the acquired cerebral injuries observed in human newborns (i.e. periventricular leukomalacias in preterm newborns and post-ischemic cortical necrosis in at term infants). We have evaluated the effects of tissue plasminogen activator inactivation (t-PA-/-) on the effects of ibotenic acid (0.01-20 microg), and on F4/80 labeling of microglia/macrophages at different stages. Three ontogenic periods have been identified. In mice injected the day of birth, postnatal (P) day 0, ibotenic acid induced neuronal migration disorders together with low local microglial activation in wild-type and t-PA-/- mice. In P2 and P5 mice, ibotenic acid induced diffuse microglial activation in the whole cortex and subcortical areas; e.g. caudate nucleus and septum. In wild-type mice, cystic lesions of the white matter were consistently observed, surrounded by macrophages. In t-PA-/- mice, noncystic lesions filled of macrophages were more frequent than cysts. Macrophages were virtually absent in the gray matter. White and gray matter lesions were reduced in t-PA-/- mice. The plasmin inhibitor aprotinin reduced white and gray matter lesions only in wild-type mice injected with high ibotenic acid doses (2.5-5 microg). During this period, a transient F4/80 immunoreactive cell population was detected in the cingulum. At P10, the salient lesion characteristic was a large gray matter lesion containing macrophage accumulation. Microglial activation was confined to the injection site in the white matter. t-PA-/- mice showed reduced lesion size under high doses (>5 microg) of ibotenic acid. Similarly, aprotinin diminished the lesion in wild-type animals exposed to 10 microg ibotenic acid. These data demonstrate that t-PA and microglia do not actively participate in the migration disorders induced in P0 mice. Conversely, t-PA was implicated in cyst formation in older (P2-P10) mice, and in their subsequent growth. t-PA was also involved in GM lesions, probably through an inflammatory process involving macrophages.

Open vs thorascopic surgical management of bronchogenic cysts.

BACKGROUND: The aim of this study was to compare the operative outcome in children undergoing open vs thoracoscopic resection of bronchogenic cysts. METHODS: The medical records of children who underwent the resection of bronchogenic cysts from 1990 through 2000 were reviewed. Four cyst resections were performed by the open technique and five using a thoracoscopic procedure. The age of the patients, length of hospital stay, duration of drainage, operating time, and outcome were investigated. RESULTS: The mean age of patients undergoing the open procedure was 3 years and 3 months; the mean age for thoracoscopy patients was 7 years and 10 months (p < 0.05). The operating time for the open procedure was 70 +/- 25 min; for the laparoscopic procedure, it was 78 +/- 6 min (p, NS), except in one case with a main bronchial tail that required conversion (320 min). Duration of surgical drainage was 6.5 +/- 3 days for the open procedure and 2.5 +/- 1 days for the thoracoscopic one (p < 0.05). Hospital stay for open patients was 12 days +/- 0 days; it was 6 +/- 1.6 days for thoracoscopic patients (p < 0.01). There were no deaths. The thoracoscopic procedure failed once due to a main bronchial tail and had to be converted to an open procedure. Other early complications included a bronchopulmonary infection after an open cyst excision and an atelectasis after a thoracoscopic cyst excision. Late complications included one reoperation for incomplete excision in each of the two groups. CONCLUSION: Bronchogenic cyst resection can be performed safely. For complete treatment of these patients, total excision of the wall cyst is needed. In selected patients, the thoracoscopic procedure may decrease the duration of surgical drainage and length of hospital stay without increasing the operating time or MSK for complications.

[Mechanisms of action of tobacco smoke on the developing brain]. / Les mécanismes d'action du tabac sur le cerveau en développement.

Maternal smoking is associated with an increased risk of intra-uterine growth retardation and conduct disorder in their children, and is a major risk factor for sudden infant death syndrome. Among the numerous compounds present in cigarette smoke, carbon monoxide and nicotine have been largely studied. They can both affect the fetal brain by inducing intra-uterine hypoxia or by acting directly on the developing brain.

Neurotoxic effects of fluorinated glucocorticoid preparations on the developing mouse brain: role of preservatives.

Prenatal betamethasone (Celestene) therapy reduces the incidence of brain damage, whereas prenatal or neonatal dexamethasone (Soludecadron) increases the risk of brain lesions or neuromotor deficits. To determine whether this increase is ascribable to the sulfites used as preservatives in Soludecadron, we investigated the effects of 12 h of exposure to pure dexamethasone, Soludecadron, pure betamethasone, Celestene, and sulfites on in vitro and in vivo death of neurons cultured under basal conditions or with excitotoxic agents (N-methyl-D-aspartate or (S)-5-bromowillardiine) or hypoxia. Apoptotic features were quantitated using a fluorescent chromatin stain (Hoechst 33258). Neuronal viability was unaffected by pure dexamethasone, pure betamethasone, or Celestene. Soludecadron or sulfites significantly increased neuronal loss. Pure dexamethasone or pure betamethasone produced a 40-50% decrease in neuronal death induced by N-methyl-D-aspartate, (S)-5-bromowillardiine, or hypoxia, whereas Soludecadron had no effect and sulfites significantly increased the neurotoxicity of excitotoxic agents. In in vivo experiments involving terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling after several i.p. injections of fluorinated glucocorticoids, Soludecadron, but not pure dexamethasone, significantly increased the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-stained cells in neocortical layers and thalamus. These experimental findings suggest that injectable dexamethasone should be used with caution during the perinatal period.