Jean Laugier

Hypoxic preconditioning reduces apoptosis in a rat model of immature brain hypoxia-ischaemia

Hypoxic events are common in newborns but their consequences on brain development have not been demonstrated. It has been reported that in newborn animal models of cerebral hypoxic-ischaemic insult, short-term hypoxia before the insult completely prevented brain damage. The mechanisms of this brain tolerance have not been fully elucidated. Using a rat model of hypoxic preconditioning at day 6 followed by carotid ligation and hypoxic insult at day 7, we found a decrease in the number of apoptotic cells 24 and 48 h after the insult in the striatum, hippocampus and cortex. We demonstrated here that regulation of apoptotic cell death is one of the mechanisms involved in tolerance to hypoxia-ischaemia induced by hypoxic preconditioning.

Effect of caffeine on cerebral blood flow velocity in preterm infants.

A continuous-wave form Doppler monitor was used to examine the effect of caffeine on cerebral blood flow velocity (CBFV) in 7 clinically stable preterm neonates suffering from apnea. Caffeine, in the form of caffeine citrate, or saline were given intravenously at loading doses of 20 mg/kg. Every subject was his own control. Placebo (saline) was systematically injected prior to caffeine citrate. Simultaneous recording of heart rate, arterial blood pressure, respiratory rate, TcPO2, TcPCO2 were made before, then at the end of the injection, and 30, 60 and 120 min after the end of each administration of either placebo or caffeine. Compared with placebo, caffeine injection was not associated with significant changes in CBFV. An increase was found in both heart-rate and respiratory rate (p less than 0.05). Mean arterial blood pressure, TcPCO2 and TcPO2 did not change significantly. Our data suggest that a caffeine citrate loading dose of 20 mg/kg as currently used at the beginning of treatment of apnea in preterm neonates has no effect on CBFV.

Enterobacteria of the Neonate

Enterobacterial digestive tract colonization of neonates under different conditions during their first days of life was studied. Our objective is to determine the frequency of antibiotic resistance under different conditions (hospitalized newborns treated or not with antibiotics, newborns in a maternity unit, mothers treated or not) thereby permitting a better appreciation of the role played by the ‘selection pressure’ created by antibiotics commonly used in perinatology. The method used was the culture of graded newborn fecal dilutions on selective media, some of which contained antibiotics. Cultures were made every day during the 1st week and at 2 weeks of age. By using this technique, enterobacteria can be quantified as a function of their variety and of their resistance to different antibiotics. In the normal neonate under the normal conditions, the most predominant enterobacterium is an Escherichia coli sensitive to antibiotics; these infants also had several varieties of resistant enterobacteria, frequently acquired from their mothers. An antibiotic treatment of the mothers following delivery had no effect on the enterobacteria of the newborns. In a hospital setting, treated neonates rapidly acquired resistant species of enterobacteria. Nontreated neonates, initially often colonized with sensitive enterobacteria, acquired resistant enterobacteria during their first days of life.

Prevention of Candida Colonization Prevents Infection in a Neonatal Unit

This study represents a 1-year surveillance period using our epidemiology-based principles published and successfully followed since 1979: weekly culture for yeasts of oral and anal swabs, treatment with oral nystatin of all colonized newborns, and good hygiene/handwashing. Colonization was demonstrated in 23 out of 791 newborns admitted from October 1998 to September 1999. Twenty-two strains of Candida were identified: 16 C. albicans, 2 C. parapsilosis, 3 C. glabrata, and 1 C. tropicalis. Symptoms were erythema of the buttocks in 6 colonized newborns. No other culture positive for Candida could be found. Previous contamination was the main source (previous stay in an intensive care unit, rarely maternal origin). Contamination in the unit was unlikely. Eradication of Candida could be observed within 1 week. These good results, controversial in the literature, were obtained following epidemiological conclusions and support our guidelines.

Caffeine and Cerebral Blood Flow Velocity in Preterm Infants

Continuous wave Doppler monitor was used to examine the effect on cerebral blood flow velocity (CBFV) of caffeine in 7 clinically stable preterm neonates suffering from apnea. Caffeine, as caffeine citrate at a loading dose of 20 mg.kg-1 BW, or saline were given intravenously. Every subject was his own control. Placebo (saline) was systematically injected prior to caffeine citrate. Simultaneous recording of heart rate, arterial blood pressure, respiratory rate, Tc PO2, and Tc PCO2 were made before, at the end of the injection, and 30, 60 and 120 min after the end of each administration of either placebo or caffeine. Compared with placebo, caffeine injection was not associated with significant changes in CBFV. An increase was found in both heart rate and respiratory rate (p less than 0.05). Mean arterial blood pressure, Tc PCO2 and Tc PO2 did not change significantly. Our data suggest that a caffeine citrate loading dose of 20 mg.kg-1 BW as currently used at the beginning of treatment of apnea in preterm neonates has no effect on CBFV.

Evolution of the Barrier Effects against an Exogenous Drug-Sensitive Escherichia coli Strain after Single or Repeated Oral Administration to Newborns and Infants Aged up to Three Months Admitted to an Intensive-Care Unit

60 neonates--42 newborns 0-30 days old and 18 infants 31-90 days old--without previous antibiotic treatment were chosen and randomized into three groups (A, B, C). The strain of Escherichia coli administered was antibiotic-sensitive and azide-resistant (E. coli AZ). The digestive implantation was quantified by an index. We studied the variations of this index between the single administration group (A) and the 5 administrations group (B) and with age in both groups. Drug-resistant enterobacteria were also numbered in each stool, and their variations were studied by comparing groups A and B to a control group (C) receiving no administration. Multiple administrations did not lead to different results from the single ones. Age played a negative role in the colonizations after single administration, but a positive one after multiple administrations. Drug-resistant enterobacteria were not affected by any procedure. The drug susceptibility of E. coli AZ was lost in only 1 infant.

Effects of phenobarbital on cerebral hemodynamics in preterm neonates.

The effect of phenobarbital on cerebral blood flow velocity (CBFV) was studied in 12 clinically stable preterm neonates to evaluate possible mechanisms underlying its protective effect on intracranial hemorrhage. Phenobarbital at loading doses of 20 mg/kg, or placebo (saline) were given intravenously. The study was a cross-over study, each infant successively received placebo, then phenobarbital. Simultaneous recording of heart rate, mean arterial blood pressure (MABP), blood gases were made before, at the end of the injection, and at 15, 30, 60, 90 and 120 min after the end of each administration of either placebo or phenobarbital. Compared with placebo, phenobarbital injection was not associated with significant changes in CBFV and MABP. Heart rate, blood gases did not change significantly. Our data suggest that the protective effect of phenobarbital may minimally be mediated by a direct effect on cerebral blood flow.

Randomized Study of Vancomycin Pharyngeal Instillation as a Prophylaxis of Bronchopulmonary Infection in Intubated Neonates

In a randomized prospective trial, we investigated whether vancomycin (chosen for local microbiological reasons) given by instillation into the oropharynx of intubated neonates could reduce the frequency of pharyngeal and tracheal colonization, and then broncho pulmonary infection. Two groups of 20 neonates intubated for an expected ventilation period of more than 7 days were included in the study. There was no statistical difference between the two groups for weight, gestational age and duration of treatment. One group (V+) received 4 drops of a 5% solution of vancomycin every 8 h. The control group (V-) had no local treatment. Oropharyngeal and tracheal aspirates were collected twice weekly for bacterial examination. During ventilation, colonization occurred in the oropharynx of 5 V+ (on day 18 +/- 10) and 18 V- (on day 5 +/- 2.5; p less than 0.001); the colonization occurred in trachea of 5 V+ (on day 19 +/- 11) and 17 V- (on day 6 +/- 3.6; p less than 0.001). The same bacteria were identified on both sides in all infants colonized. This treatment produced no adverse effects and seemed particularly valid for very low birth weight infants.

mRNA D(2) dopaminergic receptor expression after hypoxia-ischemia in rat immature brain.

Previous studies have shown a reduction of dopaminergic D2 receptors (D2R) in the striatum after hypoxia-ischemia in newborn rats. We show here an early and transient reduction of mRNA D2R in nonatrophic brains following hypoxia-ischemia. The left carotid artery of P7 rats was ligated followed by hypoxia for 2 h. The rats were sacrificed after 24 h, 48 h and 14 days. D2R mRNA was studied by in situ hybridization, the cell number by conventional histology, and neuronal and astrocyte differentiation by immunohistochemistry. A 20% reduction of striatal mRNA D2R occurred 24 h after hypoxia-ischemia, whereas no reduction was observed after 48 h and 14 days. There were no differences in total cell number and in the expression of neuronal (MAP-1, MAP-2) and astrocyte (GFAP) markers between both brain hemispheres nor between control and hypoxia-ischemia animals. The early decrease in mRNA D2R could explain the delayed reduced D2R after neonatal hypoxia-ischemia.

The Newborn at High Risk of Brain Damage

Despite marked improvements in perinatal practice, perinatal brain injury remains one of the most common complications causing chronic handicapping conditions. Experimental advances have elucidated many of the cellular and vascular mechanisms of perinatal brain damage showing a correlation between the nature of the injury and the maturation of the brain. New diagnostic tools, such as quantitative three-dimensional magnetic resonance (MR) imaging, diffusion-weighted MR imaging and proton MR spectroscopy, are presented in this review article that allow to assess brain development, detect early brain injury and monitor effects of perinatal brain injury on subsequent brain development and brain plasticity. These techniques will guide future therapeutic interventions aimed at minimizing irreversible perinatal brain injury.